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WO2009013293A1 - Cyclohexanecarboxamides substitués utiles comme inhibiteurs de bace - Google Patents

Cyclohexanecarboxamides substitués utiles comme inhibiteurs de bace Download PDF

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Publication number
WO2009013293A1
WO2009013293A1 PCT/EP2008/059606 EP2008059606W WO2009013293A1 WO 2009013293 A1 WO2009013293 A1 WO 2009013293A1 EP 2008059606 W EP2008059606 W EP 2008059606W WO 2009013293 A1 WO2009013293 A1 WO 2009013293A1
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alkyl
alkoxy
group
amino
ring
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PCT/EP2008/059606
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English (en)
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Stephen Hanessian
Dilip Kumar Maji
Zhihui Shao
Govindan Subramaniyan
Marina Tintelnot-Blomley
Gaoqiang Yang
Hongying Yun
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Novartis Ag
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Publication of WO2009013293A1 publication Critical patent/WO2009013293A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to novel amide compounds, to their preparation, to their use as medicaments and to medicaments comprising them.
  • the invention relates to a compound of the formula
  • R b is hydrogen; Ci-C 8 -alkyl; trifluoromethyl; Ci-C 8 -alkoxy; d-C 4 -alkoxy-d-C 4 - alkyl; d-C 8 -alkylthio; C 1 -C 4 -alkylthio-Ci-C 4 -alkyl; C 3 -C 8 -cycloalkyl; C 3 -C 8 -CyC- loalkyl-d-C 4 -alkyl; heterocyclyl; heterocyclyl-Ci-C 4 -alkyl; amino; d-C 8 -alkyl- amino; or dKd-Cs-alkyOamino with two identical or different d-C 8 -alkyl moieties, which two d-Cs-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted
  • R 2 and R 3 are either, independently from each other, hydrogen; Ci-C 8 -alkyl; Ci-C 4 -alkoxy-Ci-C 4 -alkyl; d-d-alkylthio-d-d-alkyl; or an aryl-d-C 4 -alkyl or heteroaryl-d-C 4 -alkyl group, which aryl-Ci-C 4 -alkyl or heteroaryl-Ci-C 4 -alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl, aryl, heteroaryl, Ci-C 6 -alkyl, hydroxy- Ci-C 4 -alkyl, Ci-C 4 -alkoxy-Ci-C 4 -alky
  • R 4 is hydrogen; hydroxy; or d-C 6 -alkoxy
  • R 5 and R 6 taken together, complete, together with the 2 carbon atoms, to which they are attached, and together with the methylene group, to which the said 2 carbon atoms are attached, a saturated ring, which ring is, in addition to the substitution by the substituents (Ri)(R 2 )(R 3 )C and R 4 and the N-substituted aminocarbonyl group depicted in the formula I, optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of d-C 8 -a!kyl, oxo, hydroxy, Ci-C 8 -alkoxy, Ci-C 4 -alkoxy- Ci-C 4 -alkyl, d-Cs-alkylthio, Ci-C 4 -alkylthio-d-C 4 -alkyl, formyl, d-Cs-alkylcarbonyl, C 1 -C 8 - alkoxycarbonyl, carbamyl, N-d-d
  • ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-C ⁇ -alkyl moieties of the N,N-di- (C 1 -C 8 - alkyl)carbamyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, CrC 8 - alkylsulfonyl, d-C 8 -alkoxysulfonyl, aminosulfonyl, N-CrC 8 -alkylaminosulfonyl, N,N-di- (Ci-C B -alkyl)aminosulfonyl with two identical or different Ci-C 8 -alkyl moieties, which two Ci-Cs-alkyl
  • ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl, aryl, heteroaryl, C r C 6 -alkyl, hydroxy-d-C 4 -alkyl, Ci-C 4 -alkoxy-d-C 4 -alkyl, C r C 4 -alkyl- carbonyl-Ci-C 4 -alkyl, trifluoromethyl, hydroxy, Ci-C 6 -alkoxy, Ci-d-alkoxy-d-d-alkoxy, Ci-C 4 -alkylcarbonyl-Ci-C 4 -alkoxy, benzyloxy, phenoxy, formyloxy, d-C 4 -alkylcarbonyl- oxy, carbamyloxy, N-Ci-d
  • R 8 is hydrogen; and R 9 is hydroxy or
