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WO2008107365A1 - New compounds - Google Patents

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Publication number
WO2008107365A1
WO2008107365A1 PCT/EP2008/052416 EP2008052416W WO2008107365A1 WO 2008107365 A1 WO2008107365 A1 WO 2008107365A1 EP 2008052416 W EP2008052416 W EP 2008052416W WO 2008107365 A1 WO2008107365 A1 WO 2008107365A1
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WIPO (PCT)
Prior art keywords
mmol
methyl
alkyl
hydroxy
title compound
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PCT/EP2008/052416
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French (fr)
Inventor
Oscar Belda
Christian Sund
Vladimir Ivanov
Daniel Wiktelius
Christer Sahlberg
Bertil Samuelsson
Åsa ROSENQUIST
Fredrik WÅNGSELL
Ingemar KVARNSTRÖM
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Medivir Ab
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Publication of WO2008107365A1 publication Critical patent/WO2008107365A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom

Definitions

  • This invention relates to novel compounds having inhibitory activity on aspartyl proteases such as renin. It further concerns pharmaceutical compositions comprising these compounds as active ingredients as well as processes for preparing these compounds and compositions and their use in the preparation of a medicament or their use in therapy.
  • Renin is an aspartyl protease with a high substrate specificity, its only known substrate is angiotensinogen. Renin cleaves the N terminus of circulating angiotensinogento angiotensin I (Ang I), which thereafter is further processed to the active peptide hormone angiotensin II (Ang II) by the less specific angiotensin-converting enzyme (ACE). Ang II increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating the sodium-ion-retaining hormone aldosterone. Ang II is known to work on at least two receptor subtypes called ATI and AT2. ATI seems to transmit most of the known functions of Ang II, while the role of AT2 is still unknown.
  • Modulation of the RAS represents a major advance in the treatment of cardiovascular diseases. Inhibition of the enzymatic activity of renin leads to a reduction in the formation of Ang I, and as a consequence, a smaller amount of Ang II is produced. The reduced concentration of that active peptide hormone is a direct cause of the hypotensive effect of renin inhibitors.
  • ACE inhibitors and ATI blockers have been accepted to treat hypertension and ACE inhibitors are used for renal protection in the prevention of congestive heart failure and myocardial infarction.
  • the rationale to develop renin inhibitors is the specificity of renin. Renin inhibitors are expected to demonstrate a different pharmaceutical profile than ACE inhibitors and ATI blockers with regard to efficacy in blocking the RAS and in safety aspects.
  • renin inhibitors Only limited clinical experience has been created with renin inhibitors because of their insufficient oral activity. The clinical development of several compounds has been stopped because of this problem together with the high cost of goods. Only one compound has entered clinical trials (Rahuel J. et al., Chem. Biol., 2000, 7, 493; Mealy N. E., Drugs of the Future, 2001, 26, 1139). Thus, renin inhibitors with good oral bioavailability and long duration of action are required.
  • the present invention concerns inhibitors of renin which exhibit beneficial potency, selectivity and/or pharmacokinetic properties. Compound 38 on page 4547 of Hanessian et al J. Med.
  • Chem., 2006, 4544-4567 describe the boc-protected peptido mimetic derivative l-benzylsulfanylmethyl-4-(l-butylcarbamoyl-2- methyl-propylcarbamoyl)-2-hydroxy-pentyl]carbamic acid tert-butyl ester, used as an intermediate in the preparation of macrocyclic peptidomimetic BACE inhibitors.
  • Compound 38 is outside the scope of the claims presented below and there is no suggestion that such intermediates could find utility as renin inhibitors.
  • Q is aryl or heterocyclyl
  • Ra is H or Ci-C 4 alkyl
  • R 1 is hydrogen, d-C ⁇ alkyl, Co-C 3 alkanediylC 3 -Cycycloalkyl or Co-C 3 alkanediylaryl, Co-
  • R 2 is hydrogen or Ci-C ⁇ alkyl
  • X' is hydrogen, fluoro, hydroxy, amino or Ci-C ⁇ alkoxy
  • X" is hydrogen, or when X' is fluoro, then X" may also be fluoro;
  • R 3 is Ci-Cealkyl
  • R 4' is Ci-Cealkyl
  • R 4 is H or Ci-C ⁇ alkyl
  • R 4 and R 4 together with the carbon atom to which they are attached define a Cs-C ⁇ Cycloalkyl
  • W is C 3 -Cycycloalkyl, aryl or heterocyclyl, wherein the cycloalkyl moiety is optionally substituted with fluoro, methyl or methoxy; wherein aryl is independently phenyl, naphthyl, or phenyl fused to Cs-C ⁇ cycloalkyl or Cs-C 6 cycloalkenyl; heterocyclyl is independently a 5 or 6 membered, saturated, partially unsaturated or heteroarylic ring containing 1 to 3 heteroatoms independently selected from S, O and N, the ring being optionally fused with a benzene ring; wherein each Ci-C ⁇ alkyl, aryl and heterocyclyl moiety above (including those in composite expressions such as alkoxy or alkanediylaryl), unless otherwise specified is optionally substituted with one, two or where valence allows three substituents independently selected from Ci-C 4 alkyl (optionally substituted with one or two substituents independently selected
  • Ci-C 4 alkyl a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (any of which cyclic amines being optionally substituted with Ci-C 4 alkyl or fluoro), Co-C3alkanediylaryl*, Co ⁇ alkanediylheterocyclyl*, C2-C3alkenyldiylC3-
  • the compounds of the invention are generally potent inhibitors of renin and thus the invention further provides the use of a compound of the formula I or a pharmaceutically acceptable salt, hydrate or N-oxide thereof for the treatment or prophylaxis of disorders mediated by the RAS, such as hypertension, heart failure and renal insufficiency .
  • the compounds of general formula (I) have several centres of chirality, conveniently the compounds display at least 75%, preferably at least 90%, such as in excess of 95%, enantiomeric purity at each of the chiral centres.
  • the chiral centre whereto the group R 3 is attached has the stereochemistry shown in structure (Ia):
  • Preferred compounds of formula (I) are those having the stereochemistry indicated in the structure of formula (Ie):
  • R 3 is Ci-C ⁇ alkyl, preferably ethyl or more preferably isopropyl.
  • R 4 is Ci-C ⁇ alkyl, preferably isopropyl or more preferably sec. butyl.
  • R 4 " is preferably hydrogen.
  • R4' and R4" together define a spiro-cycloalkyl group, for example cyclopentyl or cyclobutyl or preferably cyclopropyl.
  • X' is fluoro, or more preferably hydroxy.
  • X is hydrogen
  • a further embodiment of the invention are compounds of formula (I) or any subgroup of formula (I) wherein X' and X" are both fluoro.
  • R 1 is hydrogen, Ci-C ⁇ alkyl, Co-C 3 alkanediylC 3 -Cycycloalkyl, Co- Csalkanediylaryl or Co-C 3 alkanediylheterocyclyl, wherein each Ci-C ⁇ alkyl, cycloalkyl, aryl and heterocyclyl moiety is optionally substituted with one, two or three substituents independently selected from halo, haloCi-C 4 alkyl, Ci-C 4 alkyl, Ci-C 4 alkoxy, hydroxy and cyano.
  • R 1 Convenient values for R 1 include hydrogen, optionally substituted phenyl, optionally substituted benzyl and optionally substituted Ci-C ⁇ alkyl.
  • R 1 is hydrogen, Ci-C ⁇ alkyl or optionally substituted benzyl, especially hydrogen, methyl, ethyl or isopropyl.
  • R 1 is optionally substituted heteroarylCi-C 4 alkyl, such as heteroarylmethyl, especially where the heteroaryl is pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, any of which may be substituted as defined above, such as with 1 or 2 Ci-C4alkyl (preferably methyl), Ci-C4alkoxy (preferably methoxy), Ci-C4alkoxyCi-C3alkoxyCo-C3alkyl, preferably methoxypropoxy), cyano or halo (preferably fluoro) groups.
  • heteroarylCi-C 4 alkyl such as heteroarylmethyl
  • the heteroaryl is pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, any of which may be substituted as defined above, such as with 1 or 2 Ci-C4alkyl (preferably methyl), Ci-C4alkoxy (preferably methoxy), Ci-C4alkoxyCi-C
  • R 1 is pyridylCi-C 4 alkyl or thiazolylCi-C 4 alkyl. Further configurations for R 1 include phenylethyl, which is optionally substituted with a sulphonamide group such as methanesulphonamide or N-methyl methanesulphonamide.
  • R 1 in general are as defined above.
  • Representative values include Ci-C 4 alkyl such as methyl; halo such as fluoro; haloCi-C 4 alkyl such as fluoromethyl and trifluoromethyl; and cyano.
  • R 1 is Co-C3alkanediylaryl or Co-C3alkanediylheterocyclyl
  • the optional substituent(s) to the aryl or heterocyclyl moiety are conveniently in the para and/or ortho position.
  • favoured configurations for R 1 according to this embodiment are phenyl or benzyl substituted in the para position.
  • R 2 is Ci-C ⁇ alkyl such as methyl or ethyl, or preferably R 2 is hydrogen.
  • Z is O.
  • Z is NRa, wherein Ra is hydrogen or Ci-C 3 alkyl, preferably hydrogen or methyl.
  • the group Q is bonded either directly to Z, i.e. n is 0, or Q is bonded via a methylene, ethylene or propylene moiety, i.e. n is 1, 2 or 3 respectively.
  • Q is bonded directly to Z or via an ethylene moiety, i.e. n is 0 or 2.
  • Q is bonded via a methylene moiety, i.e. n is 1.
  • Q is aryl or heterocyclyl, optionally substituted with one, two or three substituents independently selected from Ci-C 4 alkyl (optionally substituted with one or two substituents independently selected from Co-C3alkanediylaryl, amino, carbamoyl, amido and Ci-C4alkoxyamido), C2-Cealkenyl, C 2 -C6alkynyl, C3-Cycycloalkyl, Ci-C4alkoxy, halo, haloCi-C 4 alkyl, polyhaloCi-C 4 alkyl, Ci-C 4 alkoxyCi-C 3 alkyl, Ci-C 4 alkoxyCi-C 4 alkoxyC 0 - C 3 alkyl, hydroxy, hydroxyCi-C 4 alkyl, cyano, azido, Ci-C 4 alkylcarbonyl, carbamoyl, amino, amido, a cyclic amine selected from pyrroli
  • the optional substituent (s) to Q include Ci-C 4 alkyl (optionally substituted with one or two substituents independently selected from Co-C 3 alkanediylaryl, amino, carbamoyl, amido and Ci-C4alkoxyamido), C3-Cycycloalkyl, Ci-C4alkoxy, halo, haloCi-C 4 alkyl, Ci-C 4 alkoxyCi-C 3 alkyl, Ci-C 4 alkoxyCi-C 4 alkoxyCo-C3alkyl, hydroxy, hydroxyCi-C4alkyl, cyano, azido, Ci-C4alkylcarbonyl, carbamoyl, amino, amido, a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (any of which cyclic amines being optionally substituted with Ci-C 4 alkyl or fluoro), Co-C 4 alkyl
  • Q is an optionally substituted mono or bicyclic aryl moiety such as phenyl or naphthyl.
  • Q is an optionally substituted mono- or bicyclic ring containing 1 , 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, independently selected from nitrogen, oxygen and sulphur.
  • Representative monocyclic rings according to this embodiment include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like
  • representative bicyclic rings include quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl each of which is optionally substituted wherein each of the mono and bicyclic rings is optionally substituted.
  • heterocyclyl groups for Q include pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, any of which may be substituted as defined above, such as 1 or 2 with C1-C4 alkyl (preferably methyl), Ci-C4alkoxy (preferably methoxy), Ci-C4alkoxyCi-C3alkoxyCo-C3alkyl, preferably methoxypropoxy) or halo (preferably fluoro) groups.
  • C1-C4 alkyl preferably methyl
  • Ci-C4alkoxy preferably methoxy
  • Ci-C4alkoxyCi-C3alkoxyCo-C3alkyl preferably methoxypropoxy
  • halo preferably fluoro
  • Typical values for Q include optionally substituted 5 or 6 membered aryl or heterocyclyl, preferably phenyl or pyridyl.
  • a further typical value for Q is optionally substituted naphthyl.
  • Optional substituents to Q are as defined above. Representative values include substituents independently selected from Ci-C 4 alkyl, C 3 -Cycycloalkyl, Ci-C 4 alkoxy, Ci-C 4 alkoxy-Ci- C 6 alkoxyCo-C 3 alkyl, halo and haloCi-C 4 alkyl.
  • favoured values for the optional substituents for Q include cyclopropyl, methoxy- ethoxy, fluoro, optionally substituted phenyl and benzyl, more favoured substituents are chloro, methyl or methoxy-propoxy.
  • substituents to Q include Co-C 3 alkanediylaryl which aryl is optionally substituted, Co-C3alkanediylheterocyclyl and Co-C3alkanediylheteroaryl.
  • Typical heterocyclyl and heteroaryl include, but are not limited to, pyrrolyl, pyrrolinyl, pyrazolyl, imidazolyl, oxazolyl, pyrimidinyl, pyrazinyl, morpholinyl and especially furyl, thienyl, thiazolyl and pyridyl.
  • Q is a mono-substituted 6-membered ring, wherein the substituent is preferably in one of the meta positions or in the para position.
  • Q is para-substituted phenyl.
  • Q is meta-substituted phenyl.
  • Q include phenyl which is substituted with methoxypropoxy, and phenyl which is mono- or disubstituted with chloro.
  • Q include phenyl which is substituted with phenyl or substituted phenyl such as fluoro- or chlorophenyl, cycloalkyl such as cyclopropyl, Ci-C ⁇ alkyl such as methyl, ethyl or isopropyl, or pyridyl.
  • a further embodiment for the optional substituents to Q is benzyl which is substituted at the benzylic position.
  • Suitable substituents for the benzylic position includes for example amino, amido or alkoxyamido such as Ci-C4alkylamino or tert-butoxycarbonylamino.
  • R 5 is Ci-C 4 alkyl, Ci-C 4 alkylcarbonyl or Ci-C 4 alkyloxycarbonyl and R 5 is hydrogen, methyl or especially phenyl.
  • Q is disubstituted 6-membered ring with the substituents in the two meta positions or with one substituent in the meta position and the other in the para position.
  • Preferred substituents to Q according to this embodiment are independently chloro, methoxypropoxy and methyl.
  • Q is phenyl, optionally substituted with one or two substituents independently selected from methyl, cyclopropyl, fluoro, chloro and 3-methoxy-propxy.
  • Q is phenyl, substituted in one of the meta positions and/or in the para position.
  • Suitable configurations for Q include phenyl which is substituted in the meta position with Ci-C4alkoxy-Ci-C4alkoxy, and in the para position with Ci-C4alkyl, cyano or halo.
  • More suitable configurations for Q include phenyl which is substituted in the meta position with 3-methoxy-propoxy and in the para position with methyl, ethyl, cyano, fluoro, chloro or bromo.
  • Q include phenyl which is substituted in one of the meta positions with Ci-C4alkoxy-Ci-C4alkoxy, such as methoxypropoxy and/or in the para position with optionally substituted heteroaryl or optionally substituted phenyl.
  • More suitable configurations for Q include phenyl which is substituted in one of the meta positions with 3-methoxy-propoxy and/or in the para position with pyridyl, thienyl or furyl or with optionally substituted phenyl, such as p-fluorophenyl.
  • the group W is bonded either directly to the amide nitrogen, i.e. m is 0, or W is bonded via a methylene or ethylene moiety, i.e. m is 1 or 2 respectively. In favoured embodiments of the invention W is bonded via a methylene moiety, i.e. m is 1.
  • W is Ci-C ⁇ alkyl, C 3 -Cycycloalkyl, aryl or heterocyclyl which is optionally substituted with one, two or three substituents.
  • W is an optionally substituted mono or bicyclic aryl moiety such as phenyl or naphthyl, preferably optionally substituted phenyl.
  • W is an optionally substituted mono- or bicyclic ring containing 1 , 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur.
  • Representative monocyclic rings according to this embodiment include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like
  • representative bicyclic rings include quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl each of which is optionally substituted wherein each of the mono and bicyclic rings is optionally substituted.
  • W is unsubstituted C3-C7 cycloalkyl, such as cyclopropyl.
  • a C3-C7 cycloalkyl W can be substituted, for example with fluoro, methyl or methoxy;
  • W is a monocyclic 5- or 6-membered ring.
  • the ring is preferably mono substituted with the substituent in the meta or para position.
  • W is optionally substituted phenyl.
  • W is phenyl which is substituted with fluoro chloro, methyl or cyano and the substituent is preferably in the para position.
  • the substituents are preferably in the two meta positions or in the meta and para positions.
  • Preferred optional substituents to W include one or two substituents independently selected form halo such as fluoro or chloro; C 3 -Cycycloalkyl such as cyclopropyl; haloCi-Csalkyl such as fluoromethyl and trifluoromethyl; Ci-C ⁇ alkyl such as methyl, ethyl and isopropyl.
  • halo such as fluoro or chloro
  • C 3 -Cycycloalkyl such as cyclopropyl
  • haloCi-Csalkyl such as fluoromethyl and trifluoromethyl
  • Ci-C ⁇ alkyl such as methyl, ethyl and isopropyl.
  • 'd-dalkyl' as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as for example methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl-l -propyl, 2-methyl-2-propyl. Methyl is typically preferred in many applications.
  • Ci-C 4 alkyl radicals encompasses Ci-C 4 alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 2-methyl- 1 -butyl, 2-methyl- 1-pentyl, 2-ethyl-l -butyl, 3-methyl-2-pentyl, and the like.
  • Ci-C ⁇ alkyl is Ci-C 4 alkyl.
  • C 2 -C 6 alkenyl' as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbon bonds and at least one double bond, and having from 2 to 6 carbon atoms, such as, for example, ethenyl (or vinyl), 1-propenyl, 2- propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 3- pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl and the like.
  • C 2 -Cealkenyl is C 2 -C 4 alkenyl.
  • C 2 -C 6 alkynyl' as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbon bonds and at least one triple bond, and having from 2 to 6 carbon atoms, such as, for example, ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like.
  • C 2 -Cealkynyl is C 2 -C 4 alkynyl.
  • 'C 0 -C 3 alkanediyr defines a bond (Co) or a bivalent straight or branched saturated hydrocarbon chain having from 1 to 3 carbon atoms such as, for example, methylene, ethylene, 1,3-propanediyl, 1 ,2-propanediyl, and the like, especially methylene.
  • 'C 2 -C 3 alkenediyr defines a bivalent straight or branched hydrocarbon chain having one double bond and having 2 or 3 carbon atoms such as, for example, ethenylene, 1,3-propenediyl, 1 ,2-propenediyl, and the like, especially vinylene.
  • 'C 2 -C 3 alkynediyr defines a bivalent hydrocarbon chain having 2 or 3 carbon atoms and a triple bond, i.e. ethynylene and propynylene.
  • Ci-C ⁇ alkoxy of interest include but are not limited to methoxy, ethoxy, n-propoxy and isopropoxy.
  • Ci-C4-alkoxy or Co-C3-alkoxy has the corresponding definition, adjusted as necessary for C number.
  • 'halo' is generic to fluoro, chloro, bromo and iodo. Fluoro is typically preferred in many applications.
  • the term 'haloCi-C4alkyl' as a group or part of a group, is meant to include mono- and polyhalo substituted Ci-C4alkyl, in particular Ci-C4alkyl substituted with one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Preferred is trifluoromethyl.
  • the halogen atoms may be the same or different.
  • the carbon atom to which the oxo is linked is a saturated carbon.
  • Ci-C ⁇ alkyl as a group or part of a group, unless the context suggests otherwise, includes NH 2 , NHCi-C ⁇ alkyl or N(Ci-C6-alkyl)2, wherein in the amino definitions each Ci-C ⁇ alkyl is especially Ci-C4alkyl variants. Included are also radicals wherein the two Ci-C ⁇ alkyl groups of the N(Ci-C6-alkyl)2 together with the nitrogen atom to which they are attached form a saturated cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl or morpholniyl.
  • 'Co-C 3 alkanediylaryl' as applied herein is meant to include an aryl moiety such as a phenyl or naphthyl or a phenyl fused to a Cs-C ⁇ cycloalkyl (for example indanyl), or a C 5 - C ⁇ cycloalkenyl which aryl is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1 ,2-propanediyl or 1,3-propanediyl group as defined for Ci-C3alkanediyl above.
  • aryl moiety such as a phenyl or naphthyl or a phenyl fused to a Cs-C ⁇ cycloalkyl (for example indanyl), or a C 5 - C ⁇ cycloalkenyl which aryl is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1 ,2-propanedi
  • Suitable aryl groups include but are not limited to phenyl, naphtyl, tetrahydronaphthyl, indenyl and indanyl. Unless otherwise indicated the aryl and/or its fused cycloalkyl moiety is optionally substituted with one, two or where valence allows three substituents independently selected from halo, hydroxy, nitro, cyano, carboxy, Ci-C4alkyl, C 1 - C 4 alkoxy, C 3 -C 7 cycloalkyl, haloCi-C 4 alkyl, Ci-C 4 alkoxyCi-C 3 alkyl, Ci-C 4 alkoxyCi- C4alkoxyCo-C3alkyl, Ci-C ⁇ alkanoyl, amino, amido, carbamoyl, azido, oxo, mercapto, Co- Csalkanediylaryl, Co-C 3 alkanediylheteroaryl,
  • 'C 2 -C 3 alkenediylaryl and 'C 2 -C 3 alkynediylaryl have the corresponding meanings, adjusted just for the link to the aryl moiety as defined for 'C 2 -C 3 alkenediyr and 'C 2 -C 3 alkynediyl
  • 'Co-C3alkanediylheterocyclyl' as applied herein is meant to include a 5-6 membered saturated, partly unsaturated or unsaturated heterocyclic ring containing 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulphur, the ring being optionally fused with a benzene ring.
  • heterocyclyl groups include but are not limited to pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, isothiazolyl, thiazolidinyl, thiadiazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, azetidinyl, piperidinyl,
  • the ring system is optionally substituted with one, two or where valence allows three substituents independently selected from halo, hydroxy, nitro, cyano, carboxy, Ci-C 4 alkyl, Ci-C 4 alkoxy, C 3 -Cycycloalkyl, haloCi-C 4 alkyl, Ci-C 4 alkoxyCi-C 3 alkyl, Ci-C 4 alkoxyCi-C 4 alkoxyCo-C 3 alkyl, Ci-C ⁇ alkanoyl, amino, amido, carbamoyl, azido, oxo, mercapto, Co ⁇ alkanediylaryl, Co-C 3 alkanediylheteroaryl, it being understood that heterocyclic and carbocyclic moieties in the Co-C3alkanediylaryl or Co
  • 'Heterocyclyl' has the corresponding meaning, i.e. where the Co-C3alkanediyl linkage is absent.
  • 'C 2 -C 3 a lkenediylheterocyclyl and 'C 2 -C 3 alkynediylheterocyclyl have the corresponding meanings, adjusted just for the link to the heterocyclyl moiety as defined for 'C 2 -C 3 alkenediyl' and 'C 2 -C 3 alkynediyl
  • aryl and heterocyclyl moieties within the scope of the above definitions are thus a monocyclic ring with 5 or especially 6 ring atoms, or a bicyclic ring structure comprising a 6 membered ring fused to a 5 or 6 membered ring.
  • heteroaryl' as applied herein means an aromatic heterocyclyl moiety.
  • Cycloalkyl' as applied herein is meant to include a C 3 -Cycycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, which is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1 ,2-propanediyl or 1,3-propanediyl group as defined for Ci-C3alkanediyl above.
  • the cycloalkyl group may contain an unsaturated bond.
  • the cycloalkyl moiety is optionally substituted with 1-3 substituents selected from halo, hydroxy, nitro, cyano, carboxy, C 1 - C 4 alkyl, Ci-C 4 alkoxy, haloCi-C 4 alkyl, Ci-C 4 alkoxyCi-C 4 alkyl, Ci-C ⁇ alkanoyl, amino, amido, carbamoyl, azido, oxo, mercapto, nitro Co ⁇ alkanediylaryl, Co ⁇ alkanediylheterocyclyl, it being understood that heterocyclic and carbocyclic moieties in the Co-C3alkanediylaryl or Co- C3alkanediylheterocyclyl substituent may itself be substituted as provided herein but typically not with a further Co-C 3 alkanediylaryl or Co-C 3 alkanediylheterocyclyl. 'C 3 Cv
  • 'C 2 -C 3 alkenediylcarbocyclyl and 'C 2 -C 3 alkynediylcarbocyclyl have the corresponding meanings, adjusted just for the link to the carbocyclyl moiety as defined for 'C 2 -C 3 alkenediyr and 'C 2 -C 3 alkynediyl
  • radical positions on any molecular moiety used in the definitions may be anywhere on such a moiety as long as it is chemically stable.
  • Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated.
  • pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl
  • pentyl includes 1- pentyl, 2-pentyl and 3-pentyl.
  • each definition is independent.
  • the term 'compounds of formula (I)', or 'the present compounds' or similar terms it is meant to include the compounds of formula (I), their prodrugs, TV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms.
  • prodrug' as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I).
  • Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
  • Prodrugs of a compound of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound.
  • ester prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy and/or a carboxyl group.
  • An in vivo hydrolysable ester is an ester, which is hydro lysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci-C ⁇ alkoxymethyl esters for example methoxymethyl, Ci-C ⁇ alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, Cs-CscycloalkoxycarbonyloxyCi- C ⁇ alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci-C ⁇ alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl which may be formed at any carboxy group in the compounds of this invention.
  • An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxy-methoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)- N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
  • salts of the compounds of formula (I) or any subgroup of compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric acids and the like; or organic acids such as, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • butanedioic acid maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, /?-toluenesulfonic, cyclamic, salicylic, / ⁇ -aminosalicylic, pamoic acids and the like.
  • Acid addition salt forms can be converted to the free base form by treatment with an appropriate base.
  • the compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with an appropriate organic or inorganic base.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, JV-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • Base addition salt forms can be converted to the free acid form by treatment with an appropriate acid.
  • addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) or any of the subgroups of compounds of formula (I), as well as the salts thereof, are able to form.
  • Such solvates are for example hydrates, alcoholates and the like.
  • 'quaternary amine' as used above and hereinafter defines the quaternary ammonium salts which the compounds of formula (I) or any of the subgroups of compounds of formula (I), are able to form by reaction between a basic nitrogen of a compound of formula (I) or any of the subgroups of compounds of formula (I), and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • an appropriate quaternizing agent such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates.
  • a quaternary amine has a positively charged nitrogen.
  • Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
  • iV-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called iV-oxide.
  • the compounds according to the invention may contain one or more asymmetrically substituted carbon atoms, asymmetric or chiral centre.
  • the presence of one or more of these asymmetric centres in compounds according to the invention can give rise to stereochemically isomeric forms, stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, both in pure form and mixed with each others, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
  • stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates.
  • the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e.
  • Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by application of art-known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, pp 104-107).
  • enantiomers may be separated from each other using known procedures including, for example, formation of diastereomeric mixtures by reaction with a convenient optically active auxiliary species followed by separation of the diastereomers, using for instance selective crystallisation, and finally cleavage of the auxiliary species.
  • optically active auxiliary species are optically active acids and bases such as tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • the compound will preferably be synthesized by stereospecif ⁇ c methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the compounds of formula (I) may have metal binding, chelating or complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
  • the invention relates to the compounds of formula (I) or any subgroup of compounds of formula (I) per se, the prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof.
  • One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the iV-oxides, salts, as the possible stereoisomeric forms thereof.
  • the invention further relates to methods for the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I), the prodrugs, JV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, its intermediates, and the use of the intermediates in the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I).
  • the invention also relates to the use of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof, for the manufacture of a medicament.
  • the invention relates to the use of a of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof in therapy.
  • the term 'therapy' also includes 'prophylaxis' unless there are specific indications to the contrary.
  • the terms 'therapeutic' and 'therapeutically' should be construed accordingly.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a compound of any of the subgroups of formula (I) or a pharmaceutically acceptable salt thereof as specified herein, and a pharmaceutically acceptable adjuvant, diluent or carrier for administration to a subject in need thereof.
  • a therapeutically effective amount in this context is an amount sufficient to act in a prophylactic way against, to stabilize or to reduce adverse conditions associated with RAS activity, such as or related to hypertension, heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, in affected subjects or subjects being at risk of being affected.
  • the invention further relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable adjuvant, diluent or carrier with a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) as specified herein, or a pharmaceutically acceptable salt or a solvate, prodrug, N-oxide, quaternary amine, metal complex or stereochemically isomeric form thereof as specified herein.
  • the compounds of formula (I) or any of the subgroups of formula (I) have enzyme inhibiting properties and are modulators of the renin-angiotensin system, in particular they are inhibitors of the natural enzyme renin and may be used in the treatment and/or prophylaxis of diseases such as or related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, atherosclerosis, restenosis post angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications of treatments with immunosuppressive agents, and other
  • the invention relates to a method for the treatment and/or prophylaxis of diseases or conditions which are associated with a dysregulation of the renin-angiotensin system, in particular to a method for the treatment or profylaxis of the above mentioned diseases, said method comprising administering to a patient a pharmaceutically active amount of a compound of formula (I) or any of the subgroups of formula (I).
  • the invention further provides a method of treating a disease or condition known to be related to the renin- angiotensin system which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, a solvate, prodrug, iV-oxide, quaternary amine, metal complex, or stereochemically isomeric form thereof, as hereinbefore defined.
  • the invention also provides a method of treating diseases or conditions such as or related to the above mentioned (e.g. hypertension) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, or solvate thereof as hereinbefore defined.
  • diseases or conditions such as or related to the above mentioned (e.g. hypertension) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, or solvate thereof as hereinbefore defined.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of formula I/salt/so lvate (active ingredient) may be in the range from 0.001 mg/kg to 75 mg/kg, in particular from 0.5 mg/kg to 30 mg/kg. This daily dose may be given in divided doses as necessary.
  • unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
  • DMPK parameters of the compounds of the invention are measured by conventional assays.
  • the advantageously high permeability of the invention can be assayed in the Caco-2 cell line which is commercially available and widely used in the literature.
  • the advantageosuly high bioavailability can be assayed by conventional oral dosing in appropriate animal models such as rat or cynomolgus, followed by blood sampling (measured by MS) at defined time intervals to monitor the apperance of the compounds, ie absorption.
  • Absolute bioavailability is measured in the conventional manner by reference to the time course/ AUC of an IV or IP dose of the compound, typically at 1/10 th the dose.
  • the advantageously low hepatic and other metabolism can be gauged with commercially available hepatocytes, such as XEN-025 or 1037.
  • the advantageously low P450 metabolism is measured with supersomes (Gentest Corp, USA) that is baculovirus infected insect cells transfected with human P450 iso forms, including CYP 1A2, CYP2A6, CYP2C9-Arg 144, CYP219, CYP2D6Val 374 and CYP34A, typically with P450 reductase, whereby th involvement of a given iso form in the metabolism of the test compound is determinted by UV HPLC or MS.
  • the compounds of formula (I) and pharmaceutically acceptable salts, solvates, prodrugs, iV-oxides, quaternary amines, metal complexes, or stereochemically isomeric forms thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound of formula (I) /salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w/w, of active ingredient, and, from 1 to 99.95 %w/w, more preferably from 30 to 99.90 %w/w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
  • a representative tablet within the scope of the pharmaceutical composition of the invention could have a mass of 500 - 1500 mg with a loading of active ingredient in the range 35 - 75%, with the balance being excipients, such as binders, disintegrants, antioxidants and the like.
  • compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • the oral delivery route, particularly capsules or tablets is favoured.
  • composition of this invention may also contain, or be co- administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more of the diseases or conditions referred to hereinabove.
  • a representative example are other pharmacologically active compounds such as ACE-inhibitors, neutral endopeptidase inhibitors, aldosterone antagonists, angiotensin II receptor antagonists, endothelin receptors antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholitics, beta- adrenergic antagonists, alpha-adrenergic antagonists and/or other drugs beneficial for the prevention or the treatment of the above-mentioned diseases such as 1 ibeta-hydroxy steroid dehydrogenase type 1 inhibitors and soluble guanylate cyclase activators.
  • ACE-inhibitors neutral endopeptidase inhibitors
  • aldosterone antagonists angiotensin II receptor antagonists
  • endothelin receptors antagonists vasodilators
  • calcium antagonists potassium activators
  • diuretics sympatholitics
  • beta- adrenergic antagonists alpha-adrenergic antagonists
  • Scheme 1 illustrates a synthetic route to a lactone which is a useful intermediate in the preparation of compounds of formula (I).
  • the isopropylidene derivative (Ia) achieved for example as described in Tetrahedron Lett., 1987, 28, 1143, can be transferred into the methyl glycoside (Ib) by acidic hydrolysis of the acetal group effected by treatment with a suitable acid such as sulphuric acid, in the presence of methanol.
