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WO1997047299A1 - Inhibiteurs de protease heterocyclique amidino et guanidino - Google Patents

Inhibiteurs de protease heterocyclique amidino et guanidino Download PDF

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Publication number
WO1997047299A1
WO1997047299A1 PCT/US1997/009846 US9709846W WO9747299A1 WO 1997047299 A1 WO1997047299 A1 WO 1997047299A1 US 9709846 W US9709846 W US 9709846W WO 9747299 A1 WO9747299 A1 WO 9747299A1
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alkyl
hydrogen
carboxyalkyl
hydroxyalkyl
aryl
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PCT/US1997/009846
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English (en)
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Carl R. Illig
Richard M. Soll
Tianbao Lu
Bruce E. Tomczuk
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3-Dimensional Pharmaceuticals, Inc.
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Publication of WO1997047299A1 publication Critical patent/WO1997047299A1/fr

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    • 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
    • C07D213/60—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 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—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 two double bonds between ring members or between ring members and non-ring members 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
    • C07D207/36—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to novel compounds that function as enzyme inhibitors, and particularly to a new class of non-peptidic inhibitors of proteolytic enzymes.
  • Proteases are enzymes that cleave proteins at single, specific peptide bonds. Proteases can be classified into four generic classes: serine, thiol or cysteinyl, acid or aspartyl, and metalloproteases (Cuypers et al, J. Biol. Chem.
  • Proteases are essential to a variety of biological activities, such as digestion, formation and dissolution of blood clots, reproduction and the immune reaction to foreign cells and organisms.
  • Aberrant proteolysis is associated with a number of disease states in man and other mammals.
  • the human neutrophil proteases, elastase and cathepsin G, have been implicated as contributing to disease states marked by tissue destruction. These disease states include emphysema, rheumatoid arthritis, corneal ulcers and glomerular nephritis. (Barret, in Enzyme Inhibitors as Drugs, Sandier, ed., University Park Press, Baltimore, (1980)).
  • proteases such as plasmin, C-l esterase.
  • C-3 convertase, urokinase, plasminogen activator, acrosin, and kallikreins play key roles in normal biological functions of mammals. In many instances, it is beneficial to disrupt the function of one or more proteolytic enzymes in the course of therapeutically treating a mammal.
  • Serine proteases include such enzymes as elastase (human leukocyte), cathepsin G, plasmin, C-l esterase, C-3 convertase, urokinase, plasminogen activator, acrosin, chymotrypsin, trypsin, thrombin, factor Xa and kallikreins.
  • Human leukocyte elastase is released by polymorphonuclear leukocytes at sites of inflammation and thus is a contributing cause for a number of disease states.
  • Cathepsin G is another human neutrophil serine protease.
  • Chymotrypsin and trypsin are digestive enzymes. Inhibitors of these enzymes are useful in treating pancreatitis. Inhibitors of urokinase and plasminogen activator are useful in treating excessive cell growth disease states, such as benign prostatic hypertrophy, prostatic carcinoma and psoriasis.
  • the serine protease thrombin occupies a central role in hemostasis and thrombosis, and as a multifactorial protein, induces a number of effects on platelets, endothelial cells, smooth muscle cells, leukocytes, the heart, and neurons (Tapparelli et ai, Trends in Pharmacological Sciences 74:366-376 (1993); Lefkovits and Topol, Circulation 90(3):1522-1536 (1994); Harker, Blood
  • Coagulation and Fibrinolysis 5 (Suppl 7,):S47-S58 (1994)).
  • Activation of the coagulation cascade through either the intrinsic pathway (contact activation) or the extrinsic pathway (activation by exposure of plasma to a non-endothelial surface, damage to vessel walls or tissue factor release) leads to a series of biochemical events that converge on thrombin.
  • Thrombin cleaves fibrinogen ultimately leading to a hemostatic plug (clot formation), potently activates platelets through a unique proteolytic cleavage of the cell surface thrombin receptor (Coughlin, Seminars in Hematology J7(4):270-277 (1994)), and autoamplifies its own production through a feedback mechanism.
  • inhibitors of thrombin function have therapeutic potential in a host of cardiovascular and non-cardiovascular diseases, including: myocardial infarction; unstable angina; stroke; restenosis; deep vein thrombosis; disseminated intravascular coagulation caused by trauma, sepsis or tumor metastasis; hemodialysis; cardiopulmonary bypass surgery; adult respiratory distress syndrome; endotoxic shock; rheumatoid arthritis; ulcerative colitis; induration; metastasis; hypercoagulability during chemotherapy; Alzheimer's disease: and Down's syndrome.
  • Factor Xa is another serine protease in the coagulation pathway. Factor Xa associates with factor Va and calcium on a phospholipid membrane thereby forming a prothrombinase complex. This prothrombinase complex then converts prothrombin to thrombin (Claeson, Blood Coagulation and Fihrinolysis 5:411- 436 (1994); Harker, Blood Coagulation and Fihrinolysis 5 (Suppl 7,):S47-S58 ( 1994)). Inhibitors of factor Xa are thought to offer an advantage over agents that directly inhibit thrombin since direct thrombin inhibitors still permit significant new thrombin generation (Lefkovits and Topol, Circulation 90(3): 1522- 1536
  • the present invention is directed to novel compounds having Formula /
  • novel compounds of the present invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin, or are intermediates useful for forming compounds having antithrombotic activity. Other compounds are expected to inhibit trypsin and/or chymotrypsin, and are therefore useful in treating pancreatitis.
  • compositions comprising a compound of Formula / and one or more pharmaceutically acceptable carriers or diluents.
  • the present invention is broadly directed to compounds sharing a common heteroaryl core and either an amidino or guanidino functionality.
  • the compounds share the ability to inhibit proteases, especially serine proteases, more especially trypsin-like serine proteases.
  • the compounds have the general formula /:
  • R 1 is one of alkyl, cycloalkyl. alkenyl, alkynyl, aryl, aralkyl or heteroaryl, any of which may be optionally substituted;
  • Z is one of -NR ,0 SO 2 - -SO 2 NR'°- -NR ,0 C(R y R z ⁇ -, -C(R y R z )NR 10 -, -OSO 2 - -SO 2 O-, -OC(R y R 7 )-, -C(R y R z )O-, -NR'°CO- or -CONR 10 -, where R- and R 7 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy, and R 10 is defined below;
  • X is a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or unsaturated, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S, wherein the nitrogen and sulfur heteroatoms can optionally be oxidized, the nitrogen can optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be attached to pendant groups Y and Z at any heteroatom or carbon atom that results in a stable formula; and wherein the heterocyclic ring can be optionally substituted on carbon or on a nitrogen atom if the resulting compound is stable;
  • Y is one of -O-, -NR 10 -, -S- , -CHR 10 - or a covalent bond;
  • R 6 is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C 2 . ⁇ 0 )alkyl, dialkylamino(C 2 . 10 )alkyl, carboxyalkyl or -CO 2 R w , where R w is defined below;
  • R 7 and R 8 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl;
  • R 9 is one of hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifluoromethyl;
  • R'° in each instance, is independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C 2 . 10 )alkyl, dialkylamino(C 2 _ ]0 )alkyl, alkoxycarbonylalkyl or carboxyalkyl;
  • R a , R b and R c are each independently one of hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or -C0 2 R w , where R w is alkyl, cycloalkyl, phenyl benzyl,
  • R d and R e are independently hydrogen, C, .6 alkyl, C 2 . 6 alkenyl or phenyl
  • R f is hydrogen, C,. 6 alkyl, C 2.6 alkenyl or phenyl
  • R ⁇ is hydrogen, C,_ 6 alkyl, C 2 . 6 alkenyl or phenyl
  • R h is aralkyl or C,. 6 alkyl
  • n is from zero to 8
  • o is from zero to 4
  • m is from 2 to 4.
