Benzamidine derivatives substituted by amino acid and hydroxy acid derivatives and their use as anti-coagulantsThis invention is directed to benzamidine derivatives substituted by amino acid and hydroxy acid 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.A kind of be selected from have following formula, be compound or its pharmacy acceptable salt of single stereoisomers or its form of mixtures: wherein:a is-c (r 8)=or-n=; z 1and z 2be independently-o-,-n (r 13)-,-s-or-och 2-; r 1and r 4be independently of one another hydrogen, halogen, alkyl, nitro ,-or 13,-c (o) or 13,-c (o) n (r 13) r 14,-n (r 13) r 14,-n (r 13) c (o) r 13or-n (h) s (o) 2r 16r 2for-c (nh) nh 2,-c (nh) n (h) or 13,-c (nh) n (h) c (o) or 16,-c (nh) n (h) c (o) r 13,-c (nh) n (h) s (o) 2r 16or-c (nh) n (h) c (o) n (h) r 13r 3for halogen, alkyl, haloalkyl, nitro, amino, urea groups, guanidine radicals ,-or 13,-c (nh) nh 2,-c (nh) n (h) or 13,-c (o) n (r 13) r 14,-r 15-c (o) n (r 13) r 14,-ch (oh) c (o) n (r 13) r 14,-n (r 13) r 14,-r 15-n (r 13) r 14,-c (o) or 13,-r 15-c (o) or 13,-n (r 13) c (o) r 13, (1,2)-tetrahydro-pyrimidine base (optionally being replaced), (1,2)-imidazolyl (optionally being replaced) or (1,2)-imidazolinyl (optionally being replaced) by alkyl by alkyl by alkyl; r 5and r 6be independently of one another hydrogen, halogen, alkyl, haloalkyl, nitro ,-n (r 13) r 14,-c (o) or 13,-c (o) n (r 13) r 14,-c (o) n (r 13) ch 2c (o) n (r 13) r 14,-n (r 13) c (o) n (r 13) r 14,-n (r 13) c (o) r 14,-n (r 13) s (o) 2r 16or-n (r 13) c (o) n (r 13) ch 2c (o) n (r 13) r 14r 7for-n (r 9)-(c (r 10) (r 11)) n-r 12(wherein n is 1-4) or-o-(c (r 10) (r 11)) n-r 12(wherein n is 1-6); r 8be hydrogen, alkyl or halogen; r 9for hydrogen, alkyl, aryl, aralkyl ,-r 15-c (o) or 13,-r 15-c (o) n (r 13) r 14,-r 15-n (r 13) r 14,-r 15-ch (n (r 13) r 14) c (o) or 13or-(r 15) s (o) 2r 16r 10respectively be independently alkyl, alkenyl, alkynyl group, haloalkyl, halogenated alkenyl, cycloalkyl, cycloalkylalkyl ,-c (o) or 13,-r 15-c (o) or 13,-r 15-c (o) n (r 13) r 14,-c (o) r 15-n (r 13) r 14,-r 15-c (o) r 13,-r 15-c (o) n (r 13) n (r 13) r 14,-r 15-c (r 13) (or 13)-r 15-n (r 13) (r 14) ,-c (r 13) (or 13) c (o) or 14, r 15-c (r 13) (c (o) or 13) 2,-c (r 13) (n (r 13) r 14) c (o) or 13,-r 15-c (r 13) (n (r 13) r 14) c (o) or 13,-c (r 13) (or 13) r 14,-r 15-n (r 13) (r 14) ,-r 15-n (r 13) c (o) or 16,-r 15-n (r 13) c (o) or 14,-r 15-n (r 13) c (nr 13) r 16,-r 15-n (r 13) s (o) 2r 16,-r 15-n (r 13) c (o) n (r 13) r 14,-r 15-n (r 13) c (nr 13) n (r 13) r 14,-r 15-n (r 13) c (nr 13) n (r 13) n (r 13) r 14,-r 15-n (r 13)-r 15-c (r 13) (n (r 13) r 14) c (o) or 13,-r 15-n (r 13) s (o) r 14,-r 15or 13,-r 15-on (r 13) c (nr 13) n (r 13) r 14,-r 15-os (o) 2or 13,-r 15-p (o) (or 13) r 14,-r 15-op (o) (or 13) 2,-r 15-p (o) (or 13) 2,-r 15-sr 13,-r 15-s-r 15-c (o) or 13,-r 15-s-r 15-n (r 13) r 14,-r 15-s-r 15-c (r 13) (n (r 13) r 14) c (o) or 13,-r 15-s-r 15-n (r 13) c (o) r 13,-r 15-s-r 15-n (r 13) c (o) r 13,-r 15-s-s-r 15-c (r 13) (n (r 13) r 14) c (o) or 13,-r 15-sc (o) n (r 13) r 14,-r 15-sc (s) n (r 13) r 14,-r 15-s (o) r 13,-r 15-s (o) 2r 16,-r 15-s (o) or 13,-r 15-s (o) 2or 13,-r 15-s (o) 2n (r 13) r 14,-r 15-s (o) (nr 13) r 14or r 10be respectively aryl (optionally being selected from following one or more substituting groups replaces: alkyl, halogen, haloalkyl, halogenated alkoxy, nitro ,-or 13,-sr 13,-n (r 13) r 14,-c (o) or 13,-c (o) n (r 13) r 14,-s (o) 2or 13with-op (o) (or 13) 2); or r 10be respectively aralkyl (optionally being selected from following one or more substituting groups replaces: alkyl, halogen, haloalkyl, halogenated alkoxy, cyano group, nitro ,-or 13,-sr 13,-n (r 13) r 14,-c (o) or 13,-c (o) n (r 13) r 14,-s (o) 2or 13with-op (o) (or 13) 2); or r 10be respectively heterocyclic radical (optionally being selected from following one or more substituting groups replaces: alkyl, halogen, haloalkyl, halogenated alkoxy, aralkyl ,-or 13,-c (o) or 13,-n (r 13) r 14,-c (o) n (r 13) r 14,-s (o) 2or 13with-op (o) (or 13) 2); or r 10be respectively the heterocyclic radical alkyl (wherein heterocyclic radical optionally is selected from following one or more substituting groups and is replaced: alkyl, halogen, haloalkyl, halogenated alkoxy, aralkyl ,-or 13,-sr 13,-c (o) or 13,-n (r 13) r 14,-c (o) n (r 13) r 14,-s (o) 2or 13with-op (o) (or 13) 2); or r 10be respectively adamantyl (adamantyl) (optionally replaced by following substituting group: alkyl, halogen, haloalkyl, halogenated alkoxy ,-or 13,-sr 13,-c (o) or 13,-n (r 13) r 