  • the achieved free secondary hydroxy group can then be reductively removed effected for instance by transformation of the hydroxy group into a thiocarbonyl group by reaction with thiocarbonyl diimidazole (TCDI) followed by reduction of the formed thiocarbonyl group using for instance conditions such as tributyltin hydride the presence of a radical initiator like azobis-(2-methylpropyonitrile) (AIBN) or the like to give the 2,3-dideoxy glycoside (Ic).
  • a radical initiator like azobis-(2-methylpropyonitrile) (AIBN) or the like
  • Ic 2,3-dideoxy glycoside
  • Oxidative cleavage of the methyl ether performed for example by oxidation with m-chloroperbensoesyra or the like in the presence of BF3-etherate, gives the lactone (Id).
  • the ring substituent R 3 can then be introduced for example by treatment of the lactone with a base such as LDA or equivalent followed by reaction with a suitable alkylating agent such as an alkyl halide like an alkyl bromide or alkyl iodide or a derivative of sulphonic acid such as a mesylate, triflate or tosylate or the like, thus providing the ⁇ -alkylated lactone (Ie).
  • a suitable alkylating agent such as an alkyl halide like an alkyl bromide or alkyl iodide or a derivative of sulphonic acid such as a mesylate, triflate or tosylate or the like
  • a suitable alkylating agent such as an alkyl halide like an alkyl bromide or alkyl iodide or a derivative of sulphonic acid such as a mesylate, triflate or tosylate or the like
  • the primary hydroxy group of the lactone (If) can be selectively alkylated for example by activation of the hydroxy group with dibutyltinoxide followed by reaction with a desired alkylating agent Q-(CH 2 ) D -Lg wherein Lg is a suitable leaving group such as a halide like bromide or iodide in the presence of tetrabutylammonium bromide or the like thus forming the ether derivative (2a).
  • the substituent Q-(CH 2 )D can be introduced by using the Mitsunobu conditions (Mitsunobu, 1981, Synthesis, January, 1-28; Rano et al, Tetrahedron Lett., 1995, 36, 22, 3779-3792; Krchnak et al., Tetrahedron Lett., 1995, 36, 5, 6193-6196; Richter et al., Tetrahedron Lett., 1994, 35, 27, 4705-4706) i.e. reaction of the alcohol (If) with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine followed by displacement with a desired alcohol.
  • Replacement of the hydroxy group of the secondary alcohol (2a) by azide may then be effected by transforming the hydroxy group to a leaving group, for example a derivative of sulphonic acid like a triflate or tosylate or the like by subjecting the alcohol to sulphonylating conditions such as treatment with the appropriate anhydride or halide optionally in the presence of a base, for instance pyridine, followed by displacement of the leaving group with azide for example sodium azide, thus giving the azide derivative (2b).
  • a leaving group for example a derivative of sulphonic acid like a triflate or tosylate or the like
  • sulphonylating conditions such as treatment with the appropriate anhydride or halide optionally in the presence of a base, for instance pyridine, followed by displacement of the leaving group with azide for example sodium azide, thus giving the azide derivative (2b).
  • the azide moiety can be introduced by treatment of the alcohol with diisopropyl azodicarboxylate or any other suitable azodicarboxylate, in combination with triphenylphosphine, followed by reaction with azide for example DPPA, in a solvent like THF.
  • the linear amino compound (2e) can then be achieved by opening of the lactone with a desired amino derivative (2c) in the presence of a coupling agent for example 2-hydroxypyridine and a base like isopropyl diethylamine.
  • Reduction of the azide using conditions compatible with the (CH 2 ) n -Q group, for example hydrogenation at atmospheric pressure in the presence of Lindlar Catalyst or equivalent.
  • an alkylating agent R 1 -Lg wherein Lg is a leaving group such a halide like chloride, bromide or iodide or a derivative of sulphonic acid such as a mesylate or a triflate or the like, optionally in the presence of a base, or alternatively an N- substituent may be introduced by reaction with an al
  • Lactones useful for the synthesis of compounds of formula (I) wherein Z is S or NH and n is 1 or 2 can be prepared from the diol If for example by a Mitsunobu reaction with a thiol or amino derivative respectively, as illustrated in scheme 2B.
  • the primary hydroxy group of the lactone (If) can be converted to a thioether or an amine for example by transforming it into a leaving group followed by displacement of the formed leaving group with the desired group Q-(CH 2 )D-S or Q-(CH 2 )D-NRa.
  • a convenient method to effect this transformation is by way of a Mitsunobu reaction, i.e. reaction of the hydroxy group with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine or the like followed by displacement with a desired thiol or amine to provide the thioether (2Ba) or the amine derivative (2Bb) respectively.
  • an azide derivative such as sodium azide or DPPA in the Mitsunobu reaction with the alcohol (If)
  • a further alternative to obtain the amino derivative (2Bb) is to selectively oxidize the primary hydroxy group of the alcohol (If) to the corresponding aldehyde, effected for example by treatment with Dess-Martin periodinane or by any other suitable oxidation reagent, followed by a reductive amination with the desired amino derivative Q-(CH 2 ) n -NHRa in the presence of a reducing agent like NaCNBH 3 . Replacement of the secondary hydroxy group with azide, opening of the lactone and finally reduction of the azide as described above, then provides the linear compounds (2Bc and 2Bd).
  • Compounds wherein the group Q is linked directly to a sulphur or nitrogen atom i.e. an intermediate for the preparation of compounds of formula (I) wherein Z is S or NRa and n is O, may be prepared by transformation of the primary hydroxy group of the diol (If) into a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with a desired thiol Q-SH or a amine Q-NHRa optionally in the presence of a base.
  • a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like
  • An alternative method for the preparation of compounds wherein Z is S and n is 0 is to react the diol (If) with a desired diphenyl disulphide derivative in the presence of nBusP.
  • Compounds wherein Z is NRa and n is 0 may alternatively be achieved by oxidation of the primary hydroxy group of the diol (If) followed by a reductive amination with a desired aniline derivative Q-NRa in the presence of a suitable catalyst like NaCNBH 4 or the like.
  • the oxidation can be performed either at the last step of the synthesis or on any suitable intermediate.
  • Many suitable methods for this oxidation are described in the literature for example a peroxyacid such as AcOOH, mCPBA can be used.
  • Amino derivatives (2c) to be used for the opening of the lactone in the scheme 2 above are commercially available or they can be prepared by the skilled person according to literature procedures.
  • an amino derivative useful for the preparation of compounds of formula (I) wherein Y is NH can be prepared from a suitably protected amino acid carrying the desired side chain R 4 R 4 , as illustrated in scheme 3.
  • the amino acid (3a), carrying the desired side chain R 4 R 4 can be coupled to the amine W- (CH 2 )Hi-NH 2 using any convenient method for peptide coupling known in the art.
  • a coupling agent like HATU or isobutylchloroformate in the presence of a tertiary amine such as ethyldiisopropylamine (DIEA) or N-methylmorpholine in a solvent like dimethyl formamide can be used thus providing the amide.
  • DIEA ethyldiisopropylamine
  • N-methylmorpholine in a solvent like dimethyl formamide
  • amino derivatives useful for the preparation of compounds of general formula (I) wherein Y is S can be prepared by transforming the amino acid (3 a) into an activated acid derivative such as the acid chloride or an activated ester such as the p-nitrophenyl ester or pentafluoroester, followed by reaction with a desired thio derivative SH-(CH 2 ) m -W.
  • activated acids and esters are well known to a person skilled in the field of organic synthesis and are exensively described in the literature.
  • the acid chloride can be prepared by treatment of the acid with POCI3 or phosgene or the like in the presence of a base like pyridine.
  • the azide derivative (4a), prepared for example as outlined in scheme 2, wherein Pg 1 is a hydroxy protecting group for example a benzyl group can be transformed to the corresponding amine by reduction of the azide group using any convenient reduction method such as hydrogenation in the presence of a suitable catalyst, such as Lindlars catalyst or the like in the presence of BoC 2 O to provide the boc protected derivative (4b). Protection of the secondary hydroxy group, using a protecting group (Pg 2 ) which is orthogonal to the one used for the primary hydroxy group (Pg 1 ), followed by removal of the primary hydroxy protecting group using the appropriate conditions according to the group used, such as for example catalytic hydrogenation in the case of a benzyl group provides the primary alcohol (4c).
  • a protecting group Pg 2
  • Suitable protecting groups for the above route will be recognized by the skilled person and a numerous of useful protecting groups are described in Greene "Protective Groups in Organic Synthesis", John Wiley and sons, New York (1981).
  • benzyl can be used as Pg 1 and acetyl as Pg 2 .
  • the group (CH 2 ) n -Q can then be introduced as described above.
  • Trichloroacetimidates are conveniently prepared by reaction of the corresponding alcohol with trichloroacetonitrile in the presence of a base like NaH.
  • Z' in scheme 4 is O, S or NRa may be prepared by a Mitsunobu reaction of the primary alcohol (4c) with a desired alcohol, Q-(CH 2 ) n -OH, thiol, Q-(CH 2 ) n -SH or amine Q-(CH 2 ) n -NHRa respectively as described above.
  • Z' is S or NRa
  • a leaving group for example a derivative of sulphonic acid such as a triflate, tosylate or the like which subsequently is displaced by a with a desired thiol Q-(CH 2 ) n -SH or amine Q-(CH 2 ) n-NHRa optionally in the presence of a base.
  • An alternative method for the preparation of compounds wherein Z' is S and n is 0 is to react the diol (If) with a desired diphenyl disulphide derivative in the presence of nBusP.
  • Substituted phenyl and heteroaryl derivatives Q-(CH 2 ) n - used in the schemes above are commercially available or they may be prepared according to literature procedures.
  • a method to prepare a substituted phenyl derivative useful for the preparation of compounds of formula (I) wherein Q is phenyl substituted with aminomethyl or amidomethyl and derivatives thereof is illustrated in scheme 5.
  • the hydroxy protected cyanobenzyl derivative (5 a) can be prepared by protection of commercially available cyanobenzyl alcohol, illustrated herein as 3 -cyanobenzyl alcohol, with a suitable protecting group, for example a trityl or monomethoxy trityl group using standard conditions well known in the art.
  • R 5 is H can be achieved by direct reduction of the cyano group to the methyl amino group using for instance LAH or diborane or the like, followed by protection of the afforded primary amine as previously described. Removal of the hydroxy protecting group using standard conditions such as treatment with acid in the case of trityl or monomethoxy trityl group provides the alcohol (5c). The afforded alcohol (5c) can then be used in the coupling to the primary alcohol of the lactone Ig or the linear compound 4c employing for example the Mitsunobu conditions as described in scheme 2 and 4 respectively.
  • the hydroxy group of the alcohol (5 c) can be transformed into a leaving group such as a bromide for example by treatment with bromine or carbontetrabromide in the presence of triphenylphosphine or the like thus affording the bromo derivative (5d), or the hydroxy group can be transformed into a derivative of sulphonic acid by reaction with a suitable sulphonylating agent such as a sulphonic halide or anhydride optionally in the presence of a base for example pyridine. Subsequently, the afforded compound can be coupled to the primary alcohol of the lactone If or the linear compound 4c as described in scheme 2 and 4 respectively.
  • a leaving group such as a bromide for example by treatment with bromine or carbontetrabromide in the presence of triphenylphosphine or the like thus affording the bromo derivative (5d)
  • a suitable sulphonylating agent such as a sulphonic halide or anhydride optionally in the presence
  • Scheme 6 illustrates an example to another substituted phenyl derivative, useful for the preparation of compounds of formula (I) wherein Q is phenyl which is substituted with an alkoxy-alkoxy group.
  • Q' is aryl, heteroaryl or an unsaturated group
  • Suitable reactions that can be used for the introduction of the substituent Q' are for instance the Stille reaction, wherein a tin derivative, such as a trialkyltin derivative, of the desired group Q' is reacted with the bromo derivative 6Ac in the presence of Pd(O), or the Heck coupling reaction wherein the bromo derivative 6Ac is reacted with a double bond of the desired group Q' in the presence of a Pd catalyst such as Pd(PPtLs) 4 PdCl 2 or Pd(OAc) 2 and a base such as triethylamine, potassium carbonate or the like.
  • a Pd catalyst such as Pd(PPtLs) 4 PdCl 2 or Pd(OAc) 2
  • a base such as triethylamine, potassium carbonate or the like.
  • Scheme 7 shows an alternative route to compounds of the invention, starting from Garner's aldehyde.
  • the group Q-(CH 2 ) n can then be introduced using any suitable method such as any of those described above. For example, a trichloroimidate of the desired group Q-(CH 2 ) n in the presence of TMS triflate will provide the ether derivative (7f) i.e. Z' is O.
  • the lactone may then be opened either directly with a desired amine as described above to give the amide (7h), or alternatively, the lactone may be opened by treatment with hydroxide such as lithium hydroxide, thus affording the acid (7g). Protection of the hydroxy group, using any conventional protecting group for example a silyl group such as a tert-butyl dimethylsilyl group, followed by coupling of the acid to a suitable amine using standard peptide coupling conditions such as using a coupling agent like EDAC in the presence of HOBt and a tertiary amine like triethylamine, and finally removal of the hydroxy protecting group provide the amide (7h).
  • any conventional protecting group for example a silyl group such as a tert-butyl dimethylsilyl group
  • coupling of the acid to a suitable amine using standard peptide coupling conditions such as using a coupling agent like EDAC in the presence of HOBt and a tertiary amine like triethyl
  • the hydroxy group of compound (4a) can be replaced by two fluoro atoms by oxidizing the hydroxy group to a keto group using any convenient method such as using a reagent like Dess Martin periodinane or oxone® (potassium monopersulphate triple salt) or any other suitable oxidizing agent, followed by treatment of the afforded keto compound with a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p. 2561-2578, or any other suitable fluorinating conditions, yields the difluoro compound (8a).
  • a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p. 2561-2578, or any other suitable flu
  • the monofluoro compound (8c) with the desired stereochemistry can be obtained by first inverting the stereochemistry at the steric centre whereto the hydroxy group is attached which can be performed for example by subjecting the alcohol to a Mitsunobu reaction with for instance p-nitrobenzoic acid and reagents like DIAD and PI13P followed by hydrolysis of the afforded p-nitrobenzoic ester by treatment with sodium methoxide or the like, and then subject the afforded inverted alcohol to fluorinating conditions such as treatment with DAST or deoxofluor as described above.
  • scheme 8 illustrates the replacement of the hydroxy group with fluoro or difluoro as the last step of the synthesis, the skilled person will realise that this transformation alternatively may be performed at any other suitable stage of the synthesis for example on any of the intermediates described above.
  • RV is R1 or an N-protecting group
  • the configuration of compound (9a), prepared as described above has to be inverted, for example as described in scheme 8.
  • the inverted alcohol (9b) can then be subjected to Mitsunobu conditions, i.e.
  • the azido derivative (9c) can be achieved by transformation of the hydroxy group to a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloro methane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with sodium azide or the like.
  • Reduction of the azide using any conventional reduction method such as hydrogenation in the presence of a suitable catalyst, or treatment with triphenylphosphine provides the corresponding amine (9d)
  • scheme 9 illustrates the conversion of the hydroxy group to an amine as the last step of the synthesis, the skilled person will realise that this transformation is also applicable at any other suitable stage of the synthesis for example on any of the intermediates described above.
  • any functional groups present on any of the constituent compounds used in the preparation of the compounds of the invention are appropriately protected where necessary.
  • functionalities on the natural or non-natural amino acids are typically protected as is appropriate in peptide synthesis.
  • Suitable protecting groups are described in Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981) and “The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1981), the disclosure of which are hereby incorporated by reference.
  • reaction mixture was cooled to 0 0 C and lithium aluminium hydride (450 mg) was added as a slurry in THF (18 ml), and the suspension was stirred at r.t. for Ih and then refluxed for 1 h.
  • the reaction mixture was cooled to 0 0 C and water (0.55 ml), 10%NaOH (0.55 ml) and water (1,84 ml) were added successively.
  • the resulting suspension was filtered through Celite, and the solid was washed with THF and DCM. The filtrate was evaporated and the residue partitioned between DCM and water.
  • the organic extract was dried by sodium sulfate and then evaporated.
  • Triflic anhydride (224 ⁇ l) dissolved in DCM (1.2 ml) was added dropwise under nitrogen to a stirred DCM (5.8 ml) solution cooled at 0 0 C of the alcohol 1Oe (281 mg, 0.67 mmol) and pyridine (0.16 ml). The mixture was stirred at 0 0 C for 1 h. The mixture was poured into a chilled 5% NaHSO 4 solution and extracted with DCM. The organic extract was dried through sodium sulfate and evaporated on rotavapor below r.t.
  • N,N-diisopropylethyl amine (36 ml, 200 mmol) in dichloromethane (5 ml) was then added to the reaction mixture -45 0 C during 30 min whereafter the reaction mixture was allowed to warm to 0 0 C during 10 min.
  • the reaction mixture was then transferred to a separation funnel charged with ice-cold 1 M HCl solution (130 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried and concentrated which gave the title compound (7.89 g, 99%). The residue was used in the next step without further purification.
  • the isopropyl lactone 12g (204 mg, 0.624 mmol) was treated with TFA - H 2 O (5 ml, 9:1), stirred at room temperature for 1 h, and then concentrated under vacuum. The residue was dissolved in a mixture of dioxane and a 10% solution of sodium carbonate (10 ml, 1 :1, pH ⁇ 8). BoC 2 O (204 mg, 0.936 mmol) was added in portions and the mixture was stirred at room temperature for 2 h. Dioxane was then removed under vacuum and the aqueous phase was extracted with dichloro methane, dried and concentrated.
  • N-Methylmorpholine (3 eq) and isobutylchloro formate (1 eq) was added to a stirred solution of Boc-valine (40 mg) in THF (ImI) at -15 0 C was.
  • the reaction was stirred at -15 0 C for one minute and then the appropriate amino derivative (1 eq) was added as a solution in DMF (ImI).
  • the reaction was then warmed to room temperature during a period of 30 min.
  • the solution was diluted with ethyl acetate and washed with sat. NaHCOs (aq) and concentrated in vacuo.
  • the residue was taken up in a solution of ImI 4M HCl in dioxane, stirred for one hour and then concentrated in vacuo to give the HCl salt of the amine.
  • the title compound was prepared according to general Method A, using 4-chloro benzylamine as amino derivative in step a.
  • the title compound was prepared according to general Method A, using 4-methoxy benzylamine as amino derivative in step a.
  • the title compound was prepared according to general Method A, using 3,4-dichloro benzylamine as amino derivative in step a.
  • the title compound was prepared according to general Method A, using C-pyridin-3-yl- methylamine as amino derivative in step a.
  • the title compound was prepared according to general Method A, using C-pyridin-4-yl- methylamine as amino derivative in step a.
  • Azodicarboxylic acid dipiperidide (505 mg, 2 mmol) and PPh 3 (524 mg, 2 mmol) were added to a solution of 23a (166 mg, 1 mmol) and 3-methoxypropan-l-ol (95.7 ⁇ l, 1 mmol) in CH 2 Cl 2 (10 ml) and the resulting mixture was stirred under N 2 for 17 h. The reaction mixture was then concentrated under vacuum and the residue was taken into EtOAc and washed with 10% aq. citric acid and brine. The organic phase was dried (Na 2 SO 4 ) and the solvent evaporated to give the crude product that was purified by flash chromatography on silica gel (Hex:EtOAc 10:1) to give 96 mg (40%) of the title compound.
  • Trifluoro-methanesulfonic acid 1 (4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-2-[3-(3-methoxy- propoxy)-4-methyl-benzyloxy]-ethyl ester (28a)
  • Example 30 The procedure described in Example 30 was followed but using thiazole-4-carbaldehyde instead of acetaldehyde, which gave the title compound (40% yield).
  • Example 8 The procedure described in Example 8 was followed but using 4-pyridinecarboxaldehyde instead of acetone, which gave the title compound (24% yield).
  • Example 8 The procedure described in Example 8 was followed but using 4-pyridinecarboxaldehyde instead of acetone, which gave the title compound (19% yield).
  • Example 30 The procedure described in Example 30 was followed but using 3-pyridinecarboxaldehyde instead of acetaldehyde, which gave the title compound (45% yield).
  • Example 30 The procedure described in Example 30 was followed but using thiazole-2-carbaldehyde instead of acetaldehyde, which gave the title compound (10% yield).
  • Triphenylphosphine (5.25 g, 20 mmol) and azodicarboxylic dipiperidine (5.04, 20 mmol) were added to a solution of 2-chloro-5-methyl-phenol (1.43 g, 10 mmol) and 3-methoxy- propan-1-ol (1 mL, 10 mmol) in CH 2 Cl 2 (100 mL).
  • the reaction mixture was stirred at r.t. 16 h and the evaporated into SiO 2 gel.
  • the title compound was purified by flash chromatography on silica gel (Hep:EtOAc 20:1) to give 2.0 g (80%).
  • N-Bromosuccinimide (284 mg, 1.6 mmol) and benzoyl peroxide (11 mg, 0.034 mmol) were added to a solution of 37a in CCU (6 mL) and the resulting suspension was refluxed for 1 h.
  • the reaction mixture was filtered through SiO 2 using Hep: EtOAc 10:1 as eluent. Evaporation of the solvent afforded 304 mg of the title compound (78% yield).
  • Methanesulfonyl chloride (0.47 mL, 6.07 mmol) was added to a solution of 40a (Ig, 6.06 mmol) and pyridine (1 mL, 12.4 mmol) in CH 2 Cl 2 (6 mL) at 5 0 C. The reaction mixture was then stirred at r.t. for 17 h. The reaction mixture was concentrated under vacuum and purified by flash chromatography on silica gel (Hep:EtOAc 2.5:1) to give 1.1 g (75%) of the title compound.
  • Triphenylphosphine (2.66 g, 10.16 mmol) and azodicarboxylic dipiperidine (2.56, 10.16 mmol) were added to a solution of 46a (1.0 g, 5.08 mmol) and 3-ethoxypropan-l-ol (0.59 mL, 5.08 mmol) in CH 2 Cl 2 (25 mL).
  • the reaction mixture was stirred at r.t. 16 h and then evaporated into SiO 2 gel.
  • the residue was purified by flash chromatography on silica gel (Hep:EtOAc 20:1 to 2.5:1) to give title compound 0.70 g (49%).
  • Example 30 The procedure described in Example 30 was followed but using lH-Indole-3-carbaldehyde instead of acetaldehyde, which gave the title compound (27% yield).
  • step g The procedure described in example 1 step g was followed but using 4-fluorobenzylamine instead of benzylamine, which gave the title compound in a yield of 78%.
  • Triphenylphosphine (0.44 g, 1.7 mmol) was dissolved in DCM (10 ml). Bromine (85 ⁇ l, 1.7 mmol) was added and the reaction mixture stirred for 5 min and then the obtained solution was added to [4-ethyl-3-(3-methoxy-propoxy)-phenyl] methanol (0.4 g, 1.8 mmol). The reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated and the residue purified on silica gel using hexanes 9 and ethyl acetate 1 as eluent to give 0.45 (87%) of the title compound. LC/MS confirmed the correct structure with characteristic double peaks at 289 (M+l) and 306 (M+NH 4 ).
  • step g The procedure described in example 1 step g was followed but using 4-(2-aminoethyl)- morpholine instead of benzylamine, which gave the title compound (65%).
  • Example 1 step h The procedure described in Example 1 step h was followed but using the bromide 23 d instead of benzyl bromide, whereafter the procedure described in Example 1 step i was followed, which gave the title compound (35%).
  • the lactone 60b was opened with the amine 48a according to the procedure described in
  • Example 49 step h whereafter the azide function was reduced according to the procedure described in Example 49 step i, which gave the title compound (63%)
  • the methyl ester 61b (0.73 g, 3.01 mmol) was dissolved in heptane (10 mL) and the solution was cooled to 0 0 C and stirred. DIBAL-H (9.0 mL of a 1.0 M solution in hexane, 9.0 mmol) was added dropwise. The reaction was quenched after 30 min by careful dropwise addition of 3 M HCl (10 niL). The mixture was diluted with Et 2 O (40 mL) and 1 M HCl (20 niL) and the layers were separated.
  • Example 1 step h The procedure described in Example 1 step h was followed but using 4-bromomethyl-l- fluoro-2-(3-methoxy-propoxy)-benzene (0.50 g, 1.80 mmol) instead of benzyl bromide, which gave 0.60 g (96%) of the title compound after column chromatography (elution with hexanes/ethyl acetate 10:1 - 2:1 with 1% MeOH throughout).
  • the lactone 6If (102 mg, 0.249 mmol), amine 48a (238 mg, 1.00 mmol), 2-hydroxypyridine (95 mg, 1.00 mmol) and DIPEA (48 ⁇ L, 0.275 mmol) were stirred and heated to 70 0 C for 3 days.
  • the mixture was cooled to room temperature and 3 mL of t-BuOMe was added to yield a brown suspension which was heated to 50 0 C and sonicated for 5 min, then centrifuged at 3500 rpm at 7 0 C for 12 min after which the supernatant was siphoned off. This process was repeated thrice to yield the title compound after drying in vacuo (55 mg, 34%).
  • Example 61 step d The procedure described in Example 61 step d was followed using benzyl alcohol 62a (2.60 g, 9.45 mmol) instead of 61c to yield the title compound (2.62 g, 82%) after purification by column chromatography (gradient elution with hexanes/ethyl acetate 30:1 - 1 :1).
  • Example 61 step g The procedure described in Example 61 step g was followed using lactone 62d (90 mg, 0.19 mmol) instead of 6 If.
  • the product was purified by sonication, centrifugation and siphoning off the supernatant as described in Example 1 step g using 1 mL of MeOH, t-BuOMe, MeCN, and t-Bu OMe in sequence which gave 36 mg (27%) of the title compound.
  • the product was purified by column chromatography (gradient elution from 100% DCM to

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Abstract

The invention provides compounds of the formula I wherein Q is aryl or heterocyclyl any of which is optionally substituted; Z is O, S, NRa or S(=O)p; Y is NH, NHNH, CH2NH, O, S or S(=O)p; n is 0, 1, 2 or 3; m is 0, 1 or 2; p is 1 or 2; Ra is H or C1-C4alkyl; R1 is hydrogen, C1-C6alkyl, C0-C3alkanediylC3-C7cycloalkyl, C0-C3alkanediylaryl or C0- C3alkanediylheterocyclyl; R2 is hydrogen or C1-C6alkyl; X' is hydrogen, fluoro, hydroxy, amino or C1-C6alkoxy; X' is hydrogen, or when X' is fluoro, then X' may also be fluoro; R3 is C1-C6alkyl; R4' is C1-C6alkyl; R4' is H or C1-C6alkyl; or R4' and R4' together with the carbon atom to which they are attached define a C3-C6cycloalkyl; W is C1-C6alkyl, C3-C7cycloalkyl, aryl or heterocyclyl any of which is optionally substituted; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof. The compounds of the invention are inhibitors of aspartyl proteases such as renin and are among other things useful for the treatment of conditions associated with activities of the RAS, such as hypertension, heart failure and renal insufficiency.

Description

NEW COMPOUNDS
Technical field
This invention relates to novel compounds having inhibitory activity on aspartyl proteases such as renin. It further concerns pharmaceutical compositions comprising these compounds as active ingredients as well as processes for preparing these compounds and compositions and their use in the preparation of a medicament or their use in therapy.
Background to the invention
The renin-angiotensin system (RAS) is critical for the control of blood pressure and salt balance in mammals. Renin is an aspartyl protease with a high substrate specificity, its only known substrate is angiotensinogen. Renin cleaves the N terminus of circulating angiotensinogento angiotensin I (Ang I), which thereafter is further processed to the active peptide hormone angiotensin II (Ang II) by the less specific angiotensin-converting enzyme (ACE). Ang II increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating the sodium-ion-retaining hormone aldosterone. Ang II is known to work on at least two receptor subtypes called ATI and AT2. ATI seems to transmit most of the known functions of Ang II, while the role of AT2 is still unknown.
Modulation of the RAS represents a major advance in the treatment of cardiovascular diseases. Inhibition of the enzymatic activity of renin leads to a reduction in the formation of Ang I, and as a consequence, a smaller amount of Ang II is produced. The reduced concentration of that active peptide hormone is a direct cause of the hypotensive effect of renin inhibitors.
ACE inhibitors and ATI blockers have been accepted to treat hypertension and ACE inhibitors are used for renal protection in the prevention of congestive heart failure and myocardial infarction. The rationale to develop renin inhibitors is the specificity of renin. Renin inhibitors are expected to demonstrate a different pharmaceutical profile than ACE inhibitors and ATI blockers with regard to efficacy in blocking the RAS and in safety aspects.
Only limited clinical experience has been created with renin inhibitors because of their insufficient oral activity. The clinical development of several compounds has been stopped because of this problem together with the high cost of goods. Only one compound has entered clinical trials (Rahuel J. et al., Chem. Biol., 2000, 7, 493; Mealy N. E., Drugs of the Future, 2001, 26, 1139). Thus, renin inhibitors with good oral bioavailability and long duration of action are required. The present invention concerns inhibitors of renin which exhibit beneficial potency, selectivity and/or pharmacokinetic properties. Compound 38 on page 4547 of Hanessian et al J. Med. Chem., 2006, 4544-4567, describe the boc-protected peptido mimetic derivative l-benzylsulfanylmethyl-4-(l-butylcarbamoyl-2- methyl-propylcarbamoyl)-2-hydroxy-pentyl]carbamic acid tert-butyl ester, used as an intermediate in the preparation of macrocyclic peptidomimetic BACE inhibitors. Compound 38 is outside the scope of the claims presented below and there is no suggestion that such intermediates could find utility as renin inhibitors.
Compound II on page 246 of Chen et al Bioorg. Med. Chem. Lett. 14 (2004) 245-250 discloses the compound 4-hydroxy-2,5-dimethyl-6-phenyl-hexanoic acid {2-methyl-l- [(pyridin-4-ylmethyl)-carbamoyl]-propyl} -amide used as an intermediate in the synthesis of peptidomimetic BACE inhibitors. The benzyl group attached direct to the backbone is outside the scope of the claims presented below and no suggestion is provided as to alternative utilities in the field of renin inhibition
Brief description of the Invention
In accordance with the present invention, there are provided compounds represented by the formula (I):
Figure imgf000003_0001
wherein
Q is aryl or heterocyclyl;
Z is O, S, NRa or S(=O)P; n is 0, 1, 2 or 3; m is 0, 1 or 2; p is independently 1 or 2;
Ra is H or Ci-C4alkyl;
R1 is hydrogen, d-Cβalkyl, Co-C3alkanediylC3-Cycycloalkyl or Co-C3alkanediylaryl, Co-
Csalkanediylheterocyclyl;
R2 is hydrogen or Ci-Cβalkyl;
X' is hydrogen, fluoro, hydroxy, amino or Ci-Cβalkoxy;
X" is hydrogen, or when X' is fluoro, then X" may also be fluoro;
R3 is Ci-Cealkyl;
R4' is Ci-Cealkyl; R4 is H or Ci-Cβalkyl; or R4 and R4 together with the carbon atom to which they are attached define a Cs-CδCycloalkyl;
W is C3-Cycycloalkyl, aryl or heterocyclyl, wherein the cycloalkyl moiety is optionally substituted with fluoro, methyl or methoxy; wherein aryl is independently phenyl, naphthyl, or phenyl fused to Cs-Cβcycloalkyl or Cs-C6 cycloalkenyl; heterocyclyl is independently a 5 or 6 membered, saturated, partially unsaturated or heteroarylic ring containing 1 to 3 heteroatoms independently selected from S, O and N, the ring being optionally fused with a benzene ring; wherein each Ci-Cβalkyl, aryl and heterocyclyl moiety above (including those in composite expressions such as alkoxy or alkanediylaryl), unless otherwise specified is optionally substituted with one, two or where valence allows three substituents independently selected from Ci-C4alkyl (optionally substituted with one or two substituents independently selected from Co-C3alkanediylaryl*, amino, carbamoyl, amido and Ci-C4alkoxyamido), C2-Cealkenyl,
C2-C6alkynyl, C3-C7cycloalkyl, Ci-C4alkoxy, Ci-C4alkoxyCi-C3alkyl, Ci-C4alkoxyCi-
C4alkoxyCo-C3alkyl, halo, haloCi-C4alkyl, polyhaloCi-C4alkyl, hydroxy, hydroxyCi-C4alkyl, amino, carbamoyl, amido, cyano, azido, Ci-C4alkylcarbonyl, NHS(=O)2Ci-C4alkyl, NC1-
C4alkylS(=O)2Ci-C4alkyl, a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (any of which cyclic amines being optionally substituted with Ci-C4alkyl or fluoro), Co-C3alkanediylaryl*, Co^alkanediylheterocyclyl*, C2-C3alkenyldiylC3-
C7carbocyclyl, C2-C3alkenyldiylaryl*, C2-C3alkenyldiylheterocyclyl*, C2-C3alkynyldiylC3-
C7carbocyclyl, C2-C3alkynyldiylaryl*, C2-C3alkynyldiylheterocyclyl* (wherein the asterisked aryl or heterocyclyl moiety is optionally substituted with Ci-C4alkyl, halo, hydroxy or amino); or a pharmac eutically acceptable salt, hydrate or N-oxide thereof.