  • R 8 and R 9 taken together, are oxo
  • R c is a Ci-C 8 -alkyl, Ci-C 4 -alkoxy-CrC 4 -alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl- Ci-C 4 -alkyl group, which Ci-C 8 -alkyl, Ci-C 4 -alkoxy-Ci-C 4 -alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C 3 -C 8 -cycloalkyl, C 1 - C 6 -alkyl, hydroxy-d-C 4 -alkyl, Ci-C 4 -alkoxy-Ci-C 4 -alkyl, oxo, hydroxy, d-C 6 -alkoxy, Ci-C 4
  • R f is hydrogen; a d-C 8 -alkyl or C 3 -C 8 -cycloalkyl-d-C 4 -alkyl group, which d-C 8 -al- kyl or Cs-C ⁇ -cycloalkyl-d-d-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C 3 -C 8 -cycloalkyl, d-C 6 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-d -C 4 -alky I, fluoromethyl, difluoro- methyl, trifluoromethyl, oxo, hydroxy, d-C 6 -alkoxy, d-C 4 -alkoxy-d-C 4 -alkoxy, formyloxy, d-C 4 -alkylcarbonyloxy, Ci-C 4 -alkyl
  • the C 4 -C 8 -cycloalkyl moiety which C 4 -C 8 -cycloalkyl moiety is optionally modified as defined under (a) hereinbefore to contain one hetero ring member, is optionally substituted by 1 to 4 substituents independently selected from the group, consisting of halogen, cyano, oxo, hydroxy, d-C 6 -alkoxy, CrC 4 -alkoxy-d-C 4 -alkoxy, formyloxy, d-C 4 -alkylcarbonyloxy, d-C 4 -alkoxycarbonyloxy, d-C 4 -alkylthio, C 1 -C 4 - alkylsulfinyl, d-C 4 -alkylsulfonyl, formyl, Ci-C 4 -alkylcarbonyl, d-C 4 -alkoxycarbonyl, a d-C ⁇ -alkyl, C 3 -C
  • R h being hydrogen; a d-C ⁇ -alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl-d-C 4 -alkyl group, which d-C 8 -alkyl, C 3 -C 8 -cycioalkyl or C 3 -C 8 -cycloalkyl-d-C 4 -alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C 3 -C 8 -cycloalkyl, d-C 6 -alkyl, hydroxy-d-C 4 -alkyl, C 1 -C 4 - alkoxy-d-C 4 -alkyl, oxo, hydroxy, d-Ce-alkoxy, d-C 4 -alkoxy-d-C 4 -alkoxy, formyloxy, d-C 4 -alkylcarbonyloxy,
  • a corresponding compound of the formula I may exist in pure optically active form or in the form of a mixture of optical isomers, e. g. in the form of a ra- cemic mixture. All of such pure optical isomers and all of their mixtures, including the racemic mixtures, are part of the present invention.
  • a compound of the formula I may exist in free form or in salt form, e. g. a basic compound in acid addition salt form or an acidic compound in the form of a salt with a base. All of such free compounds and salts are part of the present invention.
  • a compound of the formula I may exist in tautomeric form. All of such tautomers are part of the present invention.
  • Halogen denotes fluorine, chlorine, bromine or iodine.
  • An aryl group, ring or moiety is a naphthyl or, preferably, phenyl group, ring or moiety.
  • a heteroaryl group, ring or moiety is an aromatic 5- or 6-membered structure, in which structure 1 , 2, 3 or 4 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, such as furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridazinyl, pyrimidyl or pyridyl, and which structure can also be anellated with a phenyl ring, such as benzothiazolyl, benzoxazolyl or quinolyl.
  • structure 1 , 2, 3 or 4 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, such as furyl,
  • a heterocyclyl group, ring or moiety is a non-aromatic 5- or 6-membered cyclic structure, in which cyclic structure 1 , 2 or 3 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, such as pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl or morpholinyl.
  • Any non-cyclic carbon containing group or moiety with more than 1 carbon atom is straight- chain or branched.
  • carbon containing groups, moieties or molecules contain 1 to 8, preferably 1 to 6, preferably 1 to 4, preferably 1 or 2, carbon atoms.