  • substituted means that one or more hydrogens of the moiety are replaced with a selection from the group indicated below, provided that no atom's normal valency is exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens attached to an atom of the moiety are replaced.
  • stable compound or “stable formula”, as recited in the definition of X, is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.
  • heterocyclic rings X described herein can be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • useful heterocycles include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyI, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl
  • heterocycles are aromatic heterocycles, "heteroaryl” groups.
  • heteroaryl refers to heterocyclic groups having 5 to 10 ring atoms; 6 or 10 ⁇ electrons shared in a cyclic array; and containing carbon atoms and 1 , 2 or 3 oxygen, nitrogen or sulfur heteroatoms.
  • heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazo
  • N-oxides of nitrogen containing heteroaryl groups are contemplated.
  • additional hydrogen atoms in heterocyclic groups can be substituted with C,. 6 alkyl, C 3 . 8 cycloalkyl, phenyl, benzyl, trifluoromethyl, halogen, hydroxy (C, .g ) alkyl, cyano, nitro, carboxamido, carboxy, C M alkoxycarbonyl, C M alkoxymethyl or C M alkoxy.
  • heterocyclic groups have either five or six ring atoms.
  • Useful heteroaryl groups having five ring atoms include:
  • a 1 is O; S or N(R), wherein R is hydrogen or C,. 6 alkyl; D 1 is N or C ⁇ ; and E 1 is O or S.
  • Useful 5-membered heterocyclic groups that are partially or totally saturated include:
  • a 1 and E 1 are defined as above, and wherein R, in each instance, is independently one of hydrogen or C, .6 alkyl.
  • Useful heteroaryl groups having six ring atoms include:
  • D 2 is N; N + (O ' ) or CH; and E 2 is O or S.
  • Useful six membered heterocyclic groups that are partially or totally saturated include:
  • D 2 and E 2 are defined as above;
  • a 2 is independently O, S or N(R), where R is hydrogen or C,. 6 alkyl; and R is hydrogen, C,. 6 alkyl, hydroxy or C,_ 6 alkoxy.
  • Non-limiting examples of X include:
  • Another preferred set of values include 2,3-pyridyl, 2,4-pyridyl, 2,5-pyridyl, 2,6-pyridyl, 2,4-furanyl, 3,4-furanyl, 2,5-furanyl, 4,5-pyrimidinyl and 4,6-pyrimidinyl.
  • the groups Y and Z of Formula / are each covalently attached to a carbon atom when X is a heteroaryl ring.
  • X is a heteroaryl ring.
  • Z is attached to the 2-position of furanyl, thiofuranyl or pyrrolyl, then Y can be attached to the 3, 4, or 5 position of the ring.
  • Preferred compounds of the present invention are those wherein Y is one of divalent oxygen (-O-) or — NR 10 — and Z is one of — S0 2 NR 10 — , — SO 2 O— or — CH 2 O— .
  • R' is one of C, .12 alkyl, C 4.7 cycloalkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl or C 6 . M aryl, especially C 6 . ]0 aryl, any of which is optionally substituted.
  • Optional substituents on R 1 include one or more, preferably one or two, hydroxy, nitro, trifluoromethyl. halogen, alkoxy, aminoalkoxy, aminoalkyl, hydroxyalkyl, hydroxyalkoxy, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, carboxyalkoxy, mono(hydroxyalkyl)amino, di(hydroxyalkyl)amino, mono(carboxyalkyl)amino, di(carboxyalkyl)amino, alkoxycarbonylamino, alkoxycarbonyl, aralkoxycarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfonyl.
  • a further substituent on aryl, cycloalkyl, alkenyl, alkynyl and aralkyl moities of R 1 includes one or more, preferably one or two, alkyl moieties.
  • Preferred values of optional substituents on R 1 include hydroxy, nitro, trifiuoromefhyl, halogen, C,. 6 alkyl, C,. 6 alkoxy, C,. 6 aminoalkyl, C,. 6 aminoalkoxy, amino, mono(C M )alkylamino, di(C,. 4 )alkylamino, C 2 . 6 alkoxycarbonylamino, C 2 .
  • alkylsulfonamido amidino, guanidino, C, .6 alkyliminoamino, formyliminoamino, C 2 . 6 carboxyalkoxy, carboxyalkylamino, cyano, trifluoromethoxy, and perfluoroethoxy.
  • R 1 is heteroaryl or substituted heteroaryl.
  • Preferred R 1 heteroaryl groups include pyridyl, thienyl, chromenyl, benzoxazolyl, quinazolinyl, quinolinyl and tetrahydroquinolinyl, with pyridyl, quinazolinyl, quinolinyl and tetrahydroquinolinyl being most preferred.
  • R 1 is substituted heteroaryl, those compounds having one of the heteroaryl groups mentioned as preferred, additionally have one or more, preferably one or two, substituents that are listed in the preceding two paragraphs.
  • R 1 Useful values of R 1 include phenyl, chlorophenyl, iodophenyl, dichlorophenyl, bromophenyl, trifluoromethylphenyl, bis(trifluoromethyl)phenyl, methylphenyl, 7-butylphenyl, aminochlorophenyl, methoxyphenyl, chloromethoxyphenyl, dimethoxyphenyl, hydroxyphenyl, carboxyphenyl, aminophenyl, cyanophenyl, methylaminophenyl, «-butylaminophenyl, amidinophenyl, guanidinophenyl, formyliminoaminophenyl, acetimidoylaminophenyl, methoxycarbonylphenyl, ethoxycarbonylphenyl, carboxy methoxyphenyl, naphthyl, hydroxynaphthyl, cyclohexyl, cyclopent
  • W is one of Formulae ///, VI, VII, VIII or X.
  • R 6 includes hydrogen, C j.6 alkyl, C 3 . 8 cycloalkyl, phenyl, benzyl, trifluoromethyl, halogen, hydroxy(C, .8 )alkyl, cyano, nitro, carboxamide, carboxy, alkoxycarbonyl, alkoxymethyl and alkoxy.
  • Suitable values of R 6 include hydrogen, methyl, methoxy and trifluoromethyl.
  • R 7 and R 8 are independently hydrogen, C,.