The compounds of the invention are generally potent inhibitors of renin and thus the invention further provides the use of a compound of the formula I or a pharmaceutically acceptable salt, hydrate or N-oxide thereof for the treatment or prophylaxis of disorders mediated by the RAS, such as hypertension, heart failure and renal insufficiency .
The compounds of general formula (I) have several centres of chirality, conveniently the compounds display at least 75%, preferably at least 90%, such as in excess of 95%, enantiomeric purity at each of the chiral centres. In typical embodiments of the invention, the chiral centre whereto the group R3 is attached has the stereochemistry shown in structure (Ia):
Figure imgf000005_0001
The chiral centre to which R > 4' //rR> 4" is attached typically has the configuration shown in structure (Ib) below:
Figure imgf000005_0002
i.e. the configuration corresponds typically to that of an L-amino acid when R 4" is H.
The chiral centre to which R2 is attached typically has the configuration shown in structure (Ic) below:
Figure imgf000005_0003
The chiral centre to which X' and X" are attached has typically the configuration as shown in structure (Id) below:
Figure imgf000005_0004
Preferred compounds of formula (I) are those having the stereochemistry indicated in the structure of formula (Ie):
Figure imgf000005_0005
(Ie) R3 is Ci-Cβalkyl, preferably ethyl or more preferably isopropyl.
R4 is Ci-Cβalkyl, preferably isopropyl or more preferably sec. butyl.
R4" is preferably hydrogen.
According to alternative embodiment R4' and R4" together define a spiro-cycloalkyl group, for example cyclopentyl or cyclobutyl or preferably cyclopropyl.
Preferably X' is fluoro, or more preferably hydroxy.
Preferably X" is hydrogen.
A further embodiment of the invention are compounds of formula (I) or any subgroup of formula (I) wherein X' and X" are both fluoro.
In some embodiments, R1 is hydrogen, Ci-Cβalkyl, Co-C3alkanediylC3-Cycycloalkyl, Co- Csalkanediylaryl or Co-C3alkanediylheterocyclyl, wherein each Ci-Cβalkyl, cycloalkyl, aryl and heterocyclyl moiety is optionally substituted with one, two or three substituents independently selected from halo, haloCi-C4alkyl, Ci-C4alkyl, Ci-C4alkoxy, hydroxy and cyano.
Other embodiments allow the Ci-Cβalkyl, cycloalkyl, aryl and heterocyclyl moiety of R1 to be substituted with amino, Ci-C4alkylamino, (Ci-C4alkyl)2 amino and NRaS(=O)pCi-C4 alkyl.
Convenient values for R1 include hydrogen, optionally substituted phenyl, optionally substituted benzyl and optionally substituted Ci-Cβalkyl.
Preferably R1 is hydrogen, Ci-Cβalkyl or optionally substituted benzyl, especially hydrogen, methyl, ethyl or isopropyl.
In an alternative embodiment, R1 is optionally substituted heteroarylCi-C4alkyl, such as heteroarylmethyl, especially where the heteroaryl is pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, any of which may be substituted as defined above, such as with 1 or 2 Ci-C4alkyl (preferably methyl), Ci-C4alkoxy (preferably methoxy), Ci-C4alkoxyCi-C3alkoxyCo-C3alkyl, preferably methoxypropoxy), cyano or halo (preferably fluoro) groups.
In typical embodiments R1 is pyridylCi-C4alkyl or thiazolylCi-C4alkyl. Further configurations for R1 include phenylethyl, which is optionally substituted with a sulphonamide group such as methanesulphonamide or N-methyl methanesulphonamide.
The optional substituents to R1 in general are as defined above. Representative values include Ci-C4alkyl such as methyl; halo such as fluoro; haloCi-C4alkyl such as fluoromethyl and trifluoromethyl; and cyano.
In embodiments wherein R1 is Co-C3alkanediylaryl or Co-C3alkanediylheterocyclyl the optional substituent(s) to the aryl or heterocyclyl moiety are conveniently in the para and/or ortho position. Currently favoured configurations for R1 according to this embodiment are phenyl or benzyl substituted in the para position.
R2 is Ci-Cβalkyl such as methyl or ethyl, or preferably R2 is hydrogen.
In a preferred embodiment, Z is O.
According to another embodiment Z is NRa, wherein Ra is hydrogen or Ci-C3alkyl, preferably hydrogen or methyl.
The group Q is bonded either directly to Z, i.e. n is 0, or Q is bonded via a methylene, ethylene or propylene moiety, i.e. n is 1, 2 or 3 respectively. In favoured embodiments of the invention Q is bonded directly to Z or via an ethylene moiety, i.e. n is 0 or 2. In more favoured embodiments of the invention, Q is bonded via a methylene moiety, i.e. n is 1.
As defined above, Q is aryl or heterocyclyl, optionally substituted with one, two or three substituents independently selected from Ci-C4alkyl (optionally substituted with one or two substituents independently selected from Co-C3alkanediylaryl, amino, carbamoyl, amido and Ci-C4alkoxyamido), C2-Cealkenyl, C2-C6alkynyl, C3-Cycycloalkyl, Ci-C4alkoxy, halo, haloCi-C4alkyl, polyhaloCi-C4alkyl, Ci-C4alkoxyCi-C3alkyl, Ci-C4alkoxyCi-C4alkoxyC0- C3alkyl, hydroxy, hydroxyCi-C4alkyl, cyano, azido, Ci-C4alkylcarbonyl, carbamoyl, amino, amido, a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (any of which cyclic amines being optionally substituted with Ci-C4alkyl or fluoro), Co- C3alkanediylaryl, Co^alkanediylheterocyclyl, C2-C3alkenediylcarbocyclyl, C2- C3alkenediylaryl, C2-C3alkanediylheterocyclyl, C2-C3alkynediylcarbocyclyl, C2- C3alkynediylaryl or C2-C3alkanediylheterocyclyl (wherein the aryl or heterocyclyl moiety is optionally substituted with Ci-C4alkyl, halo, hydroxy or amino). In one embodiment , the optional substituent (s) to Q include Ci-C4alkyl (optionally substituted with one or two substituents independently selected from Co-C3alkanediylaryl, amino, carbamoyl, amido and Ci-C4alkoxyamido), C3-Cycycloalkyl, Ci-C4alkoxy, halo, haloCi-C4alkyl, Ci-C4alkoxyCi-C3alkyl, Ci-C4alkoxyCi-C4alkoxyCo-C3alkyl, hydroxy, hydroxyCi-C4alkyl, cyano, azido, Ci-C4alkylcarbonyl, carbamoyl, amino, amido, a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (any of which cyclic amines being optionally substituted with Ci-C4alkyl or fluoro), Co-C3alkanediylaryl, Co-C3alkanediylheterocyclyl, (wherein the aryl, carbocyclyl moiety is optionally substituted with Ci-C4alkyl, halo, hydroxy or amino.
According to one embodiment of the invention Q is an optionally substituted mono or bicyclic aryl moiety such as phenyl or naphthyl.
According to another embodiment of the invention, Q is an optionally substituted mono- or bicyclic ring containing 1 , 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, independently selected from nitrogen, oxygen and sulphur. Representative monocyclic rings according to this embodiment include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like, representative bicyclic rings include quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl each of which is optionally substituted wherein each of the mono and bicyclic rings is optionally substituted.
Currently preferred heterocyclyl groups for Q include pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, any of which may be substituted as defined above, such as 1 or 2 with C1-C4 alkyl (preferably methyl), Ci-C4alkoxy (preferably methoxy), Ci-C4alkoxyCi-C3alkoxyCo-C3alkyl, preferably methoxypropoxy) or halo (preferably fluoro) groups.
Typical values for Q include optionally substituted 5 or 6 membered aryl or heterocyclyl, preferably phenyl or pyridyl.
A further typical value for Q is optionally substituted naphthyl.
Optional substituents to Q are as defined above. Representative values include substituents independently selected from Ci-C4alkyl, C3-Cycycloalkyl, Ci-C4alkoxy, Ci-C4alkoxy-Ci- C6alkoxyCo-C3alkyl, halo and haloCi-C4alkyl. Currently favoured values for the optional substituents for Q include cyclopropyl, methoxy- ethoxy, fluoro, optionally substituted phenyl and benzyl, more favoured substituents are chloro, methyl or methoxy-propoxy.
Further optional substituents to Q include Co-C3alkanediylaryl which aryl is optionally substituted, Co-C3alkanediylheterocyclyl and Co-C3alkanediylheteroaryl. Typical heterocyclyl and heteroaryl include, but are not limited to, pyrrolyl, pyrrolinyl, pyrazolyl, imidazolyl, oxazolyl, pyrimidinyl, pyrazinyl, morpholinyl and especially furyl, thienyl, thiazolyl and pyridyl.
According to one embodiment of the invention Q is a mono-substituted 6-membered ring, wherein the substituent is preferably in one of the meta positions or in the para position. In a preferred configuration according to this embodiment, Q is para-substituted phenyl. In a further preferred configuration according to this embodiment, Q is meta-substituted phenyl.
Further embodiments for Q include phenyl which is substituted with methoxypropoxy, and phenyl which is mono- or disubstituted with chloro.
Further embodiments for Q include phenyl which is substituted with phenyl or substituted phenyl such as fluoro- or chlorophenyl, cycloalkyl such as cyclopropyl, Ci-Cβalkyl such as methyl, ethyl or isopropyl, or pyridyl.
A further embodiment for the optional substituents to Q is benzyl which is substituted at the benzylic position. Suitable substituents for the benzylic position includes for example amino, amido or alkoxyamido such as Ci-C4alkylamino or tert-butoxycarbonylamino.
According to this embodiment, compounds wherein Q has the structure shown below are included:
Figure imgf000009_0001
wherein R5 is Ci-C4alkyl, Ci-C4alkylcarbonyl or Ci-C4alkyloxycarbonyl and R5 is hydrogen, methyl or especially phenyl.
According to a further embodiment, Q is disubstituted 6-membered ring with the substituents in the two meta positions or with one substituent in the meta position and the other in the para position. Preferred substituents to Q according to this embodiment are independently chloro, methoxypropoxy and methyl.
Typically, Q is phenyl, optionally substituted with one or two substituents independently selected from methyl, cyclopropyl, fluoro, chloro and 3-methoxy-propxy.
In typical embodiments Q is phenyl, substituted in one of the meta positions and/or in the para position.
Suitable configurations for Q include phenyl which is substituted in the meta position with Ci-C4alkoxy-Ci-C4alkoxy, and in the para position with Ci-C4alkyl, cyano or halo.
More suitable configurations for Q include phenyl which is substituted in the meta position with 3-methoxy-propoxy and in the para position with methyl, ethyl, cyano, fluoro, chloro or bromo.
Further suitable configurations for Q include phenyl which is substituted in one of the meta positions with Ci-C4alkoxy-Ci-C4alkoxy, such as methoxypropoxy and/or in the para position with optionally substituted heteroaryl or optionally substituted phenyl.
More suitable configurations for Q include phenyl which is substituted in one of the meta positions with 3-methoxy-propoxy and/or in the para position with pyridyl, thienyl or furyl or with optionally substituted phenyl, such as p-fluorophenyl.
The group W is bonded either directly to the amide nitrogen, i.e. m is 0, or W is bonded via a methylene or ethylene moiety, i.e. m is 1 or 2 respectively. In favoured embodiments of the invention W is bonded via a methylene moiety, i.e. m is 1.
As stated above, W is Ci-Cβalkyl, C3-Cycycloalkyl, aryl or heterocyclyl which is optionally substituted with one, two or three substituents.
According to one embodiment of the invention W is an optionally substituted mono or bicyclic aryl moiety such as phenyl or naphthyl, preferably optionally substituted phenyl.
According to another embodiment of the invention, W is an optionally substituted mono- or bicyclic ring containing 1 , 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur. Representative monocyclic rings according to this embodiment include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like, representative bicyclic rings include quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl each of which is optionally substituted wherein each of the mono and bicyclic rings is optionally substituted.
In a still further embodiment W is unsubstituted C3-C7 cycloalkyl, such as cyclopropyl. Alternatively a C3-C7 cycloalkyl W can be substituted, for example with fluoro, methyl or methoxy;
Preferably, W is a monocyclic 5- or 6-membered ring.
In embodiments wherein W is a substituted 6-membered ring, the ring is preferably mono substituted with the substituent in the meta or para position.
Typically, W is optionally substituted phenyl.
In typical embodiments of the invention, W is phenyl which is substituted with fluoro chloro, methyl or cyano and the substituent is preferably in the para position.
In embodiments wherein the ring W is disubstituted the substituents are preferably in the two meta positions or in the meta and para positions.
Preferred optional substituents to W include one or two substituents independently selected form halo such as fluoro or chloro; C3-Cycycloalkyl such as cyclopropyl; haloCi-Csalkyl such as fluoromethyl and trifluoromethyl; Ci-Cβalkyl such as methyl, ethyl and isopropyl.
It is to be understood that the above defined subgroups of compounds of formulae (Ia), (Ib), (Ic), (Id) and (Ie), as well as any other subgroup defined herein, are meant to also comprise any prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes and stereo chemically isomeric forms of such compounds.
As used in the foregoing and hereinafter, the scientific and technological terms and nomenclature have the same meaning as commonly understand by a person of ordinary skill in the art, in addition, the following definitions apply unless otherwise noted.
As used herein 'd-dalkyl' as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as for example methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl-l -propyl, 2-methyl-2-propyl. Methyl is typically preferred in many applications. 'Ci-Cδalkyl' encompasses Ci-C4alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 2-methyl- 1 -butyl, 2-methyl- 1-pentyl, 2-ethyl-l -butyl, 3-methyl-2-pentyl, and the like. Of interest amongst Ci-Cβalkyl is Ci-C4alkyl.
The term 'C2-C6alkenyl' as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbon bonds and at least one double bond, and having from 2 to 6 carbon atoms, such as, for example, ethenyl (or vinyl), 1-propenyl, 2- propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 3- pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl and the like. Of interest amongst C2-Cealkenyl is C2-C4alkenyl.
The term 'C2-C6alkynyl' as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbon bonds and at least one triple bond, and having from 2 to 6 carbon atoms, such as, for example, ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like. Of interest amongst C2-Cealkynyl is C2-C4alkynyl.
'C0-C3alkanediyr defines a bond (Co) or a bivalent straight or branched saturated hydrocarbon chain having from 1 to 3 carbon atoms such as, for example, methylene, ethylene, 1,3-propanediyl, 1 ,2-propanediyl, and the like, especially methylene.
'C2-C3alkenediyr defines a bivalent straight or branched hydrocarbon chain having one double bond and having 2 or 3 carbon atoms such as, for example, ethenylene, 1,3-propenediyl, 1 ,2-propenediyl, and the like, especially vinylene.
'C2-C3alkynediyr defines a bivalent hydrocarbon chain having 2 or 3 carbon atoms and a triple bond, i.e. ethynylene and propynylene.
'Ci-Cβalkoxy' (also referred to interchangeably) as Ci-Cβalkyloxymeans a radical O-Ci- Cβalkyl wherein Ci-Cβalkyl is as defined above. Ci-Cβalkoxy of interest include but are not limited to methoxy, ethoxy, n-propoxy and isopropoxy. Ci-C4-alkoxy or Co-C3-alkoxy has the corresponding definition, adjusted as necessary for C number.
The term 'halo' is generic to fluoro, chloro, bromo and iodo. Fluoro is typically preferred in many applications. The term 'haloCi-C4alkyl' as a group or part of a group, is meant to include mono- and polyhalo substituted Ci-C4alkyl, in particular Ci-C4alkyl substituted with one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Preferred is trifluoromethyl. In case more than one halogen atom is attached to an alkyl group within the definition of haloCi-Cβalkyl, the halogen atoms may be the same or different.
As used herein, the term '(=0)' or 'oxo' forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulphur atom and a sulphonyl moiety when two of said terms are attached to a sulphur atom. Whenever a ring or ring system is substituted with an oxo group, the carbon atom to which the oxo is linked is a saturated carbon.
'Amino' as a group or part of a group, unless the context suggests otherwise, includes NH2, NHCi-Cβalkyl or N(Ci-C6-alkyl)2, wherein in the amino definitions each Ci-Cβalkyl is especially Ci-C4alkyl variants. Included are also radicals wherein the two Ci-Cβalkyl groups of the N(Ci-C6-alkyl)2 together with the nitrogen atom to which they are attached form a saturated cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl or morpholniyl.
'Carbamoyl' includes Q=O)NH2, and mono- and dialkylcarbamoyl, such as Q=O)NHC1- C6alkyl and C(=O)N(Ci-C6alkyl)2, especially C(=O)NHCi-C4alkyl and C(=O)N(Ci-C4alkyl)2. Included are also radicals wherein the two Ci-Cβalkyl groups of the dialkylcarbamoyl together with the nitrogen atom to which they are attached form a saturated cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl and morpholniyl.
'Amido' includes NHC(=0)H, alkanoylamino such as NH(C=O)C i-Cβalkyl especially NH(C=O)C i-C4alkyl, and N-alkyl alkanoylamino such as N(C i-C6alky I)(C=O)C i-C6alkyl especially N(Ci -C4alkyl)(C=O)C1-C4alkyl. The term 'alkoxyamido' is meant to include NHC(=O)Ci-C6alkoxy, such as tert-butoxycarbonylamino.
'Co-C3alkanediylaryl' as applied herein is meant to include an aryl moiety such as a phenyl or naphthyl or a phenyl fused to a Cs-Cβcycloalkyl (for example indanyl), or a C5- Cβcycloalkenyl which aryl is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1 ,2-propanediyl or 1,3-propanediyl group as defined for Ci-C3alkanediyl above. Examples of suitable aryl groups include but are not limited to phenyl, naphtyl, tetrahydronaphthyl, indenyl and indanyl. Unless otherwise indicated the aryl and/or its fused cycloalkyl moiety is optionally substituted with one, two or where valence allows three substituents independently selected from halo, hydroxy, nitro, cyano, carboxy, Ci-C4alkyl, C1- C4alkoxy, C3-C7cycloalkyl, haloCi-C4alkyl, Ci-C4alkoxyCi-C3alkyl, Ci-C4alkoxyCi- C4alkoxyCo-C3alkyl, Ci-Cβalkanoyl, amino, amido, carbamoyl, azido, oxo, mercapto, Co- Csalkanediylaryl, Co-C3alkanediylheteroaryl, it being understood that heterocyclic and arylic moieties in the Co-C3alkanediylaryl and Co-C3alkanediylhetercyclyl substituent may itself be substituted as provided herein but typically not with a further Co-C3alkanediylaryl or Co- C3alkanediylheterocyclyl. 'Aryl' has the corresponding meaning, i.e. where the Co- C3alkanediyl linkage is absent.
'C2-C3alkenediylaryl and 'C2-C3alkynediylaryl have the corresponding meanings, adjusted just for the link to the aryl moiety as defined for 'C2-C3alkenediyr and 'C2-C3alkynediyl
'Co-C3alkanediylheterocyclyl' as applied herein is meant to include a 5-6 membered saturated, partly unsaturated or unsaturated heterocyclic ring containing 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulphur, the ring being optionally fused with a benzene ring. Examples of suitable heterocyclyl groups include but are not limited to pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, isothiazolyl, thiazolidinyl, thiadiazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, triazinyl, 1 ,4-dioxanyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzo thiazinolyl, benzisothiazinolyl, benzothiazolyl, benzoxadiazolyl, benzo- 1,2,3-triazolyl, benzo- 1,2,4-triazolyl, benzotetrazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyridazinyl, benzopyrazolyl, indolyl, isoindolyl indolinyl, isoindolinyl etc, Said heterocyclyl is bonded either directly (i.e. Co), or through an intermediate methylene, ethylene or propanediyl group as defined for Ci- C3alkanediyl above. Unless otherwise indicated the ring system is optionally substituted with one, two or where valence allows three substituents independently selected from halo, hydroxy, nitro, cyano, carboxy, Ci-C4alkyl, Ci-C4alkoxy, C3-Cycycloalkyl, haloCi-C4alkyl, Ci-C4alkoxyCi-C3alkyl, Ci-C4alkoxyCi-C4alkoxyCo-C3alkyl, Ci-Cβalkanoyl, amino, amido, carbamoyl, azido, oxo, mercapto, Co^alkanediylaryl, Co-C3alkanediylheteroaryl, it being understood that heterocyclic and carbocyclic moieties in the Co-C3alkanediylaryl or Co- C3alkanediylheterocyclyl substituent may itself be substituted as provided herein but typically not with a further Co-C3alkanediylaryl or Co^alkanediylheterocyclyl. 'Heterocyclyl' has the corresponding meaning, i.e. where the Co-C3alkanediyl linkage is absent. 'C2-C3 alkenediylheterocyclyl and 'C2-C3alkynediylheterocyclyl have the corresponding meanings, adjusted just for the link to the heterocyclyl moiety as defined for 'C2-C3alkenediyl' and 'C2-C3alkynediyl
Typically aryl and heterocyclyl moieties within the scope of the above definitions are thus a monocyclic ring with 5 or especially 6 ring atoms, or a bicyclic ring structure comprising a 6 membered ring fused to a 5 or 6 membered ring.
'heteroaryl' as applied herein means an aromatic heterocyclyl moiety.
'Co-C3alkanediylC3C7Cycloalkyl' as applied herein is meant to include a C3-Cycycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, which is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1 ,2-propanediyl or 1,3-propanediyl group as defined for Ci-C3alkanediyl above. The cycloalkyl group may contain an unsaturated bond. Unless otherwise indicated the cycloalkyl moiety is optionally substituted with 1-3 substituents selected from halo, hydroxy, nitro, cyano, carboxy, C1- C4alkyl, Ci-C4alkoxy, haloCi-C4alkyl, Ci-C4alkoxyCi-C4alkyl, Ci-Cβalkanoyl, amino, amido, carbamoyl, azido, oxo, mercapto, nitro Co^alkanediylaryl, Co^alkanediylheterocyclyl, it being understood that heterocyclic and carbocyclic moieties in the Co-C3alkanediylaryl or Co- C3alkanediylheterocyclyl substituent may itself be substituted as provided herein but typically not with a further Co-C3alkanediylaryl or Co-C3alkanediylheterocyclyl. 'C3Cvcycloalkyl' has the corresponding meaning, i.e. where the Co-C3alkanediyl linkage is absent.
'C2-C3alkenediylcarbocyclyl and 'C2-C3alkynediylcarbocyclyl have the corresponding meanings, adjusted just for the link to the carbocyclyl moiety as defined for 'C2-C3alkenediyr and 'C2-C3alkynediyl
It should be noted that the radical positions on any molecular moiety used in the definitions may be anywhere on such a moiety as long as it is chemically stable.
Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated. For instance pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1- pentyl, 2-pentyl and 3-pentyl.
When any variable occurs more than one time in any constituent, each definition is independent. Whenever used hereinafter, the term 'compounds of formula (I)', or 'the present compounds' or similar terms, it is meant to include the compounds of formula (I), their prodrugs, TV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms.
The term 'prodrug' as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I). The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing prodrugs generally is hereby incorporated. Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo. Prodrugs of a compound of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound.
Preferred are pharmaceutically acceptable ester prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy and/or a carboxyl group. An in vivo hydrolysable ester is an ester, which is hydro lysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include Ci-Cβalkoxymethyl esters for example methoxymethyl, Ci-Cβalkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, Cs-CscycloalkoxycarbonyloxyCi- Cβalkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci-Cβalkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl which may be formed at any carboxy group in the compounds of this invention.
An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)- N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring. For therapeutic use, salts of the compounds of formula (I) or any subgroup of compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric acids and the like; or organic acids such as, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, /?-toluenesulfonic, cyclamic, salicylic, /^-aminosalicylic, pamoic acids and the like.
Acid addition salt forms can be converted to the free base form by treatment with an appropriate base.
The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with an appropriate organic or inorganic base. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, JV-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
Base addition salt forms can be converted to the free acid form by treatment with an appropriate acid.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) or any of the subgroups of compounds of formula (I), as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The term 'quaternary amine' as used above and hereinafter defines the quaternary ammonium salts which the compounds of formula (I) or any of the subgroups of compounds of formula (I), are able to form by reaction between a basic nitrogen of a compound of formula (I) or any of the subgroups of compounds of formula (I), and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
The iV-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called iV-oxide.
The compounds according to the invention may contain one or more asymmetrically substituted carbon atoms, asymmetric or chiral centre. The presence of one or more of these asymmetric centres in compounds according to the invention can give rise to stereochemically isomeric forms, stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, both in pure form and mixed with each others, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms 'enantiomerically pure' and 'diastereomerically pure' should be understood in a similar way, but then having regard to the enantiomeric excess, and the diastereomeric excess, respectively, of the mixture in question.
Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by application of art-known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, pp 104-107). For instance, enantiomers may be separated from each other using known procedures including, for example, formation of diastereomeric mixtures by reaction with a convenient optically active auxiliary species followed by separation of the diastereomers, using for instance selective crystallisation, and finally cleavage of the auxiliary species. Examples of optically active auxiliary species are optically active acids and bases such as tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. When a specific stereoisomer of a compound is desired, the compound will preferably be synthesized by stereospecifϊc methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
With reference to the instances where (R) or (S) is used to designate the absolute configuration of a chiral centre within a substituent, the designation is done taking into consideration the whole compound and not the substituent in isolation.
Where tautomers exist in the compounds of the invention, we disclose all individual tautomeric forms and combinations of these as individual specific embodiments of the invention.
It will be appreciated that the compounds of formula (I) may have metal binding, chelating or complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
The invention relates to the compounds of formula (I) or any subgroup of compounds of formula (I) per se, the prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof. One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the iV-oxides, salts, as the possible stereoisomeric forms thereof.
The invention further relates to methods for the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I), the prodrugs, JV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, its intermediates, and the use of the intermediates in the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I).
The invention also relates to the use of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof, for the manufacture of a medicament. Or the invention relates to the use of a of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof in therapy.
In the context of the present specification, the term 'therapy' also includes 'prophylaxis' unless there are specific indications to the contrary. The terms 'therapeutic' and 'therapeutically' should be construed accordingly.
The invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a compound of any of the subgroups of formula (I) or a pharmaceutically acceptable salt thereof as specified herein, and a pharmaceutically acceptable adjuvant, diluent or carrier for administration to a subject in need thereof. A therapeutically effective amount in this context is an amount sufficient to act in a prophylactic way against, to stabilize or to reduce adverse conditions associated with RAS activity, such as or related to hypertension, heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, in affected subjects or subjects being at risk of being affected.
The invention further relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable adjuvant, diluent or carrier with a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) as specified herein, or a pharmaceutically acceptable salt or a solvate, prodrug, N-oxide, quaternary amine, metal complex or stereochemically isomeric form thereof as specified herein.
The compounds of formula (I) or any of the subgroups of formula (I) have enzyme inhibiting properties and are modulators of the renin-angiotensin system, in particular they are inhibitors of the natural enzyme renin and may be used in the treatment and/or prophylaxis of diseases such as or related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, atherosclerosis, restenosis post angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications of treatments with immunosuppressive agents, and other diseases known to be related to the renin- angiotensin system. In one embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases or conditions which are associated with a dysregulation of the renin-angiotensin system, in particular to a method for the treatment or profylaxis of the above mentioned diseases, said method comprising administering to a patient a pharmaceutically active amount of a compound of formula (I) or any of the subgroups of formula (I).
The invention further provides a method of treating a disease or condition known to be related to the renin- angiotensin system which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, a solvate, prodrug, iV-oxide, quaternary amine, metal complex, or stereochemically isomeric form thereof, as hereinbefore defined.
The invention also provides a method of treating diseases or conditions such as or related to the above mentioned (e.g. hypertension) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, or solvate thereof as hereinbefore defined.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of formula I/salt/so lvate (active ingredient) may be in the range from 0.001 mg/kg to 75 mg/kg, in particular from 0.5 mg/kg to 30 mg/kg. This daily dose may be given in divided doses as necessary. Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
DMPK parameters of the compounds of the invention are measured by conventional assays. For example the advantageously high permeability of the invention can be assayed in the Caco-2 cell line which is commercially available and widely used in the literature. The advantageosuly high bioavailability can be assayed by conventional oral dosing in appropriate animal models such as rat or cynomolgus, followed by blood sampling (measured by MS) at defined time intervals to monitor the apperance of the compounds, ie absorption. Absolute bioavailability is measured in the conventional manner by reference to the time course/ AUC of an IV or IP dose of the compound, typically at 1/10th the dose. The advantageously low hepatic and other metabolism can be gauged with commercially available hepatocytes, such as XEN-025 or 1037. The advantageously low P450 metabolism is measured with supersomes (Gentest Corp, USA) that is baculovirus infected insect cells transfected with human P450 iso forms, including CYP 1A2, CYP2A6, CYP2C9-Arg 144, CYP219, CYP2D6Val 374 and CYP34A, typically with P450 reductase, whereby th involvement of a given iso form in the metabolism of the test compound is determinted by UV HPLC or MS. The compounds of formula (I) and pharmaceutically acceptable salts, solvates, prodrugs, iV-oxides, quaternary amines, metal complexes, or stereochemically isomeric forms thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound of formula (I) /salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w/w, of active ingredient, and, from 1 to 99.95 %w/w, more preferably from 30 to 99.90 %w/w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition. A representative tablet within the scope of the pharmaceutical composition of the invention could have a mass of 500 - 1500 mg with a loading of active ingredient in the range 35 - 75%, with the balance being excipients, such as binders, disintegrants, antioxidants and the like.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions. The oral delivery route, particularly capsules or tablets is favoured.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co- administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more of the diseases or conditions referred to hereinabove. A representative example are other pharmacologically active compounds such as ACE-inhibitors, neutral endopeptidase inhibitors, aldosterone antagonists, angiotensin II receptor antagonists, endothelin receptors antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholitics, beta- adrenergic antagonists, alpha-adrenergic antagonists and/or other drugs beneficial for the prevention or the treatment of the above-mentioned diseases such as 1 ibeta-hydroxy steroid dehydrogenase type 1 inhibitors and soluble guanylate cyclase activators.
General synthetic methodology The compounds of the present invention and intermediates useful for the synthesis of these compounds are prepared by methods and techniques known to those skilled in the art. The general schemes below illustrate typical synthetic routes to the compounds of the invention and to intermediates thereof. Alternative routes, which will be readily apparent to the ordinary skilled organic chemist, may alternatively be used to synthesize various portions of the molecules as illustrated by the general schemes and the preparative examples below.
Scheme 1 illustrates a synthetic route to a lactone which is a useful intermediate in the preparation of compounds of formula (I).
Figure imgf000023_0001
mCPBA
BF3OEt2
Figure imgf000023_0002
Scheme 1
The isopropylidene derivative (Ia) achieved for example as described in Tetrahedron Lett., 1987, 28, 1143, can be transferred into the methyl glycoside (Ib) by acidic hydrolysis of the acetal group effected by treatment with a suitable acid such as sulphuric acid, in the presence of methanol. The achieved free secondary hydroxy group can then be reductively removed effected for instance by transformation of the hydroxy group into a thiocarbonyl group by reaction with thiocarbonyl diimidazole (TCDI) followed by reduction of the formed thiocarbonyl group using for instance conditions such as tributyltin hydride the presence of a radical initiator like azobis-(2-methylpropyonitrile) (AIBN) or the like to give the 2,3-dideoxy glycoside (Ic). Oxidative cleavage of the methyl ether performed for example by oxidation with m-chloroperbensoesyra or the like in the presence of BF3-etherate, gives the lactone (Id). The ring substituent R3 can then be introduced for example by treatment of the lactone with a base such as LDA or equivalent followed by reaction with a suitable alkylating agent such as an alkyl halide like an alkyl bromide or alkyl iodide or a derivative of sulphonic acid such as a mesylate, triflate or tosylate or the like, thus providing the α-alkylated lactone (Ie). Removal of the benzyl groups using any suitable conditions well known to the skilled person, such as catalytic hydrogenation, then provides the diol (If). Compounds of formula (I) wherein Z is O and n is 1 , can then be achieved from the intermediate lactone (If) as shown in scheme 2.