  • the invention relates to a compound of the formula I, in free form or in salt form, in which
  • R b is hydrogen; d-C 8 -alkyl; trifluoromethyl; d-C 8 -alkoxy; C ! -C 4 -a IkOXy-C 1 -C 4 - alkyl; d-C 8 -alkylthio; C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl; C 3 -C 8 -cycloalkyl; C 3 -C 8 -cyc- loalkyl-C r C 4 -alkyl; heterocyclyl; hete TOCyCIyI-C 1 -C 4 -alky I; amino; d-C 8 -alkyl- amino; or di-(CrCs-alkyl)amino with two identical or different d-C 8 -alkyl moieties, which two d-Cs-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached
  • R b is hydrogen; Ci-C 8 -alkyl; trifluoromethyl; Ci-Cs-alkoxy; d-d-alkoxy-Ci-d- alkyl; Ci-C 8 -alkylthio; Ci-C 4 -alkylthio-C 1 -C 4 -a!kyl; C 3 -C 8 -cyc!oalkyl; C 3 -C 8 -cyc- loalkyl-C r C 4 -alkyl; heterocyclyl; heterocyclyl-Ci-d-alkyl; amino; d-C 8 -alkyl- amino; or di-(d-C 8 -alkyl)amino with two identical or different d-C 8 -alkyl moieties, which two d-C 8 -alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted
  • R b is d-C ⁇ -alkyl; d-C 8 -alkoxy; or trifluoromethyl or R a and R b , taken together, are straight-chain d-C 5 -alkylene and in which formula Id
  • R a is hydrogen
  • R 3 and R b taken together, are straight-chain CrC 5 -alkylene
  • R 2 and R 3 are either, independently from each other, hydrogen; d-C 8 -alkyl; Ci-C 4 -alkoxy-d-C 4 -alkyl; d-d-alkylthio-d-d-alkyl; or an aryl-d-C 4 -alkyl or heteroaryl-C r C 4 -alkyl group, which aryl-C r C 4 -alkyl or heteroaryl-d-d-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl, aryl, heteroaryl, d-C 6 -alky!, hydroxy- d-C 4 -alkyl, d-C 4 -alkoxy-d-C 4 -alky
  • R 4 is hydrogen; hydroxy; or Ci-C 6 -alkoxy; preferably hydrogen; or hydroxy; preferably hydrogen;
  • R 5 and R 6 taken together, complete, together with the 2 carbon atoms, to which they are attached, and together with the methylene group, to which the said 2 carbon atoms are attached, a saturated ring, which ring is, in addition to the substitution by the substituents (R 1 )(R 2 )(R 3 )C and R 4 and the N-substituted aminocarbonyl group depicted in the formula I, optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of Ci-C 8 -alkyl, oxo, hydroxy, Ci-C 8 -alkoxy, Ci-C 4 -alkoxy- Ci-C 4 -alkyl, d-C ⁇ -alkylthio, d-C 4 -alkylthio-d-C 4 -alkyl, formyl, Ci-C 8 -alkylcarbonyl, C 1 -C 8 - alkoxycarbonyl, carbamyl, N-
  • R 7 is a d-C ⁇ -alkyl, C 3 -C 8 -cycloalkyl or Cs-C ⁇ -cycloalkyl-d-d-alkyl group, which C 1 -C 8 - alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl-CrC 4 -alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, cyano, C 3 -C 8 -cycloalkyl, heterocyclyl, Ci-C 6 -alkyl, hydroxy-Ci-C 4 -alkyl, Ci-C 4 -alkoxy-Ci-C 4 -alkyl, oxo, hydroxy, CrC ⁇ -alkoxy, Ci-C 4 -alkoxy-Ci-C 4 -alkoxy, formyloxy, d-C 4 -alkylcarbonyl- oxy,
  • R 8 is hydrogen; and R 9 is hydroxy
  • R 8 and R 9 taken together, are oxo; preferably R 8 is hydrogen; and R 9 is hydroxy;
  • R 0 is a d-C 8 -alkyl, d-C 4 -alkoxy-Ci-C 4 -alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl- Ci-C 4 -alkyl group, which d-C 8 -alkyl, d-C 4 -alkoxy-Ci-C 4 -alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C 3 -C 8 -cycloalkyl, C 1 - C ⁇ -alkyl, hydroxy-d-C 4 -alkyl, d-d-alkoxy-d-Oi-alkyl, oxo, hydroxy, CrC 6 -alkoxy, d-d-