  • R 7 and R 8 include hydrogen, methyl, ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-carboxymethyl, 3- carboxyethyl and 4-carboxypropyl.
  • R 9 is hydrogen or C,.
  • alkyl optionally substituted by one, two or three of, preferably one of, amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, alkoxycarbonyl, aryloxycarbonly, aralkoxycarbonyl, carboalkoxy, phenyl, cyano, trifluoromethyl, acetylamino, pyridyl, thienyl, furyl, pyrrolyl or imidazolyl.
  • Suitable values of R 9 include hydrogen, methyl, ethyl, propyl, «-butyl, benzyl, phenethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, carboxymethyl and carboxyethyl.
  • R 10 is hydrogen, C,. 6 alkyl, C 6 . l0 ar(C,. 6 )alkyl, C 6 . 10 aryl, C 2-10 hydroxyalkyl C 2.10 aminoalkyl, C 2.7 carboxyalkyl, mono(C,. 4 alkyl)amino(C ⁇ . 8 )alkyl, and di(C M alkyl)amino (C
  • Suitable values of R 10 include methyl, ethyl, propyl, w-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3- hydroxypropyl, 4-hydroxybutyl, 2-aminoethyl, 2-carboxymethyl, 3-carboxyethyl, 4-carboxypropyl and 2-(dimethylamino)ethyl.
  • R a , R and R c in Formula I are hydrogen, hydroxy, C 1-6 alkyl, C,. 6 alkoxy, cyano or -CO 2 R w , where R w , in each instance, is preferably one of C M alkyl, C 4 . 7 cycloalkyl or benzyl.
  • Suitable values of R a , R b and R c include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, ethoxy, cyano, -CO 2 CH 3 , -CO 2 CH 2 CH 3 and -CO 2 CH 2 CH 2 CH 3 .
  • R a , R b and R c are each hydrogen. Also preferred at R a , R b and R c is the group -C0 2 R ⁇ where R" is one of
  • R d -R h arc defined as above.
  • R a , R b and R c are -CO 2 R w , where R w is one of one of these moieties, the resulting compounds are prodrugs that possess desirable formulation and bioavailability characteristics.
  • a preferred value for each of R d , R e , and R E is hydrogen
  • a preferred value for R f is methyl
  • preferred values for R h include benzyl and /er/-butyl.
  • n is from 1 to 6, more preferably from 1 to 4, and most preferably 1 or 2.
  • o is from 0 to 3, most preferably 0. 1 or 2.
  • m is 2 or 3.
  • a useful subgenus of compounds falling within the scope of the present invention include compounds of Formula / wherein:
  • R 1 is one of C 6 . ]0 aryl, pyridinyl, pyrimidinyl, quinizolinyl, quinolinyl or tetrahydroquinolinyl, any of which is optionally substituted by one or two of hydroxy, nitro, trifluoromethyl, halogen, C, .6 alkyl, C,. 6 alkoxy, C,_ 6 aminoalkyl,
  • Z is one of-SO 2 O ⁇ , -S0 2 NR 10 - -C(R y R z )O- or -OC(R y R z )-, where R y and R z are each hydrogen;
  • each D 2 is independently N; N + (O " ) or CH; W is one of
  • Y is one of-O-, -S-, -NR 10 -. or a covalent bond
  • R 6 is one of hydrogen, C, .6 alkyl, C 6. , 0 ar(C,. 6 )alkyl, C 6 ., 0 aryl, C 2-I0 hydroxyalkyl, C 2.10 aminoalkyl, mono(C M )alkylamino(C 2.8 )alkyl, di(C,. 4 )alkylamino(C 2 . 8 )alkyl or C 2.10 carboxyalkyl;
  • R 7 is one of hydrogen, C,. 6 alkyl, C 2. , 0 carboxyalkyl or C 2.!0 hydroxyalkyl;
  • R 8 is one of hydrogen, C,. 6 alkyl, C 2. , 0 carboxyalkyl or C 2. , 0 hydroxyalkyl;
  • R 9 is hydrogen; or C,. 10 alkyl, optionally substituted with amino, mono(C,. 4 )alkylamino, C,. 6 alkoxy, hydroxy, carboxy, phenyl, alkyloxycarbonyl, aralkoxycarbonyl, C,. 6 acylamino, cyano or trifluoromethyl;
  • R 10 in each instance, is independently hydrogen, C,. 6 alkyl, benzyl, phenyl, C 2 . 10 hydroxyalkyl, C 2 . )0 aminoalkyl, C M monoalkylamino(C 2 . 8 )alkyl, C,_ 4 dialkylamino(C 2 . 8 )alkyl or C 2. , 0 carboxyalkyl;
  • R a , R b and R c are each independently one of hydrogen, C M alkyl, hydroxy, C, .4 alkoxy, phenoxy, C M alkyloxycarbonyl, benzyloxycarbonyl, cyano,
  • R h is benzyl, methyl, ethyl, isopropyl, sec-butyl or /-butyl, and where R 1 is hydrogen or C,_ 6 alkyl; - n is from zero to 8; o is from zero to 4; and m is from 2 to 4.
  • An especially preferred group of compounds include compounds of Formula / wherein:
  • R 1 is one of C,. g alkyl, phenyl or naphthyl, optionally substituted by one or two of chloro, methoxy, trifluoromethyl, amino or dimethylamino;
  • Z is one of -SO,O-, -SO.NR 10 -, -CH 2 O- or -OCH 2 -;
  • Y is one of O, NR 10 or a covalent bond
  • W is one of:
  • R 5 is one of hydrogen, C, .6 alkyl, C 2 . 10 hydroxyalkyl or C 2 . 10 carboxyalkyl
  • R 6 is hydrogen, C, .4 alkyl, C 2 . 4 hydroxyalkyl, C 2 . 4 carboxyalkyl, C 2 . 4 aminoalkyl, dimethylamino(C 2 . 8 )alkyl, or methylamino(C 2 . 8 )alkyl;
  • R 7 is one of hydrogen, C, .6 alkyl, C 2.10 hydroxyalkyl or C 2.10 carboxyalkyl
  • R 8 is one of hydrogen, C, .6 alkyl, C 2 _ 10 hydroxyalkyl or C 2. , 0 carboxyalkyl
  • R is one of hydrogen or C M alkyl
  • R'° in each instance, is independently one of hydrogen, C M alkyl, C 2 . 4 hydroxyalkyl, C 2.4 carboxyalkyl, C 2.4 aminoalkyl, dimefhylamino(C 2 _ 8 )alkyl, methylamino(C 2.8 )alkyl;
  • R a , R b and R c are hydrogen, hydroxy
  • R h is benzyl or r-butyl, and where R f is hydrogen or methyl; n is from zero to 4; o is 0, 1 or 2; and m is 2 or 3.
  • alternative embodiments of the present invention include compounds of Formula / in which two "R" groups together form a saturated or unsaturated hydrocarbon bridge, thus forming an additional cyclic moiety in the resulting compounds.