Figure imgf000024_0001
2e 2f
Scheme 2
The primary hydroxy group of the lactone (If) can be selectively alkylated for example by activation of the hydroxy group with dibutyltinoxide followed by reaction with a desired alkylating agent Q-(CH2)D-Lg wherein Lg is a suitable leaving group such as a halide like bromide or iodide in the presence of tetrabutylammonium bromide or the like thus forming the ether derivative (2a). Alternatively, the substituent Q-(CH2)D can be introduced by using the Mitsunobu conditions (Mitsunobu, 1981, Synthesis, January, 1-28; Rano et al, Tetrahedron Lett., 1995, 36, 22, 3779-3792; Krchnak et al., Tetrahedron Lett., 1995, 36, 5, 6193-6196; Richter et al., Tetrahedron Lett., 1994, 35, 27, 4705-4706) i.e. reaction of the alcohol (If) with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine followed by displacement with a desired alcohol. Replacement of the hydroxy group of the secondary alcohol (2a) by azide may then be effected by transforming the hydroxy group to a leaving group, for example a derivative of sulphonic acid like a triflate or tosylate or the like by subjecting the alcohol to sulphonylating conditions such as treatment with the appropriate anhydride or halide optionally in the presence of a base, for instance pyridine, followed by displacement of the leaving group with azide for example sodium azide, thus giving the azide derivative (2b). Alternatively, the azide moiety can be introduced by treatment of the alcohol with diisopropyl azodicarboxylate or any other suitable azodicarboxylate, in combination with triphenylphosphine, followed by reaction with azide for example DPPA, in a solvent like THF. The linear amino compound (2e) can then be achieved by opening of the lactone with a desired amino derivative (2c) in the presence of a coupling agent for example 2-hydroxypyridine and a base like isopropyl diethylamine. Reduction of the azide using conditions compatible with the (CH2)n-Q group, for example hydrogenation at atmospheric pressure in the presence of Lindlar Catalyst or equivalent. If desired, the afforded primary amine can be substituted effected by way of any convenient method for example by reaction with an alkylating agent R1 -Lg wherein Lg is a leaving group such a halide like chloride, bromide or iodide or a derivative of sulphonic acid such as a mesylate or a triflate or the like, optionally in the presence of a base, or alternatively an N- substituent may be introduced by reaction with an aldehyde R1Q=O)H in a reductive amination reaction using any suitable reductive agent such as NaBH3CN or the like.
An intermediate lactone useful for the preparation of compounds of formula (I) wherein the group Q is bound directly to the oxygen atom, i.e. Z is O and n is 0, can be prepared as shown in scheme 2A.
as above
Figure imgf000025_0001
2Ac
Scheme 2 A
Treatment of the diol (If) with triphenylphosphine and an azodicarboxylate for example DIAD provides the epoxide (2Aa). Opening of the epoxide with a desired nucleophile Q-OH in the presence of a base, such as potassium carbonate or the like, provides the ether derivative (2Ab). Subsequent replacement of the secondary hydroxy group with azide, opening of the lactone and finally reduction of the azide as described above, provides the linear amine (2Ac).
Lactones useful for the synthesis of compounds of formula (I) wherein Z is S or NH and n is 1 or 2, can be prepared from the diol If for example by a Mitsunobu reaction with a thiol or amino derivative respectively, as illustrated in scheme 2B.
Figure imgf000026_0001
Scheme 2B
The primary hydroxy group of the lactone (If) can be converted to a thioether or an amine for example by transforming it into a leaving group followed by displacement of the formed leaving group with the desired group Q-(CH2)D-S or Q-(CH2)D-NRa. A convenient method to effect this transformation is by way of a Mitsunobu reaction, i.e. reaction of the hydroxy group with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine or the like followed by displacement with a desired thiol or amine to provide the thioether (2Ba) or the amine derivative (2Bb) respectively. Alternatively, the amine (2Bb) may be achieved by using an azide derivative, such as sodium azide or DPPA in the Mitsunobu reaction with the alcohol (If), followed by reduction of the azide to the primary amine and subsequent alkylation of the amine with a suitable alkylating agent Q- CH2-Lg, or by performing a reductive amination with a suitable aldehyde Q-CH(=O). A further alternative to obtain the amino derivative (2Bb) is to selectively oxidize the primary hydroxy group of the alcohol (If) to the corresponding aldehyde, effected for example by treatment with Dess-Martin periodinane or by any other suitable oxidation reagent, followed by a reductive amination with the desired amino derivative Q-(CH2)n-NHRa in the presence of a reducing agent like NaCNBH3. Replacement of the secondary hydroxy group with azide, opening of the lactone and finally reduction of the azide as described above, then provides the linear compounds (2Bc and 2Bd).
Compounds wherein the group Q is linked directly to a sulphur or nitrogen atom, i.e. an intermediate for the preparation of compounds of formula (I) wherein Z is S or NRa and n is O, may be prepared by transformation of the primary hydroxy group of the diol (If) into a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with a desired thiol Q-SH or a amine Q-NHRa optionally in the presence of a base. An alternative method for the preparation of compounds wherein Z is S and n is 0 is to react the diol (If) with a desired diphenyl disulphide derivative in the presence of nBusP. Compounds wherein Z is NRa and n is 0 may alternatively be achieved by oxidation of the primary hydroxy group of the diol (If) followed by a reductive amination with a desired aniline derivative Q-NRa in the presence of a suitable catalyst like NaCNBH4 or the like.
Compounds of formula (I) wherein Z is a sulphone i.e. S(=O)2 may be obtained by oxidation of the sulphur of corresponding thioether derivative. The oxidation can be performed either at the last step of the synthesis or on any suitable intermediate. Many suitable methods for this oxidation are described in the literature for example a peroxyacid such as AcOOH, mCPBA can be used.
Amino derivatives (2c) to be used for the opening of the lactone in the scheme 2 above are commercially available or they can be prepared by the skilled person according to literature procedures. For example, an amino derivative useful for the preparation of compounds of formula (I) wherein Y is NH can be prepared from a suitably protected amino acid carrying the desired side chain R4 R4 , as illustrated in scheme 3.
Figure imgf000027_0001
3a 3b
Scheme 3
The amino acid (3a), carrying the desired side chain R4 R4 , can be coupled to the amine W- (CH2)Hi-NH2 using any convenient method for peptide coupling known in the art. For example, a coupling agent like HATU or isobutylchloroformate in the presence of a tertiary amine such as ethyldiisopropylamine (DIEA) or N-methylmorpholine in a solvent like dimethyl formamide can be used thus providing the amide. Subsequent removal of the N- protecting group using the appropriate conditions according to the protecting group used, such as acidic treatment in the case of a Boc-group, provides the free amine (3b).
Similarly, amino derivatives useful for the preparation of compounds of general formula (I) wherein Y is S can be prepared by transforming the amino acid (3 a) into an activated acid derivative such as the acid chloride or an activated ester such as the p-nitrophenyl ester or pentafluoroester, followed by reaction with a desired thio derivative SH-(CH2)m-W. Procedures for the formation of activated acids and esters are well known to a person skilled in the field of organic synthesis and are exensively described in the literature. For example, the acid chloride can be prepared by treatment of the acid with POCI3 or phosgene or the like in the presence of a base like pyridine.
An alternative route to compounds of formula (I) which can be valuable for example when it is desired to introduce various groups Q-(CH2)n at a late stage of the synthesis, is shown in scheme 4.
Figure imgf000028_0001
4a 4b
Figure imgf000028_0002
deprot. p, OH, SH or NHRa
*" orthogonal protecting groups
Figure imgf000028_0003
4e
Scheme 4
The azide derivative (4a), prepared for example as outlined in scheme 2, wherein Pg1 is a hydroxy protecting group for example a benzyl group can be transformed to the corresponding amine by reduction of the azide group using any convenient reduction method such as hydrogenation in the presence of a suitable catalyst, such as Lindlars catalyst or the like in the presence of BoC2O to provide the boc protected derivative (4b). Protection of the secondary hydroxy group, using a protecting group (Pg2) which is orthogonal to the one used for the primary hydroxy group (Pg1), followed by removal of the primary hydroxy protecting group using the appropriate conditions according to the group used, such as for example catalytic hydrogenation in the case of a benzyl group provides the primary alcohol (4c). Suitable protecting groups for the above route will be recognized by the skilled person and a numerous of useful protecting groups are described in Greene "Protective Groups in Organic Synthesis", John Wiley and sons, New York (1981). For example benzyl can be used as Pg1 and acetyl as Pg2. The group (CH2)n-Q can then be introduced as described above. For example, compounds wherein Z is O and n is l,can be prepared by reaction of the primary alcohol (4c) with an alkylating agent Q-(CH2)D-Lg wherein Lg is a halide like a bromide, chloride or iodide or a derivative of sulphonic acid such as a triflate or mesylate or the like in the presence of a base like NaH or the like, or a trichloroacetimidate of a desired group, Q- (CH2)n-O-C(=NH)Cl3 may be reacted with the primary alcohol (4c) in the in the presence of a Lewis acid such as BFsOEt2. Trichloroacetimidates are conveniently prepared by reaction of the corresponding alcohol with trichloroacetonitrile in the presence of a base like NaH.
Compounds wherein Z' in scheme 4 is O, S or NRa may be prepared by a Mitsunobu reaction of the primary alcohol (4c) with a desired alcohol, Q-(CH2) n-OH, thiol, Q-(CH2) n-SH or amine Q-(CH2) n-NHRa respectively as described above. Compounds wherein Z' is S or NRa may alternatively be prepared by transforming the primary hydroxy group of the alcohol (4c) to a leaving group for example a derivative of sulphonic acid such as a triflate, tosylate or the like which subsequently is displaced by a with a desired thiol Q-(CH2) n-SH or amine Q-(CH2) n-NHRa optionally in the presence of a base. An alternative method for the preparation of compounds wherein Z' is S and n is 0 is to react the diol (If) with a desired diphenyl disulphide derivative in the presence of nBusP. Compounds wherein Z' is NRa and n is 0 may alternatively be achieved by oxidation of the primary hydroxy group of the alcohol (4c) followed by a reductive amination with a desired aniline derivative Q-NRa in the presence of a suitable catalyst like NaCNBH4 or the like.
Substituted phenyl and heteroaryl derivatives Q-(CH2)n- used in the schemes above are commercially available or they may be prepared according to literature procedures. A method to prepare a substituted phenyl derivative useful for the preparation of compounds of formula (I) wherein Q is phenyl substituted with aminomethyl or amidomethyl and derivatives thereof is illustrated in scheme 5.
Figure imgf000029_0001
5c 5d
Scheme 5
The hydroxy protected cyanobenzyl derivative (5 a) can be prepared by protection of commercially available cyanobenzyl alcohol, illustrated herein as 3 -cyanobenzyl alcohol, with a suitable protecting group, for example a trityl or monomethoxy trityl group using standard conditions well known in the art. Subsequent alkylation of the cyano group effected for example by way of an organo metallic reaction such as a Grignard reaction or an organo lithium reaction or the like, using the suitable conditions such as treatment with the desired alkyl magnesium halide in an ethereal solvent like diethyl ether or THF or the like followed by reduction of the intermediate imine for example by LAH and finally protection of the afforded amine by treatment with the suitable agent such as di-t-butyldicarbonate, provides the carbamate (5b). The corresponding carbamate wherein the benzylic carbon is unsubstituted, i.e. R5 is H can be achieved by direct reduction of the cyano group to the methyl amino group using for instance LAH or diborane or the like, followed by protection of the afforded primary amine as previously described. Removal of the hydroxy protecting group using standard conditions such as treatment with acid in the case of trityl or monomethoxy trityl group provides the alcohol (5c). The afforded alcohol (5c) can then be used in the coupling to the primary alcohol of the lactone Ig or the linear compound 4c employing for example the Mitsunobu conditions as described in scheme 2 and 4 respectively. Alternatively, the hydroxy group of the alcohol (5 c) can be transformed into a leaving group such as a bromide for example by treatment with bromine or carbontetrabromide in the presence of triphenylphosphine or the like thus affording the bromo derivative (5d), or the hydroxy group can be transformed into a derivative of sulphonic acid by reaction with a suitable sulphonylating agent such as a sulphonic halide or anhydride optionally in the presence of a base for example pyridine. Subsequently, the afforded compound can be coupled to the primary alcohol of the lactone If or the linear compound 4c as described in scheme 2 and 4 respectively.
Scheme 6 illustrates an example to another substituted phenyl derivative, useful for the preparation of compounds of formula (I) wherein Q is phenyl which is substituted with an alkoxy-alkoxy group.
DIBAL
Figure imgf000030_0001
6c 6d
Scheme 6 Alkylation of the phenolic hydroxy group of ester (6a) using for example the Mitsunobu, such as in the presence Of Ph3P, an azodicarboxylate like DIAD and the suitable alcohol followed by reduction of the ester function using any convenient reduction method known in the art provides benzylic alcohol (6b). The afforded alcohol (6b) can then either be used directly in the coupling to the primary hydroxyl group of the lactone If or the linear compound 4c employing the Mitsunobu conditions, or the a hydroxy group can be transferred to a leaving group, such as a halide like bromide, and subsequently coupled to the primary hydroxyl group of the lactone If or the linear compound 4c as described above.
Even though the strategy in scheme 6 is illustrates the introduction of a methoxy-ethoxy substituent to the phenyl ring, the skilled person will easily realise that the same methodology can be applied for the introduction of other O-linked substituents, such as substituents with other chain lengths. Furthermore, despite the fact that scheme 5 and 6 are illustrated with a 1,3 substituted phenyl derivative as starting compound, the skilled person will realise that the same methodology is also applicable to other phenyl derivatives, for example the corresponding 1,2- or 1 ,4-disubstituted derivatives.
A route to an intermediate useful for the preparation of compounds wherein Q is phenyl which is substituted with an unsaturated substituent, such as an aryl or heteroaryl or with a group linked via an unsaturated carbon chain such as via an ethendiyl or ethyndiyl link, is illustrated in scheme 6A
Figure imgf000031_0001
2, 2A or 2B
Q' is aryl, heteroaryl or an unsaturated group
Figure imgf000031_0002
Scheme 6 A Transformation of the bromo substituted benzoic acid 6Aa, optionally carrying any additional substituents for example an alkoxy-alkoxy chain, into the corresponding benzyl bromide derivative 6Ab as described in Scheme 6, followed by coupling to the lactone (If) as outlined in scheme 2, 2A or 2B provides the actone derivative 6Ac. A further substituent to the benzene ring, such as an optionally substituted aryl or heteroaryl group, can then be introduced using for instance a Pd-catalyzed cross coupling reaction. Many cross coupling reactions are described in the literature and belong to the general knowledge to a person skilled in the art of organic synthesis. For example the Suzuki conditions may be used, i.e. reaction of the bromo derivative 6Ac with the boronic acid of a desired substituent Q' in the presence of a palladium catalyst such as Pd(PPtLs)4 or Pd(OAc)2 or the like and a suitable base such as potassium carbonate or potassium fluoride or the like, thus providing the Q'- substituted compound 6Ad. Other suitable reactions that can be used for the introduction of the substituent Q' are for instance the Stille reaction, wherein a tin derivative, such as a trialkyltin derivative, of the desired group Q' is reacted with the bromo derivative 6Ac in the presence of Pd(O), or the Heck coupling reaction wherein the bromo derivative 6Ac is reacted with a double bond of the desired group Q' in the presence of a Pd catalyst such as Pd(PPtLs)4 PdCl2 or Pd(OAc)2 and a base such as triethylamine, potassium carbonate or the like.
Scheme 7 shows an alternative route to compounds of the invention, starting from Garner's aldehyde.
Figure imgf000033_0001
7h
Scheme 7
α-Alkylation of the aldehyde (7a) by reaction with a suitable propiolic acid ester, for example the methyl ester, in the presence of a base like buthyllithium followed by reduction of the triple bond for example by catalytic hydrogenation using a catalyst like palladium on carbon provides the alcohol (7b). Heating of the afforded hydroxy ester in the presence of acetic acid effects the ring closing and thus affords lactone (7c). The afforded lactone can then be alkylated at the α-carbon with a desired group R as described above, i.e. by treatment of the lactone with a base such as LDA optionally followed by addition of tripyrrolidine phosphorus oxide and finally addition of the alkylating agent or by any other suitable alkylation method which provides the alkylated lactone (7d). Cleavage of the cyclic aminal by treatment with acid such as TFA followed by reaction with BoC2O in order to reprotect the amino function affords the primary alcohol (7e). The group Q-(CH2)n can then be introduced using any suitable method such as any of those described above. For example, a trichloroimidate of the desired group Q-(CH2)n in the presence of TMS triflate will provide the ether derivative (7f) i.e. Z' is O. The lactone may then be opened either directly with a desired amine as described above to give the amide (7h), or alternatively, the lactone may be opened by treatment with hydroxide such as lithium hydroxide, thus affording the acid (7g). Protection of the hydroxy group, using any conventional protecting group for example a silyl group such as a tert-butyl dimethylsilyl group, followed by coupling of the acid to a suitable amine using standard peptide coupling conditions such as using a coupling agent like EDAC in the presence of HOBt and a tertiary amine like triethylamine, and finally removal of the hydroxy protecting group provide the amide (7h).
An intermediate towards compounds of formula (I) wherein X' is F and X" is H or X' and X" are both F can be prepared by replacement of the hydroxy group of compound 4a with flouro or difluoro as exemplified in scheme 8 illustrated with Q as a phenyl group and Z as an ether.
Figure imgf000034_0001
4a δa
1 ) DIAD, Ph3P, p-NO2-benzoic acid
2) NaOMe
Figure imgf000034_0002
Scheme 8
The hydroxy group of compound (4a) can be replaced by two fluoro atoms by oxidizing the hydroxy group to a keto group using any convenient method such as using a reagent like Dess Martin periodinane or oxone® (potassium monopersulphate triple salt) or any other suitable oxidizing agent, followed by treatment of the afforded keto compound with a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p. 2561-2578, or any other suitable fluorinating conditions, yields the difluoro compound (8a). The monofluoro compound (8c) with the desired stereochemistry can be obtained by first inverting the stereochemistry at the steric centre whereto the hydroxy group is attached which can be performed for example by subjecting the alcohol to a Mitsunobu reaction with for instance p-nitrobenzoic acid and reagents like DIAD and PI13P followed by hydrolysis of the afforded p-nitrobenzoic ester by treatment with sodium methoxide or the like, and then subject the afforded inverted alcohol to fluorinating conditions such as treatment with DAST or deoxofluor as described above. Even though scheme 8 illustrates the replacement of the hydroxy group with fluoro or difluoro as the last step of the synthesis, the skilled person will realise that this transformation alternatively may be performed at any other suitable stage of the synthesis for example on any of the intermediates described above.
Compounds according to the invention wherein X' is amino may be prepared from the corresponding alcohol by replacement of the hydroxy group with an amino group, performed either as the last step of the synthesis or at any other convenient stage. A variety of methods for this transformation are described in the literature. An example is illustrated in scheme 9 wherein the hydroxy group is transformed into a leaving group and subsequently displaced by azide.
Figure imgf000035_0001
9a 9b
Figure imgf000035_0002
9c 9d
RV is R1 or an N-protecting group
Scheme 9
In order to get the desired configuration at the steric centre whereto the X' is attached in the final compound, the configuration of compound (9a), prepared as described above, has to be inverted, for example as described in scheme 8. The inverted alcohol (9b) can then be subjected to Mitsunobu conditions, i.e. treatment with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine followed by reaction with azide, for example diphenylphosphoryl azide (DPPA) or HN3 to give the azido derivative (9c) Alternatively the azido derivative (9c) can be achieved by transformation of the hydroxy group to a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloro methane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with sodium azide or the like. Reduction of the azide using any conventional reduction method such as hydrogenation in the presence of a suitable catalyst, or treatment with triphenylphosphine provides the corresponding amine (9d)
Even though scheme 9 illustrates the conversion of the hydroxy group to an amine as the last step of the synthesis, the skilled person will realise that this transformation is also applicable at any other suitable stage of the synthesis for example on any of the intermediates described above.
Any functional groups present on any of the constituent compounds used in the preparation of the compounds of the invention are appropriately protected where necessary. For example functionalities on the natural or non-natural amino acids are typically protected as is appropriate in peptide synthesis. Those skilled in the art will appreciate that the selection and use of appropriate protecting groups depend upon the reaction conditions. Suitable protecting groups are described in Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1981), the disclosure of which are hereby incorporated by reference.
Detailed Description
Various embodiments of the compounds of the invention and key intermediates towards such compounds will now be described by way of illustration only with reference to the following non-limiting examples.
Example 1
Step a
Figure imgf000036_0001
5-(l,2-Bis-benzyloxyethyl)-2-methoxytetrahydrofuran-3-ol (Ia)
Sulfuric acid (13 mL, 240 mmol) was added dropwise to a solution of 5-(l,2-bis-benzyloxy- ethyl)-2,2-dimethyl-tetrahydro-furo[2,3-d][l,3]dioxole (prepared as described by Hanessian et al in Tetrahedron Lett., 1987, 28, 1142) (30.2 g, 78.6 mmol) in MeOH (180 mL) at 0 0C. The reaction mixture was then stirred at room temperature for 2 h, cooled down to 0 0C and carefully neutralized with sat. aq. NaHCOs. Methanol was distilled off under reduced pressure and the residue was taken into EtOAcZH2O. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4) and the solvent evaporated to give the crude product as a yellow oil. Purification by flash chromatography on silica gel (Hex:EtOAc 10:1 to 2.5:1) afforded 18.7 g (67%) of the title compound as a colourless oil (mixture of anomers).
Figure imgf000037_0001
Imidazole- 1-carbothioic acid O-[5-(l,2-bis-benzyloxyethyl)-2-methoxytetrahydrofuran-3-yll ester (Ib)
A solution of the alcohol Ia (14.2 g, 39.7 mmol) and l,l '-thiocarbonyldiimidazole (7.1 g, 39.8 mmol) in THF (120 mL) was refluxed under N2 for 2 h. The reaction mixture was concentrated under vacuum and the residue was purified by flash chromatography on silica gel (Hex:EtOAc 2.5:1) which gave the title compound (15.8 g, 85%) (mixture of anomers).
Step c
Figure imgf000037_0002
2-(l,2-Bis-benzyloxyethyl)-5-methoxytetrahydrofuran (Ic)
A solution of compound Ib (15.8 g, 33.8 mmol) and AIBN (0.55 g, 3.3 mmol) in toluene was heated to 100 0C under N2. Tributyltinhydride (13.6 mL, 50.6 mmol) was then added carefully dropwise (gas evolution). The reaction mixture was stirred further 20 min at 100 0C after the addition was completed. Evaporation of the solvent afforded a syrup that was purified by flash chromatography on silica gel (Hex:EtOAc 20:1 to 2.5:1) which gave the title compound (8.2 g, 71%) (mixture of anomers).
Figure imgf000037_0003
5-(l,2-Bis-benzyloxyethyl)-dihydrofuran-2-one (Id)
A solution of compound Ic (10.7 g, 31.29 mmol) and m-CPBA (19.6 g, 62.5 mmol) in dichloromethane (10 mL) was treated with BFsOEt2 (2 mL, 15.8 mmol) at 0 0C. The reaction mixture was then allowed to warm up to room temperature and stirring was continued for 17 h. Evaporation of the solvent afforded the crude product that was purified by flash chromatography on silica gel (Hex:EtOAc 20:1 to 2.5:1) which gave the title compound (6.1 g, 60%) as a colourless oil.
Figure imgf000038_0001
5 -( 1 ,2-Bis-benzyloxyethyl)-3 -isopropyldihydrofuran-2-one (Ie)
A solution of compound Id (3.1 g, 9.51 mmol) in THF (30 mL) was added to a 1 M solution of LDA in THF (20 mL, 20 mmol) at -60 0C under N2. The reaction mixture was then treated with tris(pyrrolidinophosphine) oxide (15 mL) followed by iodopropane (3.8 mL, 38.1 mmol). Stirring at -60 0C was continued for 1 h and the reaction mixture was quenched with aq. NH4CI. The phases were separated and the aqueous phase was extracted with 1BuOMe. The combined organic extracts were dried (Na2SO4) and the solvent evaporated. The residue was purified by flash chromatography on silica gel (Hex:EtOAc 10:1) which gave the title compound (1.2 g, 34%) as a colourless oil.
Figure imgf000038_0002
5 -( 1 ,2-Dihydroxyethyl)-3 -isopropyldihydrofuran-2-one (If)
A solution of compound Ie (2.58 g, 7.01 mmol) in MeOH (50 mL) was hydrogenated in the presence of 10% Pd/C at 3 bar H2 pressure. Filtration of the catalyst and evaporation of the solvent afforded the title compound (1.2 g, 92%) as a white solid.
Figure imgf000038_0003
2-Amino-N-benzyl-3-methyl-butyramide (1 g)
A solution of Boc- VaI-OH (2.5 g, 12.5 mmol), EtN1Pr (5 mL, 28.7 mmol) and HATU (4.55 g, 12 mmol) in DMF (7 mL) was stirred for 5 min at 0 0C before adding benzylamine (1.25 mL, 12.5 mmol). The reaction mixture was stirred for 20 min and then concentrated under vacuum. The residue was taken into EtOAcZH2O and the organic phase was washed with H2O, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography on silica gel (Hex:EtOAc 2.5:1) to give the boc-protected title compound (3.1 g, 82%) as a white solid. The solid was dissolved in TFA and the resulting solution was stirred at room temperature for Ih. Evaporation of the solvent afforded an oil which was taken into CH2Cl2 and washed with 1 M NaOH. The organic phase was dried (Na2SO4) and concentrated which gave the title compound as a colourless oil (99%).
Figure imgf000039_0001
5 -( 1 -Hydroxy-2-benzyloxyethyl)-3 -isopropyl-dihydrofuran-2-one ( 1 h) A solution of compound If (0.6 g, 3.19 mmol) and Bu2SnO (1.0 g, 4.0 mmol) in toluene (50 mL) was refluxed with a Dean-Stark trap for 4 h. The reaction mixture was cooled down to 90 0C and benzyl bromide (0.43 mL, 3.66 mmol) and Bu4NBr (1.18 g, 3.66 mmol) were added. Stirred further 22 h at 90 0C, concentrated under vacuum and the residue purified by flash chromatography on silica gel (Hex:EtOAc 10:1 to 2.5:1) to give the title compound (0.7 g) as a colourless oil.
Step i
Figure imgf000039_0002
5-(l-Azido-2-benzyloxyethyl)-3-isopropyldihydrofuran-2-one (Ii)
A solution of compound Ih (278 mg, 1 mmol) and pyridine (140 μL, 1.7 mmol) in CH2Cl2 (5 mL) was treated with Tf2O (220 μL, 1.3 mmol) at room temperature Stirred for 30 min and quenched with H2O. The product was extracted into CH2Cl2 and the combined extracts were dried (Na2SO4) and the solvent evaporated to give a yellow oil that was dissolved in DMF (1 mL). Sodium azide (325 mg, 5 mmol) was added and the resulting suspension was stirred at 60 0C for 1 h. The reaction mixture was concentrated under vacuum and the residue was purified by flash chromatography on silica gel (Hex:EtOAc 2.5:1) which gave the title compound (180 mg, 59%) as a colourless oil.
Step i
Figure imgf000040_0001
5-Azido-6-benzyloxy-4-hydroxy-2-isopropylhexanoic acid (1 -benzylcarbamoyl-2- methylpropyP-amide (Ij)
A mixture of compound Ii (200 mg, 0.66 mmol), the amine Ig (665 mg, 3.2 mmol), 2- hydroxypyridine (296 mg, 3.1 mmol) and EtN1Pr (200 μL, 1.15 mmol) was heated to 70 0C for 3 days. The reaction mixture was cooled down to room temperature and taken into EtO Ac/1 M HCl. The organic phase was washed with 1 M HCl, dried (Na2SO4) and evaporated to give a yellow solid that was triturated into hot 1BuOMe which gave the title compound (235 mg, 70%) as a white solid.
Figure imgf000040_0002
5-Amino-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid (1 -benzylcarbamoyl-2- methylpropyD-amide (Ik)
A solution of the azide Ij in EtOAc:MeOH (50:1, 8 mL) was hydrogenated in the presence of
Pd Lindlar. Filtration of the product and evaporation of the solvent afforded an oil that was purified by preparative HPLC (5% acetonitrile in H2O with 0.1% TFA to 30% acetonitrile) which gave the title compound (52 mg, 38%) as its TFA salt.
1H-NMR (J6-DMSO) δ (ppm): 0.77-0.86, 1.45, 1.62-1.72, 1.89, 2.30, 3.10, 3.44-3.57, 4.16-
4.24, 4.29, 4.32, 4.45, 4.51, 5.29, 7.17-7.38, 7.72, 7.77, 8.47.
Example 2
Figure imgf000040_0003
5-Benzylamino-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid (1 -benzylcarbamoyl-2- methylpropyD-amide (2)
A solution of the amine Ik (10.4 mg, 0.021 mmol), benzaldehyde (2.1 μL, 0.021 mmol) and AcOH (6 μL, 0.10 mmol) in MeOH (327 μL) was treated with NaBH3CN (1.6 mg, 0.025 mmol). The resulting solution was stirred at room temperature for 16 h. The solvent was evaporated under vacuum and the residue was taken into EtOAc and washed with 2 M NaOH. The organic phase was dried (Na2SO4) and concentrated to give 14.9 mg of a white solid that was purified by preparative HPLC (20% acetonitrile in H2O with 0.1% TFA to 47% acetonitrile) which gave the title compound (5.5 mg, 46%) as its TFA salt. 1H-NMR (CD3OD) δ (ppm): 0.85-0.96, 1.35-1.39, 1.47-1.56, 1.73-1.87, 1.96-2.06, 2.35, 3.14, 3.66-3.78, 4.14-4.26, 4.33, 4.41, 4.55, 4.59, 7.19-7.45.
Example 3
Step a
Figure imgf000041_0001
[4-(l-Benzylcarbamoyl-2-methylpropylcarbamoyl)-l-benzyloxymethyl-2-hydroxy-5- methylhexyll-carbamic acid tert-butyl ester (3 a)
A solution of compound Ij (235 mg, 0.46 mmol) and BoC2O (150 mg, 0.69 mmol) in EtOAc (1 mL) was hydrogenated in the presence of Pd Lindlar. The catalyst was filtered off and the solvent evaporated to give a residue that was purified by flash chromatography (Hex:EtOAc 2.5:1 to 1 :2) which gave the title compound (225 mg, 84%).
Figure imgf000041_0002
4-( 1 -Benzylcarbamoyl-2-methyl-propylcarbamoyl)-2-(2-benzyloxy- 1 -tert- butoxycarbonylamino-ethyl)-5-methylhexanoic acid methyl ester (3b)
A solution of compound 3a (225 mg, 0.386 mmol) and DMAP (71 mg, 0.58 mmol) in CH2Cl2 (1 mL) was treated with Ac2O (55 μL, 0.58 mmol) at room temperature The reaction mixture was stirred for 15 min and then diluted with CH2Cl2, washed with 2 M HCl and sat. aq. NaHCO3 and dried (Na2SO4). Evaporation of the solvent afforded a white solid which was purified by flash chromatography (Hex:EtOAc 2.5:1) which gave the title compound (157 mg, 65%).
Step c
Figure imgf000041_0003
Acetic acid 3 -( 1 -benzylcarbamoyl-2-methylpropylcarbamoyl)- 1 -( 1 -tert- butoxycarbonylamino-2-hydroxy-ethyl)-4-methylpentyl ester (3c)
A solution of compound 3b (151 mg, 0.24 mmol) in MeOH (10 mL) was hydrogenated in the presence of 10% Pd/C. The catalyst was filtered off and the solvent evaporated which gave the title compound (128 mg).
Figure imgf000042_0001
5-Amino-4-hydroxy-2-isopropyl-6-(3-methoxybenzyloxy)-hexanoic acid (1 - benzylcarbamoyl-2-methylpropyl)-amide (3 d)
Compound 3c (32 mg, 0.06 mmol) was dissolved in THF (0.25 niL) and treated with 60% NaH (24 mg, 0.06 mmol). After stirring for 10 min 3-methoxybenzylbromide was added and the reaction mixture was allowed to further stir for 17h. Evaporation of the solvent afforded a residue that was taken into CH2Cl2 and the resulting solution was washed with H2O, dried (Na2SO4) and concentrated. The residue was dissolved in TFA and stirred 30 min at room temperature Evaporation of the volatiles afforded an oil that was purified by preparative HPLC (10% acetonitrile in H2O with 0.1% TFA to 40% acetonitrile) which gave the title compound (1.7 mg, 3%, after 3 steps) as its TFA salt.
1H-NMR (J6-DMSO) δ (ppm): 0.72-0.85, 1.44, 1.65, 1.87, 2.28, 3.18, 4.04-4.31, 4.49, 5.28, 6.80-6.97, 7.17-7.31, 7.70, 7.76, 8.44.
