Patent NZ-334264-A (NZ)
Title: Benzamidine derivatives substituted by cyclic amino acid or cyclic hydroxy acid derivatives and their use as anti-coagulants
Inventor: KOCHANNY MONICA
IPC: A61K31/4725
Filed: 1997-09-11
Abstract: A compound selected from the formulae above wherein: Z1 and Z2 are independently --O--, --N(R9)--, --S--, --S(O)--, --S(O)2 --, or --OCH2 --; R1 and R4 are each independently hydrogen, halo, alkyl, nitro, --OR9, --C(O)OR9, --C(O)N(R9)R10, --N(R9)R10, --N(R9)C(O)R9, or --N(H)S(O)2 R12 ; R2 is --C(NH)NH2, --C(NH)N(H)OR9, --C(NH)N(H)C(O)OR12, --C(NH)N(H)C(O)R9, --C(NH)N(H)S(O)2 R12, or --C(NH)N(H)C(O)N(H)R9 ; R3 is hydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino, --OR9, --C(NH)NH2, --C(NH)N(H)OR9, --C(O)N(R9)R10, --R11 --C(O)N(R9)R10, --CH(OH)C(O)N(R9)R10, --N(R9)R10, --R11 --N(R9)R10, --C(O)OR9, --R11 --C(O)OR9, --N(R9)C(O)R9, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl); R5 and R6 are independently hydrogen, halo, alkyl, haloalkyl, nitro, --N(R9)R10, --C(O)OR9, --C(O)N(R9)R10, --C(O)N(R9)CH2 C(O)N(R9)R10, --N(R9)C(O)N(R9)R10, --N(R9)C(O)R10, or - N(R9)S(O)2 R12 ; R7 is --N(R9)--(C(R9)(R10))n --R13 (where n is 0 to 4), --O--(C(R9)(R10))n --R13 (where n is 0 to 4), or --N(R14)R15 ; each R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); R11 is a straight or branched alkylene chain; R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); R13 is a mono-, bi- or tri-cyclic carbocyclic ring system containing from 3 to 15 carbon atoms which may be partially or fully saturated or aromatic, wherein the carbon atoms may be optionally oxidized and wherein the carbocyclic ring system is substituted by --(C(R9)(R10))m --R16 (where m is 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, --N(R9)R10, --C(O)OR9, or --C(O)N(R9)R10 ; or R13 is a mono-, bi- or tri-cyclic heterocyclic ring system containing from 3 to 15 ring members including carbon and 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, wherein the carbon, nitrogen and sulfur atoms may be optionally oxidized and wherein the heterocyclic ring system may be partially or fully saturated or aromatic and is substituted by --(C(R9)(R10))m --R16 (where m is 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, --N(R9)R10, --C(O)OR9, or --C(O)N(R9)R10 ; R14 and R15, together with the nitrogen atom, form a mono-, bi- or tri-cyclic heterocyclic ring system containing from 3 to 15 ring members including carbon and 1 to 3 additional hetero atoms selected from nitrogen, oxygen and sulfur atoms, wherein the carbon, nitrogen, or sulfur atoms may be optionally oxidized and wherein the heterocyclic ring system may be partially or fully saturated or aromatic and is substituted by --(C(R9)(R10))m --R16 (where m is 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, --N(R9)R10, --C(O)OR9, or --C(O)N(R9)R10 ; and R16 is --C(O)OR9 or --C(O)N(R9)R10 ; provided that when R7 is --N(R9)--(C(R9)(R10)n --R13 (where n is 0), R13 can not be phenyl, naphthyl or piperidinyl substituted by --C(O)OR9 ; when R7 is --O--(C(R9)(R10))n --R13 (where n is 0), R13 can not be phenyl, naphthyl, piperidinyl or pyrrolidinyl substituted by --C(O)OR9 ; and when R7 is --N(R14)R15, R14 and R15, together with the nitrogen atom, can not be piperazinyl or piperidinyl substituted by --C(O)OR9 as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof. These compounds are useful in treating thrombotic disorders.