  • R f is hydrogen; a d-C 8 -alkyl or Ca-Cs-cycloalkyl-d-d-alkyl group, which Ci-C 8 -al- kyl or C 3 -C 8 -cycloalkyl-d-C 4 -alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C 3 -C 8 -cycloalkyl, d-C ⁇ -aikyl, hydroxy-d-C 4 -alkyl, d-C 4 -alkoxy-Ci-C 4 -alkyl, fluoromethyl, difluoro- methyl, trifluoromethyl, oxo, hydroxy, d-C 6 -alkoxy, formyloxy, d-C 4 -alkylcarbonyloxy, C r C 4 -alkylthio, Ci-C 4 -alkylsulfinyl, CrC ⁇ alkyl
  • the d-C ⁇ -cycloalkyl moiety which C 4 -C 8 -cycloalkyl moiety is optionally modified as defined under (a) hereinbefore to contain one hetero ring member, is optionally substituted by 1 to 4 substituents independently selected from the group, consisting of halogen, cyano, oxo, hydroxy, d-C 6 -alkoxy, d-C 4 -alkoxy-d-C 4 -alkoxy, formyloxy, d-d-alkylcarbonyloxy, d-C 4 -alkoxycarbonyloxy, d-C 4 -alkylthio, C 1 -C 4 - alkylsulfinyl, d-C 4 -alkylsulfonyl, formyl, C 1 -C 4 -alkylcarbonyl, CrC ⁇ alkoxycarbonyl, a d-C ⁇ -alkyl, C 3 -C 8 -cycl
  • R h being hydrogen; a C r C 8 -alkyl, C 3 -C 8 -cycloalkyl or Ca-C ⁇ -cycloalkyl-d-d-alkyl group, which Ci-C 8 -alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl-d-C 4 -alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C 3 -C 8 -cycloalkyl, CrC 6 -alkyl, hydroxy-d-C 4 -alkyl, C 1 -C 4 - alkoxy-C r C 4 -alkyl, oxo, hydroxy, d-C 6 -alkoxy, d-d-alkoxy-d-d-alkoxy, formyloxy, d-C 4 -alkylcarbonyloxy, d-d-alkylthio,
  • R c is d-Cs-alkyl
  • R d and Re are, independently from each other, hydrogen; or d-C ⁇ -alkyl; and in which formula Ih k is 0;
  • R f is an aryl-Crd-alkyl group, which aryl-d -C 4 -alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C 3 -C 8 -cycloalkyl, C 3 -C8-cycloalkyl-d-C 4 -alkyl, aryl, hetero- aryl, d-C 6 -alkyl, hydroxy-d-C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, d-C 4 -alkylcarbo- nyl-d-d-alkyl, trifluoromethyl, hydroxy, CrC 6 -alkoxy, d-C 4 -alkoxy-d-d-alkoxy, d-C 4 -alkylcarbonyl-d-C 4 -alkoxy
  • R c is d-Ce-alkyl
  • R d and R e are, independently from each other, hydrogen; or d-C 8 -alkyl; and in which formula Ih k is 0; and Rf is an aryl-Ci-C 4 -alkyl group, which aryl-d-C 4 -alkyl group is optionally ring-substituted by 1 or 2 substituents independently selected from the group, consisting of
  • R c is d-Ce-alkyl
  • R d and R e are, independently from each other, hydrogen; or C r C 8 -alkyl; and in which formula Ih k is O; and
  • R f is an aryl-C r C 4 -alkyl group ring-substituted by 1 or 2 substituents independently selected from the group, consisting of Ci-C 6 -alkyl; preferably R 10 is a group of the formula (CH 2 ) k N(H)R f (Ih), in which formula Ih k is 0; and
  • R f is an aryl-CrC 4 -alkyl group ring-substituted by 1 or 2 substituents independently selected from the group, consisting of Ci-C ⁇ -alkyl.
  • the preferred embodiments (1 ) to (7) are preferred independently, collectively or in any combination or sub-combination.
  • the invention relates to one or more than one of the compounds of the formula I mentioned in the Examples hereinafter, in free form or in salt form.