Example 4 Step a
Figure imgf000042_0002
2,2,2-Trichloro-acetimidic acid naphthalen-1-ylmethyl ester (4a)
A solution of 1-naphthalenemethanol (15.8 mg, 0.1 mmol) in Et2O (0.5 mL) was treated with 60% NaH (1.4 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 5 min. before adding trichloroacetonitrile (10 μL, 0.1 mmol) at once. The resulting solution was stirred 2 h concentrated under vacuum and used immediately in the next step.
Figure imgf000043_0001
5-Amino-4-hydroxy-2-isopropyl-6-(naphthalen- 1 -ylmethoxy)-hexanoic acid (1 - benzylcarbamoyl-2-methylpropyl)-amide (4b)
To a solution of the imidate 4a in CH2Cl2 (0.1 mL) was added a solution of the alcohol 3c in CH2Cl2 (0.25 mL) followed by a catalytic amount OfBFsOEt2 (1 μL). The reaction mixture was stirred at room temperature for 17 h. The resulting solution was diluted with CH2Cl2, washed with sat. aq. NaHCOs, dried (Na2SO4) and evaporated to give a residue that was filtered through silica gel (Hex:EtOAc 2.5:1) to give 11 mg of an oil that was taken into THF/MeOH. To the resulting solution was added 2 M NaOH (0.5 mL) and the reaction mixture was allowed to stir 15 min. at room temperature before evaporation of the volatiles under vacuum. The residue was taken into TFA and the resulting solution was concentrated under vacuum to give a white solid that was purified by preparative HPLC (10% acetonitrile in H2O with 0.1% TFA to 40% acetonitrile) which gave the title compound (0.8 mg, 2%, after 3 steps) as its TFA salt.
1H-NMR (CD3OD) δ (ppm): 0.83-0.99, 1.53-1.62, 1.71-1.87, 1.97, 2.31, 3.18, 3.55, 3.59-3.74, 4.13, 4.35, 4.57, 5.02, 5.07, 7.20-7.34, 7.43-7.60, 7.84-7.92, 8.15, 8.50.
Example 5 Step a
Figure imgf000043_0002
2-Amino-3-methyl-pentanoic acid benzylamide (5a) The procedure described in example 1 step g was followed but using 2-tert- butoxycarbonylamino-3-methylpentanoic acid instead of Boc- VaI-OH, which gave the title compound (88% yield).
Figure imgf000044_0001
5- { 1 -Hydroxy-2-[3-(3-methoxypropoxy)-benzyloxyl-ethyU -3-isopropyldihydrofuran-2-one
(5b)
The procedure described in Example 1 step h was followed but using 3-(3-methoxy-propoxy)- benzyl bromide instead of benzyl bromide, which gave the title compound (67% yield).
Figure imgf000044_0002
5- { 1 -Azido-2-[3-(3-methoxypropoxy)-benzyloxy"|-ethyU -3-isopropyldihydrofuran-2-one (5c) Compound 5b was reacted according to the procedure described in Example 1 step i, which gave the title compound (10% yield).
Figure imgf000044_0003
5-Azido-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-benzyloxy"|-hexanoic acid (1 - benzylcarbamoyl-2-methylbutyl)-amide (5 d)
A mixture of compound 5c (10 mg, 0.026 mmol), the amine 5a (20.6 mg, 0.094 mmol), 2- hydroxypyridine (9 mg, 0.094 mmol) and EtN1Pr (7.7 μL, 0.044 mmol) was heated to 70 0C for 4 days. The reaction mixture was cooled down to room temperature and taken into EtO Ac/1 M HCl. The organic phase was washed with 1 M HCl, dried (Na2SO4) and evaporated which gave the title compound (22 mg) and 2-hydroxypyridine as an off white solid. No further purification was made.
Step e
Figure imgf000045_0001
5-Amino-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-benzyloxyl-hexanoic acid (1 - benzylcarbamoyl-2-methylbutyl)-amide (5 e)
A solution of the azide 5d in EtOAc/MeOH was hydrogenated in the presence of Pd Lindlar.
The catalyst was filtered off and the solvent evaporated to give an oil that was purified by preparative HPLC (20% acetonitrile in H2O with 0.1% TFA to 60% acetonitrile) which gave the title compound (2.0 mg, 11%) as its TFA salt.
1H-NMR (CD3OD) δ (ppm): 0.83-0.96, 1.13, 1.48-1.64, 1.74-1.88, 1.96-2.05, 2.34, 3.17, 3.34,
3.55, 3.60-3.65, 4.05, 4.23, 4.30-4.42, 4.52, 4.56, 6.85, 6.94, 7.20-7.33, 7.82, 8.50.
Example 6 Step a
Figure imgf000045_0002
5-[ 1 -Hydroxy-2-(naphthalen- 1 -ylmethoxy)-ethyll-3-isopropyldihydrofuran-2-one (6a) The procedure described in Example 1 step h was followed but using 1-bromomethyl- naphthalene instead of benzyl bromide, which gave the title compound (90% yield).
Figure imgf000046_0001
5-[ 1 -Azido-2-(naphthalen- 1 -ylmethoxy)-ethyll-3-isopropyldihydrofuran-2-one (6b) Compound 6a was reacted according to the procedure described in Example 1 step i, which gave the title compound (32% yield).
Step c
Figure imgf000046_0002
5-Azido-4-hydroxy-2-isopropyl-6-(naphthalen- 1 -ylmethoxy)-hexanoic acid ( 1 -benzylcarbamoyl-2-methylbutyl)-amide (6c)
A mixture of compound 6b (38 mg, 0.108 mmol), the amine 5a (86 mg, 0.39 mmol), 2- hydroxypyridine (37 mg, 0.39 mmol) and EtN1Pr (32 μL, 0.18 mmol) was heated to 70 0C for 4 days. The reaction mixture was cooled down to room temperature and taken into EtO Ac/1 M HCl. The organic phase was washed with 1 M HCl, dried (Na2SO4) and evaporated to give an off white solid that was triturated from hot 1BuOMe which gave the title compound (29 mg, 47%) as a white solid.
Figure imgf000046_0003
5-Amino-4-hvdroxy-2-isopropyl-6-(naphthalen- 1 -ylmethoxy)-hexanoic acid ( 1 -benzylcarbamoyl-2-methylbutyl)-amide (6d)
The azide group of compound 6c was reduced according to the procedure described in Example 5 step e, which gave the title compound (53% yield).
1H-NMR (CD3OD) δ (ppm): 0.77-0.92, 1.08, 1.44-1.60, 1.70-1.86, 2.31, 3.17, 3.50-3.57, 3.60-3.72, 4.20, 4.29-4.43, 5.02, 5.08, 7.19-7.32, 7.42-7.59, 7.80, 7.83-7.91, 8.15, 8.50.
Example 7 Step a
Figure imgf000047_0001
5-[ 1 -Hydroxy-2-(naphthalen-2-ylmethoxy)-ethyll-3-isopropyldihydrofuran-2-one (7a) The procedure described in Example 1 step h was followed but using 1-bromomethyl- naphthalene instead of benzyl bromide, which gave the title compound (67% yield).
Step b
Figure imgf000047_0002
5-[ 1 -Azido-2-(naphthalen-2-ylmethoxy)-ethyll-3-isopropyldihydrofuran-2-one (7b) Compound 7a was reacted according to the procedure described in Example 1 step i, which gave the title compound (67% yield).
Ster
Figure imgf000048_0001
5-Azido-4-hydroxy-2-isopropyl-6-(naphthalen-2-ylmethoxy)-hexanoic acid ( 1 -benzylcarbamoyl-2-methylbutyl)-amide (7c)
Compound 7b was reacted according to the procedure described in Example 6 step c, which gave the title compound (87% yield).
Figure imgf000048_0002
5-Amino-4-hydroxy-2-isopropyl-6-(naphthalen-2-ylmethoxy)-hexanoic acid ( 1 -benzylcarbamoyl-2-methylbutyl)-amide (7d)
The azide group of compound 7c was reduced according to the procedure described in Example 5 step e, which gave the title compound (30% yield).
1H-NMR (CD3OD) δ (ppm): 0.77-0.93, 1.09, 1.45-1.64, 1.72-1.89, 2.33, 3.19, 3.30, 3.54-3.71, 4.22, 4.29-4.42, 4.74, 7.20-7.31, 7.46-7.53, 7.79-7.88, 8.49.
Example 8
Figure imgf000048_0003
4-Hydroxy-2-isopropyl-5-isopropylamino-6-(naphthalen- 1 -ylmethoxy)-hexanoic acid (1 - benzylcarbamoyl-2-methylbutyl)-amide (8) A solution of the amine 5a (70 mg, 0.128 mmol), acetone (10 μL, 0.136 mmol) and AcOH (11 μL, 0.19 mmol) in MeOH (500 μL) was treated with NaBH3CN (8 mg, 0.13 mmol). The resulting solution was stirred at room temperature for 16 h. The solvent was evaporated under vacuum and the residue was taken into CH2Cl2 and washed with 2 M NaOH. The organic phase was dried (Na2SO4) and concentrated to give a white foam that was purified by preparative HPLC (20% acetonitrile in H2O with 0.1% TFA to 47% acetonitrile) which gave the title compound 34 mg (38%) as its TFA salt.
1H-NMR (CD3OD) δ (ppm): 0.84-0.90, 1.10, 1.23, 1.56, 1.76, 1.91, 2.34, 3.22, 3.40, 3.63, 3.72-3.78, 4.23, 4.36-4.43, 5.02, 5.11, 7.24-7.30, 7.47-7.60, 7.90, 8.18, 8.56.
Example 9
Figure imgf000049_0001
5-Benzylamino-4-hydroxy-2-isopropyl-6-(naphthalen- 1 -ylmethoxy)-hexanoic acid (1 - benzylcarbamoyl-2-methylbutyl)-amide (9)
A solution of the amine 5a (11.4 mg, 0.021 mmol), benzaldehyde (2.1 μl, 0.021 mmol) and
AcOH (6 μl, 0.1 mmol) in MeOH (350 μL) was treated with NaBH3CN (1.6 mg, 0.025 mmol). The resulting solution was stirred at room temperature for 16 h. The solvent was evaporated under vacuum and the residue was taken into CH2Cl2 and washed with 2 M
NaOH. The organic phase was dried (Na2SO4) and concentrated to give a white foam that was purified by preparative HPLC (20% acetonitrile in H2O with 0.1% TFA to 47% acetonitrile) which gave the title compound (10 mg, 63%) as its TFA salt.
1H-NMR (CD3OD δ (ppm): 0.77-0.91, 1.10, 1.45-1.57, 1.71-1.87, 2.31, 3.15, 3.67, 3.73-3.83,
4.05, 4.12, 4.19-4.25, 4.29-4.43, 5.03, 5.10, 7.20-7.42, 7.46-7.61, 7.82, 7.91, 8.21, 8.50.
Example 10 Step a
Figure imgf000049_0002
3-(4-Methoxytrityloxymethyl)benzonitrile (IQa) 3-(hydroxymethyl)benzonitrile (2 g, 15 mmol) was dissolved in dry pyridine (120 ml). 4- methoxytrityl chloride (6 g, 19.5 mmol) was added and the mixture was stirred over night at room temperature (r.t.). The reaction was quenched with ethanol (EtOH), evaporated on rotavapor and the residue partitioned between dichloromethane (DCM) and saturated aqueous sodium bicarbonate. The organic phase was dried by sodium sulfate and evaporated. Silica gel column chromatography (gradient 30%DCM / hexane - DCM) gave the title compound (5.98 g, 98%). 1H-NMR (400MHz, CDCl3): δ 7.70-7.25 (m, 16H), 6.85 (d, 2H), 4.23 (s, 2H), 3.81 (s, 3H).
Figure imgf000050_0001
(\R,S)-\ -(t-Butoxycarbonylamino)- 1 -(3-(4-methoxytrityloxymethyl)phenyl) ethane ( 1 Ob) The cyano derivative 10a (2.4 g, 5.92 mmol) was dissolved in dry THF (18 ml) and added dropwise over 20 min under nitrogen to a cooled (0 0C) 3M diethylether solution of methylmagnesiumbromide (3.95 ml). The mixture was then stirred at r.t. for 30 min, and then at 60 0C for 2 h. The reaction mixture was cooled to 0 0C and lithium aluminium hydride (450 mg) was added as a slurry in THF (18 ml), and the suspension was stirred at r.t. for Ih and then refluxed for 1 h. The reaction mixture was cooled to 0 0C and water (0.55 ml), 10%NaOH (0.55 ml) and water (1,84 ml) were added successively. The resulting suspension was filtered through Celite, and the solid was washed with THF and DCM. The filtrate was evaporated and the residue partitioned between DCM and water. The organic extract was dried by sodium sulfate and then evaporated. The residue was dissolved in ethyl acetate (15 ml) and di-t-butyldicarbonate was added (2.6 g, 11.85 mmol) and the mixture was stirred at r.t. over night. The reaction was quenched with MeOH, evaporated and the residue was partitioned between DCM and saturated aqueous sodium bicarbonate. The organic extract was dried by sodium sulfate and evaporated. Purification by silica gel column chromatography (gradient 50%DCM / hexane - 75%DCM - DCM) gave the title compound (2.81 g, 91%). 1H-NMR (400MHz, CDCl3): δ 7.53-7.23 (m, 16H), 6.85 (d, 2H), 4.78 (br, s, 2H) CH, NH, 4.17 (s, 2H), 3.80 (s, 3H), 1.45-1.42 (m, 12H) Me, t-but.
Step c
Figure imgf000050_0002
(\R,S)-\ -(t-Butoxycarbonylamino)- 1 -(3-(hvdroxymethyl)phenyl)ethane ( 1 Oc) Compound 10b was dissolved in a mixture of 80% acetic acid (150 ml) and dioxane (20 ml) and was stirred at r.t. for 1 h. The solvents were removed by evaporation and the residue was co-evaporated once from acetonitrile and once from toluene. Silica gel column chromatography (gradient 0 - 1A - 2%EtOH / DCM) gave the title compound (1.50 g, quant.). 1H-NMR (400MHz, CDCl3): δ 7.36-7.22 (m, 4H), 4.81 (br, s, 2H) CH, NH, 4.71 (s, 2H), 1.80 (s, IH) OH, 1.45-1.38 (m, 12H) Me, t-but.
Figure imgf000051_0001
(IR, S)-I -(3 -(Bromomethyl)phenyl)- 1 -(t-butoxycarbonylamino)ethane ( 1 Od) Carbontetrabromide (0.66 g, 2.51 mmol) dissolved in DCM (3 ml) was added dropwise to a solution of the alcohol 10c (0.6 g, 2.39 mmol) and triphenylphosphine (0.87 g, 2.63 mmol) in DCM (8 ml) and the resulting solution was stirred at r.t. over night. The solvent was removed by evaporation on rotavapor and silica gel column chromatography (DCM) gave of title compound (0.48 g, 64%).
1H-NMR (400MHz, CDCl3): δ 7.35-7.21 (m, 4H), 4.79 (br, s, 2H) CH, NH, 4.50 (s, 2H), 1.48-1.40 (m, 12H) Me, t-but.
Step e
Figure imgf000051_0002
2,3-Dideoxy-6-O-(3-((li?,y)-l-(t-butoxycarbonylamino)ethyl)benzyl)-2-isopropyl-D-glucono- 1.4-lactone αθe)
The lactone If (185 mg, 0.98 mmol) and dibutyltin oxide (319 mg, 1.28 mmol) were slurried in benzene (30 ml) and the mixture was refluxed through a Dean-Stark tube for 3 h. Then the temperature was settled to 80 0C and the bromo compound 1Od (355 mg, 1.13 mmol) and tetrabutylammonium bromide (365 mg, 1.13 mmol) were added and the mixture was stirred over night. The suspension was filtered and the filtrate evaporated. Silica gel column chromatography (gradient 0 - 1A - 1 - 2%EtOH/DCM) gave the title compound (281 mg, 68%). MS m/z 480.3 (M+NH4+MeCN)+. 1H-NMR (CDCl3): δ 7.31-7.16 (m, 4H), 4.78 (br, s, 2H) CH, NH, 4.52 (s, 2H), 4.40 (m, IH), 3.81 (m, IH), 3.60 (dd, IH), 3.51 (dd, IH), 2.58 (m, IH), 2.51 (br, s, IH) OH, 2.29 (m, IH), 2.17-2.01 (m, 2H), 1.42-1.36 (m, 12H) Me, t-but.,0.99 (d, 3H), 0.90 (d, 3H).
Step f
Figure imgf000052_0001
5-Azido-2,3,5-trideoxy-6-O-(3-((li?,61-l-(t-butoxycarbonylamino)ethyl) benzyl)-2-isopropyl- D-glucono-l,4-lactone (IQf)
Triflic anhydride (224 μl) dissolved in DCM (1.2 ml) was added dropwise under nitrogen to a stirred DCM (5.8 ml) solution cooled at 0 0C of the alcohol 1Oe (281 mg, 0.67 mmol) and pyridine (0.16 ml). The mixture was stirred at 0 0C for 1 h. The mixture was poured into a chilled 5% NaHSO4 solution and extracted with DCM. The organic extract was dried through sodium sulfate and evaporated on rotavapor below r.t. The residue was dissolved in dimethylformamide (DMF, 5.8 ml) and then sodium azide (173 mg, 2.67 mmol) was added and the mixture was stirred at 70 0C for 1 h. The solvent was removed by evaporation and the residue was partitioned between DCM and water. The organic extract was dried by sodium sulfate and evaporated. Silica gel column chromatography (gradient 10% EtOAc / hexane - 30% EtOAc / hexane) gave the title compound (178 mg, 60%). MS mlz 505.1 (M+NH4+MeCN)+.
1H-NMR (CDCl3): δ 7.34-7.20 (m, 4H), 4.79 (br, s, 2H) CH, NH, 4.57, 4.56 (2xs, 2H), 4.50 (m, IH), 3.78 (m, 2H), 3.72 (m, IH), 2.72 (m, IH), 2.19-2.11 (m, 3H), 1.46-1.36 (m, 12H) Me, t-but., 1.01 (d, 3H), 0.91 (d, 3H).
Figure imgf000052_0002
(2i?.4&5y)-5-Azido-6-(3-((li?.y)-l-(t-butoxycarbonylamino)ethvπbenzyloxy)-4-hvdroxy-2- isopropyl-hexanoic acid ((5Vl-benzylcarbamoyl-2-methyl-propyl)-amide (IQg) The lactone 1Of (178 mg, 0.4 mmol), 2-hydroxypyridine (42 mg, 0.44 mmol) and (S)-2- amino-N-benzyl-3-methylbutyramide (140 mg, 0.68 mmol) were dissolved in DMF (1-2 ml) and then evaporated on rotavapor. Diisopropylethylamine (280 μl) was added to the oily residue and the mixture was vigorously stirred at 70 0C for 88 h (3-4 days). The volatile matter was removed by evaporation on rotavapor and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic extract was then extracted with 5% citric acid, dried by sodium sulfate and evaporated. Silica gel column chromatography (gradient 0 - 1 - VA - 2%EtOH/DCM) gave the title compound (157 mg 60 %). MS mlz 653.3 (M+H)+.
1H-NMR (CDCl3): δ 7.32-7.17 (m, 9H), 6.58 (br, s, IH) NH, 6.41 (br, s, IH) NH, 4.95 (br, s, IH) NH, 4.80 (br, s, IH) CH, 4.56-4.20 (m, 5H), 3.51-3.36 (m, 3H), 2.74 (br, s, IH) OH, 2.20-1.58 (m, 6H) CH2, 2xCH, NH2, 1.46-1.34 (m, 12H) Me, t-but, 0.96-0.84 (8xs, 12H).
Figure imgf000053_0001
(2i?,4ιS,561-5-Amino-6-(3-(l-(t-butoxycarbonylamino)ethyπbenzyloxy)-4-hydroxy-2- isopropyl-hexanoic acid ((5Vl-benzylcarbamoyl-2-methyl-propyl)-amide (IQh) The azide derivative 1Og (157 mg, 0.24 mmol) was dissolved in EtOH (6 ml). 5% Pd on calcium carbonate (Lindlar catalyst, 250 mg) was added and the mixture was stirred under atmospheric pressure of hydrogen for 5 h. The mixture was filtered through Celite and the filtrate was evaporated. An additional filtration of the residue redissolved in EtOH was done through a 0.2 μm PTFE filter. Evaporation gave the title compound as a solid (143 mg, 95 %). MS mlz 627 A (M+H)+.
1H-NMR (CDCl3): δ 7.31-7.15 (m, 9H), 6.56 (br, s, IH) NH, 6.39 (br, s, IH) NH, 5.00 (br, s, 2H) NH, 4.79 (br, s, IH) CH, 4.57-4.22 (m, 5H), 3.70 (m, 3H), 2.95 (br, s, IH) OH, 2.19 (m, IH), 2.13 (octette, IH), 1.82 (octette, IH), 1.74 (m, IH), 1.46-1.33 (m, 12H) Me, t-but., 0.97- 0.84 (8xs, 12H).
Example 11 Step a
Figure imgf000054_0001
1 -(t-Butoxycarbonylamino)- 1 -(3 -(4-methoxytrityloxymethyl)phenyl)-( Ii?, S)- 1 -phenylmethane
(Ha)
3-(4-methoxytrityloxymethyl)benzonitrile (10a) (1.6 g, 3.95 mmol) was treated with phenylmagnesiumbromide, followed by reduction with lithium aluminium hydride, hydrolysis and treatment of the crude amine with di-t-butyldicarbonate, according to the procedure described in Example 10, step b, which gave the title compound (2.04 g, 88%).
1H-NMR (400MHz, CDCl3): δ 7.47-7.18 (m, 21H), 6.82 (d, 2H), 5.90 (br, s, IH) CH, 5.12
(br, s, IH) NH, 4.13 (s, 2H), 3.79 (s, 3H), 1.43 (br, s, 9H) t-but.
Step b
Figure imgf000054_0002
1 -(t-Butoxycarbonylamino)- 1 -(3 -(hydroxymethyl)phenyl)-( Ii?, S)- 1 -phenylmethane (l ib) Compound 11a (2.04 g, 3.48 mmol) was treated with 80% acetic acid according to the procedure described in Example 10, step c, which gave the title compound (1.06 g, 97%). 1H-NMR (400MHz, CDCl3): δ 7.33-7.16 (m, 9H), 5.90 (br, s, IH) CH, 5.15 (br, s, IH) NH, 4.65 (d, 2H), 1.69 (t, IH) OH, 1.43 (br, s, 9H) t-but.
Ster
Figure imgf000054_0003
1 -(3 -(Bromomethyl)phenyD- 1 -(t-butoxycarbonylamino)-( Ii?, S)- 1 -phenylmethane (l ie) Compound 1 Ib (1.04 g, 3.40 mmol) was treated with triphenylphosphine and carbon tetrabromide according to the procedure described in Example 10, step d, which gave the title compound (0.75 g, 58%).
1H-NMR (400MHz, CDCl3): δ 7.34-7.15 (m, 9H), 5.89 (br, s, IH) CH, 5.13 (br, s, IH) NH, 4.45 (s, 2H), 1.43 (br, s, 9H) t-but.
Step d
Figure imgf000055_0001
2,3-Dideoxy-6-O-(3-(l-(t-butoxycarbonylamino)-(li?,61-l-phenylmethyl) benzyl)-2- isopropyl-D-glucono-l,4-lactone (l id)
The lactone If (IOO mg, 0.53 mmol) was alkylated with the bromo derivative 1 Ic according to the procedure described in Example 10, step e, which gave the title compound (180 mg, 70%).
MS mlz 542.2 (M+AcO)".
1H-NMR (CDCl3): δ 7.31-7.13 (m, 9H), 5.90 (br, s, IH) CH, 5.12 (br, s, IH) NH, 4.52 (s,
2H), 4.53 (s, 2H), 4.39 (m, IH), 3.82 (m, IH), 3.60 (dd, IH), 3.53 (dd, IH), 2.61 (m, IH),
2.50 (br, s, IH) OH, 2.30 (m, IH), 2.17-2.01 (m, 2H), 1.42 (s, 9H) t-but.,1.01 (d, 3H), 0.92 (d,
3H).
Step e
Figure imgf000055_0002
5-Azido-2,3,5-trideoxy-6-O-(3-(l-(t-butoxycarbonylamino)-(li?,5)-l-phenylmethyl)benzyl)-
2-isopropyl-D-glucono-l,4-lactone (1 Ie)
The alcohol 1 Id (180 mg, 0.37 mmol) was treated with triflic anhydride, followed by sodium azide according to the procedure described in Example 10, step f, which gave the title compound (120 mg, 63%). MS mlz 567 '.1 (M+AcO)".
1H-NMR (CDCl3): δ 7.34-7.18 (m, 9H), 5.91 (br, s, IH) CH, 5.20 (br, s, IH) NH, 4.54 (s,
2H), 4.51 (m, 2H), 3.74 (d, IH), 3.72 (s, IH), 3.62 (m, IH), 2.71 (m, IH), 2.21-2.10 (m, 2H),
1.43 (s, 9H) t-but., 1.01 (d, 3H), 0.92 (d, 3H).
Step f
Figure imgf000056_0001
(2ig.4S.5S)-5-Azido-6-(3-(l-(t-butoxycarbonylaminoV(li?.S)-l-phenylmethvπ benzyloxyV4- hydroxy-2-isopropyl-hexanoic acid ((S)-l-benzylcarbamoyl-2-methyl-propyl)-amide (Hf) The lactone 1 Ie (120 mg, 0.24 mmol) was reacted with (5)-2-amino-N-benzyl-3- methylbutyramide according to the procedure described in Example 10, step g, which gave the title compound (96 mg, 57%). MS mlz 715.3 (M+H)+.
1H-NMR (CDCl3): δ 7.31-7.15 (m, 14H), 6.63 (br, s, IH) NH, 6.45 (br, s, IH) NH, 5.94 (br, s, IH) CH, 5.36 (br, s, IH) NH, 4.53-4.18 (m, 5H), 3.65 (m, 3H), 3.38 (m, IH), 2.96 (br, s, IH) OH, 2.19 (m, IH), 2.10 (octette, IH), 1.82 (octette, IH), 1.68 (m, IH), 1.42 (s, 9H) t-but., 0.93-0.84 (8xs, 12H).
Figure imgf000056_0002
(2i?,4ιS,561-5-amino-6-(3-(l-(t-butoxycarbonylamino)-l-phenylmethyπ benzyloxy)-4- hydroxy-2-isopropyl-hexanoic acid ((S)-l-benzylcarbamoyl-2-methyl-propyl)-amide d ig) The azide 1 If (96 mg, 0.134 mmol) was reduced according to the procedure described in Example 10, step h, which gave the title compound (90 mg, 97%). MS mlz 689.3 (M+H)+. 1H-NMR (CDCl3): δ 7.33-7.15 (m, 14H), 6.83 (br, s, IH) NH, 6.59 (br, s, IH) NH, 5.91 (br, s, IH) CH, 5.46 (br, s, IH) NH, 4.46-4.21 (m, 5H), 3.50-3.30 (m, 3H), 2.73 (br, s, IH) OH, 2.40 (br, s, 2H) NH2, 2.20 (m, IH), 2.11 (octette, IH), 1.79 (octette, IH), 1.68-155 (m, IH), 1.42 (s, 9H) t-but., 0.94-0.82 (8xs, 12H).
Example 12 Step a
Figure imgf000057_0001
2,2-Dimethyl-oxazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 4-methyl ester (12a) 2,2-Dimethoxypropane (50 ml, 400 mmol) and boron trifluoride etherate (0.35 ml, 2.8 mmol) was added to a solution of N-Boc serine methyl ester (1, 10.0 g, 45.6 mmol) in acetone (165 ml). The resulting orange solution was stirred at room temperature for 2.5 h until disappearance of starting material. 0.9 ml triethylamine was then added to the reaction mixture whereafter the solvent was removed under reduced pressure. The residue was partitioned between diethyl ether and sat. NaHCOs, the organics extracts were combined, dried and concentrated which gave the title compound (10.5 g, 90%) which was used without further purification.
Figure imgf000057_0002
4-Hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (12b) A 250-ml two-necked flask was equipped with a magnetic stirring bar, reflux condenser bearing a drying tube and a dropping funnel. The flask was charged with tetrahydrofuran (100 ml) and lithium aluminium hydride (2.16 g, 57.0 mmol). While the suspension in the flask was stirred, a solution of the ester 12a (9.90 g, 38.2 mmol) in THF (50 ml) was added dropwise during 20 min. The reaction was monitored by thin layer chromatography. When the reaction was finished, the mixture was cooled in an ice bath and a solution of 10% potassium hydroxide (20 ml) was added dropwise during 10 min. The mixture was stirred for 2 h at room temperature, whereafter the white precipitate was removed by filtration through celite. The combined organic filtrates were washed with 100 ml of aqueous phosphate buffer (pH 7), and the aqueous layer was extracted with ether. The combined organic phases were dried and concentrated which gave the title compound (8.3 g, 94%). The residue was used without further purification.
Step c
Figure imgf000057_0003
4-Formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (12c) A solution of dimethylsulfoxide (8.10 g, 103.71 mmol) in dichloromethane (10 ml) was added dropwise during 25 min to a solution of oxalyl chloride (6.58 g, 51.9 mmol) in dichloromethane (80 ml) at -78 0C. At the end of the addition the reaction solution was warmed up to -60 0C, and a solution of the alcohol 12b (8.0 g, 34.6 mmol) in dichloromethane (60 ml) was added dropwise during 50 min. N,N-diisopropylethyl amine (36 ml, 200 mmol) in dichloromethane (5 ml) was then added to the reaction mixture -45 0C during 30 min whereafter the reaction mixture was allowed to warm to 0 0C during 10 min. The reaction mixture was then transferred to a separation funnel charged with ice-cold 1 M HCl solution (130 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried and concentrated which gave the title compound (7.89 g, 99%). The residue was used in the next step without further purification.
Figure imgf000058_0001
4-(l-Hydroxy-3-methoxycarbonyl-prop-2-ynyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (12b)
BuLi (71.5 ml, 114 mmol, 1.6 M in hexanes) was added dropwise to a solution of methyl propiolate (10.5 ml, 125 mmol) in ether (300 ml) at -780C. The solution was stirred at this temperature for 1 h, then a solution OfZnBr2 (31.6 g, 140 mmol) in ether (200 ml) was added via canula. The mixture was stirred at room temperature for ~2 h, then cooled down to -200C and of the aldehyde 12c (10.4 g, 45.7 mmol) in ether (80 ml) was added. The mixture was stirred at room temperature overnight, then the reaction was quenched by addition of sturated NH4Cl at 0 0C. The mixture was extracted with ether, dried and concentrated. The residue was purified by column chromatography, eluted with ethyl acetate - iso-hexane 1 :4, which gave the title compound (5.8 g, 20.4 mmol, 45%).
Step e
Figure imgf000058_0002
4-(l-Hydroxy-3-methoxycarbonyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert- butyl ester (12e) Compound 12d (4.6 g, 14.70 mmol) was dissolved ethyl acetate (50 ml) and a catalytic amount of Pd/C was added. The mixture was stirred under an atmosphere of hydrogen for ~3 h, then filtered through celite and concentrated which gave the title compound (4.5 g, 14.20 mmol, 97%). The residue was used in the next step without further purification.
Step f
Figure imgf000059_0001
Acetic acid (420 μl) was added to a solution of compound 12e (4.5 g, 14.20 mmol) in toluene (100 ml). The reaction mixture was refluxed for 4-5 h, until the starting material disappeared. The solvent was removed under vacuum and the residue was purified by column chromatography (Rf 0.40, toluene - acetone 6:1) which gave the title compound (3.7 g, 13.2 mmol, 93%).
Figure imgf000059_0002
4-(4-Isopropyl-5-oxo-tetrahydro-furan-2-yl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert- butyl ester (12g)
A solution of BuLi in hexanes (1.6 M, 2.3 ml, 3.67 mmol) was added dropwise to a solution of DIPA (494 μl, 3.50 mmol) in THF (3 ml) at -78 0C under an atmosphere of argon whereafter the mixture was stirred at this temperature for 30 min. A solution of the lactone 12f (500 mg, 1.75 mmol) in THF (3 ml) was then added to the solution followed by TPPO (tripyrrolidine phosphorus oxide, 3.0 ml) under vigorous stirring. 1PrI (700 μl, 7.0 mmol) was added dropwise and the reaction mixture was stirred at this temperature for 2 h, followed by another 2 h at room temperature. The reaction was then quenched by addition of sat. NH4Cl, extracted with TBME, dried and concentrated. The residue was purified by column chromatography which gave the title compound (380 mg, 1.16 mmol, 66%).