  • Alternative embodiments include compounds of Formula / wherein R 1 , Z, X, Y and n are defined as above; W is
  • R 7 and R 9 are taken together to form — (CH 2 ) q — , where q is 1 , 2 or 3;
  • R 6 , R a , R b and R c are defined as above; or
  • R 7 is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl; R 6 and R 9 are taken together to form — (CH 2 )— (CH 2 )— (CH 2 ) p — , where p is 1 , 2 or 3; and
  • R a is hydrogen or hydroxy
  • R c is hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbamoyloxy, cyano or — CO 2 R w — , where R" is as defined above;
  • R 7 is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl;
  • R 9 is one of hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifluoromethyl; or
  • R a and R c are taken together to form — CH 2 — (CH 2 ) S — , where s is l or 2;
  • R 6 is hydrogen, alkyl, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or — CO 2 R w — , where R w is as defined above;
  • R 7 is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl;
  • R 9 is one of hydrogen, alkyl, cycloalkyl or aryl. wherein said alkyl, cycloalkyl or aryl can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifluoromethyl.
  • the present invention is considered to include stereoisomers as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in selected compounds of the present series.
  • the compounds of Formula / may also be solvated, especially hydrated. Hydration may occur during manufacturing of the compounds or compositions comprising the compounds, or the hydration may occur over time due to the hygroscopic nature of the compounds.
  • aryl as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
  • heteroaryl refers to groups having 5 to 14 ring atoms; 6, 10 or 14 ⁇ electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indolyl, in
  • aralkyl or "arylalkyl” as employed herein by itself or as part of another group refers to C,. 6 alkyl groups having an aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl.
  • cycloalkyl as employed herein by itself or as part of another group refers to cycloalkyl groups containing 3 to 9 carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
  • halogen or "halo"as employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine with chlorine being preferred.
  • the following schemes exemplify the synthesis of compounds of the present invention. A narrowly defined group of 6-ring membered heteraryl moieties are employed as exemplary starting materials. It will be understood that the following methods are broadly applicable to the full scope of the present invention by substituting the appropriate heterocyclic starting material for the starting materials disclosed in the schemes.
  • Scheme Ia illustrates the preparation of compounds of Formula / where -Z-R 1 is -OS0 2 -R', Y is divalent oxygen ( — O — ), X is a nitrogen containing 6- member heteroaryl group and W is a guanidino moiety of Formula HI or an amidino moiety of Formula 77.
  • R', D 2 , R 7 , R 8 , R 9 , R a , R b , R c and n are as defined above for Formula 7;
  • P a is a hydroxyl protecting group or hydrogen, and
  • P b is an amino protecting group.
  • Heteroaryl diols such as the 6-membered heteroaryl group 101 (where P a is H), are converted to monosulfonates 102 by treatment with appropriate sulfonyl chlorides.
  • Examples of 101 include 4,6-dihydroxy-2-methylpyrimidine and 2,4- dihydroxypyridine (available from Aldrich Chemical Co. Milwaukee, WI).
  • other available heteroaryl diols can be employed, such as 2,4- dihydroxy-3-phenylisoxazole (available from Lancaster Synthesis Inc., Windham, NH).
  • Preferred conditions include treating heteroaryl diol 101 with a sulfonyl chloride in a biphasic system composed of ether and an aqueous phase saturated with NaHCO 3 .
  • the reaction may be effected first by deprotonating 101 with a strong base, most preferably NaH, in a polar organic solvent, such as DMF or tetrahydrofuran, followed by treating the deprotonated alcohol with the sulfonyl chloride.
  • a strong base most preferably NaH
  • a polar organic solvent such as DMF or tetrahydrofuran
  • diol 101 in a typical organic solvent, such as methylene chloride, may be converted to 102 by treating the diol with sulfonyl chloride in the presence of an amine base, such as N-mefhylmorpholine.
  • Heteroaryl diols 101 may be monoprotected (P a is a protecting group) with a variety of protecting groups known in the art, such as esters and benzyl ethers (Green, T.W. & Wuts, P.G.M., Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, Inc., New York (1991)). Deprotection of the hydroxyl groups is routinely accomplished using reaction conditions well-known in the art. For example, deprotection of benzyl ethers may be effected through catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran. Deprotection of an acetate is accomplished by basic hydrolysis, most preferably with sodium hydroxide in aqueous tetrahydrofuran.
  • Preferred coupling conditions include using a trialkylphosphine or triarylphosphine, such as triphenylphosphine, in a suitable solvent, such as tetrahydrofuran or methylene chloride, and a dialkyl azodicarboxylate, such as diethyl azodicarboxylate, or an (azodicarbonyl)diamine, such as l,l'-(azodicarbonyl)dipiperidine (Tsunoda et ai, Tetrahedron Letters 34:1639 (1993)).
  • an amine base such as N-methylmorpholine.
  • the amine terminus of 103 is protected with a protecting group P b that is readily removed from 104.
  • Amino-protecting groups are well known in the art (Greene, T.W. & Wuts, P.G.M., Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, Inc., New York (1991)). Deprotection of the amino group is effected by employing reaction conditions that are well known in the art.
  • the /-butoxycarbonyl (BOC) may be removed by exposure to strongly acidic medium, such as hydrogen chloride, in a suitable solvent, such as dioxane, or a mixed trifluoroacetic acid/methylene chloride solvent system.
  • strongly acidic medium such as hydrogen chloride
  • a suitable solvent such as dioxane, or a mixed trifluoroacetic acid/methylene chloride solvent system.
  • Benzyloxycarbonyl (CBZ) groups may be removed by hydrogen using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran.
  • the resulting amine is then converted to guanidine 105 using standard reagents such as aminoiminomethanesulfonic acid (Miller, A.E. & Bischoff, J.J., Synthesis, 111 (1986)) or lH-pyrazole-1-carboxamidine hydrochloride (Bernatowicz, M.S. et ai, J. Org. Chem. 57(8):2497 (1992)).
  • the resulting amine is then converted to amidine 105' in a manner similar to the procedure described by Nagahara et ai, J. Med. Chem.
  • the amine is treated with an appropriate imidate in the presence of a base, such as N,N-diisopropylethylamine, in an appropriate solvent, such as DMF.
  • a base such as N,N-diisopropylethylamine
  • the amine is treated with an appropriate imidate in the presence of a base, such as sodium hydroxide, in an appropriate solvent, such as methanol.
  • Scheme lb illustrates the preparation of compounds of the present invention where -Z-R' is -OCH 2 -R', Y is divalent oxygen, and W is a guanidino moiety of Formula 777 or an amidino moiety of Formula 77.
  • R 1 D 2 , R 7 , R 8 , R 9 , R a , R b , R c , n, P a and P b are each as defined above.
  • Heteroaryl ethers 108 are synthesized in a fashion analogous to synthesis of 105.
  • Heteroaryl diol 101 P is H
  • aryl ether derivative 106 by treating 101 with a strong base, preferably NaH, in a suitable solvent such as DMF, followed by addition of a reactive alkyl or benzyl compound R'CH 2 X (where X is a reactive functional group, such as iodide, chloride, bromide or alkylsulfonate).