  • the invention relates to a process for the preparation of a compound of the formula I, in free form or in salt form, comprising the steps of
  • R 1 , R 2 , R 3 , R 4 , Rs and R 6 are as defined for the formula I and L 1 is a leaving group, in free form or in salt form, with a compound of the formula in which R 7 , Re, Rg and R 10 are as defined for the formula I, in free form or in salt form, or
  • a leaving group L 1 , L 2 , L 3 or L 4 is, e. g., halogen, such as F, Cl or Br, hydroxy or Ci-C 8 - alkoxy, such as methoxy, preferably Cl or hydroxy.
  • the reactions can be effected according to conventional methods, for example as described in the Examples.
  • Salts may be prepared from free compounds in known manner, and vice-versa.
  • the starting materials of the formulae II, III, IV, V, Vl and VII are known or may be prepared according to conventional procedures starting from known compounds, for example as described in the Examples.
  • Compounds of the formula I, in free form or in pharmaceutically acceptable salt form, hereinafter often referred to as "agents of the invention" exhibit valuable pharmacological properties, when tested in vitro or in vivo, and are, therefore, useful in medicaments.
  • agents of the invention are inhibitors of aspartic proteases and can be used for the treatment of a condition, disease or disorder involving processing by such enzymes.
  • agents of the invention inhibit beta-secretase and, thus, the generation of beta-amyloid and the subsequent aggregation into oligomers and fibrils.
  • the inhibiting properties of an agent of the invention towards proteases can be evaluated, e. g., in a test as described hereinafter.
  • Recombinant BACE (extracellular domain, expressed in baculovirus and purified using standard methods) at 0.1 to 10 nM concentrations is incubated with the test compound at various concentrations for 1 hour at room temperature in 10 to 100 mM acetate buffer, pH 4.5, containing 0.1 % CHAPS.
  • Synthetic fluorescence-quenched peptide substrate derived from the sequence of APP and containing a suitable fluorophore-quencher pair, is added to a final concentration of 1 to 5 ⁇ M, and the increase in fluorescence is recorded at a suitable excitation / emission wavelength in a microplate spectro-fluorimeter for 5 to 30 minutes in 1 -minute intervals.
  • IC 5O values are calculated from percentage of inhibition of BACE-activity as a function of the test compound concentration.
  • Test 2 Inhibition of human BAC E-2
  • Recombinant BACE-2 (extracellular domain, expressed in baculovirus and purified using standard methods) at 0.1 to 10 nM concentrations is incubated with the test compound at various concentrations for 1 hour at room temperature in 10 to 100 mM acetate buffer, pH 4.5, containing 0.1 % CHAPS.
  • Synthetic peptide substrate derived from the sequence of APP and containing a suitable fluorophore-quencher pair, is added to a final concentration of 1 to 5 ⁇ M, and the increase in fluorescence is recorded at a suitable excitation / emission wavelength in a microplate spectro-fluorimeter for 5 to 30 minutes in 1 -minute intervals.
  • IC 50 values are calculated from percentage of inhibition of BACE-2-activity as a function of the test compound concentration.
  • Test 3 Inhibition of human cathepsin D Recombinant cathepsin D (expressed as procathepsin D in baculovirus, purified using standard methods and activated by incubation in sodium formate buffer pH 3.7) is incubated with the test compound at various concentrations for 1 hour at room temperature in sodium formate or sodium acetate buffer at a suitable pH within the range of pH 3.0 to 5.0.
  • Synthetic peptide substrate Mca-Gly-Lys-Pro-lle-Leu-Phe-Phe-Arg-Leu-Lys(DNP)-D-Arg-NH 2 is added to a final concentration of 1 to 5 ⁇ M, and the increase in fluorescence is recorded at excitation of 325 nm and emission at 400 nm in a microplate spectro-fluorimeter for 5 to 30 minutes in 1 -minute intervals.
  • IC 5 O values are calculated from the percentage of inhibition of cathepsin D-activity as a function of the test compound concentration.
  • Test 4 Inhibition of cellular release of amyloid peptide 1-40
  • Chinese hamster ovary cells are transfected with the gene for amyloid precursor protein.
  • the cells are plated at a density of 8000 cells/well into 96-well microtiter plates and cultivated for 24 hours in DMEM cell culture medium containing 10 % FCS.