Figure imgf000060_0001
[2-Benzyloxy- 1 -(4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-ethyll-carbamic acid tert-butyl ester (12h)
The isopropyl lactone 12g (204 mg, 0.624 mmol) was treated with TFA - H2O (5 ml, 9:1), stirred at room temperature for 1 h, and then concentrated under vacuum. The residue was dissolved in a mixture of dioxane and a 10% solution of sodium carbonate (10 ml, 1 :1, pH ~8). BoC2O (204 mg, 0.936 mmol) was added in portions and the mixture was stirred at room temperature for 2 h. Dioxane was then removed under vacuum and the aqueous phase was extracted with dichloro methane, dried and concentrated. The residue was dissolved in dichloromethane and cooled to 00C, and benzyl 2,2,2-trichloroacetimidate (174 μl, 0.936 mmol) and TMS-triflate (22 μl) was added. The reaction mixture was stirred at room temperature until the reaction was complete and then washed with sat. sodium bicarbonate, dried and concentrated. The residue was purified by column chromatography (Rf 0.60 ethyl acetate - iso-hexane 1 :2) which gave the title compound (143 mg, 0.379 mmol, 61%).
Step i
Figure imgf000060_0002
6-Benzyloxy-5-tert-butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl- hexanoic acid (12i)
LiOH (1 M sol in water, 2.98 ml, 2.98 mmol) was added to a solution of the lactone 12h (750 mg, 1.99 mmol) in dioxane-water (12 ml, 2:1). The reaction mixture was stirred at room temperature until the starting material had disappeared (~1 h). The solvents were removed under vacuum and the residue partitioned between ether and 10% citric acid, the organic phase was dried and concentrated. The residue was dissolved in DMF (20 ml) whereafter imidazole (3.0 g, 44 mmol) and TBDMSCl (3.0 g, 20 mmol) was added and the solution was stirred at room temperature for 2 days. The reaction was quenched by addition of methanol, whereafter the mixture was stirred at room temperature for 2 h, and then concentrated. The residue was purified by column chromatography (Rf 0.65 ethyl acetate - iso-hexane 1 :2) which gave the title compound (502 mg, 0.98 mmol, 50%).
General method A step a
Figure imgf000061_0001
N-Methylmorpholine (3 eq) and isobutylchloro formate (1 eq) was added to a stirred solution of Boc-valine (40 mg) in THF (ImI) at -15 0C was. The reaction was stirred at -15 0C for one minute and then the appropriate amino derivative (1 eq) was added as a solution in DMF (ImI). The reaction was then warmed to room temperature during a period of 30 min. The solution was diluted with ethyl acetate and washed with sat. NaHCOs (aq) and concentrated in vacuo. The residue was taken up in a solution of ImI 4M HCl in dioxane, stirred for one hour and then concentrated in vacuo to give the HCl salt of the amine.
Figure imgf000061_0002
To a solution of 6-benzyloxy-5-tert-butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)- 2-isopropyl-hexanoic acid compound (12i, 25 mg) in DMF (3ml) were added HATU (1.5 eq), HOAt (1.5 eq) and NMM (3 eq) and the requisite amine from step a. The reaction was stirred overnight at RT and then diluted with EtOAc and washed with IM HCl and brine. The organic phase was concentrated and the residue was taken up in 4M HCl in dioxane, stirred for Ih and then concentrated and purified by prep-HPLC.
Example 13
Figure imgf000061_0003
5-Amino-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid [2-methyl- 1 -(4-methyl- benzylcarbamovD-propyll -amide (13) The title compound was prepared according to general Method A, using 4-methyl benzylamine as amino derivative in step a.
Example 14
Figure imgf000062_0001
5-Amino-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid |"l-(4-chloro-benzylcarbamoyl)- 2-methyl-propyl] -amide (14)
The title compound was prepared according to general Method A, using 4-chloro benzylamine as amino derivative in step a.
Example 15
Figure imgf000062_0002
5-Amino-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid |"l-(4-methoxy- benzylcarbamoyl)-2-methyl-propyl]-amide (15)
The title compound was prepared according to general Method A, using 4-methoxy benzylamine as amino derivative in step a.
Example 16
Figure imgf000062_0003
5-Amino-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid [l-(3,4-dichloro- benzylcarbamoyl)-2-methyl-propyl] -amide (16)
The title compound was prepared according to general Method A, using 3,4-dichloro benzylamine as amino derivative in step a.
Example 17
Figure imgf000063_0001
5-Amino-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid (2-methyl- 1 -[(pyridin-3- ylmethyl)-carbamoyl] -propyl) -amide (17)
The title compound was prepared according to general Method A, using C-pyridin-3-yl- methylamine as amino derivative in step a.
Example 18
Figure imgf000063_0002
5-Amino-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid (2-methyl- 1 -[(pyridin-4- ylmethyD-carbamoyl] -propyl) -amide (18)
The title compound was prepared according to general Method A, using C-pyridin-4-yl- methylamine as amino derivative in step a.
Example 19 Step a
Figure imgf000063_0003
5-Azido-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid (1 -benzylcarbamoyl-2-methyl- butyP-amide (19a)
A mixture of the lactone (Ii) (54 mg, 0.178 mmol), the amine (5a) (143 mg, 0.653 mmol), 2- hydroxypyridine (62 mg, 0.653 mmol) and EtN1Pr2 (100 μl, 0.575 mmol) was heated to 70 0C for 3 days. The reaction mixture was cooled to r.t. and taken into EtO Ac/1 M HCl. The organic phase was washed with 1 M HCl, dried (Na2SO4) and evaporated to give a yellow solid that was triturated into hot 1BuOMe to give 65 mg (70%) of the title compound as a white solid. LC-MS: 524 (M+l).
Figure imgf000064_0001
5-Amino-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid (1 -benzylcarbamoyl-2-methyl- propyD-amide (19b)
A solution of the azide (19a) in EtOAc:MeOH (50:1, 8 niL) was hydrogenated in the presence of Pd Lindlar. Filtration of the product and evaporation of the solvent afforded an oil that was purified by preparative HPLC (5% acetonitrile in H2O with 0.1% TFA to 30% acetonitrile) to give 52 mg (38%) of the title compound as its TFA salt. LC-MS: 498 (M+ 1)
Example 20 Step a
Figure imgf000064_0002
2-Amino-4-methyl-pentanoic acid benzylamide (20a)
To a solution pre-cooled to 0 0C of Boc-Leu-OH (0.5g , 2.16 mmol), benzylamine (0.38 ml, 3.46 mmol), di-isopropyl-ethylamine (3.6 ml) in 10 ml DMF was added HATU (1.1 g). The solution was stirred at 0 0C for 30 min, then 2 hours at room temperature. The reaction mixture was evaporated, distributed between water and ethyl acetate, the organic phase was washed with water, brine, dried over sodium sulfate, evaporated and purified by column chromatography (hexane/ethyl acetate 3:1) to give 520 mg of pure boc-protected amine (79%). The solid was dissolved in TFA/DCM (1 :1) and the resulting solution was stirred at r.t. for Ih. Evaporation of the solvent afforded an oil that was taken into CH2Cl2 and washed with 1 M NaOH. The organic phase was dried (Na2SO4) and concentrated which gave the title compound as a colorless oil (75% over two steps). LC-MS: 221 (M+ 1)
Figure imgf000065_0001
5-Azido-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid (1 -benzylcarbamoyl-3-methyl- butvD-amide (20b)
The procedure described in Example 19 step a was followed but using the amine 20a instead of 5a which give the title compound in 62% yield. LC-MS: 524 (M+ 1)
Figure imgf000065_0002
5-Amino-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid (1 -benzylcarbamoyl-3-methyl- butyP-amide (20c)
The azide of compound 20b was reduced according to the procedure described in Example 19 step b which gave the title compound (34% yield), LC-MS: 498 (M+l).
Example 21 Step a
Figure imgf000065_0003
2-Amino-3-ethyl-pentanoic acid benzylamide (21a)
The procedure described in Example 20 step a was followed but using (l-carbamoyl-2-ethyl- butyl)-carbamic acid tert-butyl ester instead of Boc-Leu-OH which give the title compound in 78% yield over two steps. LC-MS: 524 (M+l)
Figure imgf000066_0001
5-Azido-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid (1 -benzylcarbamoyl-2-ethyl- butyP-amide (21b)
The procedure described in Example 19 step a was followed but using the amine 21a instead of 5a which give the title compound in 74% yield. LC-MS: 538 (M+ 1)
Figure imgf000066_0002
5-Amino-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid (1 -benzylcarbamoyl-2-ethyl- butyP-amide (21c)
The azide of compound 21b was reduced according to the procedure described in Example 19 step b which gave the title compound (55% yield), LC-MS: 512 (M+ 1).
Example 22 Step a
H
BocHN
H
OH
[4-(l-Benzylcarbamoyl-2-methyl-propylcarbamoyl)-l-benzyloxymethyl-2-hydroxy-5- methyl-hexyll-carbamic acid tert-butyl ester (22a)
A solution of the azide Ij (235 mg, 0.46 mmol) and BoC2O (150 mg, 0.69 mmol) in EtOAc (1 ml) was hydrogenated in the presence of Pd Lindlar. The catalyst was filtered off and the solvent evaporated. The residue was purified by flash chromatography (Hex:EtOAc 2.5:1 to 1 :2) which gave the title compound (225 mg, 84%). LC-MS: 584 (M+ 1)
Figure imgf000067_0001
[4-(l-Benzylcarbamoyl-2-methyl-propylcarbamoyl)-l-benzyloxymethyl-2-methoxy-5- methyl- hexyll-carbamic acid tert-butyl ester (22b)
To a solution of the alcohol 22a (8.8 mg, 0.015 mmol) DCM (ImI) proton sponge (1,8- bis(dimethylamino)naphthalene) (4.7mg, 0.022 mmol) was added followed by addition of trimethyloxonium tetrafluoroborate (3.25 mg, 0.022 mmol). The mixture was stirred at r.t. for 3h, quenched by addition of brine, diluted with DCM, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC (20% acetonitrile in H2O with 0.1% TFA to 70% acetonitrile) which gave the title compound (2.25 mg, 25%), LC-MS: 598 (M+ 1).
Ster
Figure imgf000067_0002
5-Amino-6-benzyloxy-2-isopropyl-4-methoxy-hexanoic acid (1 -benzylcarbamoyl-2-methyl- ethyP-amide (22c)
2.25 mg of the boc protected compound 22b was stirred in a mixture of DCM (0.6ml) and TFA (0.3ml) for 3h. Then toluene was added (3 ml) and the solvents were evaporated in vacuo. The residue was purified by preparative HPLC (5% acetonitrile in H2O with 0.1% TFA to 40% acetonitrile) which gave the title compound (1 mg, 53%),LC-MS: 498 (M+l).
Example 23 Step a
Figure imgf000067_0003
3-Hydroxy-4-methyl-benzoic acid methyl ester (23 a)
Thionyl chloride (96 μl, 1.31 mmol) was carefully added to a solution of 3-hydroxy-4- methylbenzoic acid (200 mg, 1.31 mmol) in MeOH (2 ml). The resulting solution was then heated at 45 0C for 17 h. Evaporation of the solvent afforded a white solid that was purified by flash chromatography on silica gel (Hex:EtOAc 10:1) to give 168 mg (86%) of the title compound.
Step b
Figure imgf000068_0001
3-(3-Methoxy-propoxy)-4-methyl-benzoic acid methyl ester (23b)
Azodicarboxylic acid dipiperidide (505 mg, 2 mmol) and PPh3 (524 mg, 2 mmol) were added to a solution of 23a (166 mg, 1 mmol) and 3-methoxypropan-l-ol (95.7 μl, 1 mmol) in CH2Cl2 (10 ml) and the resulting mixture was stirred under N2 for 17 h. The reaction mixture was then concentrated under vacuum and the residue was taken into EtOAc and washed with 10% aq. citric acid and brine. The organic phase was dried (Na2SO4) and the solvent evaporated to give the crude product that was purified by flash chromatography on silica gel (Hex:EtOAc 10:1) to give 96 mg (40%) of the title compound.
Stet
Figure imgf000068_0002
[3 -(3 -Methoxy-propoxy)-4-methyl-phenyl] -methano 1 (23 c)
Diisobutylaluminum hydride 1.0 M solution in hexanes (2.5 mL, 2.5 mmol) was added carefully to 23b (96 mg, 0.403 mmol) under N2. The resulting solution was stirred 30 min and then carefully quenched with 1 M HCl. The product was extracted into EtOAc, and the combined organic extracts were dried (Na2SO4). Evaporation of the solvent afforded 84 mg (100%) of the title compound.
Step d
Figure imgf000068_0003
4-Bromomethyl-2-(3 -methoxy-propoxy)- 1 -methyl-benzene (23 d)
Bromine (24 μl, 0.48 mmol) was added to a solution of PPh3 (126 mg, 0.48 mmol) in CH2Cl2
(2 ml). The resulting solution was stirred for 5 min and then 23c (84 mg, 0.4 mmol) was added at once. The reaction mixture was stirred for 20 min and then concentrated under vacuum. The residue was purified by flash chromatography (Hex:EtOAc 35:1) to give 68 m£ (52%) of the title compound as a white solid.
Step e
Figure imgf000069_0001
5- { 1 -Hydroxy-2-[3-(3-methoxy-propoxy)-4-methyl-benzyloxyl-ethyl| -3-isopropyl-dihydro- furan-2-one (23 e)
The procedure described in Example 1 step h was followed but using 23 d instead of benzyl bromide, which gave the title compound (56% yield).
Figure imgf000069_0002
5- { 1 -Azido-2-[3-(3-methoxy-propoxy)-4-methyl-benzyloxyl-ethyl| -3-isopropyl-dihydro- furan-2-one (23 f)
Compound 23 e was reacted according to the procedure described in Example 1 step i, which afforded the title compound (93%).
Stet
Figure imgf000069_0003
2-Amino-3-methyl-pentanoic acid 4-methyl-benzylamide (23g) The procedure described in example 5 step a was followed but using 4-methylbenzylamine instead of benzylamine, which gave the title compound (76%).
Step h
Figure imgf000070_0001
5-Azido-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-methyl-benzyloxyl-exanoic acid [2-methyl-l-(4-methyl-benzylcarbamoyl)-butyl] -amide (23h)
A mixture of compound 23f (53 mg, 0.13 mmol), the amine 23g (106 mg, 0.46 mmol), 2- hydroxypyridine (44 mg, 0.46 mmol) and EtN1Pr (25 μl, 0.29 mmol) was heated to 70 0C for 5 days. The reaction mixture was cooled down to room temperature and taken into EtO Ac/1 M HCl. The organic phase was washed with 1 M HCl, dried (Na2SO4) and evaporated. The residue was purified by preparative HPLC (20% acetonitrile in H2O with 0.1% TFA to 60% acetonitrile) which gave 12 mg (14%) of the title compound as a white solid.
Ster
Figure imgf000070_0002
5-Amino-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-methyl-benzyloxyl-hexanoic acid [2-methyl-l-(4-methyl-benzylcarbamoyl)-butyl] -amide (23i)
A solution of azide 23h (12 mg, 0.019 mmol) in MeOH (15 ml) was hydrogenated in the presence of Pd Lindlar. The catalyst was filtered off and the solvent evaporated. The residue was purified by preparative HPLC (20% acetonitrile in H2O with 0.1% TFA to 60% acetonitrile) which gave 4.7 mg (50%) of the title compound as its TFA salt.
1H-NMR (CD3OD) δ (ppm): 0.78-0.96, 1.05-1.17, 1.47-1.62, 1.73-1.86, 2.00-2.08, 2.17, 2.24-
2.36, 3.15, 3.49-3.64, 4.06, 4.21, 4.31, 4.51, 6.84, 6.89, 7.06-7.18, 7.80, 8.43.
Example 24 Step a
Figure imgf000071_0001
5-[2-(3,4-Dichloro-benzyloxy)-l-hydroxy-ethyll-3-isopropyl-dihydro-furan-2-one (24a) The procedure described in Example 1 step h was followed but using 3,4-dichlorobenzyl bromide instead of benzyl bromide, which gave the title compound (56% yield).
Step b
Figure imgf000071_0002
5-[l-Azido-2-(3,4-dichloro-benzyloxy)-ethyll-3-isopropyl-dihydro-furan-2-one (24b) Compound 24a was reacted according to the procedure described in Example 1 step i, which afforded the title compound (79%).
Ster
Figure imgf000071_0003
5-Azido-6-(3,4-dichloro-benzyloxy)-4-hydroxy-2-isopropyl-hexanoic acid [2-methyl-l-(4- methyl-benzylcarbamoyD-butyl] -amide (24c)
A mixture of compound 24b (132 mg, 0.35 mmol), the amine 23g (287 mg, 1.23 mmol), 2- hydroxypyridine (117 mg, 1.23 mmol) and EtN1Pr (100 μL, 0.57 mmol) was heated to 70 0C for 5 days. The reaction mixture was cooled down to room temperature and taken into EtO Ac/1 M HCl. The organic phase was washed with 1 M HCl, dried (Na2SO4) and evaporated. The residue was triturated from MeO1Bu which gave 70 mg (33%) of the title compound as a white solid.
Step d
Figure imgf000072_0001
5-Amino-6-(3,4-dichloro-benzyloxy)-4-hydroxy-2-isopropyl-hexanoic acid [2-methyl-l-(4- methyl-benzylcarbamoyl)-butyl] -amide (24d)
Compound 24c was reacted according to the procedure described in Example 23 step i, which afforded the title compound (33%).
1H-NMR (CD3OD) δ (ppm): 0.80-0.96, 1.05-1.18, 1.46-1.65, 1.73-1.89, 2.28, 2.30-2.39, 3.18,
3.50-3.69, 4.18-4.24, 4.25-4.37, 4.52-4.57, 7.07-7.17, 7.27-7.32, 7.50, 7.58, 7.80, 8.44.
Example 25 Step a
Figure imgf000072_0002
[2-Benzyloxy- 1 -(4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-ethyll-methyl-carbamic acid tert- butyl ester (25a)
A solution of compound Ih (85 mg, 0.31 mmol) and pyridine (100 μL, 1.24 mmol) in CH2Cl2 (2 ml) was treated with Tf2O (200 μl, 1.19 mmol) at 0 0C. Stirred for 15 min and quenched with H2O. The product was extracted to into CH2Cl2 and the combined extracts were dried (Na2SO4) and the solvent evaporated to give a residue that was dissolved in THF (0.5 ml). The resulting solution was added to a 2 M solution of methylamine in THF (2 ml, 4 mmol) at 0 0C and the reaction mixture was stirred at 0 0C for 3 h and then concentrated under vacuum to a yellow solid that was taken into MeOH (ImI) and treated with BoC2O (87 mg, 0.4 mmol) and DMAP (37 mg, 0.3 mmol). The reaction mixture was stirred for 24 h and then evaporated into silica gel and purified by flash chromatography into silica gel (Hex:EtOAc 10:1 to 2.5:1) which afforded 15 mg (12%) of the title compound.
Step b
Figure imgf000073_0001
6-Benzyloxy-4-hydroxy-2-isopropyl-5-methylamino-hexanoic acid [2-methyl- 1 -(4-methyl- benzylcarbamoyl)-butyl] -amide (25b)
A mixture of compound 25a (15 mg, 0.038 mmol), the amine 23g (42 mg, 0.18 mmol), 2- hydroxypyridine (17 mg, 0.18 mmol) and EtN1Pr (25 μl, 0.14 mmol) was heated to 70 0C for 5 days. The reaction mixture was cooled down to room temperature and taken into EtO Ac/1 M HCl. The organic phase was washed with 1 M HCl, dried (Na2SO4) and evaporated. The residue was taken into TFA (1 ml) and stirred for 30 min. Concentrated under vacuum which afforded the crude product that was purified by preparative HPLC (10% acetonitrile in H2O with 0.1% TFA to 40% acetonitrile) which gave 12 mg (50%) of the title compound as its TFA salt.
1H-NMR (CD3OD) δ (ppm): 0.80-0.94, 1.05-1.18, 1.48-1.59, 1.72-1.84, 1.89, 2.25-2.37, 2.64, 3.08, 3.60-3.66, 3.69-3.75, 4.19-4.27, 4.28-4.34, 4.56, 7.07-7.18, 7.27-7.40, 7.80, 8.45.
Example 26
Figure imgf000073_0002
5-(Cyclohexylmethyl-amino)-4-hydroxy-2-isopropyl-6-(naphthalen-l-ylmethoxy)-hexanoic acid (l-benzylcarbamoyl-2-methyl-butyl)-amide (26)
The procedure described in Example 8 was followed but using cyclohexanecarboxaldehyde instead of acetone, which gave the title compound (27% yield).
1H-NMR (CD3OD) δ (ppm): 0.61-0.76, 0.81, 0.84-0.94, 1.01-1.22, 1.42-1.69, 1.72-1.84, 1.85-
1.93, 2.32, 2.58, 3.18, 3.59, 3.64-3.70, 3.74-3.80, 4.23, 4.30-4.45, 5.04, 7.20-7.35, 7.43-7.61,
7.80, 7.87-7.95, 8.18, 8.53. Example 27
Figure imgf000074_0001
4-Hydroxy-2-isopropyl-6-(naphthalen- 1 -ylmethoxy)-5 - [(pyridin-3 -ylmethyD-amino] - hexanoic acid (l-benzylcarbamoyl-2-methyl-butyl)-amide (27)
The procedure described in Example 8 was followed but using 3-pyridinecarboxaldehyde instead of acetone, which gave the title compound (41% yield).
1H-NMR (CD3OD) δ (ppm): 0.77-0.93, 1.02-1.16, 1.46-1.59, 1.72-1.83, 1.88, 2.33, 3.24,
3.63-3.72, 3.77-3.89, 4.17-4.25, 4.29-4.44, 5.03-5.14, 7.19-7.34, 7.46-7.64, 7.83, 7.91, 8.21,
8.52.
Example 28 Step a
Figure imgf000074_0002
Trifluoro-methanesulfonic acid 1 -(4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-2-[3-(3-methoxy- propoxy)-4-methyl-benzyloxy]-ethyl ester (28a)
Compound 23e (0.62 g, 1.63 mmol) was reacted with Tf2O (0.414 mL, 2.46 mmol) in CH2Cl2 (20 mL) in the presence of pyridine (0.42 mL, 5.2 mmol) at 0 0C. After 1 h the reaction mixture was quenched with water and the product was extracted into CH2Cl2. The combined organic extracts were dried (Na2SO4) and the solvent evaporated to give 0.9 g (100%) of the title compound as a yellow oil.
Step b
Figure imgf000075_0001
3-Isopropyl-5- {2-[3-(3-methoxy-propoxy)-4-methyl-benzyloxy"|- 1 -methylamino-ethyU - dihydro-furan-2-one (28b)
Compound 28a (99mg, 0.19 mmol) was reacted with methylamine 2 M in THF (0.5 mL, 1 mmol) in THF (0.5 mL) at 0 0C for 4 h. Concentrated under vacuum to afford 104 mg of the crude title compound as a yellow solid.
Figure imgf000075_0002
4-Hydroxy-2-isopropyl-6-[2-(3-methoxy-propoxy)-4-methyl-benzyloxy]-5-methylamino- hexanoic acid [2-methyl-l-(4-methyl-benzylcarbamoyl)-butyl] -amide (28c)
The procedure described in example 23 step h was followed but using 28b instead of 23f, which gave the title compound (1%).
MS Electrospray ionization, eluting with acetonitrile / ammonium acetate buffer, [M+H]+
628.5
Example 29 Step a
Figure imgf000075_0003
2-Amino-3-methyl-pentanoic acid 3,4-dichloro-benzylamide (29a) The procedure described in example 1 step g was followed but using 3,4-dichlorobenzylamine instead of benzylamine, which gave the title compound (76%).
Figure imgf000076_0001
5-Azido-4-hydroxy-2-isopropyl-6-[2-(3-methoxy-propoxy)-4-methyl-benzyloxyl-hexanoic acid [2-methyl-l-(3,4-dichloro-benzylcarbamoyl)-butyll-amide (29b) The procedure described in example 23 step h was followed but using 29a instead of 23g, which gave the title compound (49%).
Ster
Figure imgf000076_0002
5-Amino-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-methyl-benzyloxyl-hexanoic acid [l-(3,4-dichloro-benzylcarbamoyl)-2-methyl-butyll-amide (29c)
A solution of azide 29b (37 mg, 0.053 mmol) in MeOH (15 mL) was hydrogenated in the presence of Pd Lindlar. The catalyst was filtered off and the solvent evaporated. The residue was purified by preparative HPLC (20% acetonitrile in H2O with 0.1% TFA to 60% acetonitrile) which gave 7.1 mg (17%) of the title compound as its TFA salt.
MS, Electrospray ionization, eluting with acetonitrile / ammonium acetate buffer, [M+H]4
668.4
Example 30
Figure imgf000077_0001
5 -Ethylamino^-hydroxy^-isopropyl-ό- [3 -(3 -methoxy-propoxy)-4-methyl-benzyloxy] - hexanoic acid [2-methyl-l-(4-methyl-benzylcarbamoyl)-butyl] -amide (30)
A solution of compound 23i (20 mg, 0.032 mmol), acetaldehyde (1.8 μL, 0.032 mmol) and
AcOH (6 μL, 0.10 mmol) in MeOH (500 μL) was treated with NaBH3CN (2.4 mg, 0.038 mmol). The resulting solution was stirred at r.t. for 16 h. The solvent was evaporated under vacuum and the residue was taken into CH2Cl2 and washed with 2 M NaOH. The organic phase was dried (Na2SO4) and concentrated to give a white foam that was purified by preparative HPLC (20% acetonitrile in H2O with 0.1% TFA to 47% acetonitrile) to give 12 mg (48%) of the title compound as its TFA salt.
MS, Electrospray ionization, eluting with acetonitrile / ammonium acetate buffer. [M+H]+
643.8.
Example 31
Figure imgf000077_0002
4-Hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-methyl-benzyloxy"|-5-[(thiazol-4- ylmethyl)-amino"|-hexanoic acid [2-methyl-l-(4-methyl-benzylcarbamoyl)-butyl] -amide (31)
The procedure described in Example 30 was followed but using thiazole-4-carbaldehyde instead of acetaldehyde, which gave the title compound (40% yield).
MS, Electrospray ionization, eluting with acetonitrile / ammonium acetate buffer [M+H]+
713.1.
Example 32
Figure imgf000078_0001
4-Hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-methyl-benzyloxy"|-5-[(thiazol-5- ylmethyl)-amino"|-hexanoic acid [2-methyl-l-(4-methyl-benzylcarbamoyl)-butyl] -amide (32)
The procedure described in Example 30 was followed but using thiazole-5-carbaldehyde instead of acetaldehyde, which gave the title compound (42% yield).
MS, electrospray ionization, eluting with acetonitrile/ammonium acetate buffer, [M+H]+
711.6.
Example 33
Figure imgf000078_0002
4-Hydroxy-2-isopropyl-6-(naphthalen- 1 -ylmethoxy)-5 - [(pyridin-4-ylmethyl)-aminol - hexanoic acid (l-benzylcarbamoyl-2-methyl-butyD-amide (33)
The procedure described in Example 8 was followed but using 4-pyridinecarboxaldehyde instead of acetone, which gave the title compound (24% yield).
MS, electrospray ionization, eluting with acetonitrile/ammonium acetate buffer, [M+H]+
639.5.
Example 34
Figure imgf000078_0003
4-Hydroxy-2-isopropyl-6-(naphthalen- 1 -ylmethoxy)-5 - [(pyridin-2-ylmethyl)-amino] - hexanoic acid (l-benzylcarbamoyl-2-methyl-butyl)-amide (33)
The procedure described in Example 8 was followed but using 4-pyridinecarboxaldehyde instead of acetone, which gave the title compound (19% yield).
MS, electrospray ionization, eluting with acetonitrile/ammonium acetate buffer, [M+H]+
639.5.
Example 35
Figure imgf000079_0001
4-Hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-methyl-benzyloxy]-5-[(pyridin-3- ylmethyl)-amino"|-hexanoic acid [2-methyl-l-(4-methyl-benzylcarbamoyl)-butyl] -amide (35)
The procedure described in Example 30 was followed but using 3-pyridinecarboxaldehyde instead of acetaldehyde, which gave the title compound (45% yield).
MS, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer [M+H]+
705.4.
Example 36
Figure imgf000079_0002
4-Hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-methyl-benzyloxy"|-5-[(thiazol-2- ylmethyl)-amino"|-hexanoic acid [2-methyl-l-(4-methyl-benzylcarbamoyl)-butyl] -amide (36)
The procedure described in Example 30 was followed but using thiazole-2-carbaldehyde instead of acetaldehyde, which gave the title compound (10% yield).
MS, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer, [M+H]+
711.3.
Example 37 Step a
Figure imgf000080_0001
1 -Chloro-2-(3-methoxy-propoxy)-4-methyl-benzene (37a)
Triphenylphosphine (5.25 g, 20 mmol) and azodicarboxylic dipiperidine (5.04, 20 mmol) were added to a solution of 2-chloro-5-methyl-phenol (1.43 g, 10 mmol) and 3-methoxy- propan-1-ol (1 mL, 10 mmol) in CH2Cl2 (100 mL). The reaction mixture was stirred at r.t. 16 h and the evaporated into SiO2 gel. The title compound was purified by flash chromatography on silica gel (Hep:EtOAc 20:1) to give 2.0 g (80%).
Figure imgf000080_0002
4-Bromomethyl- 1 -chloro-2-(3-methoxy-propoxy)-benzene (37b)
N-Bromosuccinimide (284 mg, 1.6 mmol) and benzoyl peroxide (11 mg, 0.034 mmol) were added to a solution of 37a in CCU (6 mL) and the resulting suspension was refluxed for 1 h. The reaction mixture was filtered through SiO2 using Hep: EtOAc 10:1 as eluent. Evaporation of the solvent afforded 304 mg of the title compound (78% yield).
Step c
Figure imgf000080_0003
5- {2-[4-Chloro-3-(3-methoxy-propoxy)-benzyloxyl- 1 -hydroxy-ethyll -3-isopropyl-dihydro- furan-2-one (37c)
The procedure described in Example 1 step h was followed but using 37b instead of benzyl bromide, which gave the title compound (54% yield).
Figure imgf000081_0001
5- { 1 -Azido-2-[4-chloro-3-(3-methoxy-propoxy)-benzyloxyl-ethyl| -3-isopropyl-dihydro- furan-2-one (37d)
Compound 37c was reacted according to the procedure described in Example 1 step i, which afforded the title compound (72%).
Step e
Figure imgf000081_0002
5-Azido-6-[4-chloro-3-(3-methoxy-propoxy)-benzyloxyl-4-hydroxy-2-isopropyl-hexanoic acid [2-methyl-l-(4-methyl-benzylcarbamoyl)-butyl] -amide (37e) The procedure described in example 23 step h was followed but using 37d instead of 23 f, which gave the title compound (74%).
Step f
Figure imgf000081_0003
5-Amino-6-[4-chloro-3-(3-methoxy-propoxy)-benzyloxyl-4-hydroxy-2-isopropyl-hexanoic acid r2-methyl-l-(4-methyl-benzylcarbamoyl)-butvH -amide (37f) Compound 37e was reacted according to the procedure described in Example 23 step i, which afforded the title compound (36%).
MS, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer, [M+H]+
634.3
Example 38 Step a
Figure imgf000082_0001
2-Amino-3-methyl-pentanoic acid 3,4-dichloro-benzylamide (38a)
The procedure described in example 1 step g was followed but using 3,4-dichlorobenzylamine instead of benzylamine, which gave the title compound (76%).
Step b
Figure imgf000082_0002
5-Azido-6-[4-chloro-3-(3-methoxy-propoxy)-benzyloxyl-4-hydroxy-2-isopropyl-hexanoic acid [l-(3,4-dichloro-benzylcarbamoyl)-2-methyl-butyll-amide (38b) The procedure described in example 37 step e was followed but using 38a instead of 37d, which gave the title compound (49%).
Step c
Figure imgf000082_0003
5-Amino-6-[4-chloro-3-(3-methoxy-propoxy)-benzyloxyl-4-hydroxy-2-isopropyl-hexanoic acid ri-(3,4-dichloro-benzylcarbamoyl)-2-methyl-butvH-amide (38c) Compound 38b was reacted according to the procedure described in Example 23 step i, which afforded the title compound (16%).
MS, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer, [M+H]+
688.2.
Example 39 Step a
Figure imgf000083_0001
Benzothiazole-2-carboxylic acid ethyl ester (39a)
A mixture of 2-aminothiophenol (5.0 g, 40 mmol) and diethyl oxalate (10.8 mL, 80 mmol) was refluxed for 4 h. The yellow solution was cooled down to r.t. and the poured into an ice cold solution of cone. HCIiH2OiEtOH (1 :3:1, 100 mL) with vigorous stirring. The crystals that formed were filtered and dried under vacuum to give 4.6 g (56%) of the title compound.