  • a strong base preferably NaH
  • R'CH 2 X where X is a reactive functional group, such as iodide, chloride, bromide or alkylsulfonate.
  • suitable alcohol protecting groups such as esters, to suppress over-alkylation
  • the protecting group may then be removed using well-known techniques, for example by hydrolysis with aqueous NaOH, when an ester protecting group is employed.
  • Heteroaryl ether alcohol 106 is then converted to guanidine 108 using the conditions described for formation of 105, and converted to amidino compound 108' using conditions described for the formation of 105'.
  • Scheme 77 ⁇ depicts synthetic routes to additional compounds of Formula 7 where -Z-R' is -NR'°SO 2 -R', Y is divalent oxygen and W is a guanidino moiety of Formula 777 or an amidino moiety of Formula 77.
  • R 1 , D 2 , R 7 , R 8 , R l ⁇ , R a , R b , R c , n, P a and P b are as defined above.
  • a nitroheteroaryl alcohol 109 may be coupled to compound 103 by standard techniques.
  • An example of a useful nitroheteroaryl alcohol is 2-hydroxy-3-nitropyridine (available from Aldrich).
  • the reaction is effected by the Mitsunobu reaction (where L is OH).
  • L is OH
  • 109 may be treated with a base, such as NaH, in a suitable solvent such as DMF or THF, followed by addition of 103 (where L is a reactive group, such as Cl, Br, I or alkylsulfonate).
  • L is a reactive group, such as Cl, Br, I or alkylsulfonate.
  • the nitro group is thereafter reduced, for example, by catalytic reduction using palladium on carbon in a suitable solvent such as ethanol or tetrahydrofuran.
  • R'SO 2 Cl an appropriate sulfonyl chloride
  • 111 can be synthesized from an aminoheteroaryl alcohol by selective sulfonylation with an appropriate sulfonyl chloride (R'SO 2 Cl) in the presence of a weak base, such as pyridine, followed by coupling with 103.
  • a weak base such as pyridine
  • useful aminoheteroaryl alcohol starting materials include 3-amino-5-hydroxypyrazole and 2-amino-3-hydroxypyridine (both available from Aldrich).
  • Removal of the amine protecting group P b of 111 may be accomplished by techniques known in the art.
  • the /-butoxycarbonyl (BOC) is removed by exposure to a strongly acidic medium, such as hydrogen chloride in a suitable solvent, such as dioxane or trifluoroacetic acid in methylene chloride.
  • Benzyloxycarbonyl (CBZ) groups are removed by catalytic hydrogen using palladium on carbon as a catalyst in solvents, such as ethanol or tetrahydrofuran.
  • solvents such as ethanol or tetrahydrofuran.
  • the deprotected amine is converted to guanidine 112 using standard reagents, such as aminoiminomethanesulfonic acid (Miller, A.E. & Bischoff, J.J., Synthesis, 777(1986)) or lH-pyrazole-1-carboxamidine hydrochloride
  • N-Substituted sulfonamide derivative 113 is obtained by alkylation of 111 employing a suitable alkylating agent (R'°X) in the presence of a base, most preferably Cs 2 CO 3 used in a polar solvent such as DMF. Deprotection and guanidinylation are then executed in a manner similar to the conversion of 111 to 112.
  • the amine 111 can also be converted to amidine 112' in a manner similar to the procedure described by Nagahara et. al., J. Med. Chem. 57(8): 1200-1207 (1994) as illustrated below in Scheme lib.
  • Amine 111 is treated with an appropriate imidate in the presence of a base such as N,N-diisopropylethylamine in an appropriate solvent such as DMF.
  • the amine is treated with an appropriate imidate in the presence of a base such as sodium hydroxide as base in an appropriate solvent such as methanol.
  • N-Substituted sulfonamide dervative 113' is obtained by alkylation of 111 employing a suitable alkylating agent (R'°X) in the presence of a base, most preferably Cs 2 C0 3 using a polar solvent such as DMF. Deprotection and amidinylation to form 113' are then executed in a manner similar to the conversion of 111 to 113.
  • R'°X suitable alkylating agent
  • R ⁇ D 2 , R 7 , R 8 , R 9 , R 10 , R a , R b , R c , n, P a and P b are as defined above.
  • halogen in this case Cl
  • the halogen is ortho to a R1SQ2CI nitrogen in the ring.
  • a nitroheteroarylamine 114 is converted to a sulfonamide by treatment with an appropriate sulfonyl chloride R'SO 2 Cl in the presence of a weak base, such as N-methylmorpholine.
  • a weak base such as N-methylmorpholine.
  • useful nitroheteroaryl amine starting materials include 2-amino-5-nitrothiazole and 3-amino-4-nitrofurozan (both available from Aldrich).
  • the resulting sulfonamide nitrogen is alkylated with a suitable alkylating agent (R I0 X) in the presence of a base, preferably an alkali metal carbonate such as Cs 2 CO 3 or K 2 CO 3 , using a polar solvent, such as DMF, to provide intermediate 115.
  • a base preferably an alkali metal carbonate such as Cs 2 CO 3 or K 2 CO 3
  • a polar solvent such as DMF
  • the resulting amine is coupled to a carboxylic acid, 116, to provide amide 117.
  • Amide coupling may be performed using any of a number of common peptide coupling reagents.
  • one of 1 ,3-dicyclohexylcarbodiimide or Castro's reagent (BOP) are employed (B. Castro et ai, Tetrahedron Lett.
  • 117 may be formed by coupling the sulfonamidoheteroarylamine with the corresponding acid chloride of acid 116 in the presence of an acid scavenger, such as N-methylmorpholine.
  • Amide 117 is converted to amine 118 by reduction of the amide functionality with an appropriate hydride reagent, preferably borane-THF complex or chlorotrimethylsilane and lithium borohydride. This reaction occurs in a suitable polar solvent, such as THF. Removal of the amine protecting group P b and formation of the guanidine, as described in Scheme 77, provides the desired compound 119.
  • the amide nitrogen may be alkylated using a strong base, such as sodium hydride, in a suitable polar solvent such as DMF, followed by treatment with an alkylating agent (R 1(> X) to afford intermediate 120.
  • a strong base such as sodium hydride
  • a suitable polar solvent such as DMF
  • R 1(> X) an alkylating agent
  • Reduction of the amide, as executed in the formation of 118, to give 121 followed by deprotection and guanidinylation as previously described provides the analogous compound 122 or amidinylation to provide 122'.
  • R 1 , D 2 , R b , R c , R 7 , R 8 and n are each as defined above.
  • Monosulfonylated heteroaryl diols 102 are converted to cyano derivatives 124 by exposing 102 to a base, most preferably sodium hydride in a suitable solvent such as DMF, followed by addition of 123, where L is a reactive group such as iodide, chloride, bromide, alkyl sulfonate, or aryl sulfonate.
  • a base most preferably sodium hydride in a suitable solvent such as DMF
  • L is a reactive group such as iodide, chloride, bromide, alkyl sulfonate, or aryl sulfonate.
