Claims for Patent: 5,736,555

Summary for Patent: 5,736,555

Title:	Heterocyclic compounds and their use as angiotensin antagonists
Abstract:	Compounds shown by the above formula or salt thereof show a strong angiotensin II antagonistic activity and hypotensive action and CNS activity, and are useful as therapeutic agents of circulatory diseases such as hypertensive diseases and heart diseases (e.g. hypercardia, heart failure, cardiac infarction), strokes, cerebral apoplexy, nephritis, atherosclerosis, Alzheimer's disease, senile dementia, etc.
Inventor(s):	Takehiko Naka, Yoshiyuki Inada
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US08/685,012
Patent Claims:	1. A compound or a salt thereof of the formula: ##STR75## wherein R1 is an optionally substituted hydrocarbon residue which is optionally bound through a hetero-atom;R2 is a group of the formula: ##STR76## wherein i is --O-- or --S-- and j is >c=0 or >c=S; R3 is optionally esterified or amidated carboxyl, tetrazolyl, trifluoromethanesulfonic amide, phosphoric acid or sulfonic acid, which may be protected with optionally substituted lower alkyl or acyl and the group of the formula ##STR77## has a structure selected from the group consisting of ##STR78## wherein in addition to R1 and R3, a substituent selected from the group consisting of halogen, nitro, cyano, an optionally substituted amino group, groups represented by the formula --U--R6, wherein U stands for a bond, --O--, --S-- or --CO--, and R6 stands for hydrogen or an optionally substituted lower alkyl group, groups represented by the formula --(CH2)1 --CO--D', wherein D' stands for hydrogen, hydroxyl group, optionally substituted amino, or optionally substituted alkoxy or groups represented by the formula --OCH(R7)OCO8, wherein R7 stands for hydrogen, 1-6C straight-chain or branched lower alkyl group or a 5-7C cycloalkyl group, and R8 stands for a 1-6C straight-chain or branched lower alkyl group, a 2-8C lower alkenyl group, a 5-7C cycloalkyl group, a 1-3C lower alkyl group substituted with a 5-7C cycloalkyl group or an aryl group, a 2-3C lower alkenyl group substituted with 5-7C cycloalkyl or an aryl group, an optionally substituted aryl group, a 1-6C straight-chain or branched lower alkoxy group, a 2-8C straight-chain or branched lower alkenyloxy group, a 5-7C cycloalkyloxy group, a 1-3C lower alkoxy group substituted with 5-7C cycloalkyl or an aryl group, a 2-3C alkenyloxy group substituted with 5-7C cycloalkyl or an optionally substituted aryl group, or an aryloxy group, and l denotes 0 or 1; and tetrazolyl, trifluoromethanesulfonic acid amide, phosphoric acid or sulfonic acid, each optionally protected with alkyl or acyl, may be provided, wherein one or more of these substituents may optionally be substituted simultaneously on optional positions of the ring; wherein when two or more of these substituents exist, they may be bonded to each other to form a 5- to 6-membered optionally substituted aromatic hydrocarbon residue or a heterocyclic residue optionally containing hetero atom, taken together with the two ring-forming atoms; and wherein these rings may further be substituted with any of the above-described substituents, and wherein h is CH2, C═O, C═S, S--(O)m, --NR9 -- or --O-- wherein m denotes an integer of 0-2 and R9 is hydrogen or lower (1-4C) alkyl, and excluding the compound 2-ethoxy-1((2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl) benzimidazole-7-carboxylic acid and its physiologically acceptable salts. 2. A compound or a salt thereof according to claim 1, wherein R1 is lower (C2-4) alkyl which may be bound through --O--, --NH-- or --S--. 