  • the test compound is added to the cells at various concentrations, and the cells are cultivated for 24 hours in the presence of the test compound.
  • the supematants are collected, and the concentration of amyloid peptide 1-40 is determined using sandwich ELISA.
  • the potency of the compound is calculated from the percentage of inhibition of amyloid peptide release as a function of the test compound concentration.
  • agents of the invention show activity at concentrations below 50 ⁇ M.
  • Example 6 shows an IC 50 value of 4.22 ⁇ M in Test 1.
  • agents of the invention are useful, e. g., in the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, such as a neurodegenerative condition, disease or disorder, e. g.
  • BACE-2 beta-site APP-cleaving enzyme 2
  • cathepsin D which are close homologues of the pepsin-type aspartyl proteases and beta-secretase
  • the appropriate dosage will vary depending on, e. g., the compound employed as active pharmaceutical ingredient, the host, the mode of administration, the nature and severity of the condition, disease or disorder or the effect desired.
  • a daily dosage of from about 0.1 to about 100, preferably from about 1 to about 50, mg/kg of animal body weight.
  • an indicated daily dosage is in the range of from about 0.5 to about 2000, preferably from about 2 to about 200, mg of an agent of the invention conveniently administered, for example, in divided doses up to four times a day or in sustained release form.
  • An agent of the invention may be administered by any conventional route, in particular en- terally, preferably orally, e. g. in the form of a tablet or capsule, or parenterally, e. g. in the form of an injectable solution or suspension.
  • the invention in a further aspect, relates to an agent of the invention for use as a medicament, e. g. for the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or for the suppression of the metastasis process associated with tumor cells.
  • the invention relates to the use of an agent of the invention as active pharmaceutical ingredient in a medicament, e. g. for the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or for the suppression of the metastasis process associated with tumor cells.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an agent of the invention as active pharmaceutical ingredient in association with at least one pharmaceutically acceptable carrier or diluent.
  • Such a composition may be manufactured in conventional manner, e. g. by mixing its components.
  • Unit dosage forms contain, e. g., from about 0.1 to about 1000, preferably from about 1 to about 500, mg of an agent of the invention.
  • An agent of the invention can be administered as sole active pharmaceutical ingredient or as a combination with at least one other active pharmaceutical ingredient effective, e. g., in the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or in the suppression of the metastasis process associated with tumor cells.
  • Such a pharmaceutical combination may be in the form of a unit dosage form, which unit dosage form comprises a predetermined quantity of each of the at least two active components in association with at least one pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical combination may be in the form of a package comprising the at least two active components separately, e. g. a pack or dispenser-device adapted for the concomitant or separate administration of the at least two active components, in which these active components are separately arranged.
  • the invention relates to such pharmaceutical combinations.
  • the invention relates to the use of an agent of the invention for the manufacture of a medicament for the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or for the suppression of the metastasis process associated with tumor cells.
  • the invention relates to a method for the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or for the suppression of the metastasis process associated with tumor cells, in a subject in need of such treatment, prevention or suppression, which method comprises administering to such subject an effective amount of an agent of the invention.
  • building block A3a (10 mg, 0.042 mmol) in DCM (1.5 ml) are added under argon at 0 0 C pyridine (34.0 ⁇ l, 0.42 mmol) and CH 2 CHCOCI (17.1 ⁇ l, 0.21 mmol). The mixture is stirred for 30 min, quenched with aqueous 1 N hydrochloric acid (0.5 ml) and extracted with DCM. The organic layer is washed with water, dried over sodium sulfate and evaporated. The purification of the residue by column chromatography yields a colorless oil.
  • a solution of building block A5a) (0.437 g, 1.44 mmol), mercuric chloride (1.57 g, 5.82 mmol) and perchloric acid (0.62 ml of a 70% aqueous solution, 4.35 mmol) in methanol (35 ml) is heated to reflux for 2 h.
  • the reaction mixture is neutralized with saturated aqueous bicarbonate solution and extracted with DCM.
  • the combined organic layers are washed with brine, dried over sodium sulfate and concentrated to yield a diastere- omeric mixture of the ester as a thick gum.
  • This product is, together with sodium methoxide in methanol (0.5 M, 5 ml), heated to reflux for 48 h.