Figure imgf000083_0002
Benzothiazole-2-carbaldehyde (39b)
A solution of 39a in CH2Cl2 (10 mL) was cooled down to -50 0C and a 1.0 M solution of DIBAL-H in hexanes (1.5 mL, 1.5 mmol) was then added slowly dropwise. When the addition was completed the reaction mixture was warmed up to r.t. and carefully quenched with EtOAc and 2 M HCl. The product was extracted into CH2Cl2, dried (Na2SO4) and evaporated to give an orange oil that was purified by flash chromatography on silica gel (Hep:EtOAc 10:1) to give 25 mg (11%).
Ster
Figure imgf000083_0003
5-[(Benzothiazol-2-ylmethyl)-aminol-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4- methyl-benzyloxyl-hexanoic acid [2-methyl- 1 -(4-methyl-benzylcarbamoyl)-butyl]-amide (39c) The procedure described in Example 30 was followed but using 39b instead of acetaldehyde, which gave the title compound (6% yield).
MS, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer, [M+H]+
761.4.
Example 40 Step a
Figure imgf000084_0001
(3-Amino-phenyl)-acetic acid methyl ester (40a)
Thionyl chloride (4.8 mL, 66.16 mmol) was carefully added drop wise to MeOH (100 mL) at 0 0C. To the resulting solution was added a suspension of 3-amino-phenylacetic acid (5.0 g, 33.08 mmol) in MeOH (100 mL) and the reaction mixture was refluxed for 2 h. Then MeOH was distilled off and the residue was partitioned between EtOAc and sat. aq. NaHCO3. The phases were separated and the organic phase was washed with sat. aq. NaHCO3, dried (Na2SO4) and evaporated to give 4.77 (87%) of the title compound.
Figure imgf000084_0002
(3-Methanesulfonylamino-phenyl)-acetic acid methyl ester (40b)
Methanesulfonyl chloride (0.47 mL, 6.07 mmol) was added to a solution of 40a (Ig, 6.06 mmol) and pyridine (1 mL, 12.4 mmol) in CH2Cl2 (6 mL) at 5 0C. The reaction mixture was then stirred at r.t. for 17 h. The reaction mixture was concentrated under vacuum and purified by flash chromatography on silica gel (Hep:EtOAc 2.5:1) to give 1.1 g (75%) of the title compound.
Step c
Figure imgf000084_0003
[3-(Methanesulfonyl-methyl-amino)-phenyll-acetic acid methyl ester (40c)
A suspension of 40b (1.1 g, 4.52 mmol), K2CO3 (6.2 g, 45.2 mmol) and methyl iodide (0.84 mL, 13.56 mmol) in acetonitrile (50 mL) was stirred at r.t. for 17 h. The reaction mixture was then concentrated under vacuum and the residue partitioned between CH2Cl2 and water. The organic phase was dried (Na2SO4) and evaporated to give 1.13 g (100%) of the title compound.
Figure imgf000085_0001
N-Methyl-N- [3 -(2-oxo-ethyl)-phenyll -methanesulfonamide (4Od) A 1.0 M solution of DIBAL-H in hexanes (4.3 mL, 4.3 mmol) was added dropwise to a solution of 40c (1.1 g, 4.28 mmol) in CH2Cl2 (20 mL) at -78 0C. The reaction mixture was carefully quenched with EtOAc and 2 M HCl and the product extracted into CH2Cl2. The combined organic extracts were dried (Na2SO4) and the solvent evaporated to give 0.77 g (79%) of the title compound.
Stet
Figure imgf000085_0002
4-Hydroxy-2-isopropyl-5 - (2- [3 -(methanesulfonyl-methyl-amino)-phenyll -ethylamino I -6- [3 -
(3-methoxy-propoxy)-4-methyl-benzyloxyl-hexanoic acid [2-methyl- 1 -(4-methyl- benzylcarbamoyl)-butyl] -amide (4Oe)
The procedure described in Example 30 was followed but using 4Od instead of acetaldehyde, which gave the title compound (39% yield).
MS, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer, [M+H]+
825.5.
Example 41 Step a
Figure imgf000085_0003
3-Hvdroxy-4-nitro-benzoic acid methyl ester (41a) Thionyl chloride (2.7 mL, 37.0 mmol) was added dropwise carefully to a solution of 3- hydroxy-4-nitro-benzoic acid in MeOH (50 mL) and the resulting suspension was refluxed for 30 min. The resulting solution was cooled down to r.t. and water (50 mL) was added. The precipitated that formed was filtered and dried to give 6.3 g of the title compound (95% yield)
Figure imgf000086_0001
4-nitro-3-(3-ethoxy-propoxy)-benzoic acid methyl ester (41b)
Triphenylphosphine (2.66 g, 10.16 mmol) and azodicarboxylic dipiperidine (2.56, 10.16 mmol) were added to a solution of 46a (1.0 g, 5.08 mmol) and 3-ethoxypropan-l-ol (0.59 mL, 5.08 mmol) in CH2Cl2 (25 mL). The reaction mixture was stirred at r.t. 16 h and then evaporated into SiO2 gel. The residue was purified by flash chromatography on silica gel (Hep:EtOAc 20:1 to 2.5:1) to give title compound 0.70 g (49%).
Step c
Figure imgf000086_0002
4-amino-3-(3-ethoxy-propoxy)-benzoic acid methyl ester (41c)
A solution of 46b (0.7 g, 2.47 mmol) in MeOH (20 mL) was reduced with hydrogen in the presence of 10% Pd/C. The catalyst was filtered off and the solvent evaporated to give the title compound: 0.62 g (100%).
Figure imgf000086_0003
4-chloro-3-(3-ethoxy-propoxy)-benzoic acid methyl ester (4Id)
A solution of 46c (0.62 g, 2.47 mmol) in concentrated aq. HCl (1 mL) was cooled down to 0 0C by adding cracked ice to it. To the resulting mixture was added a solution of sodium nitrite (173 mg, 2.5 mmol) in water (1 mL) keeping the temperature below 5 0C. After the addition was completed the reaction mixture was stirred for 5 min. before adding a solution of CuCl (257 mg, 2.6 mmol) in HCl (1 mL) at 5 0C (gas evolution was observed). The reaction mixture was stirred at r.t. for 2 h and then extracted with EtOAc. The combined extracts were washed with H2O, dried (Na2SO4) and evaporated into SiO2. The residue was purified by flash chromatography on silica gel (Hep:EtOAc 10:1) to give title compound (435 mg, 65%).
Step e
Figure imgf000087_0001
[4-Chloro-3-(3-ethoxy-propoxy)-phenyll-methanol (41 e)
A solution of 46d (435 mg, 1.60 mmol) in heptane (10 mL) was treated with 1.0 M DIBAL-H in heptane (4.5 mL, 4.5 mmol) under N2 at 0 0C. The reaction mixture was stirred for 15 min. and then quenched carefully with 2 M HCl and diluted with EtOAc. The aqueous phase was extracted with EtOAc and the combined organic extracts were dried (Na2SO4) and the solvent evaporated to give the title compound (365 mg, 93%).
Figure imgf000087_0002
4-Bromomethyl- 1 -chloro-2-(3-ethoxy-propoxy)-benzene (4If)
Bromine (0.092 mL, 1.79 mmol) was added carefully dropwise to a solution of triphenylphosphine (469 mg, 1.79 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at r.t. for 5 min. and then 46e (365 mg, 1.49 mmol) was added. The resulting mixture was stirred 2 h and then evaporated into silica gel. The residue was purified by flash chromatography on silica gel (Hep:EtOAc 50:1 to 20:1) to give title compound (297 mg,
65%).
Figure imgf000087_0003
5- {2-|"4-Chloro-3-(2-ethoxy-propoxy)-benzyloxy|- 1 -hydroxy-ethyll -3-isopropyl-dihydro- furan-2-one (4Ig) The procedure described in Example 1 step h was followed but using 46f instead of benzyl bromide, which gave the title compound (57% yield).
Step h
Figure imgf000088_0001
5- { 1 -Azido-2-[4-chloro-3-(2-ethoxy-propoxy)-benzyloxy"|-ethyU -3-isopropyl-dihydro-furan- 2-one (4Ih)
Compound 46f was reacted according to the procedure described in Example 1 step i, which afforded the title compound (84%).
Step i
Figure imgf000088_0002
5-Azido-6-[4-chloro-3-(3-ethoxy-propoxy)-benzyloxyl-4-hydroxy-2-isopropyl-hexanoic acid [2-methyl- 1 -(4-fluoro-benzylcarbamoyl)-butyll-amide (41 i)
The procedure described in example 23 step h was followed but using 43a instead of 23 f, which gave the title compound (9%).
Step i
Figure imgf000089_0001
5-Amino-6-[4-chloro-3-(3-ethoxy-propoxy)-benzyloxyl-4-hydroxy-2-isopropyl-hexanoic acid
[2-methyl- 1 -(4-fluoro-benzylcarbamoyl)-butyll-amide (4 Ij)
Compound 46i was reacted according to the procedure described in Example 23 step i, which afforded the title compound (99%).
MS, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer, [M+H]+
652.3.
Example 42
Figure imgf000089_0002
4-Hydroxy-5-[(lH-indol-2-ylmethyl)-aminol-2-isopropyl-6-[3-(3-methoxy-propoxy)-4- methyl-benzyloxyl-hexanoic acid [2-methyl- l-(4-methyl-benzylcarbamoyl)-butyl] -amide (42)
The procedure described in Example 30 was followed but using lH-Indole-3-carbaldehyde instead of acetaldehyde, which gave the title compound (27% yield).
MS, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer, [M+H]+
743.4.
Example 43 Step a
Figure imgf000089_0003
2-Amino-3-methyl-pentanoic acid 4-fluoro-benzylamide (43a)
The procedure described in example 1 step g was followed but using 4-fluorobenzylamine instead of benzylamine, which gave the title compound (94%). Step b
Figure imgf000090_0001
5-Azido-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-methyl-benzyloxyl-hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyll -amide (43b)
The procedure described in example 23 step h was followed but using 43a instead of 23 g, which gave the title compound (49%).
Ster
Figure imgf000090_0002
5-Amino-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-methyl-benzyloxyl-hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyll -amide (43 c)
The procedure described in example 29 step c was followed but using 43b instead of 29b, which gave the title compound (81%).
MS, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer, [M+H]+
618.3.
Example 44
Figure imgf000090_0003
4-Hydroxy-2-isopropyl-5 - (2- [3 -(methanesulfonyl-methyl-amino)-phenyll -ethylamino I -6- [3 -
(3-methoxy-propoxy)-4-methyl-benzyloxyl-hexanoic acid [ 1 -(4-fluoro-benzylcarbamoyl)-2- methyl-butyl] -amide (44)
The procedure described in Example 40 step e was followed but using 43c instead of 4Od which gave the title compound (14% yield).
MS, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer, [M+H]+
829.6.
Example 45 Step a
Figure imgf000091_0001
3-Isopropyl-5- {2-[3-(3-methoxy-propoxy)-4-methyl-benzyloxyl- 1 -phenylamino-ethyU - dihydro-furan-2-one (45a)
Compound 28a (59mg, 0.12 mmol) in THF (0.5 mL) was reacted with aniline (16.4 μL, 0.18 mmol) in the presence of triethylamine (16.7 μL, 0.12 mmol) at 0 0C for 17 h. Concentrated under vacuum and purified by flash chromatography on silica gel (Hep:EtOAc 10:1 to 2.5:1) to give 29 mg (53%) of title compound.
Figure imgf000091_0002
4-Hydroxy-2-isopropyl-6- [3 -(3 -methoxy-propoxy)-4-methyl-benzyloxy] -5 -phenylamino- hexanoic acid ri-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl"|-amide (45b) Compound 45a was reacted according to the procedure described in Example 43 step b, which afforded the title compound (48%).
MS, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer, [M+H]+
694.
Example 46
Figure imgf000092_0001
4-Hydroxy-2-isopropyl-6-(naphtalen- 1 -ylmethoxy)-5-phenethylamino-hexanoic acid (1 - benzylcarbamoyl-2-methyl-butyT)-amide (46)
The procedure described in example 8 was followed using a mixture of the amine from example 5a (17 mg ), phenylacetaldehyde (4.5 μL) and AcOH (10 μL) in MeOH (500 μL)which was treated with NaBH3CN (3 mg). 2.2 mg (10%) of the TFA salt of the title compound was obtained. LC/MS confirmed the identity of the compound with a M+l ion at 652. The purity as determined by HPLC at 224 nm was 90% using a C3 column eluting with a mixture of 70% acetonitrile and 30% 10 mM ammonium acetate.
Example 47
Figure imgf000092_0002
4-Hydroxy-5 - [( 1 H-indol-3 -ylmethyD-amino] -2-isopropyl-6-(naphthalene- 1 -ylmethoxy)- hexanoic acid (l-benzylcarbamoyl-2-methyl-butyl)-amide (47)
The procedure described in example 46 was followed using indole-3-carboxaldehyde instead of phenylacetaldehyde. Purification on silica gel gave the title compound (1.3 mg, 7%). LC/MS [M+l] 677. Purity as determined by HPLC using a DAD detector was above 95%.
Example 48 Step a
Figure imgf000093_0001
2-Amino-3-methyl-pentanoic acid 4-fluoro-benzylamide (48a)
The procedure described in example 1 step g was followed but using 4-fluorobenzylamine instead of benzylamine, which gave the title compound in a yield of 78%.
Figure imgf000093_0002
{ 1 -Benzyloxymethyl-4-[ 1 -(4-fluoro-benzylcarbamoyl)-2-methyl-butylcarbamoyll-2-hydroxy- 5 -methyl- hexyU-carbamic acid tert-butyl ester (48b)
A mixture of compound 48a (133 mg, 0.56 mmol), example 12h (60 mg, 0.16 mmol), 2- hydroxypyridine (55 mg) and DIPEA (50 μl) was heated at 70 0C for 4 days. The reaction mixture was evaporated and the residue purified on silica gel using hexanes:ethyl acetate 1 : 1 as eluent which gave 63 mg of the title compound.
Figure imgf000093_0003
5-Amino-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid [l-(4-fluoro-benzylcarbamoyl)- 2-methyl-butyl] -amide (48c)
Compound 48b (63 mg, 0.10 mmol) was dissolved in DCM (3 ml) at 0 0C and cold TFA (3 ml) was added. The reaction mixture was stirred at room temperature over nigh and then evaporated which gave 75 mg of a residue. Purification of the residue on prep LC using TFA and acetonitrile as eluent gave 9 mg of the TFA salt of the title compound. LC/MS confirmed the correct structure with a M+l ion at 516.
Example 49 Step a
Figure imgf000094_0001
4-Bromo-3-(3-methoxy-propoxy)-benzoic acid methyl ester (49a)
4-Bromo-3-hydroxy-benzoic acid methyl ester [4.2 g, 18 mmol (prepared according J. Med. Chem. 2005, pp. 1596-1609)] and 3-methoxy-l-propanol (9.5 g, 36.4 mmol) were dissolved in dichloromethane [DCM (200 ml)]. Triphenylphosphine (9.5 g, 36.4 mmol) and 1, 1 '- (azodicarbonyl) dipiperidine (9.2 g, 36.4 mmol) were added and the reaction mixture was stirred at room temperature over night. The reaction mixture was filtered, the solvent evaporated and the afforded residue was purified on several silica gel columns eluted with hexanes/ethyl acetate 9:1 which gave 4.15 g (75%) of the title compound with a purity of 80% according to GC.
Figure imgf000094_0002
3-(3-Methoxy-propoxy)-4-vinyl-benzoic acid methyl ester (49b)
The bromoderivative 49a (455 mg, 1.5 mmol), dichlorobis(triphenylphosphine)-palladium(II)
(105 mg), lithium chloride (190 mg) and 2,6-di-ter£-butyl-4-methylphenol (10 mg) were dissolved in DMF (8 ml). The air was carefully removed and replaced by argon.
Tributyl(vinyl)tin (0.48 ml, 1.65 mmol) was added and the reaction mixture was stirred at +
60 0C over night. Thereafter, ethyl acetate and sat. potassium fluoride were added and the mixture was stirred at room temperature for 1 h. The organic phase was evaporated and the residue purified on 2 silica gel columns eluted with hexanes/ ethyl acetate 9:1 which gave 224 mg (75%) of the title product.
1H-NMR (400MHz, CDCl3): δ 7.62-7.50 (m, 3H), 7.06 (dd, IH), 5.87 (d, IH), 5.37 (d, IH),
4.15 (t, 2H), 3.91 (s, 3H), 3.58 (t, 2H), 3.36 (s, 3H), 2.13-2.07 (m, 2H).
Step c
Figure imgf000094_0003
4-Ethyl-3-(3-methoxy-propoxy)-benzoic acid methyl ester (Example 49c) 3-(3-Methoxy-propoxy)-4-vinyl-benzoic acid methyl ester (0.5 g, 2 mmol) was dissolved in 95% ethanol (25 ml). 10% Pd on carbon (100 mg) was added and the reaction mixture was stirred under hydrogen at atmospheric pressure for 4 h. Filtration and evaporation of solvents gave about 0.5 g of the title product. LC/MS confirmed the correct structure with a M+l of
253.
Figure imgf000095_0001
[4-Ethyl-3-(3-methoxy-propoxy)-phenyll methanol (49d)
4-Ethyl-3-(3-methoxy-propoxy)-benzoic acid methyl ester ( 0.5 g, 2 mmol) was dissolved in DCM (20 ml) and the solution was cooled to 0° C. DIBAL-H [1.0 M solution in DCM (7 ml, 7 mmol)] was added and the reaction mixture was stirred for Ih at room temperature. Sat. ammonium chloride was carefully added followed by 1.5 M HCl and DCM. The organic phase was evaporated and the residue was purified by chromatography on silica gel eluted with hexanes/ ethyl acetate 3:2 which gave the title compound (0.45 g, 100%). 1H-NMR (400MHz, CDCl3): δ 7.12 (d, IH), 6.88-6.85 (m, 2H), 4.64 (s, 2H), 4.07 (t, 2H), 3.58 (t, 2H), 3.35 (s, 3H), 2.63 (q, 2H), 2.10-2.03 (m, 2H), 1.19 (t, 3H).
Step e
Figure imgf000095_0002
4-Bromomethyl- 1 -ethyl-2-(3-methoxy-propoxy)-benzene (49e)
Triphenylphosphine (0.44 g, 1.7 mmol) was dissolved in DCM (10 ml). Bromine (85 μl, 1.7 mmol) was added and the reaction mixture stirred for 5 min and then the obtained solution was added to [4-ethyl-3-(3-methoxy-propoxy)-phenyl] methanol (0.4 g, 1.8 mmol). The reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated and the residue purified on silica gel using hexanes 9 and ethyl acetate 1 as eluent to give 0.45 (87%) of the title compound. LC/MS confirmed the correct structure with characteristic double peaks at 289 (M+l) and 306 (M+NH4).
Step f
Figure imgf000096_0001
5 - (2- [4-Ethyl-3 -(3 -methoxy-propoxy)-benzyloxy] - 1 -hydroxy-ethyl-3 -isopropyl-dihydro- furan-2-one (49f)
The procedure described in example 1 step h was followed using 4-bromomethyl-l-ethyl-2-
(3-methoxy-propoxy)-benzene (0.45 g, 1.6 mmol) instead of benzyl bromide, which gave 0.48 g (78%) of the title compound.
1H-NMR (400MHz, CDCl3): δ 7.11 (d, IH), 6.83-6.81 (m, 2H), 4.50 (d, 2H), 4.44-4.40 (m,
IH), 4.06 (t, 2H), 3.88-3.82 (m, IH), 3.63-3.51 (m, 4H), 3.36 (s, 3H), 2.66-2.58 (m, 3H), 2.46
(d, IH), 2.35-2.28 (m, IH), 2.18-2.03 (m, 4H), 1.19 (t, 3H), 1.02 (d, 3H), 0.93 (d, 3H).
Figure imgf000096_0002
5- { 1 -Azido-2-[4-etyl-3-(3-methoxy-propoxy)-benzyloxyl-ethyU -3-isopropyl-dihydro-furan- 2-one (49g)
The procedure described in example 1 step, i was followed but using 5-{2-[4-ethyl-3-(3- methoxy-propoxy)-benzyloxy]-l-hydroxy-ethyl-3-isopropyl-dihydro-furan-2-one (0.48 g, 1.2 mmol). The title compound was afforded in a yield of 64%. LC/MS confirmed the correct structure with a M+NH4 ion at 537.
Figure imgf000096_0003
5-Azido-6-[4-ethyl-3-(3-methoxy-propoxy)-benzyloxyl-4-hydroxy-2-isopropyl-hexanoic acid [ 1 -(4-fluoro-benzylcarbamoyl)-2-methyl-butyll -amide (49h)
A mixture of the lactone 49g, (68 mg, 0.16 mmol)], the amine 48a (80 mg, 0.34 mmol), 2- hydroxypyridine (100 mg) and DIPEA (100 μl) was heated at 70 0C for 4 days. The reaction mixture was evaporated and the residue purified on silica gel using ethyl acetate/hexanes 1 :2 as eluent which gave 34 mg of the title compound. LC/MS confirmed the structure with a M+l ion at 658.
Step i
Figure imgf000097_0001
5-Amino-6-[4-ethyl-3-(3-methoxy-propoxy)-benzyloxyl-4-hydroxy-2-isopropyl-hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl] -amide (49i)
A solution of example 49h (34 mg, 0.05 mmol) in ethanol (7.5 ml) was hydrogenated at atmospheric pressure in the presence of Lindlars catalyst. The reaction mixture was filtered and the solvent evaporated which gave 30 mg of a crude product that was purified on preparative LC (ammonium acetate and acetonitrile) to give 2.8 mg of the title compound. LC/MS confirmed the structure with a M+l ion at 632.4 and a M+sodium ion at 654.4.
Example 50 Step a
Figure imgf000097_0002
5 - [2-(3 ,5 -Difluoro-benzyloxy)- 1 -hydroxy-ethyl] -3 -isopropyl-dihydro-furan-2-one (5 Oa) The procedure described in example 1, step h was followed but using 3,5-difluorobenzyl bromide (150 μl) instead of benzyl bromide, which gave the title compound (242 mg, 77%). 1H-NMR (400MHz, CDCl3): δ 6.85-6.83 (m, 2H), 6.76-6.72 (m, IH), 4.54 (d, 2H), 4.45-4.41 (m, IH), 3b.89 (broad m, IH), 3.66-3.55 (m, 2H), 2.65-2.60 (m, IH), 2.46 (broad d, IH), 2.37-2.30 (m, IH), 2.19-2.06 (m, 2H), 1.03 (d, 3H), 0.94 (d, 3H).
Figure imgf000098_0001
5-[l-Azido-2-(3,5-difluoro-benzyloxy)-ethyl]-3-isopropyl-dihydro-furan-2-one (50b) The procedure described in example 1, step i was followed but using compound 50a (121 mg, 0.38 mmol). The title compound was afforded in a yield of 24%. LC/MS confirmed the correct structure with a M+NH4 ion at 357.
Figure imgf000098_0002
5-Azido-6-(3,5-difluoro-benzyloxy)-4-hydroxy-2-isopropyl-hexanoic acid [l-(4-fluoro- benzylcarbamoyl)-2-methyl-butyl] -amide (5 Oc)
A mixture of the lactone 50b (about 30 mg, about 0.1 mmol)], the amine 48a (40 mg, 0.17 mmol), 2-hydroxypyridine (50 mg) and DIPEA (50 μl) was heated at 70 0C for 4 days. The reaction mixture was evaporated and the residue was treated with acetonitrile at room temperature for 2 days. Centrifugation and removal of the solvent gave 77 mg of the title product with a HPLC purity at 220 nm of 95.5 %. LC/MS confirmed the structure with a M+l ion at 578.
Figure imgf000098_0003
5-Amino-6-(3,5-difluoro-benzyloxy)-4-hydroxy-2-isopropyl-hexanoic acid [l-(4-fluoro- benzylcarbamoyl)-2-methyl-butyl] -amide (5 Od)
A solution of compound 50c (77 mg) in ethanol (10 ml) was hydrogenated at atmospheric pressure in the presence of Lindlars catalyst. The reaction mixture was filtered and the solvent evaporated which gave a crude product that was purified on silica gel using chloroform/ ethanol 9.5:0.5 as eluent which gave 29 mg of the title compound. LC purity at 220 nm was about 99% using a C3 column eluting with 6 parts acetonitrile and 4 parts 10 mM ammonium acetate buffer. LC/MS confirmed the structure with a M+l ion at 552.3.
Example 51
Figure imgf000099_0001
6-(3,5-Difluoro-benzyloxy)-4-hydroxy-2-isopropyl-5-(3-methyl-benzylamino)-hexanoic acid [ 1 -(4-fluoro-benzylcarbamoyl)-2-methyl-butyll -amide (51)
The procedure described in example 8 was followed using a mixture of the amine from example 50, step d (26 mg, 0.047 mmol), m-tolylaldehyde (6 μL) and AcOH (12 μL) in MeOH (650 μL) which was treated with NaBH3CN (3.5 mg). Purification on preparative HPLC gave 12.1 mg of the TFA salt of the titled compound. The purity as determined by HPLC at 205 nm was about 99% using a C3 column eluting with a mixture of 60% acetonitrile and 40% 10 mM ammonium acetate. LC/MS confirmed the structure with a M+l ion at 656.4.
Example 52 Step a
Figure imgf000099_0002
5-r2-(3,5-Difluoro-benzyloxy)-l-methylamino-ethyll-3-isopropyl-dihvdro-furan-2-one (52a) Compound 50a (121 mg, 0.38 mmol) was treated as described in Example 1, step i, but using 2 M methylamine in THF (1 mmol) instead of sodium azide. The title compound was present in the crude reaction mixture as indicated by LC/MS with a M+l ion at 328. No purification was made and the crude product was used in the next step.
Figure imgf000100_0001
6-(3,5-Difluoro-benzyloxy)-4-hydroxy-2-isopropyl-5-methylamino-hexanoic acid [l-(4- fluoro-benzylcarbamoyl)-2-methyl-butyll-amide (52b)
A mixture of compound 52a, compound 48a (45 mg, 0.27 mmol), 2-hydroxypyridine (50 mg) and DIPEA (50 μl) was heated at 70 0C for 4 days. The reaction mixture was dissolved in ethyl acetate and washed with brine. Evaporation of the solvent gave a crude product that was purified on a C8 column eluting with 60% acetonitrile and 40% 10 mM ammonium acetate to give 1.6 mg of the title product. HPLC purity at 205 nm on a C3 column eluting with 60% acetonitrile and 40% 10 mM ammonium acetate was about 95%. LC/MS confirmed the structure with a M+l ion at 566.3.
Example 53 Step a
Figure imgf000100_0002
2-Amino-3-methyl-pentanoic acid 4-cyano-benzylamide (53a)
The procedure described in example 1 step g was followed but using 4-cyanobenzylamine instead of benzylamine which gave the title compound (43%).
Figure imgf000101_0001
5-Azido-6-[4-ethyl-3-(3-methoxy-propoxy)-benzyloxyl-4-hydroxy-2-isopropyl-hexanoic acid [ 1 -(4-cyano-benzylcarbamoyl)-2-methyl-butyll-amide (53b)
A mixture the lactone 49g (15 mg, 0.036 mmol)], the amine 53a (40 mg, 0.16 mmol), 2- hydroxypyridine (50 mg) and DIPEA (50 μl) was heated at 70 0C for 4 days. The reaction mixture was evaporated and the residue purified by preparative LC/MS to afford 3 mg of the title compound. LC/MS confirmed the structure with a M+l ion at 665.
Ster
Figure imgf000101_0002
5-Amino-6-[4-ethyl-3-(3-methoxy-propoxy)-benzyloxyl-4-hydroxy-2-isopropyl-hexanoic acid [l-(4-cyano-benzylcarbamoyl)-2-methyl-butyl"|-amide (53c) A solution of example 53b (3 mg) in methanol (5 ml) was hydrogenated at atmospheric pressure in an H-Cube instrument using Lindlars catalyst as the catalyst. The reaction mixture was evaporated and 3 mg of the title product was obtained with a LC purity at 220 nm of 94%. LC/MS confirmed the structure with a M+l ion at 639.
Example 54 Step a
Figure imgf000101_0003
2-Amino-3-methyl-pentanoic acid (2-morpholin-4-ethyl)-amide (54a)
The procedure described in example 1 step g was followed but using 4-(2-aminoethyl)- morpholine instead of benzylamine, which gave the title compound (65%).
Figure imgf000102_0001
5-Azido-6-[4-ethyl-3-(3-methoxy-propoxy)-benzyloxyl-4-hydroxy-2-isopropyl-hexanoic acid [2-methyl- 1 -(2-morpholin-4-yl-ethylcarbamoy 1 -butyl]-amide (54b)
A mixture of the lactone 49g (57 mg, 0.136 mmol)], the amine 54a (100 mg, 0.4 mmol), 2- hydroxypyridine (100 mg) and DIPEA (100 μl) was heated at 70 0C for 1 week. The reaction mixture was evaporated and the residue purified by preparative LC/MS to afford the title compound. LC/MS confirmed the structure with a M+l ion at 663.
Ster
Figure imgf000102_0002
5-Amino-6-[4-ethyl-3-(3-methoxy-propoxy)-benzyloxyl-4-hydroxy-2-isopropyl-hexanoic acid [2-methyl- 1 -(2-morpholin-4-yl-ethylcarbamoy 1 -butyl]-amide (54c) A solution of example 54b (about 3 mg) in methanol (5 ml) was hydrogenated at atmospheric pressure in an H-Cube instrument using Lindlars catalyst as the catalyst. The reaction mixture was evaporated and 2.9 mg of crude material was obtained. Final purification on preparative LC/MS afforded 1.3 mg of the title product. LC/MS confirmed the structure with a M+l ion at 637.
Example 55 Step a
Figure imgf000102_0003
2-Amino-3-methyl-pentanoic acid 4-cyano-benzylamide (55a)
The procedure described in example 1 step g was followed but using 4-cyanobenzylamine instead of benzylamine, which gave the title compound (43%).
Figure imgf000103_0001
5-Azido-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-methyl-benzyl oxyl-hexanoic acid [l-(4-cyano-benzylcarbamoyl)-2-methyl-butyll-amide (55b) The procedure described in example 23 step h was followed but using the amine 55a instead of 23g, which gave the title compound (20%).
Figure imgf000103_0002
5 - Amino-4-hydroxy-2-isopropyl-6- [3 -(3 -methoxy-propoxy)-4-methyl-benzyl oxyl-hexanoic acid [l-(4-cyano-benzylcarbamoyl)-2-methyl-butyll-amide (55c)
A solution of azide 55b (13 mg, 0.02 mmol) in MeOH (15 mL) was hydrogenated in the presence of Pd Lindlar which gave the title compound (13 mg, 94%).
MS [M+H]+ 625.3, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer.
Example 56 Step a
Figure imgf000103_0003
2-Amino-3-methyl-pentanoic acid 4-chloro-benzylamide (56a)
The procedure described in example 1 step g was followed but using 4-chlorobenzylamine instead of benzylamine, which gave the title compound (76%).
Figure imgf000104_0001
5-Azido-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-methyl-benzyl oxyl-hexanoic acid [l-(4-chloro-benzylcarbamoyl)-2-methyl-butyll-amide (56b) The procedure described in example 23 step h was followed but using 56a instead of 23g, which gave the title compound (30%).
Figure imgf000104_0002
5 - Amino-4-hydroxy-2-isopropyl-6- [3 -(3 -methoxy-propoxy)-4-methyl-benzyl oxyl-hexanoic acid [l-(4-chloro-benzylcarbamoyl)-2-methyl-butyll-amide (56c)
A solution of azide 56b (17 mg, 0.025 mmol) in MeOH:EtOAc (10:10 mL) was hydrogenated in the presence of Pd Lindlar which gave 16 mg (99%) of the title compound.
MS [M+H]+ 634.3, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer.
Example 57
Figure imgf000104_0003
5-Azido-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-methyl-benzyl oxyl-hexanoic acid ri-(4-chloro-benzylcarbamoyl)-2-methyl-butvH-amide (57) The procedure described in example 8 was followed but using 3-(lH-Imidazol-4-yl)- propionaldehyde instead of acetone, which gave the title compound (37%).
MS [M+H]+ 722.3, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer.
Example 58 Step a
Figure imgf000105_0001
5-Azido-6-[4'-fluoro-2-(3-methoxy-propoxy)-biphenyl-4-ylmethoxyl-4-hydroxy-2-isopropyl- hexanoic acid [l-(4-chloro-benzylcarbamoyl)-2-methyl-butyl"|-amide (58a) The lactone 64b was opened by the amine 56a according to the procedure described in Example 61 step g, which gave the title compound (30%).
Figure imgf000105_0002
5-Amino-6-[4'-fluoro-2-(3-methoxy-propoxy)-biphenyl-4-ylmethoxyl-4-hydroxy-2-isopropyl- hexanoic acid [l-(4-chloro-benzylcarbamoyl)-2-methyl-butyll-amide (58b)
A solution of the azide 58a (53 mg, 0.072 mmol) in MeOH (30 mL) was hydrogenated in the presence of Pd Lindlar which gave 42 mg (82%) of the title compound.