3. A compound or a salt thereof according to claim 1, wherein R3 is a group of the formula: --CO--D wherein D is hydroxy, amino, N-lower (C1-4) alkylamino, N,N-di-lower (C1-4) alkylamino, lower (C1-6) alkoxy whose alkyl moiety is optionally substituted with a hydroxyl group, amino, dimethylamino, diethylamino, piperidino, morpholino, halogen, lower C1-6 alkoxy, lower (C1-6) alkylthio or optionally substituted dioxolenyl, or a group of the formula: --O--CH(R4)--OCOR5 wherein R4 is hydrogen, lower (C1-6) alkyl, lower (C2-6) alkenyl or lower (C3-8) cycloalkyl; and R5 is lower (C1-6) alkyl, lower (C2-6) alkenyl, lower (C3-8) cycloalkyl, lower (C1-3) alkyl substituted with lower (C3-8) cycloalkyl or aryl, lower (C2-3) alkenyl optionally substituted with lower (C3-8) cycloalkyl or aryl, aryl, lower (C1-6) alkoxy, lower (C2-8) alkenyloxy, lower (C3-8) cycloalkyloxy, lower (C1-3) alkoxy substituted with lower (C3-8) cycloalkyl or aryl, lower (C1-3) alkenyloxysubstituted with lower (C3-8) cycloalkyl or aryl, or aryloxy. 4. A compound or a salt thereof according to claim 1, wherein R3 is a group of the formula: --CO--D" wherein D" is hydroxy, amino, N-lower (C1-4) alkylamino, N, N-di-lower (C1-4) alkylamino or lower (C1-4) alkoxy whose alkyl moiety may be substituted by hydroxy, amino, halogen, lower (C2-6) alkanoyloxy, 1-lower (C1-6) alkoxycarbonyl or lower (C1-4) alkoxy, or tetrazolyl optionally protected with lower (C1-4) alkyl or acyl. 5. A compound or salt thereof according to claim 1, wherein R3 is optionally esterified carboxyl. 6. A compound or a salt thereof according to claim 1, wherein the group of the formula: ##STR79## is benzimidazole, thienoimidazole or imidazopyridine structure. 7. A compound or a salt thereof according to claim 1, wherein the group ##STR80## 8. A compound or a salt thereof according to claim 1, wherein R3 is optionally esterified or amidated carboxyl. 9. A compound or a salt thereof according to claim 8, wherein R3 is a group of the formula: --CO--D wherein D is hydroxy, optionally substituted amino or optionally substituted alkoxy. 10. A compound or a salt thereof according to claim 9, wherein the optionally substituted alkoxy is lower (C1-6) alkoxy whose alkyl moiety may be substituted by hydroxy, optionally substituted amino, halogen, lower (C1-6) alkoxy, lower (C1-6) alkylthio or optionally substituted dioxolenyl, or a group of the formula: --O--CH(R4)--OCOR5 wherein R4 is hydrogen, lower (C1-6) alkyl, lower (C2-6) alkenyl or lower (C3-8) cycloalkyl; and R5 is lower (C1-6) alkyl, lower (C2-6) alkenyl, lower (C3-8) cycloalkyl, lower (C2-3) alkyl substituted with lower (C3-8) cycloalkyl or aryl, lower (C2-3) alkenyl optionally substituted with lower (3-8) cycloalkyl or aryl, aryl, lower (C1-6) alkoxy, lower (C2-8) alkenyloxy, lower (C3-8) cycloalkyloxy, lower (C1-3) alkoxy substituted with lower (C3-8) cycloalkyl or aryl, lower (C2-3) alkenyloxy substituted with lower (C3-8) cycloalkyl or aryl, or aryloxy. 11. A compound or a salt thereof according to claim 8, wherein R3 is carboxy. 12. A compound or a salt thereof according to claim 1, wherein R1 is alkyl, alkenyl, alkynyl or cycloalkyl which may be bound through a group of the formula: --N(R9)-- wherein R9 is hydrogen or lower (C1-4) alkyl, --O-- or --S(O)m -- wherein m is an integer of 0 to 2 and which may be substituted with hydroxy, optionally substituted amino, halogen, lower (C1-4) alkoxy or lower (C1-4) alkylthio. 13. A compound or a salt thereof according to claim 1, wherein R1 is aryl or aralkyl which may be bound through a group of the formula: --N(R9)-- wherein R9 is hydrogen or lower (C1-4) alkyl, --O-- or --S(O)m -- wherein m is an integer of 0 to 2 and which may be substituted with halogen, nitro, optionally substituted amino, lower (C1-4) alkoxy, lower (C1-4) alkylthio or lower (C1-4) alkyl. 14. A compound or a salt thereof according to claim 1, wherein R1 is lower (C1-8) alkyl or lower (C2-8) alkenyl which may be bound through a group of the formula: --N(R9)-- wherein R9 is hydrogen or lower (C1-4) alkyl, --O-- or --S(O)m-- wherein m is an integer of 0 to 2 and which may be substituted with hydroxy, amino, N-lower (C1-4) alkylamine, N,N-dilower (C1-4) alkylamino, halogen, lower (C1-4) alkoxy or lower (C1-4) alkylthio. 15. A compound or a salt thereof according to claim 1, wherein R1 is lower (C1-5) alkyl or lower (C2-5) alkenyl which may be bound through a group of the formula: --N(R9)-- wherein R9 is hydrogen or lower (C1-4) alkyl, --O-- or --S(O)m-- wherein m is an integer of 0 to 2 and which may be substituted with hydroxy, amino, halogen or lower (C1-4) alkoxy. 