  • the nitrile is submitted to amidine formation conditions such as those described by Nagahara et. ai, J. Med. Chem.
  • nitrile is first exposed to a strong acid, preferably hydrogen chloride, in a suitable alcoholic solvent, preferably methanol or ethanol, which converts the nitrile to an imidate.
  • a strong acid preferably hydrogen chloride
  • a suitable alcoholic solvent preferably methanol or ethanol
  • the imidate is treated with an appropriate amine HNR b R c to effect formation of 125.
  • heteroarylamidines 128 are prepared from 102 using appropriate heteroarylnitrilc derivatives 126.
  • Scheme V illustrates the preparation of amidinohydrazone compounds of the present invention wherein W is Formula X.
  • R'"L is the same as 133, except that the keto or aldehyde group is protected with a suitable protecting group, P c , and the remaining groups are as defined above.
  • Diols 101 (where P is H) are converted to monosulfonylated diols 102 by treatment with appropriate sulfonyl chlorides as discussed above in Scheme 7.
  • Preferred coupling conditions include using a trialkylphosphine or triarylphosphine, such as triphenylphosphine, in a suitable solvent such as tetrahydrofuran or methylene chloride, and a dialkyl azodicarboxylate, such as diethyl azodicarboxylate.
  • Typical P b are well known in the art, such as esters and benzyl ethers (Green, T.W.
  • monosulfonylated diols 102 may be treated with a base, such as sodium hydride in a solvent such as DMF and then treated with 129. Removal of P b is routinely accomplished using the reaction conditions well-known in the art. For example, deprotection of benzyl ethers may be effected through catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran.
  • Deprotection of an acetate is accomplished by basic hydrolysis, most preferably with sodium hydroxide in aqueous tetrahydrofuran.
  • the resulting alcohol is then oxidized using routine procedures for the oxidation of alcohols (see for Example Carey F.A, Sundberg, R.J., Advanced Organic Chemistry, Part B: Reactions and Synthesis, 3rd edition, Plenum Press. New
  • L OH or a reactive leaving group such as halide, alkyl sulfonate, or aryl sulfonate.
  • monosulfonylated diol 102 may be treated with a base, such as sodium hydride in a solvent such as DMF and then treated with 133.
  • the aldehyde or ketone protecting group may then be removed to afford 129 using standard conditions well known in the art, for example, TsOH in acetone (Green,
  • Compound 129 is then treated with an aminoguanidine 130, such as aminoguanidine or 2-hydrazinoimidazoline, optionally in the presence of an acid, such as nitric acid, hydrogen chloride, or hydrogen bromide, to afford 131.
  • aminoguanidine 130 such as aminoguanidine or 2-hydrazinoimidazoline
  • an acid such as nitric acid, hydrogen chloride, or hydrogen bromide
  • Useful solvents include, for example, ethanol or methanol, which may contain other solvents such as methylene chloride or tetrahydrofuran.
  • R 9 and the R 7 on the carbon atom adjacent to the carbon to which R 9 is attached together form a methylene linkage can be synthesized by employing as R"L in Scheme Va cyclic ketone having a reactive group L that is attached directly or indirectly to the carbocyclic ring.
  • suitable reagents for R'L include 2-hydroxycyclopentanone, 3- hydroxycyclopentanone, 2 -hydroxy cyclohexanone and 3-hydroxycyclohcxanone.
  • R 6 and R b of Formula X are taken together with the nitrogens to which they are attached to form a ring structure are prepared by substituting a heterocyclic amine 134 (below) for the aminoguanidine 130 in Scheme V.
  • the pharmaceutically acceptable acid addition salts those salts in which the anion does not contribute significantly to toxicity or pharmacological activity of the organic cation, are preferred.
  • the acid addition salts are obtained either by reaction of an organic base of Formula 7 with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods detailed in the literature available to any practitioner skilled in the art.
  • useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, cyclamic acid, pivalic acid and the like; useful inorganic acids are hydrohalide acids such as HC1, HBr, HI; sulfuric acid; phosphoric acid and the like.
  • Preferred acids for forming acid addition salts include HC1 and acetic acid.
  • the compounds of the present invention represent a novel class of potent inhibitors of metallo, acid, thiol and serine proteases.
  • serine proteases inhibited by compounds within the scope of the invention include leukocyte neutrophil elastase, a proteolytic enzyme implicated in the pathogenesis of emphysema; chymotrypsin and trypsin, digestive enzymes; pancreatic elastase, and cathepsin G, a chymotrypsin-like protease also associated with leukocytes; thrombin and factor Xa, proteolytic enzymes in the blood coagulation pathway.
  • thermolysin a metalloprotease, and pepsin, an acid protease
  • compounds of the present invention are also contemplated uses of compounds of the present invention.
  • the compounds of the present invention are preferably employed to inhibit trypsin-like proteases.
  • an end use application of the compounds that inhibit chymotrypsin and trypsin is in the treatment of pancreatitis.
  • the potency and other biochemical parameters of the enzyme-inhibiting characteristics of the compounds of the present invention is readily ascertained by standard biochemical techniques well-known in the art.
  • Actual dose ranges for their specific end-use application will, of course, depend upon the nature and severity of the disease state of the patient or animal to be treated, as determined by the attending diagnostician. It is expected that a useful dose range will be about 0.01 to 10 mg per kg per day for an effective therapeutic effect.
  • Compounds of the present invention that are distinguished by their ability to inhibit either factor Xa or thrombin may be employed for a number of therapeutic purposes.
  • As factor Xa or thrombin inhibitors compounds of the present invention inhibit thrombin production. Therefore, these compounds are useful for the treatment or prophylaxis of states characterized by abnormal venous or arterial thrombosis involving either thrombin production or action.
  • thrombosis states include, but are not limited to, deep vein thrombosis; disseminated intravascular coagulopathy which occurs during septic shock, viral infections and cancer; myocardial infarction; stroke; coronary artery bypass; hip replacement; and thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PCTA).
  • PCTA percutaneous transluminal coronary angioplasty
  • the compounds of the present invention find additional use in the treatment or prophylaxis of adult respiratory distress syndrome; inflammatory responses, such as edema; reperfusion damage; atherosclerosis; and restenosis following an injury such as balloon angioplasty, atherectomy, and arterial stent placement.
  • the compounds of the present invention may be useful in treating neoplasia and metastasis as well as neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.
  • the compounds of the present invention may be administered in an effective amount within the dosage range of about 0.1 to about 500 mg/kg, preferably between 0.1 to 10 mg/kg body weight, on a regimen in single or 2-4 divided daily doses.
  • the compounds of the present invention may be used in combination with thrombolytic agents such as tissue plasminogen activator, streptokinase, and urokinase. Additionally, the compounds of the present invention may be used in combination with other antithrombotic or anticoagulant drugs such as, but not limited to, fibrinogen antagonists and thromboxane receptor antagonists.
  • thrombolytic agents such as tissue plasminogen activator, streptokinase, and urokinase.
  • other antithrombotic or anticoagulant drugs such as, but not limited to, fibrinogen antagonists and thromboxane receptor antagonists.
