Back to results
US 6,306,884 B1Granted
Benzamidine derivatives and their use as anti-coagulants
AssigneeBerlex Laboratories, Inc.
InventorsBrad O. Buckman, David D. Davey, William J. Guilford, Michael M. Morrissey, Howard P. Ng, Gary B. Phillips, Shung C. Wu, Wei Xu
Life of this patent
Estimating the term…
Abstract
This invention is directed to benzamidine derivatives which are useful as anti-coagulants. This invention is also directed to pharmaceutical compositions containing the compounds of the invention, and methods of using the compounds to treat disease-states characterized by thrombotic activity.
Claims14
A compound of selected from the group consisting of the following formulae:
- wherein
- A is —N═;
- Z1 and Z2 are independently —N(R8)— or —S—;
- R1 and R3 are independently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, —N(R8)R9, —C(O)OR8, —C(O)N(R8)R9, —C(O)N(W)CH2C(O)N(R8)R9, —N(R8)C(O)N(R8)R9, —N(R8)C(O)R8, —N(R8)S(O)2R12, or —N(R8)C(O)N(R8)CH2C(O)N(R8)R9;
- R2 is hydrogen;
- halo;
- alkyl;
- haloalkoxy;
- —OR8;
- —C(O)OR8;
- —C(O)N(R8)R9;
- —N(R8)R9;
- —C(O)N(R8)(CH2)mC(O)OR8 (where m is 0 to 3);
- —N(R8)(CH2)nC(O)OR8 (where n is 1 to 3);
- —N((CH2)nN(R8)R9)(CH2)nC(O)OR8 (where each n is 1 to 3);
- —O(CH2)nC(O)N(R8)R9 (where n is 1 to 3);
- —O(CH2)pC(O)OR8 (where p is 1 to 6);
- —N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3);
- morpholin-4-yl;
- 3-tetrahydrofuranoxy;
- or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of —OR8, —C(O)N(R8)R9, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl));
- or R2 is piperazin-1-yl (optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is 1-piperazinoyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is piperidin-1-yl (optionally substituted by one or more substituents selected from the group consisting of carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is (3,4)-piperidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkylcarbonyl, carboxy, —C(O)N(R8)R9, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, and tetrazolylalkyl);
- or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, carboxyalkyl, —C(O)N(R8)R9, alkoxycarbonylalkyl and aralklyl);
- or R2 is 3-pyrrolidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkyl, aralkyl, amidino, 1-iminoethyl, carboxy, carboxyalkyl, —C(O)N(R8)R9, alkoxycarbonyl and alkoxycarbonylalkyl);
- R4 and R7 are independently hydrogen, halo, alkyl, nitro, —OR8, —C(O)OR8, —C(O)N(R8)R9, —N(R8)R9, —N(H)C(O)R8, or —N(H)S(O)2R12;
- R5 is —C(NH)NH2, —C(NH)N(H)OR8, —C(NH)N(H)C(O)OR12, —C(NH)N(H)S(O)2R12, —C(NH)N(H)C(O)N(R8)R9, or —C(NH)N(H)C(O)R8;
- R6 is halo, alkyl, haloalkyl, haloalkoxy, nitro, amino, ureido, guanidino, —OR8, —C(NH)NH2, —C(NH)NHOH, —C(O)R10, —(CH2)mC(O)N(R8)R9 (where m is 0 to 3), —CH(OH)C(O)N(R8)R9, —(CH2)mN(R8)R9 (where m is 0 to 3), —(CH2)mC(O)OR8 (where m is 0 to 3), —N(H)C(O)R8, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);
- each R8 and R9 is independently hydrogen, alkyl, aryl, or aralkyl;
- R10 is hydrogen, alkyl, aryl, aralkyl, 1-pyrrolidinyl, 4-morpolinyl, 4-piperazinyl, 4-(N-methyl)piperazinyl, or piperidin-1-yl;
- and
- R12 is alkyl, aryl or aralkyl;
- or a pharmaceutically acceptable salt thereof.