14,-c (o) n (r 13) r 14,-s (o) 2or 13with-op (o) (or 13) 2); or r 10be respectively the adamantyl alkyl (wherein adamantyl is optionally replaced by following substituting group: alkyl, halogen, haloalkyl, halogenated alkoxy ,-or 13,-sr 13,-c (o) or 13,-n (r 13) r 14,-c (o) n (r 13) r 14,-s (o) 2or 13with-op (o) (or 13) 2); r 11be hydrogen, alkyl, cycloalkyl or aryl independently of one another; r 12for-c (o) or 13or-c (o) n (r 13) r 14r 13and r 14independently of one another for hydrogen, alkyl, aryl (optionally replaced by following radicals: halogen, alkyl, hydroxyl, alkoxyl group, aralkoxy, amino, dialkylamino, single alkylamino, nitro, cyano group, carboxyl, carbalkoxy, ami...
아미노산 및 히드록시산 유도체로 치환된 벤즈아미딘 유도체 및항응고제로서의 그의 용도본 발명은 항응고제로서 유용한 아미노산 및 히드록시산 유도체로 치환되는 벤즈아미딘 유도체에 관한 것이다. 또한, 본 발명은 본 발명의 화합물을 포함하는 제약 조성물 및 혈전 활성에 의해 특징지어지는 질병 상태를 치료하기 위한 상기 화합물의 사용 방법에 관한 것이다.단일 입체 이성질체 또는 그들의 혼합물로서 하기 화학식으로 구성되는 군으로부터 선택되는 화합물 또는 그의 제약적으로 허용가능한 염. [이미지] 상기 식에서, A는 -C(R8)= 또는 -N=이고, Z1 및 Z2는 독립적으로 -O-, N(R13)-, -S- 또는 -OCH2-이며, R1 및 R4는 각각 독립적으로 수소, 할로, 알킬, 니트로, -OR13, -C(O)OR13, -C(O)N(R13)R14, -N(R13)R14, -N(R13)C(O)R13 또는 -N(H)S(O)2R16이고, R2는 -C(NH)NH2, -C(NH)N(H)OR13, -C(NH)N(H)C(O)OR16, -C(NH)N(H)C(O)R13, -C(NH)N(H)S(O)2R16 또는 -C(NH)N(H)C(O)N(H)R13이며, R3은 할로, 알킬, 할로알킬, 니트로, 아미노, 우레이도, 구아니디노, -OR13, -C(NH)NH2, -C(NH)N(H)OR13, -C(O)N(R13)R14, -R15C(O)N(R13)R14, -CH(OH)C(O)N(R13)R14, -N(R13)R14, -R15N(R13)R14, -C(O)OR13, -R15C(O)OR13, -N(R13)C(O)R13, 임의로 알킬로 치환된 (1,2)-테트라히드로피리미디닐, 임의로 알킬로 치환된 (1,2)-이미다졸릴 또는 임의로 알킬로 치환된 (1,2)-이미다졸리닐이고, R5 및 R6은 독립적으로 수소, 할로, 알킬, 할로알킬, 니트로, -N(R13)R14, -C(O)OR13, -C(O)N(R13)R14, -C(O)N(R13)CH2C(O)N(R13)R14, -N(R13)C(O)N(R13)R14, -N(R13)C(O)R14, -N(R13)S(O)2R16 또는 -N(R13)C(O)N(R13)-CH2C(O)N(R13)R14이며, R7은 -N(R9)-(C(R10)(R11))n-R12 (식 중, n은 1 내지 4임) 또는 -O-(C(R10)(R11))n-R12 (식 중, n은 1 내지 6임)이고, R8은 수소, 알킬 또는 할로이며, R9는 수소, 알킬, 아릴, 아르알킬, -R15-C(O)OR13, -R15-C(O)N(R13)R14, -R15-N(R13)R14, -R15-CH(N(R13)R14)C(O)OR13 또는 -R15-S(O)2R16이고, 각 R10은 독립적으로 알킬, 알케닐, 알키닐, 할로알킬, 할로알케닐, 시클로알킬, 