  • the neutrophil elastase inhibitory properites of compounds within the scope of the present invention are determined by the following method.
  • Neutrophil elastase is prepared by the procedure described by Baugh et ai, Biochemistry 15: 836 (1979). Enzyme assays are conducted substantially according to the procedure disclosed by Nakajima et ai, J. Biol. Chem. 254: 4027 (1979), in assay mixtures containing 0.10 M Hepes (N-2-hydroxyethylpiperazine- N'-2-ethanesulfonic acid) buffer, pH 7.5; 0.5 M NaCl; 10% dimethylsulfoxide; and 1.50 x 10 "4 M MeOSuc-Ala-Ala-Pro-Val-p-nitroanilide as substrate. Inhibitors are evaluated by comparing enzymatic activity measured in the presence and absence of inhibitor.
  • Cathepsin G inhibitory properties of compounds within the scope of the present invention are determined by the following method.
  • a preparation of partially purified human Cathepsin G is obtained by the procedure of Baugh et ai , Biochemistry 15: 836 (1979).
  • Leukocyte granules are a major source for the preparation of leukocyte elastase and cathepsin G (chymotrypsin-like activity).
  • Leukocytes are lysed and granules are isolated.
  • the leukocyte granules are extracted with 0.20 M sodium acetate, pH 4.0, and extracts are dialyzed against
  • Enzyme preparations are assayed in 2.00 mL of 0.10 M Hepes buffer, pH 7.5, containing 0.50 M NaCl, 10% dimethyl sulfoxide and 0.0020 M Suc-Ala-Ala-Pro-Phe-p-nitroanilide as a substrate. Hydrolysis of the p-nitroanilide substrate is monitored at 405 nm and at 25°.
  • Human ⁇ -thrombin and human factor Xa can be obtained from Enzyme Research Laboratories (South Bend, Indiana).
  • Bovine trypsin can be obtained from Sigma. Kj Determinations
  • test compound is prepared in DMSO, and diluted into an assay buffer consisting of 50mM HEPES, 200 mM NaCl, pH 7.5. The final concentration for each of the substrates is listed below. In general, substrate concentrations are lower than the experimentally determined value for K m .
  • Test compounds are prepared as a 0.16 mg/mL solution in DMSO. Dilutions are prepared in DMSO yielding 8 final concentrations encompassing a 200-fold concentration range. Enzyme solutions are prepared at the concentrations listed below in assay buffer.
  • Thrombin activity is assessed as the ability to hydrolyze the substrate Sue- Ala- Ala-Pro- Arg-pN A.
  • Factor Xa activity is assessed as the ability to hydrolyze the substrate Bz- Ile-Glu-Gly-Arg-pNA.
  • Chymotrypsin activity is assessed as the ability to hydrolyze the substrate Suc-Ala-Ala-Pro-Phe-pNA.
  • Final DMSO concentration is 0.3%.
  • Useful dose range for the application of compounds of the present invention as neutrophil elastase inhibitors and as Cathepsin G inhibitors will of course depend upon the nature and severity of the disease state, as determined by the attending diagnostician, with the range of 0.01 to 10 mg/kg of body weight, per day, being useful for the aforementioned disease states.
  • Compounds of the present invention that inhibit urokinase or plasminogen activator are potentially useful in treating excessive cell growth disease state.
  • the compounds of the present invention may also be useful in the treatment of benign prostatic hypertrophy and prostatic carcinoma, the treatment of psoriasis, and in their use as abortifacients.
  • the potency and other biochemical parameters of the enzyme inhibiting characteristics of the compounds of the present invention are readily ascertained by standard biochemical techniques well-known in the art. Actual dose ranges for their specific end-use application will, of course, depend upon the nature and severity -46-
  • chymotrypsin is supplied as a standard reagent for use in clinical quantitation of chymotrypsin activity in pancreatic juices and feces. Such assays are diagnostic for gastrointestinal and pancreatic disorders.
  • Pancreatic elastase is also supplied commercially as a reagent for quantitation of ⁇ ,-antitrypsin in plasma.
  • Compounds of the present invention can be used to enhance the accuracy and reproducibility of this assay by titrametric standardization of the commercial elastase supplied as a reagent. See, U.S. Patent
  • proteases present in such extracts can be inhibited during purification steps by compounds of the present invention, which bind tightly to various proteolytic enzymes.
  • compositions of the invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention.
  • animals Foremost among such animals are humans, although the invention is not intended to be so limited.
  • compositions of the present invention can be administered by any means that achieve their intended purpose.
  • administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular routes.
  • administration can be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • the new pharmaceutical preparations can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • compositions of the present invention are manufactured in a manner that is, itself, known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or poly vinyl pyrrolidone.
  • fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth,
  • disintegrating agents can be added, such as, the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as, sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as, magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings that, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as, acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations which can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as, glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules that may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as, fatty oils or liquid paraffin.
  • stabilizers may be added.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water- soluble salts, alkaline solutions and cyclodextrin inclusion complexes.
  • Especially preferred alkaline salts are ammonium salts prepared, for example, with Tris, choline hydroxide, Bis-Tris propane, N-methylglucamine, or arginine.
  • One or more modified or unmodified cyclodextrins can be employed to stabilize and increase the water solubility of compounds of the present invention.
  • Useful cyclodextrins for this purpose are disclosed in U.S. Patent Nos. 4,727,064, 4,764,604, and 5,024,998.
  • suspensions of the active compounds as appropriate oily injection suspensions can be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
  • Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • the following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered and obvious to those skilled in the art are within the spirit and scope of the invention.

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Abstract

L'invention concerne des inhibiteurs d'enzymes protéolitiques: composés aminido, amidinohydrazone et benzamidino à noyau central hétérocyclique, représentés par la formule R1-Z-X-Y-W, ou bien leurs solvats, leurs hydrats ou leurs sels pharmaceutiquement acceptables. Dans ladite formule, X est une fraction hétérocyclique, W est une fraction spécifique amidino, amidinohydrazone ou guanidino, R1, Y et Z étant définis par ailleurs aux fins de l'invention. On décrit également des procédés relatifs à la fabrication de ces composés et à leur utilisation pour inhiber les protéases (par exemple, thrombine). La structure (A) est une illustration du type de composés considérés.