32 more elements
A compound selected from the group consisting of the following formulae:
- wherein
- A is —N═;
- Z1 and Z2 are independently —O —N(R) or —S;
- R1 and R3 are independently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, —N(R8)R9, —C(O)ORW, —C(O)N(R8)R9, —C(O)N(R8)CH2C(O)N(R8)R9, —N(R8)C(O)N(R8)R9, —N(R8)C(O)R8, —N(R8)S(O)2R12, or —N(R8)G(O)N(R8)OH2C(O)N(R8)R9;
- R2 is hydrogen;
- halo;
- alkyl;
- haloalkoxy;
- —OR8;
- —C(O)ORI;
- —C(O)N(R8)R9;
- —N(R8)R9;
- —C(O)N(R8)(CH2)mC(O)OR8 (where m is 0 to 3);
- —N(R8)(CH2)nC(O)OR8 (where n is 1 to 3);
- —N((CH2)nN(R8)R9)(CH2)nC(O)OR8 (where each n is 1 to 3);
- —O(CH2)nC(O)N(R8)R9 (where n is 1 to 3);
- —O(CH2)pC(O)OR8 (where p is 1 to 6);
- —N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3);
- morpholin-4-yl;
- 3tetrahydrofuranoxy;
- or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of —OR8, —C(O)N(R8)R9, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl));
- or R2 is piperazin-1-yl (optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is 1-piperazinoyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is piperidin-1-yl (optionally substituted by one or more substituents selected from the group consisting of carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, carboxyalkyl, —C(O)N(R8)R9, alkoxycarbonylalkyl and aralklyl);
- R4 and R7 are independently hydrogen, halo, alkyl, nitro, R8, —C(O)OR8, —C(O)N(R8)R9, —N(RW)R9, —N(H)C(O)R8, or —N(H)S(O)2R12;
- R5 is —C(NH)NH2, —C(NH)N(H)OR8, —C(NH)N(H)C(O)OR12, —C(NH)N(H)S(O)2R12, —C(NH)N(H)C(O)N(R8)R9, or —C(NH)N(H)C(O)R8;
- R6 is halo, alkyl, haloalkyl, haloalkoxy, nitro, amino, ureido, guanidino, —OR8, —C(NH)NH2, —C(NH)NHOH, —C(O)R10, —(CH2)mC(O)N(R8)R9 (where m is 0 to 3), —CH(OH)C(O)N(R8)R9, —(CH2)mN(R8)R9 (where m is 0 to 3), —(CH2)mC(O)OR8 (where m is 0 to 3), —N(H)C(O)R8, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);
- each R8 and R9 is independently hydrogen, alkyl, aryl, or aralkyl;
- R10 is hydrogen, alkyl, aryl, aralkyl, 1-pyrrolidinyl, 4-morpolinyl, 4-piperazinyl, 4-(Nmethyl)piperazinyl, or piperidin-1-yl;
- and
- R12 is alkyl, aryl or aralkyl;
- or a pharmaceutically acceptable salt thereof.
30 more elements
A pharmaceutical composition useful in treating a human having a disease-state characterized by thrombotic activity, which composition comprises a therapeutically effective amount of a compound selected from the group consisting of the following formulae:
- wherein
- A is —N═;
- Z1 and z2 are independently —N(R8)— or —S—;
- R1 and R3 are independently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, —N(R8)R9, —C(O)OR8, —C(O)N(R8)R9, —C(O)N(R8)CH2C(O)N(R8)R9, —N(R8)C(O)N(R8)R9, —N(R8)C(O)R8,—N(R8)S(O)2R12 or —N(R8)C(O)N(R8)CH2C(O)N(R8)R9;
- R2 is hydrogen;
- halo;
- alkyl;
- haloalkoxy;
- —OR8;
- —C(O)OR8;
- —C(O)N(R8)R9;
- —N(R8)R9;
- C(O)N(R8)(CH2)mC(O)OR8 (where m is 0 to 3);
- —N(R8)(CH2)nC(O)OR8 (where n is 1 to 3);
- —N((CH2)nN(R8)R)(CH2)nC(O)OR8 (where each n is 1 to 3);
- —O(CH2)nC(O)N(R8)R9 (where n is 1 to 3);
- —O(CH2)pC(O)OR8 (where p is 1 to 6);
- —N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3);
- morpholin-4-yl;
- 3-tetrahydrofuranoxy;
- or R2 is aryloxy (optionally substituted by one or more substuents independently selected from the group consisting of —OR8, —C(O)N(R8)R9, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)imidazolinyl (optionally substituted by alkyl));