MS [M+H]+ 714.3, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer.
Example 59 Step a
Figure imgf000106_0001
5-Azido-6-[4'-fluoro-2-(3-methoxy-propoxy)-biphenyl-4-ylmethoxyl-4-hydroxy-2-isopropyl- hexanoic acid [l-(4-cyano-benzylcarbamoyl)-2-methyl-butyll-amide (59a) The lactone 64b was opened by the amine 55a according to the procedure described in procedure described in Example 61 step g, which gave the title compound (18%).
Figure imgf000106_0002
5-Amino-6-[4'-fluoro-2-(3-methoxy-propoxy)-biphenyl-4-ylmethoxyl-4-hydroxy-2-isopropyl- hexanoic acid [l-(4-cyano-benzylcarbamoyl)-2-methyl-butyl"|-amide (59b)
A solution of azide 59a (13 mg, 0.018 mmol) in 10% CH2Cl2 in MeOH (50 mL) was hydrogenated in the presence of Pd Lindlar which gave 20 mg (100%) of the title compound.
MS [M+H]+ 705.4, electrospray ionization, eluting with acetonitrile / ammonium acetate buffer.
Example 60 Step a
Figure imgf000106_0003
The procedure described in Example 1, step e was followed but using ethyl iodide instead of iodopropane, whereafter the benzyl groups were removed as described in Example 1, step f which gave the title compound. 1H-NMR (400MHz, DMSO): δ 5.14 (d, IH), 4.70 (t, IH), 4.51-4.49 (m, IH), 3.63-3.65 (m, IH), 3.33-3.38 (m, 2H), 2.58.2.59 (m, IH), 2.35-2.29 (m, IH), 1.86-1.80 (m, IH), 1.67-1.65 (m, IH), 1.39-1.37 (m, IH), 0.92-0.88 (t, 3H).
Step b
Figure imgf000107_0001
5- { 1 -Hydroxy-2-[3-(3-methoxy-propoxy)-4-methyl-benzyloxy"|-ethyl| -3-ethyl-dihydro-furan- 2-one (60b)
The procedure described in Example 1 step h was followed but using the bromide 23 d instead of benzyl bromide, whereafter the procedure described in Example 1 step i was followed, which gave the title compound (35%).
step c
Figure imgf000107_0002
5 - Amino-2-ethyl-4-hydroxy-6- [3 -(3 -methoxy-propoxy)-4-methyl-benzyloxy] -hexanoic acid
[ 1 -(4-fluoro-benzylcarbamoyl)-2-methyl-butyl] -amide (60c)
The lactone 60b was opened with the amine 48a according to the procedure described in
Example 49 step h, whereafter the azide function was reduced according to the procedure described in Example 49 step i, which gave the title compound (63%)
MS [M+H]+ 604.1.
Example 61 Step a
Figure imgf000108_0001
4-Fluoro-3-hydroxy-benzoic acid methyl ester (61a)
4-Fluoro-3-hydroxybenzoic acid (0.90 g, 5.77 mmol) was dissolved in 9 rnL of MeOH and the mixture was cooled to 0 0C and stirred. Thionyl chloride (0.45 mL, 6.23 mmol) was carefully added drop wise, after which the mixture was heated to reflux for 30 min and then cooled to room temperature. The solvent volume was reduced to approx 4 mL by rotary evaporation, and the residue was cooled on ice. 15 mL of water was added, and the mixture was allowed to stand for 15 min with ice cooling. A white precipitate was formed which was filtered off, washed with cold water (10 mL) and air dried. The product was dissolved in toluene (20 mL) which was evaporated in vacuo to yield 0.73 g of the title compound (74%). LC/MS [M-H]" 169.
Step b
Figure imgf000108_0002
4-Fluoro-3-(3-methoxy-propoxy)-benzoic acid methyl ester (61b) The procedure described in Example 49 step a was followed using 4-fluoro-3-hydroxy- benzoic acid methyl ester (0.69 g, 4.06 mmol) instead of 4-bromo-3-hydroxy-benzoic acid methyl ester, which gave the title compound (0.76 g, 77%) after silica gel column chromatography (gradient elution with hexanes/ethyl acetate 20:1 - 6:1).
Step c
Figure imgf000108_0003
[4-Fluoro-3-(3-methoxy-propoxy)-phenyl]-methanol (61 c)
The methyl ester 61b (0.73 g, 3.01 mmol) was dissolved in heptane (10 mL) and the solution was cooled to 0 0C and stirred. DIBAL-H (9.0 mL of a 1.0 M solution in hexane, 9.0 mmol) was added dropwise. The reaction was quenched after 30 min by careful dropwise addition of 3 M HCl (10 niL). The mixture was diluted with Et2O (40 mL) and 1 M HCl (20 niL) and the layers were separated. The aqueous phase was extracted with Et2O (40 mL) and the combined organic phases were washed with 1 M HCl (30 mL) and brine (30 mL), dried (MgSO4), filtered and evaporated to yield the title compound (0.50 g, 78%).
Step d
Figure imgf000109_0001
4-Bromomethyl- 1 -fluoro-2-(3-methoxy-propoxy)-benzene (61 d)
The benzyl alcohol 61c (0.50 g, 2.33 mmol) and triphenylphosphine (0.64 g, 2.45 mmol) was dissolved in DCM (7 mL) and the solution was stirred and cooled to 0 0C on an ice bath. A solution of tetrabromo methane (0.85 g, 2.57 mmol) in DCM (7 mL) was added dropwise after which the cooling bath was removed and stirring was continued for 2 h. Additional triphenylphosphine (64 mg) was added and stirring was continued for 2 h. 1.5 g of SiO2 was added and the solvent was evaporated. The product was purified by column chromatography (gradient elution with hexanes/ethyl acetate 50:1 - 20:1) which gave the title compound (0.54 g, 84%).
Step e
Figure imgf000109_0002
5- {2-[4-Fluoro-3-(3-methoxy-propoxy)-benzyloxy]- 1 -hydroxy-ethyl} -3-isopropyl-dihydro- furan-2-one (6Ie)
The procedure described in Example 1 step h was followed but using 4-bromomethyl-l- fluoro-2-(3-methoxy-propoxy)-benzene (0.50 g, 1.80 mmol) instead of benzyl bromide, which gave 0.60 g (96%) of the title compound after column chromatography (elution with hexanes/ethyl acetate 10:1 - 2:1 with 1% MeOH throughout).
LC/MS [M+H]+ 385, [M+Na]+ 407.
Step f
Figure imgf000110_0001
5- { 1 -Azido-2-[4-fluoro-3-(3-methoxy-propoxy)-benzyloxy]-ethyl} -3-isopropyl-dihydro- furan-2-one (6If)
The alcohol 61e (0.59 g, 1.53 mmol) was reacted according to the procedure described in Example 1 step i, which gave the title compound (0.47 g, 73%).
Step g
Figure imgf000110_0002
5-Azido-6-[4-fluoro-3-(3-methoxy-propoxy)-benzyloxy]-4-hydroxy-2-isopropyl-hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl] -amide (6Ig)
The lactone 6If (102 mg, 0.249 mmol), amine 48a (238 mg, 1.00 mmol), 2-hydroxypyridine (95 mg, 1.00 mmol) and DIPEA (48 μL, 0.275 mmol) were stirred and heated to 70 0C for 3 days. The mixture was cooled to room temperature and 3 mL of t-BuOMe was added to yield a brown suspension which was heated to 50 0C and sonicated for 5 min, then centrifuged at 3500 rpm at 7 0C for 12 min after which the supernatant was siphoned off. This process was repeated thrice to yield the title compound after drying in vacuo (55 mg, 34%).
Step h
Figure imgf000110_0003
5 - Amino-6- [4-fluoro-3 -(3 -methoxy-propoxy)-benzyloxy] -4-hydroxy-2-isopropyl-hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl] -amide (6Ih) A solution of azide 61g (55 mg, 0,085 mmol) in MeOH (35 mL) was hydrogenated at atmospheric pressure in the presence of Lindlars catalyst. The mixture was filtered and the solvent evaporated, and the residue redissolved in 1,4-dioxane (3 mL) and freeze dried to yield 52 mg (98%) of the title compound. LC/MS [M+H]+ 623.3, [M+Na]+ 644.2. Purity according to HPLC was >95%.
Example 62 Step a
Figure imgf000111_0001
[4-Bromo-3-(3-methoxy-propoxy)-phenyl]-methanol (62a)
The procedure described in Example 61 step c was followed using methyl ester 49a (3.00 g,
9.90 mmol) instead of 61b to yield the title compound (2.60 g, 95%).
Step b
Figure imgf000111_0002
1 -Bromo-4-bromomethyl-2-(3-methoxy-propoxy)-benzene (62b)
The procedure described in Example 61 step d was followed using benzyl alcohol 62a (2.60 g, 9.45 mmol) instead of 61c to yield the title compound (2.62 g, 82%) after purification by column chromatography (gradient elution with hexanes/ethyl acetate 30:1 - 1 :1).
Step c
Figure imgf000111_0003
5- {2-[4-Bromo-3-(3-methoxy-propoxy)-benzyloxy]- 1 -hydroxy-ethyl} -3-isopropyl-dihydro- furan-2-one (62c) The procedure described in Example 1 step h was followed using 62b (2.62 g, 7.75 mmol) instead of benzyl bromide, which gave 3.21 g (85%) of the title compound after column chromatography (gradient elution with hexanes/ethyl acetate 7:1 - 1 :1 with 1% MeOH throughout).
LC/MS [M+H]+ 445/447 , [M+Na]+ 467/469.
Step d
Figure imgf000112_0001
5- { 1 -Azido-2-[4-bromo-3-(3-methoxy-propoxy)-benzyloxy]-ethyl} -3-isopropyl-dihydro- furan-2-one (62d)
Alcohol 62c (153 mg, 0.336 mmol) was reacted according to the procedure described in Example 1 step i which gave the title compound (121 mg, 77%).
Step e
Figure imgf000112_0002
5-Azido-6-[4-bromo-3-(3-methoxy-propoxy)-benzyloxy]-4-hydroxy-2-isopropyl-hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl] -amide (62e)
The procedure described in Example 61 step g was followed using lactone 62d (90 mg, 0.19 mmol) instead of 6 If. The product was purified by sonication, centrifugation and siphoning off the supernatant as described in Example 1 step g using 1 mL of MeOH, t-BuOMe, MeCN, and t-Bu OMe in sequence which gave 36 mg (27%) of the title compound.
Step f
Figure imgf000113_0001
5-Amino-6-[4-bromo-3-(3-methoxy-propoxy)-benzyloxy]-4-hydroxy-2-isopropyl-hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl] -amide (62f)
Azide 62e (30 mg, 0.042 mmol) was dissolved in MeOH (10 niL) and THF (ImL). Water (1 drop) was added, followed by triphenylphosphine (22 mg, 0.085 mmol). The reaction was stirred for 3 days, and 44 mg of triphenylphosphine was added in portions during this time.
The product was purified by column chromatography (gradient elution from 100% DCM to
10:1 DCM:5% NH3/MeOH). Further purification by preparative HPLC (40% MeCN in H2O with 10 mM NH4Ac to 80% MeCN) gave the title compound after freeze drying (6.1 mg,
21%).
LC/MS [M+H]+ 682.3/684.2. Purity according to HPLC was >99%.
Example 63 Step a
Figure imgf000113_0002
4-[2-Hydroxy-2-(4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-ethoxymethyl]-2-(3-methoxy- propoxy)-benzonitrile (63 a)
Bromide 62c (1.00 g, 2.25 mmol) was dissolved in DMF (4 mL) in a screw-cap tube and degassed by 5 vacuum/N2 cycles. Tetrakis(triphenylphoshine)palladium(0) (Pd(PPh)4), (0.13 g, 0.11 mmol), and zinc cyanide (0.17 g, 1.48 mmol) were added while flushing the reaction vessel with N2. The tube was sealed and the reaction was heated to 85 0C. Since product formation was slow, the temperature was raised to 110 ° after 5 h and 0.07 g zinc cyanide and 0.06 g Pd(PPh)4 were added. The reaction was stirred at 110 0C for 20 h, after which the temperature was increased to 160 0C and 0.06 g Pd(PPh)4 was added and stirring was continued for 24 h. The reaction was allowed to cool to room temperature, and Et2O (25 ml) and water (25 mL) were added and the mixture was filtered through celite, which was further washed with ethyl acetate (50 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (3 X 15 mL), and the combined organic phases were washed with 1 M HCl (40 mL) and brine (40 mL), dried (MgSO4), filtered and concentrated in vacuo. The product was purified by column chromatography (gradient elution with hexanes/ethyl acetate 4:1 - 1 :1 with 1% MeOH throughout) which gave 0.57 g (65%) of the title compound.
Step b
Figure imgf000114_0001
4-[2-Azido-2-(4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-ethoxymethyl]-2-(3-methoxy- propoxy)-benzonitrile (63b)
Alcohol 63a (130 mg, 0.332 mmol) was reacted according to the procedure described in Example 1 step i, which gave the title compound (163 mg) which was used in the next step without further purification.
Step c
Figure imgf000114_0002
5-Azido-6-[4-cyano-3-(3-methoxy-propoxy)-benzyloxy]-4-hydroxy-2-isopropyl-hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl] -amide (63 c)
The procedure described in Example 61 step g was followed using crude lactone 63b (109 mg, approx 0.26 mmol) instead of 6 If. The product was purified by sonication, centrifugation and siphoning off the supernatant as described in Example 1 step g using 1 mL of MeOH, t- BuOMe, MeCN, and t-Bu OMe in sequence which gave 64 mg (38%) of the title compound.
Step d
Figure imgf000115_0001
5-Amino-6-[4-cyano-3-(3-methoxy-propoxy)-benzyloxy]-4-hydroxy-2-isopropyl-hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl] -amide (63 d)
The procedure described in Example 61 step h was followed using azide 63c (60 mg, 0.091 mmol) instead of 61g which gave the title compound (55 mg, 98%).
LC/MS [M+H]+ 629.3. Purity according to HPLC was 96%.
Example 64 Step a
Figure imgf000115_0002
5- {2-[4'-Fluoro-2-(3-methoxy-propoxy)-biphenyl-4-ylmethoxy]- 1 -hydroxy-ethyl} -3- isopropyl-dihydro-furan-2-one (64a)
A microwave reactor tube was charged with bromide 62c (0.20 g, 0.45 mmol), 4- fluorobenzeneboronic acid (0.75 g, 0.54 mmol), l,l '-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex ((dppfhPdCk) (18 mg, 0.022 mmol), 3.8 mL of a 7:3:2 mixture of dimethoxyethane, ethanol and water, and 0.33 mL of a 2M aqueous solution Of KsPO4. The mixture was degassed by 5 vacuum/N2 cycles, and subsequently heated to 140 0C for 10 min in a microwave reactor. The reaction mixture was diluted with saturated aqueous NaHCOs solution (10 mL) and Et2O (10 mL) and the phases were separated. The aqueous layer was extracted with Et2O (2 X 10 mL), and the combined organic phases were washed with brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo. The product was purified by column chromatography (gradient elution with hexanes/ethyl acetate 4:1 - 1 :1 with 1% MeOH throughout) which gave the title compound (164 mg, 80%).
Step b
Figure imgf000116_0001
5- { 1 -Azido-2-[4'-fluoro-2-(3-methoxy-propoxy)-biphenyl-4-ylmethoxy]-ethyl} -3-isopropyl- dihydro-furan-2-one (64b)
Alcohol 64a (164 mg, 0.356 mmol) was reacted according to the procedure described in Example 1 step i, which gave the title compound (166 mg, 96%).
Step c
Figure imgf000116_0002
5-Azido-6-[4'-fluoro-2-(3-methoxy-propoxy)-biphenyl-4-ylmethoxy]-4-hydroxy-2-isopropyl- hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl]-amide (64c) The procedure described in Example 61 step g was followed using lactone 64b (93 mg, approx 0.20 mmol) instead of 6 If. The product was purified by sonication, centrifugation and siphoning off the supernatant as described in Example 61 step g using 1 mL of MeOH, t- BuOMe, and t-BuOMe in sequence, which gave 34 mg (24%) of the title compound.
Step d
Figure imgf000116_0003
5-Amino-6-[4'-fluoro-2-(3-methoxy-propoxy)-biphenyl-4-ylmethoxy]-4-hydroxy-2-isopropyl- hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl]-amide (64d) The procedure described in Example 61 step h was followed using azide 64c (34 mg, 0.047 mmol) instead of 61g which gave the title compound (32 mg, 97%). LC/MS [M+H]+ 698.3. Purity according to HPLC was 97%.
Example 65 Step a
Figure imgf000117_0001
5- {2-[4-Furan-3-yl-3-(3-methoxy-propoxy)-benzyloxy]- 1 -hydroxy-ethyl} -3-isopropyl- dihydro-furan-2-one (65a)
The procedure described in Example 64 step a was followed using 3-furylboronic acid instead of 4-fluorobenzeneboronic acid with a heating time of 5 min. The product was purified by column chromatography (gradient elution with hexanes/ethyl acetate 5:1 - 1 :1 with 1% MeOH throughout) which gave the title compound (138 mg, 71%).
Step b
Figure imgf000117_0002
5- { 1 -Azido-2-[4-furan-3-yl-3-(3-methoxy-propoxy)-benzyloxy]-ethyl} -3-isopropyl-dihydro- furan-2-one (65b)
Alcohol 65a (138 mg, 0.319 mmol) was reacted according to the procedure described in Example 1 step i, which gave the title compound along with some byproducts. Purification by preparative HPLC (60% MeCN in H2O with 10 mM NH4Ac to 75% MeCN) gave the title compound after freeze drying (33 mg, 23%).
Step c
Figure imgf000118_0001
5 - Azido-6- [4-furan-3 -yl-3 -(3 -methoxy-propoxy)-benzyloxy] ^-hydroxy^-isopropyl- hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl] -amide (65 c) The procedure described in Example 61 step g was followed using lactone 65b (33 mg, approx 0.072 mmol) instead of 61f. The product was purified by diluting the reaction mixture with DCM (10 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was evaporated and redispersed in t-BuOMe (1 ml), sonicated, centrifuged, and the supernatant siphoned off as described in Example 61 step g which gave 18 mg (34%) of the title compound with some minor impurities. The product was used as such without further purification in the next step.
Step d
Figure imgf000118_0002
5 - Amino-6- [4-furan-3 -yl-3 -(3 -methoxy-propoxy)-benzyloxy] -4-hydroxy-2-isopropyl- hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl]-amide (65d)
The procedure described in Example 61 step h was followed using crude azide 65c (18 mg, approx 0.026 mmol) instead of 61g which gave the title compound (9 mg, 52%) after purification by preparative HPLC (40% MeCN in H2O with 10 mM NH4Ac to 75% MeCN) and freeze drying.
LC/MS [M+H]+ 670.5. Purity as determined by HPLC was 99%.
Example 66 Step a
Figure imgf000119_0001
5- { 1 -Hydroxy-2-[3-(3-methoxy-propoxy)-4-pyridin-4-yl-benzyloxy]-ethyl} -3-isopropyl- dihydro-furan-2-one (66a)
The procedure described in Example 64 step a was followed using 4-pyridineboronic acid instead of 4-fluorobenzeneboronic acid. The reaction was irradiated for 5 min after which 20 mg of 4-pyridineboronic acid and 10 mg of (dppfhPdC^ was added, and the reaction was irradiated for 5 more minutes. The product was purified by column chromatography (gradient elution with hexanes/ethyl acetate 5:1 - pure ethyl acetate with 1% MeOH throughout) which gave the title compound (96 mg, 48%).
Step b
Figure imgf000119_0002
5- { 1 -Azido-2-[3-(3-methoxy-propoxy)-4-pyridin-4-yl-benzyloxy]-ethyl} -3-isopropyl- dihydro-furan-2-one (66b)
Alcohol 66a (96 mg, 0.216 mmol) was reacted according to the procedure described in Example 1 step i, which gave the title compound along with some byproducts. Purification by preparative HPLC (50% MeCN in H2O with 10 mM NH4Ac to 65% MeCN) followed by freeze drying gave the title compound (16 mg, 16%).
Step c
Figure imgf000119_0003
5-Azido-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-pyridin-4-yl-benzyloxy]- hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl]-amide (66c) The procedure described in Example 61 step g was followed using the lactone 66b (16 mg, 0.072 mmol) instead of 6 If. The product was purified by diluting the reaction mixture with DCM (10 mL) and saturated aqueous NaHCOs solution (10 mL). The phases were separated and the organic phase was evaporated and redispersed in t-BuOMe (1 ml), sonicated, centrifuged, and the supernatant siphoned off (process repeated 4 times) as described in Example 61 step g, which gave 15 mg (62%) of the title compound.
Step d
Figure imgf000120_0001
5 - Amino-4-hydroxy-2-isopropyl-6- [3 -(3 -methoxy-propoxy)-4-pyridin-4-yl-benzyloxy] - hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl]-amide (66d)
The procedure described in Example 61 step h was followed using azide 66c (15 mg, approx
0.021 mmol) instead of 61g which gave the title compound (11 mg, 70%) after purification by preparative HPLC (40% MeCN in H2O with 10 mM NH4Ac to 65% MeCN) and freeze drying.
LC/MS [M+H]+ 681.4. Purity as determined by HPLC was 99%.
Example 67 Step a
Figure imgf000120_0002
5- { 1 -Hydro xy-2-[3-(3-methoxy-propoxy)-4-thiophen-2-yl-benzyloxy]-ethyl} -3-isopropyl- dihydro-furan-2-one (67a)
The procedure described in Example 64 step a was followed using 2-thiopheneboronic acid instead of 4-fluorobenzeneboronic acid. The reaction was irradiated for 5 min after which 20 mg of 2-thiopheneboronic acid and 10 mg of (dppf^PdC^ was added, and the reaction was irradiated for 5 more minutes. The product was purified by column chromatography (gradient elution with hexanes/ethyl acetate 5:1 - pure ethyl acetate with 1% MeOH throughout) which gave the title compound (116 mg, 57%).
Step b
Figure imgf000121_0001
5- { 1 -Azido-2-[3-(3-methoxy-propoxy)-4-thiophen-2-yl-benzyloxy]-ethyl} -3-isopropyl- dihydro-furan-2-one (67b)
The alcohol 67a (116 mg, 0.259 mmol) was reacted according to the procedure described in Example 1 step i, which gave the title compound (96 mg, 78%)
Step c
Figure imgf000121_0002
5-Azido-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-thiophen-2-yl-benzyloxy]- hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl]-amide (67c) The procedure described in Example 61 step g was followed using lactone 67b (96 mg, 0.020 mmol) instead of 6 If. The product was purified by diluting the reaction mixture with DCM (10 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was evaporated and redispersed in t-BuOMe (1 ml), sonicated, centrifuged, and the supernatant siphoned off three times as described in Example 61 step g which gave 40 mg (28%) of the title compound with some minor impurities, the product was used as such without further purification in the next step.
Step d
Figure imgf000122_0001
5-Amino-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-thiophen-2-yl-benzyloxy]- hexanoic acid [l-(4-fluoro-benzylcarbamoyl)-2-methyl-butyl]-amide (67d)
The procedure described in Example 61 step h was followed using crude azide 67c (40 mg, approx 0.056 mmol) instead of 6 Ig, which gave the title compound (0.66 mg, 1.7%) after purification by preparative HPLC (55% MeCN in H2O with 10 mM NH4Ac to 70% MeCN) and freeze drying.
LC/MS [M+H]+ 686.3. Purity as determined by HPLC was 99%.
Biological Examples
To evaluate the enzymatic inhibition of renin exhibited by the compounds of the invention, an assay using Fluorescence Resonance Energy Transfer (FRET) to generate a spectroscopic response to peptidase cleavage, was used. The activity was measured by a continuous detection of increased fluorescence intensity exhibited by the clevage product (peptide- EVANS). The enzyme used in the assay was recombinant human renin (supplied by Proteos), the substrate consisted of a peptide which in one end is linked to a fluorophore, 5- (aminoethyl)aminonaphtalene sulphonate (EDANS), and in the other end to a non-fluorescent chromophore, 4'-dimethylaminoazobenzene (Dabcyl), typically Arg-Glu(ED ANS)-Ile-His- Pro-Phe-His-Leu-Val-Ile-His-Thr-Lys(DABCYL)-Arg (Sigma- Aldrich). The cleavage site by human renin is the peptide bond between Leu and VaI. The compounds were tested at a range of concentrations whereas the enzyme and substrate concentrations were fixed. The assay used employs the enzyme at a concentration of 6.25nM in an assay buffer consisting of of 0.1 mM Tris-HCl, 0.05 M NaCl, 0.5 mM EDTA, 0.05% CHAPS at pH=7.4. The substrate was prepared at a 20 μM stock solution in DMSO. To each well of a 96-well polypropylene plate was added the enzyme containing assay buffer (90.0 μl) and inhibitor of different concentrations (1 μl). To contrail wells were added DMSO (1 μl) instead of inhibitor. The renin enzyme was preactivated by incubation at 37 0C for 20 min whereafter the reactions were started by addition of substrate, 10 μl/well, thus giving a total volume of 100 μl/well and a substrate concentration of 2 μM. The assay was performed during 20 min at 37 0C. The total concentration of DMSO was not above 1 %. Product fluorescence (emission filter 340 nM, excitation filter 500 nM) was monitored with a Thermo Labsystems Fluoroskan Ascent plate reader. The Ki was determined by Prism Software. Activity of the inhibitors was determined by measuring the fluorescence at λeX 340nm and λeπ 500nm. Percent inhibition is calculated as follows: % Inhibition is equal to the (Fluorescence^ inhibitor - FhiorQscmcQbackground); divided by the (Fluorescence mmus inhibitor - FluorescenceδΩC£gro»«rf);
For example, Table 1 shows the Ki- value expressed in nM for a representative selection of compounds according to the invention when tested in an renin enzyme assay such as the one described above. Category A indicates < 50 nM inhibition, category B indicates 51 - 200 nM inhibition and category C indicates > 200 nM:
Figure imgf000123_0001
Figure imgf000124_0001
Selectivity for/against other related enzymes, such as cathepsin D or BACE is determined with the corresponding FRET assays for the respective recombinant enzyme, which are commercially available and extensively described in the literature.
All references referred to in this application, including patent and patent applications, are incorporated herein by reference to the fullest extent possible.
Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.
The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims:

Claims

Claims
1. A compound according to formula I
[ft
Figure imgf000125_0001
wherein
Q is aryl or heterocyclyl;
Z is O, S, NRa or S(=O)p; n is 0, 1 , 2 or 3; m is 0, 1 or 2; p is independently 1 or 2;
Ra is H or C|-C4alkyl;
R1 is hydrogen, C|-C6alk> l, Co-C3alkanediylC3-C7cycloalkyl or Co-C^alkanediylaryl, Co-
C3alkanediylheterocyclyl
R2 is hydrogen or Ci-Cβalkyl;
X' is hydrogen, fluoro, hydroxy, amino or Ci-Cβalkoxy;
X" is hydrogen, or when X' is fluoro, then X" may also be fluoro;
R3 is Cι-C6alkyl;
R4 ' is C,-C6alkyl;
R4 is H or Ci -C^alkyl; or R4 and R4 together with the carbon atom to which they are attached define a Cj-Cδcycloalkyl;
W is cycloalkyl, aryl or heterocyclyl; wherein aryl is independently phenyl, naphthyl, or phenyl fused to Cs-Cδcycloalkyl or C5-C6 cycloalkenyl; heterocyclyl is independently a 5 or 6 membered, saturated, partially unsaturated or heteroarylic ring containing 1 to 3 heteroatoms independently selected from S, O and N, the ring being optionally fused with a benzene ring; wherein each Cι-C6alkyl, aryl and heterocyclyl moiety above (including those in composite expressions such as alkoxy or alkanediylaryl), unless otherwise specified is optionally substituted with one, two or where valence allows three substituents independently selected from Ci-C4alkyl (optionally substituted with one or two substituents independently selected from Co-Cjalkanediylaryl*, amino, carbamoyl, amido and Ci-C4alkoxyamido), C2-Cealkenyl, C2-Cealkynyl, C3-Cycycloalkyl, Ci-C4alkoxy, C1- C4alkoxyCi-C3alkyl, Ci-C4alkoxyCi-C4alkoxyCo-C3alkyl, halo, haloCi-C4alkyl, polyhaloCi-C4alkyl, hydroxy, hydroxyCi-C4alkyl, amino, aminoCi-C4alkyl, carbamoyl, amido, cyano, azido, Ci-C4alkylcarbonyl, NHS(=O)2Ci-C4alkyl, NCi-C4alkylS(=O)2Ci- C4alkyl, a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (any of which cyclic amines being optionally substituted with Ci-C4alkyl or fluoro), Co-C3alkanediylaryl*, Co^alkanediylheterocyclyl*, C2-C3alkenyldiylC3- Cycarbocyclyl, C2-C3alkenyldiylaryl*, C2-C3alkenyldiylheterocyclyl*, C2- C3alkynyldiylC3-Cycarbocyclyl, C2-C3alkynyldiylaryl* or C2-C3alkynyldiylheterocyclyl* (wherein the asterisked aryl or heterocyclyl moiety is optionally substituted with Ci- C4alkyl, halo, hydroxy or amino); or a pharmaceutically acceptable salt, hydrate or N-oxide thereof.
2. A compound according to claim 1, wherein Q is an optionally substituted 5 or 6 membered aryl or heterocyclyl, preferably phenyl or pyridyl.
3. A compound according to claim 1, wherein Q is optionally substituted naphthyl.
4. A compound according to any of claims 1 to 3, wherein the optional substituents are selected from Ci-C4alkyl, C3-Cycycloalkyl, Ci-C4alkoxy, Ci-C4alkoxyCi-C6alkoxyCo- C3alkyl, halo and haloCi-C4alkyl.
5. A compound according to claim 2, wherein Q is phenyl, optionally substituted with one or two substituents independently selected from methyl, cyclopropyl, fluoro, chloro and 3- methoxy-propoxy.
6. A compound according to claim 5 wherein Q is phenyl which is substituted in one of the meta positions and/or in the para position.
7. A compound according to claim 6, wherein Q is phenyl, substituted in one of the meta positions with 3-methoxy-propoxy and in the para position with methyl, ethyl, cyclopropyl, fluoro, chloro or cyano.
8. A compound according to claim 6, wherein Q is phenyl, substituted in one of the meta positions with Ci-C4alkoxy-Ci-C4alkoxy, such as 3-methoxy-propoxy and/or in the para position with optionally substituted phenyl or optionally substituted heteroaryl.
9. A compound according to claim 8, wherein the substituent in the para position is p- fluorophenyl, pyridyl, thienyl or furyl.
10. A compound according to any preceding claim, wherein R1 is hydrogen, Ci-Cβalkyl, pyridylCi-Csalkyl thiazolylCi-Csalkyl or benzyl.
11. A compound according to claim 10, wherein R1 is hydrogen, methyl, ethyl or isopropyl.
12. A compound according to any preceding claim, wherein W is optionally substituted phenyl.
13. A compound according to claim 12, wherein W is phenyl, substituted with fluoro, chloro, methyl or cyano and the substituent is preferably in the para position.
14. A compound according to any preceding claim, wherein m is 1.
15. A compound according to any preceding claim, wherein n is 1.
16. A compound according to any preceding claim, wherein Z is O.
17. A compound according to any preceding claim, wherein R3 is ethyl or isopropyl.
18. A compound according to any preceding claim, wherein R4 is sec-butyl and R4 is H.
19. A compound according to any preceding claim, wherein R2 is hydrogen.
20. A compound according to any preceding claim, wherein X' is hydroxy and X" is hydrogen.
21. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of the preceding claims in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
22. Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 15, in the treatment or prevention of hypertension heart failure, glaucoma, cardiac infarction, kidney failure or restenosis, preferably hypertension.
PCT/EP2008/052416 2007-03-02 2008-02-28 New compounds WO2008107365A1 (en)

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Publication number Priority date Publication date Assignee Title
US8916556B2 (en) 2005-04-15 2014-12-23 The University Of North Carolina At Chapel Hill Pharmaceutical formulations comprising neurotrophin mimetics
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EP2498782A4 (en) * 2009-11-12 2014-03-12 Pharmatrophix Inc CRYSTALLINE FORMS OF MIMETIC NEUROTROPHIN COMPOUNDS AND THEIR SALTS
US9271986B2 (en) 2009-11-12 2016-03-01 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
EP3470402A1 (en) * 2009-11-12 2019-04-17 Pharmatrophix Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US10273219B2 (en) 2009-11-12 2019-04-30 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US10532988B2 (en) 2009-11-12 2020-01-14 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US11225467B2 (en) 2009-11-12 2022-01-18 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts

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