US 6,476,016 B2 · Cyclic oxyguanidine pyrazinones as protease inhibitors

Abstract

Cyclic oxyguanidine pyrazinone compounds are described, including compounds of the Formula I: wherein R3, R4, R5, W, and A are as set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof. The compounds of the 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. Compositions for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation are described. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. Additionally, the compounds can be detectably labeled and employed for in vivo imaging of thrombi.

A compound of Formula I:

or a hydrate or pharmaceutically acceptable salt thereof;
wherein:
W is hydrogen, R1, R1OCO, R1CO, R1(CH2)sNHCO, or (R1)2CH(CH2)sNHCO, wherein s is 0-4;
R1 is
R2,
R2(CH2)tC(R12)2, where t is 0-3, and each R12 can be the same or different,
(R2)(OR12)CH(CH2)p, where p is 1-4,
(R2)2(OR12)C(CH2)p, where p is 1-4,
R2C(R12)2(CH2)t, wherein t is 0-3, each R12 can be the same or different, wherein (R12)2 can also form a ring with C represented by C3-7 cycloalkyl,
R2CF2C(R12)2(CH2)q, wherein q is 0-2, and each R12 can be the same or different, wherein (R12)2, can also form a ring with C represented by C3-7 cycloalkyl,
R2CH2C(R12)2(CH2)q, wherein q is 0-2, and each R12 can be the same or different, wherein (R12)2 can also form a ring with C represented by C3-7 cycloalkyl,
(R2)2CH(CH2)r, where r is 0-4and each R2 can be the same or different, and wherein (R2)2 can also form a ring with CH represented by C3-7 cycloalkyl, C7-12 bicyclic alkyl, C10-16 tricyclic alkyl or a 5- to 7-membered mono- or 9- or 10- membered bicyclic heterocyclic ring which is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl,
R2O(CH2)p, wherin p is 2-4,
(R2)2CF(CH2)r, wherein r is 0-4 and each R2 can be the same or different, wherein (R2)2 can also form a ring with C represented by C3-7 cycloalkyl, C7-2 bicyclic alkyl, C10-16 tricyclic alkyl, or a 5- to 7-membered mono- or 9- or 10- membered bicyclic heterocyclic ring which is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl,
R2CF2C(R12)2;
R2 is
phenyl, naphthyl, or biphenyl, each of which is unsubstituted or substituted with one or more of C1-4 alkyl, C1-4 alkoxy, halogen, hydroxy, CF3, OCF3, COOH, CONH2, or SO2NH2,
a 5- to 7-membered mono- or a 9- to 10-membered bicyclic heterocyclic ring or non-heterocyclic ring which can be saturated or unsaturated, wherein the heterocyclic ring is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl, each of which is optionally substituted with halogen or hydroxy, and wherein the heterocyclic or non-heterocyclic ring is unsubstituted or substituted with halogen or hydroxy,
C1-7 alkyl, unsubstituted or substituted with one or more of hydroxy, COOH, amino, aryl, C3-7 cycloalkyl, CF3, N(CH3)2, or C1-3 alkylaryl,
CF3,
C3-7 cycloalkyl, unsubstituted or substituted with aryl,
C7-12 bicyclic alkyl, or
C10-16 tricyclic alkyl;
R3 is
hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkynyl, optionally substituted C6-10 aryl, optionally substituted C6-10 ar(C1-6)alkyl, trifluoromethyl, halogen, C1-6 hydroxyalkyl, cyano, nitro, carboxamido, —CO2Rx, —CH2ORx or —ORx,
where Rx, in each instance, is independently one of hydrogen, C1-6 alkyl or C3-7 cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;
R4 is
hydrogen or halogen;
R12 is
hydrogen
phenyl, naphthyl, or biphenyl, each of which is unsubstituted with one or more of C1-4 alkyl, C1-4 alkoxy, halogen, hydroxy, CF3, OCF3, COOH, or CONH2,
a 5- to 7-membered mono- or a 9- to 10-membered bicyclic heterocyclic ring which is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl,
C1-4 alkyl, unsubstituted or substituted with one or more of hydroxy, COOH, amino, or aryl,
CF3,
C3-7 cycloalkyl,
C7-12 bicyclic alkyl, or
C10-16 tricyclic alkyl;
R5 is hydrogen, C1-4 alkyl, or C2-4 alkenyl;
A is one of
Ra, Rb and Rc are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO2Rw, where
Rw is alkyl, cycloalkyl, phenyl, benzyl,
where Rd and Re are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl;
each n is from zero to 4;
each m is from zero to 4;
and
each j is from zero to 4;
provided that n, m and j are not all zero.

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Cyclic oxyguanidine pyrazinones as protease inhibitors

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Cyclic oxyguanidine pyrazinones as protease inhibitors

Life of this patent

Abstract

Claims25