시클로알킬알킬, -C(O)OR13, -R15-C(O)OR13, -R15-C(O)N(R13)R14, -C(O)-R15-N(R13)R14, -R15-C(O)R13, -R15-C(O)N(R13)N(R13)R14, -R15-C(R13)(OR13)-R15-N(R13)(R14), -C(R13)(OR13)C(O)OR14, -R15-C(R13)(C(O)OR13)2, -C(R13)(N(R13)R14)C(O)OR13, -R15-C(R13)(N(R13)R14)C(O)OR13, -C(R13)(OR13)R14, -R15-N(R13)R14, -R15-N(R13)C(O)OR16, -R15-N(R13)C(O)OR14, -R15-N(R13)C(NR13)R16, -R15-N(R13)S(O)2R16, -R15-N(R13)C(O)N(R13)R14, -R15-N(R13)C(NR13)N(R13)R14, -R15-N(R13)C(NR13)N(R13)N(R13)R14, -R15-N(R13)-R15-C(R13)(N(R13)R14)C(O)OR13, -R15-N(R13)S(O)R14, -R15OR13, -R15-ON(R13)C(NR13)N(R13)R14, -R15-OS(O)2OR13, -R15-P(O)(OR13)R14, -R15-OP(O)(OR13)2, -R15-P(O)(OR13)2, -R15-SR13, -R15-S-R15-C(O)OR13, -R15-S-R13-N(R13)R14, -R15-SR15-C(R13)(N(R13)R14)C(O)OR13, -R15-S-R15-N(R13)C(O)OR13, -R15-S-R15-N(R13)C(O)OR13, -R15-S-SR15-C(R13)(N(R13)R14)C(O)OR13, -R15SC(O)N(R13)R14, -R15-SC(S)N(R13)R14, -R15-S(O)R13, -R15-S(O)2R16, -R15-S(O)OR13, -R15-S(O)2OR13, -R15-S(O)2N(R13)R14 또는 -R15-S(O)(NR13)R14이거나, 각 R10은 알킬, 할로, 할로알킬, 할로알콕시, 니트로, -OR13, -SR13, -N(R13)R14, -C(O)OR13, -C(O)N(R13)R14, -S(O)2OR13 및 -OP(O)(OR13)2로 구성되는 군으로부터 선택되는 1개 이상의 치환체로 임의로 치환되는 아릴이거나, 각 R10은 알킬, 할로, 할로알킬, 할로알콕시, 시아노, 니트로, -OR13, -SR13, -N(R13)R14, -C(O)OR13, -C(O)N(R13)R14, -S(O)2OR13 및 -OP(O)(OR13)2로 구성되는 군으로부터 선택되는 1개 이상의 치환체로 임의로 치환되는 아르알킬이거나, 각 R10은 알킬, 할로, 할로알킬, 할로알콕시, 아르알킬, -OR13, -C(O)OR13, -N(R13)R14, -C(O)N(R13)R14, -S(O)2OR13 및 -OP(O)(OR13)2로 구성되는 군으로부터 선택되는 1개 이상의 치환체로 임의로 치환되는 헤테로시클릴이거나, 각 R10은 헤테로시클릴 라디칼이 알킬, 할로, 할로알킬, 할로알콕시, 아르알킬, -OR13, -SR13, -C(O)OR13, -N(R13)R14, -C(O)N(R13)R14, -S(O)2OR13 및 -OP(O)(OR13)2로 구성되는 군으로부터 선택되는 1개 이상의 치환체로 임의로 치환되는 헤테로시클릴알킬이거나, 각 R10은 알킬, 할로, 할로알킬, 할로알콕시, -OR13, -SR13, -C(O)OR13, -N(R13)R14, -C(O)N(R13)R14, -S(O)2OR13 및 -OP(O)(OR13)2로 임의로 치환되는 아다만틸이거나, 각 R10은 아다만틸 라디칼이 알킬, 할로, 할로알킬, 할로알콕시, -OR13, -SR13, -C(O)OR13, -N(R13)R14, -C(O)N(R13)R14, -S(O)2OR13 및 -OP(O)(OR13)2로 임의로 치환되는 아다만틸알킬이고, 각 R11은 독립적으로 수소, 알킬, 시클로알킬 또는 아릴이며, R12는 -C(O)OR13 또는 -C(O)N(R13)R14이고, 각 R13 및 R14는 독립적으로 수소, 알킬, 아릴 (할로, 알킬, 히드록시, 알콕시, 아르알콕시, 아미노, 디알킬아미노, 모노알킬아미노, 니트로, 시아노, 카르복시, 알콕시카르보닐, 아미노카르보닐, 모노알킬아미노카르보닐 또는 디알킬아미노카르보닐로 임의로 치환됨) 또는 아르알킬 (할로, 알킬, 아릴, 히드록시, 알콕시, 아르알킬, 아미노, 디알킬아미노, 모노알킬아미노, 니트로, 시아노, 카르복시, 알콕시카르보닐, 아미노카르보닐, 모노알킬아미노카르보닐 또는 디알킬아미노카르보닐로 임의로 치환됨)이며, R15는 직쇄 또는 분지쇄 알킬렌이고, R16은 알킬, 아릴 (할로, 알킬, 히드록시, 알콕시, 아르알콕시, 아미노, 디알킬아미노, 모노알킬아미노, 니트로, 시아노, 카르복시, 알콕시카르보닐, 아미노카르보닐, 모노알킬아미노카르보닐 또는 디알킬아미노카르보닐로 임의로 치환됨) 또는 아르알킬 (할로, 알킬, 아릴, 히드록시, 알콕시, 아르알킬, 아미노, 디알킬아미노, 모노알킬아미노, 니트로, 시아노, 카르복시, 알콕시카르보닐, 아미노카르보닐, 모노알킬아미노카르보닐 또는 디알킬아미노카르보닐로 임의로 치환됨)이다.