  • reaction mixture is stirred at rt for 3 h and then quenched with aqueous ammonium chloride solution.
  • organic layer is diluted with EtOAc, washed with hydrochloric acid (1 N) and sodium bicarbonate solution, dried and concentrated.
  • the residue is purified by chromatography (EtOAc:hexanes 1 :1) to yield a colorless oil.
  • Building block A1 b) (200 mg, 0.86 mmol) is dissolved in CH 3 OH (10 ml) in a thick-walled tube. Raney-Ni (50% in water, 1.5 ml) is added, followed by a catalytic amount of H 2 PtCI 6 . The mixture is stirred under H 2 (60 psi) for 14 h (until TLC shows the full consumption of the starting material). The catalyst is filtered off, and the filtrate is evaporated to yield the crude amine, which is dissolved in DCM (3.3 ml) and water (1.6 ml). Sodium carbonate (159 mg, 1.4 mmol) is added, and the mixture is stirred for 10 min.
  • building block A6b 38 mg, 0.16 mmol
  • acetone (2 ml) and saturated sodium bicarbonate solution 0.5 ml
  • sodium bromide 4 mg, 0.04 mmol
  • TEMPO TEMPO
  • trichloroisocyanuric acid 73 mg, 0.32 mmol
  • the mixture is stirred overnight at a temperature between O 0 C and rt.
  • lsopropanol (1 ml) is added.
  • the mixture is filtered through a pad of Celite, and the filter cake is washed with EtOAc.
  • the combined filtrates are washed with 1 N aqueous hydrochloric acid (2 ml) and brine, dried over sodium sulfate and concentrated to yield the title compound.
  • a solution of building block A9b) in CH 3 OH (10 ml) is overnight subjected to reduction in the presence of Raney-Ni (20 mg) and H 2 PtCI 6 (5 mg) under a hydrogen atmosphere (60 psi).
  • the mixture is filtered, and to the filtrate is added BOC 2 O in dioxane and aqueous 1 N NaOH.
  • the mixture is stirred for 12 h, neutralized with 0.1 N aqueous hydrochloric acid and extracted with EtOAc.
  • the extract is dried over sodium sulfate and evaporated.
  • Example 1 (1 R,3S)-3-(1-Acetvlamino-1-methvl-ethyl)-cvclohexanecarboxvlic acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide
  • the title compound is prepared in a manner analogous to that described in Example 1 starting from building block A4 and building block B1.
  • Example 5 (1 R,3S)-3-(1 -Acetylamino-cyclopentyl)-cyclohexanecarboxy lie acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide
  • the title compound is prepared in a manner analogous to that described in Example 6 starting from building block A2 and building block B2.
  • Example 8 (1 R,3S)-3-f1-IVIethvl-1-(methvl-propionvl-amino)-ethvll-cvclohexanecar- boxylic acid [(1S,2R)-1-benzyl-2-hydroxy-3-(3-isopropyl-benzylamino)-propyl]-amide
  • the title compound is prepared in a manner analogous to that described in Exampie 6 starting from building block A6 and building block B2.
  • Example 10 (1 R,3S)-3-H -Methyl-1 -(2-oxo-piperidin-1 -vD-ethyll-cvclohexanecarboxylic acid t(1S,2R)-1-benzyl-2-hydroxy-3-(3-isopropyl-benzylamino)-propyl]-amide
  • Example 11 (1R.3S)-3-((S)-1-Acetvlamino-2-methvl-propyl)-cvclohexanecarboxvlic acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide
  • Example 12 f(S)-1-r(1 R,3R)-3-((1S.2S.4R)-1-Benzvl-4-butylcarbamovl-2-hvdroxv- pentylcarbamoyl)-1-hydroxy-cyclohexyl]-butyl ⁇ -carbamic acid tert-butyl ester (assignment of stereochemistry of amino substituent arbitrary)
  • Example 12 The title compound of Example 12 (10 mg) is treated with TMSI (15 ⁇ l) in 0.5 ml of DCM. The mixture is stirred at 0 0 C for 30 min and then evaporated. The residue is dissolved in DCM. To the solution are added solid sodium bicarbonate and acetyl chloride (10 ⁇ l, 10 eqivalents). The mixture is diluted with EtOAc, washed with aqueous sodium carbonate solution, dried over sodium sulfate and evaporated to yield the title compound.