PCT/US1997/009846 1996-06-12 1997-06-11 Inhibiteurs de protease heterocyclique amidino et guanidino WO1997047299A1 (fr)

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US6020357A (en) * 1996-12-23 2000-02-01 Dupont Pharmaceuticals Company Nitrogen containing heteroaromatics as factor Xa inhibitors
US6191159B1 (en) 1998-03-27 2001-02-20 Dupont Pharmaceuticals Company Disubstituted pyrazolines and triazolines as factor Xa inhibitors
US6221898B1 (en) 1996-07-04 2001-04-24 Astra Aktiebolag Amidino derivatives and their use as thrombin inhibitors
US6271237B1 (en) 1997-12-22 2001-08-07 Dupont Pharmaceuticals Company Nitrogen containing heteromatics with ortho-substituted P1s as factor Xa inhabitors
WO2001090093A1 (fr) * 2000-05-22 2001-11-29 Biovitrum Ab Inhibiteurs de 11-beta-hydroxy-steroide-deshydrogenase de type 1
US6399644B1 (en) 1999-04-02 2002-06-04 Ruth R. Wexler Aryl sulfonyls as factor XA inhibitors
US6417200B1 (en) 1997-06-26 2002-07-09 Eli Lilly And Company Antithrombotic agents
US6548512B1 (en) 1996-12-23 2003-04-15 Bristol-Myers Squibb Pharma Company Nitrogen containing heteroaromatics as factor Xa inhibitors
US6569874B1 (en) 1996-12-23 2003-05-27 Bristol-Myers Squibb Company Thiazoles as factor Xa inhibitors
US6903085B1 (en) 1999-08-24 2005-06-07 Astrazeneca, Ab Substituted piperidine compounds useful as modulators of chemokine receptor activity
US6958350B2 (en) 2001-02-19 2005-10-25 Astrazeneca Ab Chemical compounds
US6960602B2 (en) 2001-03-22 2005-11-01 Astrazeneca Ab Piperidine derivatives as modulators of chemokine receptors
US6962905B1 (en) 1999-04-21 2005-11-08 Astrazeneca Ab Pharmaceutical formulation comprising a low molecular weight thrombin inhibitor and its prodrug
US7192973B2 (en) 2001-11-15 2007-03-20 Astrazeneca Ab Piperidine derivatives and their use as modulators of chemokine receptor activity (especially CCR5)
US7294636B2 (en) 2003-05-09 2007-11-13 Astrazeneca Ab Chemical compounds
US7820704B2 (en) 2004-04-20 2010-10-26 Transtech Pharma, Inc. Substituted heteroaryl derivatives, compositions, and methods of use
EP2602248A1 (fr) * 2011-12-05 2013-06-12 University Of Leicester Nouveaux composés pyrroliques
US8563742B2 (en) 2008-08-29 2013-10-22 High Point Pharmaceuticals, Llc Substituted aminothiazole derivatives, pharmaceutical compositions, and methods of use
WO2014195705A1 (fr) * 2013-06-04 2014-12-11 University Of Leicester Nouveaux dérivés de pyrrole

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US5021578A (en) * 1985-12-21 1991-06-04 Hoechst Aktiengesellschaft Certain perfluoroloweralkoxy-2-pyridyloxy propionates having herbicidal activity
US5104889A (en) * 1986-08-04 1992-04-14 Otsuka Pharmaceutical Factory, Inc. Thiazole derivatives
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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7074820B2 (en) 1996-07-04 2006-07-11 Astrazeneca Ab Amidino derivatives and their use as thrombin inhibitors
US6221898B1 (en) 1996-07-04 2001-04-24 Astra Aktiebolag Amidino derivatives and their use as thrombin inhibitors
US6569874B1 (en) 1996-12-23 2003-05-27 Bristol-Myers Squibb Company Thiazoles as factor Xa inhibitors
US6962935B2 (en) 1996-12-23 2005-11-08 Bristol-Myers Squibb Pharma Company Oxygen or sulfur containing heteroaromatics as factor Xa inhibitors
US6020357A (en) * 1996-12-23 2000-02-01 Dupont Pharmaceuticals Company Nitrogen containing heteroaromatics as factor Xa inhibitors
US6548512B1 (en) 1996-12-23 2003-04-15 Bristol-Myers Squibb Pharma Company Nitrogen containing heteroaromatics as factor Xa inhibitors
US6417200B1 (en) 1997-06-26 2002-07-09 Eli Lilly And Company Antithrombotic agents
US6677369B2 (en) 1997-06-26 2004-01-13 Eli Lilly And Company Antithrombotic agents
US6271237B1 (en) 1997-12-22 2001-08-07 Dupont Pharmaceuticals Company Nitrogen containing heteromatics with ortho-substituted P1s as factor Xa inhabitors
US6548525B2 (en) 1997-12-22 2003-04-15 Bristol-Myers Squibb Pharma Company Nitrogen containing heteroaromatics with ortho-substituted P1's as factor Xa inhibitors
EP1064270B1 (fr) * 1998-03-27 2004-10-06 Bristol-Myers Squibb Pharma Company Pyrazolines et triazolines disubstituees, utilisees en tant qu'inhibiteurs du facteur xa
US6436985B2 (en) 1998-03-27 2002-08-20 Bristol-Myers Squibb Pharma Company Disubstituted pyrazolines and triazolines as factor Xa inhibitors
US6191159B1 (en) 1998-03-27 2001-02-20 Dupont Pharmaceuticals Company Disubstituted pyrazolines and triazolines as factor Xa inhibitors
US6630468B2 (en) 1998-03-27 2003-10-07 Donald J. P. Pinto Disubstituted pyrazolines and triazolines as factor Xa inhibitors
US6689770B2 (en) 1999-04-02 2004-02-10 Bristol-Myers Squibb Pharma Company Aryl sulfonyls as factor Xa inhibitors
US6399644B1 (en) 1999-04-02 2002-06-04 Ruth R. Wexler Aryl sulfonyls as factor XA inhibitors
US6962905B1 (en) 1999-04-21 2005-11-08 Astrazeneca Ab Pharmaceutical formulation comprising a low molecular weight thrombin inhibitor and its prodrug
US6903085B1 (en) 1999-08-24 2005-06-07 Astrazeneca, Ab Substituted piperidine compounds useful as modulators of chemokine receptor activity
WO2001090093A1 (fr) * 2000-05-22 2001-11-29 Biovitrum Ab Inhibiteurs de 11-beta-hydroxy-steroide-deshydrogenase de type 1
US6958350B2 (en) 2001-02-19 2005-10-25 Astrazeneca Ab Chemical compounds
US6960602B2 (en) 2001-03-22 2005-11-01 Astrazeneca Ab Piperidine derivatives as modulators of chemokine receptors
US7192973B2 (en) 2001-11-15 2007-03-20 Astrazeneca Ab Piperidine derivatives and their use as modulators of chemokine receptor activity (especially CCR5)
US7294636B2 (en) 2003-05-09 2007-11-13 Astrazeneca Ab Chemical compounds
US7820704B2 (en) 2004-04-20 2010-10-26 Transtech Pharma, Inc. Substituted heteroaryl derivatives, compositions, and methods of use
US8563742B2 (en) 2008-08-29 2013-10-22 High Point Pharmaceuticals, Llc Substituted aminothiazole derivatives, pharmaceutical compositions, and methods of use
EP2602248A1 (fr) * 2011-12-05 2013-06-12 University Of Leicester Nouveaux composés pyrroliques
US9221756B2 (en) 2011-12-05 2015-12-29 University Of Leicester Pyrrole derivatives
WO2014195705A1 (fr) * 2013-06-04 2014-12-11 University Of Leicester Nouveaux dérivés de pyrrole

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