- or R2 is piperazin-1-yl (optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is 1-piperazinoyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is piperidin-1-yl (optionally substituted by one or more substituents selected from the group consisting of carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is (3,4)-piperidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkylcarbonyl, carboxy, —C(O)N(R8)R9, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, and tetrazolylalkyl);
- or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, carboxyalkyl, —C(O)N(R8)R9, alkoxycarbonylalkyl and aralklyl);
- or R2 is 3-pyrrolidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkyl, aralkyl, amidino, 1-iminoethyl, carboxy, carboxyalkyl, —C(O)N(R8)R9, alkoxycarbonyl and alkoxycarbonylalkyl);
- R4 and R7 are independently hydrogen, halo, alkyl, nitro, —OR8, —C(O)OR8, —C(O)N(R8)R9, —N(R8)R9, —N(H)C(O)R8, or —N(H)S(O)2R12;
- R5 is —C(NH)NH2, —C(NH)N(H)OR8, —C(NH)N(H)C(O)OR 2, —C(NH)N(H)S(O)2R12, —C(NH)N(H)C(O)N(R8)R9, or —C(NH)N(H)C(O)R8;
- R6 is halo, alkyl, haloalkyl, haloalkoxy, nitro, amino, ureido, guanidino, —OR8, —C(NH)NH2, —C(NH)NHOH, —C(O)Rlo, —(CH2)mC(O)N(R8)R9 (where m is 0 to 3), —CH(OH)C(O)N(R8)R9, —(CH2)mN(R8)R9 (where m is 0 to 3), —(CH2)mC(O)OR8 (where m is 0 to 3), —N(H)C(O)R8, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);
- each R8 and R9 is independently hydrogen, alkyl, aryl, or aralkyl;
- R10 is hydrogen, alkyl, aryl, aralkyl, 1-pyrrolidinyl, 4-morpolinyl, 4-piperazinyl, 4-(N-methyl)piperazinyl, or piperidin-1-yl;
- and
- R12 is alkyl, aryl or aralkyl;
- or a pharmaceutically acceptable salt thereof;
- and a pharmaceutically acceptable excipient.
33 more elements
A method of treating a human having a disease state characterized by thrombotic activity, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound selected from the group consisting of the following formulae:
- wherein
- A is or —N═;
- Z1 and Z2 are independently —N(R8)— or —S—:
- R1 and R3 are independently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, —N(R8)R9, —C(O)OR8, —C(O)N(R8)R9, —C(O)N(R8)CH2C(O)N(R8)R9, —N(R8)C(O)N(R8)R9, —N(R8)C(O)R8, —N(R8)S(O)2R12, or —N(R8)C(O)N(R8)CH2C(O)N(R8)R9;
- —N(R8)C(O)R8, —N(R8)S(O)2R12, or
- R2 is hydrogen;
- halo;
- alkyl;
- haloalkoxy;
- —OR8;
- —C(O)OR6;
- —C(O)N(R8)R9;
- —N(R8)R9;
- —C(O)N(R8)(CH2)mC(O)OR8 (where m is 0 to 3);
- —N(R8)(CH2)nC(O)OR8 (where n is 1 to 3);
- —N((CH2)nN(R8)R)(CH2)nC(O)OR8 (where each n is 1 to 3);
- —O(CH2)nC(O)N(R8)R9 (where n is 1 to 3);
- —O(CH2)pC(O)OR8 (where p is 1 to 6);
- —N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3);
- morpholin-4-yl;
- 3-tetrahydrofuranoxy;
- or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of —OR8, —C(O)N(R8)R9, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl));
- or R2 is piperazin-1-yl (optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is 1-piperazinoyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, carboxy, C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is piperidin-1-yl (optionally substituted by one or more substituents selected from the group consisting of carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is (3,4)-piperidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkylcarbonyl, carboxy, —C(O)N(R8)R9, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, and tetrazolylalkyl);
- or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, carboxyalkyl, —C(O)N(R8)R9, alkoxycarbonylalkyl and aralklyl);