  • HRMS (M + I) + 532.3442; calculated M + 531.3672.
  • Example 14 f(R)-1-f(1 R,3R)-3-((1S.2S.4R)-1-Benzvl-4-butvlcarbamovl-2-hvdroxy-pen- tylcarbamoyl)-1-hydroxy-cyclohexyl]-butyl ⁇ -carbamic acid tert-butyl ester (assignment of stereochemistry of amino substituent arbitrary)
  • Example 15 (1 R,3R)-3-((R)-1 -Acetylamino-butyl)-3-hydroxy-cyclohexanecarboxylic acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide (assignment of stereochemistry of amino substituent arbitrary)
  • Example 14 The title compound is prepared in a manner analogous to that described in Example 13 starting from the title compound of Example 14.
  • Example 16 (1 R,3R)-3-Hydroxy-3-(1 -methy lcarbamoyl-buty l)-cyclohexanecarboxylic acid ((1 S,2S ,4R)-1 -benzyl-4-butylcarbamoyl-2-hydroxy-penty l)-amide

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Abstract

L'invention porte sur de nouveaux composés amides représentés par la formule (I) dans laquelle toutes les variables sont telles que définies dans la description, sous forme libre ou sous forme de sel, sur leur préparation, sur leur utilisation comme médicaments et sur des médicaments les comprenant.
PCT/EP2008/059606 2007-07-24 2008-07-22 Cyclohexanecarboxamides substitués utiles comme inhibiteurs de bace WO2009013293A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
WO2012107153A1 (fr) 2011-02-08 2012-08-16 Merck Patent Gmbh Dérivés d'aminostatine pour le traitement de l'arthrose
FR2989376A1 (fr) * 2012-04-17 2013-10-18 Centre Nat Rech Scient Nouveaux composes difonctionnels d'origine naturelle
WO2014015934A1 (fr) 2012-07-24 2014-01-30 Merck Patent Gmbh Dérivés d'hydroxystatine pour le traitement de l'arthrose
WO2014127881A1 (fr) 2013-02-25 2014-08-28 Merck Patent Gmbh Dérivés de 2-amino-3,4-dihydroquinazoline et leur utilisation comme inhibiteurs de la cathepsine d
WO2015018472A1 (fr) 2013-08-06 2015-02-12 Merck Patent Gmbh Application intra-articulaire de pepstatine dans l'arthrose

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021600A1 (fr) * 1999-09-17 2001-03-29 Lg Chem Investment Ltd. Inhibiteur de caspases
US20030125257A1 (en) * 2001-12-20 2003-07-03 Manfred Brockhaus Assay for identifying beta secretase inhibitors
US20040121947A1 (en) * 2000-12-28 2004-06-24 Oklahoma Medical Research Foundation Compounds which inhibit beta-secretase activity and methods of use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021600A1 (fr) * 1999-09-17 2001-03-29 Lg Chem Investment Ltd. Inhibiteur de caspases
US20040121947A1 (en) * 2000-12-28 2004-06-24 Oklahoma Medical Research Foundation Compounds which inhibit beta-secretase activity and methods of use thereof
US20030125257A1 (en) * 2001-12-20 2003-07-03 Manfred Brockhaus Assay for identifying beta secretase inhibitors

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
WO2012107153A1 (fr) 2011-02-08 2012-08-16 Merck Patent Gmbh Dérivés d'aminostatine pour le traitement de l'arthrose
FR2989376A1 (fr) * 2012-04-17 2013-10-18 Centre Nat Rech Scient Nouveaux composes difonctionnels d'origine naturelle
WO2014015934A1 (fr) 2012-07-24 2014-01-30 Merck Patent Gmbh Dérivés d'hydroxystatine pour le traitement de l'arthrose
WO2014127881A1 (fr) 2013-02-25 2014-08-28 Merck Patent Gmbh Dérivés de 2-amino-3,4-dihydroquinazoline et leur utilisation comme inhibiteurs de la cathepsine d
WO2015018472A1 (fr) 2013-08-06 2015-02-12 Merck Patent Gmbh Application intra-articulaire de pepstatine dans l'arthrose

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