16. A compound or a salt thereof according to claim 1, wherein R2 is 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group. 17. A compound or a salt thereof according to claim 1, wherein R2 is 2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl group. 18. A compound or a salt thereof according to claim 1, wherein R2 is 2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl group. 19. A compound or a salt according to claim 1, wherein the group of the formula: ##STR81## is benzimidazole or imidazopyridine. 20. A compound or a salt according to claim 19, wherein R2 is 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl or 2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl. 21. A compound or a salt according to claim 1, wherein the group of the formula: ##STR82## has a structure selected from the group consisting of ##STR83## 22. A compound or a salt according to claim 21, wherein R2 is 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl or 2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl. 23. A compound or a salt thereof of formula: ##STR84## wherein R1 is lower (C1-5) alkyl which may be bound through --O--, --NH-- or --S-- and which may be substituted with hydroxy, amino, N-lower (C1-4) alkylamino, N,N-di-lower (C1-4) alkylamino, halogen, lower (C1-4) alkoxy or lower (C1-4) alkylthio; R2 is a group of the formula: ##STR85## wherein i is --O-- or --S-- and j is >c=0 or >c=S; R3 is optionally esterified or amidated carboxyl, tetrazolyl, trifluoromethanesulfonic amide, phosphoric acid or sulfonic acid, which may be protected with optionally substituted lower alkyl or acyl and the group of the formula ##STR86## has a structure selected from the group consisting of ##STR87## wherein in addition to R1 and R2, a substituent selected from the group consisting of a halogen, nitro, cyano, an optionally substituted amino group, groups represented by the formula --U--R6, wherein U stands for a bond, --O--, --S-- or --CO--, and R6 stands for hydrogen or an optionally substituted lower alkyl group, groups represented by the formula --(CH2)1 --CO--D', wherein D' stands for hydrogen, hydroxyl group, optionally substituted amino, or optionally substituted alkoxy or groups represented by the formula --OCH(R7)OCO8, wherein R7 stands for hydrogen, 1-6C straight-chain or branched lower alkyl group or a 5-7C cycloalkyl group, and R8 stands for a 1-6C straight-chain or branched lower alkyl group, a 2-8C lower alkenyl group, a 5-7C cycloalkyl group, a 1-3C lower alkyl group substituted with a 5-7C cycloalkyl group or an aryl group, a 2-3C lower alkenyl group substituted with 5-7C cycloalkyl or an aryl group, an optionally substituted aryl group, a 1-6C straight-chain or branched lower alkoxy group, a 2-8C straight-chain or branched lower alkenyloxy group, a 5-7C cycloalkyloxy group, a 1-3C lower alkoxy group substituted with 5-7C cycloalkyl or an aryl group, a 2-3C alkenyloxy group substituted with 5-7C cycloalkyl or an optionally substituted aryl group, or an aryloxy group, and l denotes 0 or 1; and tetrazolyl, trifluoromethanesulfonic acid amide, phosphoric acid or sulfonic acid, each optionally protected with alkyl or acyl, may be provided, wherein one or more of these substituents may optionally be substituted simultaneously on optional positions of the ring; wherein when two or more of these substituents exist, they may be bonded to each other to form a 5- to 6-membered optionally substituted aromatic hydrocarbon residue or a heterocyclic residue optionally containing hetero atom, taken together with the two ring-forming atoms; and wherein these rings may further be substituted with any of the above-described substituents,and excluding the compound 2-ethoxy-1-((2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)benzimidazole-7-carboxylic acid and its physiologically acceptable salts thereof. 24. A pharmaceutical composition for antagonizing angiotensin II which comprises a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutical acceptable carrier, excipient or diluent. 25. A method for antagonzing angiotensin II in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.