- or R2 is 3-pyrrolidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkyd, aralkyl, amidino, 1-iminoethyl, carboxy, carboxyalkyl, —C(O)N(R8)R9, alkoxycarbonyl and alkoxycarbonylalkyl);
- R4 and R7 are independently hydrogen, halo, alkyl, nitro, —OR8, —C(O)OR8, —C(O)N(R8)R8, —N(R8)R9, —N(H)C(O)R8, or —N(H)S(O)2R12;
- R5 is —C(NH)NH2, —C(NH)N(H)OR8, —C(NH)N(H)C(O)OR12, —C(NH)N(H)C(O)2R12, —C(NH)N(H)C(O)N(R8)R9, or C(NH)N(H)C(O)R8;
- R6 is halo, alkyl, haloalkyl, haloalkoxy, nitro, amino, ureido, guanidino, —OR8, —C(NH)NH2, —C(NH)NHOH, —C(O)R10, —(CH2)mC(O)N(R8)R9 (where m is 0 to 3), —CH(OH)C(O)N(R8)R9, (CH2)mN(R8)R9 (where m is 0 to 3), —(CH2)mC(O)OR8 (where m is 0 to 3), —N(H)C(O)R8, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);
- each R8 and R9 is independently hydrogen, alkyl, aryl, or aralkyl;
- R10 is hydrogen, alkyl, aryl, aralkyl, 1-pyrrolidinyl, 4-morpolinyl, 4-piperazinyl, 4-(NVmethyl)piperazinyl, or piperidin-1-yl;
- and
- R12 is alkyl, aryl or aralkyl;
- or a pharmaceutically acceptable salt thereof.
33 more elements
A pharmaceutical composition useful in treating a human having a disease-state characterized by thrombotic activity, which composition comprises a therapeutically effective amount of a compound selected from the group consisting of the following formulae:
- wherein
- A is —N═;
- Z1 and Z2 are independently —O—, —N(R8) or —S—;
- R1 and R 3 are independently hydrogen, halo, alkyl, haloalkl, alkoxy, haloalkoxy, nitro, —N(R8)R9, —C(O)OR8, —C(O)N(R8)R9, —C(O)N(R8)CH2C(O)N(R8)R9, —N(R8)C(O)N(R8)R9, —N(R8)C(O)R8, —N(R8)C(O)2R12, or —N(R8)C(O)N(R8)CH2C(O)N(R)R9;
- R2 is hydrogen;
- halo;
- alkyl;
- haloalkoxy;
- —OR8;
- —C(O)OR8;
- —C(O)N(R8)R9;
- —N(R 8)R9;
- —C(O)N(R8)(CH2)C(O)OR8 (where m is 0 to 3);
- —N(R8)(CH2)nC(O)OR8 (where n is 1 to 3);
- —N((CH2)nN(R8)R9)(CH2)nC(O)OR8 (where each n is 1 to 3);
- —O(CH2)nC(O)N(R8)R9 (where n is 1 to 3);
- —O(CH2)pC(O)OR8 (where p is 1 to 6);
- —N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3);
- morpholin-4-yl;
- 3tetrahydrofuranoxy;
- or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of —OR8, —C(O)N(R3)R9, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxy,arbonylalkyl, carboxyalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl));
- or R2 is piperazin-1-yl (optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is 1-piperazinoyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is piperidin-1-yl (optionally substituted by one or more substituents selected from the group consisting of carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, carboxyalkyl, C(O)N(R8)R9, alkoxycarbonylalkyl and aralklyl);
- R4 and R7 are independently hydrogen, halo, alkyl, nitro, —OR8, —C(O)OR8, —C(O)N(R8)R9, —N(R8)R9, —N(H)C(O)R8, or —N(H)C(O)2R12;
- R5 is —C(NH)NH2, —C(NH)N(H)OR8, —C(NH)N(H)C(O)OR12, —C(NH)N(H)S(O)2R12, —C(NH)N(H)C(O)N(R8)R9, or —C(NH)N(H)C(O)R8;
- R6 is halo, alkyl, haloalkyl, haloalkoxy, nitro, amino, ureido, guanidino, —OR8, C(NH)NH2, —C(NH)NHOH, —C(O)R10, —(CH2)mC(O)N(R8)R9 (where m is 0 to 3), —CH(OH)C(O)N(R8)R9, —(CH2)mN(R8)R9 (where m is 0 to 3), —(CH2)mC(O)OR8 (where m is 0 to 3), —N(H)C(O)R8, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);
- each R8 and R9 is independently hydrogen, alkyl, aryl, or aralkyl;
- R10 is hydrogen, alkyl, aryl, aralkyl, 1-pyrrolidinyl, 4-morpolinyl, 4-piperazinyl, 4-(N-methyl)piperazinyl, or piperidin-1-yl;
- and
- R12 is alkyl, aryl or aralkyl;
- or a pharmaceutically acceptable salt thereof;
- and a pharmaceutically acceptable excipient.
