Benzamidine derivatives and their use as anti-coagulants

A pharmaceutical composition useful in treating a human having a thrombotic complication associated with myocardial infraction, deep vein thrombosis following orthopedic surgery, transient ischemic attack, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, acute promyelocytic leukemia, diabetes, multiple myelomas, septic shock, purpura fulminanas, adult respiratory distress syndrome, angina, or aortic valve or vascular prosthesis, which composition comprises a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound selected from the group consisting of the following formulae:

• wherein
• Z1 is —O—, —N(R8)—, —S—, or —CH2O—;
• Z2 is —O—, —N(R8)—, —S—, or —OCH2—;
• 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)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;
• and a pharmaceutically acceptable excipient thereof.

A method of treating a human having a thrombotic complication associated with myocardial infraction, deep vein thrombosis following orthopedic surgery, transient ischemic attack, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, acute promyelocytic leukemia, diabetes, multiple myelomas, septic shock, purpura fulminanas, adult respiratory distress syndrome, angina, or aortic valve or vascular prosthesis, 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
• Z1 is —O—, —N(R8)—, —S—, or —CH2O—;
• Z2 is —O—, —N(R8)—, —S—, or —OCH2—;
• 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)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.