31 more elements
A method of treating a human having a disease-state characterized by thrombotic activity, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound selected from the group consisting of the following formulae:
- wherein
- A is —N═;
- Z1 and Z2 are independently —O—, —N(R8) or —S—;
- R1 and R3 are independently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, —N(R8)R, —C(O)OR8, —C(O)N(R8)R9, —C(O)N(R8)CH2C(O)N(R8)R9, —N(R8)C(O)N(R8)R9, —N(R8)G(O)R8, —N(R8)C(O)2R12, or —N(R8)C(O)N(R8)CH2C(O)N(R8)R9;
- R2 is hydrogen;
- halo;
- alkyl;
- haloalkoxy;
- —OR8;
- —C(O)OR8;
- —C(O)N(R8)R9;
- —N(R8)R9;
- —C(O)N(R8)(CH2)nC(O)OR8 (where m is 0 to 3);
- —N(R8)(CH2)nC(O)OR8 (where n is 1 to 3);
- —N((CH2)nN(R8)R9)(CH2)nC(O)OR8 (where each n is 1 to 3);
- —O(CH2)nC(O)N(R8)R9 (where n is 1 to 3);
- —O(CH2)pC(O)OR8 (where p is 1 to 6);
- —N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3);
- morpholin-4-yl;
- 3-tetrahydrofuranoxy;
- or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of —OR8, —C(O)N(R8)R9, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl));
- or R2 is piperazin-1-yl (optionally substittted by one or more substituents independently selected from the group consisting of alkyl, carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is 1-piperazinoyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is piperidin-1-yl (optionally substituted by one or more substituents selected from the group consisting of carboxy, —C(O)N(R8)R9, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
- or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, carboxyalkyl, —C(O)N(R8)R9, alkoxycarbonylalkyl and aralklyl);
- R4 and R7 are independently hydrogen, halo, alkyl, nitro, —OR8, —C(O)OR8, —C(O)N(R8)R9, —N(R8)R9, —N(H)C(O)R8, or —N(H)S(O)2R12;
- R5 is —C(NH)NH2, —C(NH)N(H)OR8, —C(NH)N(H)C(O)OR12, —C(NH)N(H)C(O)2R12, —C(NH)N(H)C(O)N(R8)R9, or —C(NH)N(H)C(O)R8;
- R6 is halo, alkyl, haloalkyl, haloalkoxy, nitro, amino, ureido, guanidino, —OR8, —C(NH)NH2, —C(NH)NHOH, —C(O)R10, —(CH2)mC(O)N(R8)R9 (where m is 0 to 3), —CH(OH)C(O)N(R8)R9, —(CH2)mN(RF)R9 (where m is 0 to 3), —(CH2)mC(O)OR8 (where m is 0 to 3), —N(H)C(O)R8, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);
- each R8 and R9 is independently hydrogen, alkyl, aryl, or aralkyl;
- R10 is hydrogen, alkyl, aryl, aralkyl, 1-pyrrolidinyl, 4-morpolinyl, 4-piperazinyl, 4-(AVmethyl)piperazinyl, or piperidin-1-yl;
- and
- R12 is alkyl, aryl or aralkyl;
- or a pharmaceutically acceptable salt thereof.
30 more elements
Dependencies are inferred from the claim text.