Claims for Patent: 5,270,317

Summary for Patent: 5,270,317

Title:	N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present
Abstract:	The invention relates to N-substituted heterocyclic derivatives and its salts.These derivatives have the formula ##STR1## in which the substituents are as defined in the specification.Application: Angiotensin II antagonists
Inventor(s):	Claude Bernhart, Jean-Claude Breliere, Jacques Clement, Dino Nisato, Pierre Perreault, Claude Muneaux, Yvette Muneaux
Assignee:	Sanofi Aventis France
Application Number:	US07/794,497
Patent Claims:	1. A compound of the formula ##STR43## in which: R1 and R2 are similar or different and are each independently hydrogen or a group selected from a C1 -C6 alkyl, a C1 -C4 alkoxy, an amino, an aminomethyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is C1 -C4, a cyano, a tetrazolyl, a methyltetrazolyl, a methylsulfonylamino, a trifluoromethylsulfonylamino, a trifluoromethylsulfonylaminomethyl, an N-cyanoacetamide, an N-hydroxyacetamide, an N-(4-carboxy-1,3-thiazol-2-yl)acetamide, a ureido, a 2-cyanoguanidinocarbonyl, a 2-cyanoguanidinomethyl, an imidazol-1-ylcarbonyl and a 3-cyano-2-methylisothioureidomethyl, with the proviso that at least one of the substituents R1 or R2 is other than hydrogen;R3 is a hydrogen, a C1 -C6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C2 -C6 alkenyl, a C3 -C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1 -C3, or a phenylalkenyl in which the alkenyl is C2 -C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C1 -C4 alkyl, a C1 -C4 halogenoalkyl, a C1 -C4 polyhalogenoalkyl, a hydroxyl or a C1 -C4 alkoxy; andeither R4 and R5 are each independently a C1 -C6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C1 -C3, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a C1 -C4 perfluoroalkyl, a hydroxyl and a C1 -C4 alkoxy; or R4 and R5 together form a group of the formula ═CR7 R8, in which R7 is hydrogen, a C1 -C4 alkyl or a phenyl and R8 is a C1 -C4 alkyl or a phenyl; or else R4 and R5 together are either a group of the formula (CH2)n or a group of the formula (CH2)p Y-(CH2)q, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a C1 -C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C1 -C3, or a group N--R6, in which R6 is a hydrogen, a C1 -C4 alkyl, a phenylalkyl in which the alkyl is C1 -C3, a C1 -C4 alkylcarbonyl, a C1 -C4 halogenoalkylcarbonyl, a C1 -C4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R4 and R5, together with the carbon atom to which they are bonded, form an indane or an adamantane; p+q=m; n is an integer between 2 and 11; and m is an integer between 2 and 5; or R4 is a C1 -C6 alkyl which is unsubstituted or substituted by one or more halogen atoms; and R5 is a cycloalkyl or a cycloalkylmethyl, the cycloalkyl being C3 -C7, which is unsubstituted or substituted by one or more halogen atoms; or R4 and R5 are each a cyclopropyl; X is an oxygen atom or sulfur atom; and z and t are zero or one is zero and the other is one; and its salts. 2. A compound according to claim 1 wherein R1 is in the ortho position and is a carboxyl or tetrazolyl group and R2 is hydrogen. 3. A compound according to claim 1 wherein R4 and R5 form a cyclopentane or a cyclohexane with the carbon to which they are bonded. 4. A compound according to claim 1 wherein R4 is methyl and R5 is cyclohexyl. 5. A compound according to claim 1 wherein R3 is a linear C1 -C6 alkyl group. 6. A compound according to claim 1 wherein X is oxygen. 7. A compound according to claim 1 wherein z=t=0. 8. A compound according to claim 1 which is 2-n-butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one or one of its salts with acids or bases. 9. A compound according to claim 1 which is 2-n-butyl-4-methyl-4-cyclohexyl-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one or one of its salts with acids or bases. 10. A pharmaceutical composition in which a compound according to claim 1 is present as the active principle. 11. A pharmaceutical composition in which 0.1 to 1000 mg of a compound according to claim 1 is present in associated with a beta-blocking compound. 12. A pharmaceutical composition in which 0.1 to 1000 mg of a compound according to claim 1 is present in associated with a diuretic. 13. A pharmaceutical composition in which 0.1 to 1000 mg of a compound according to claim 1 is present in association with a non-steroidal antiinflammatory. 14. A pharmaceutical composition in which 0.1 to 1000 mg of a compound according to claim 1 is present in association with a calcium antagonist. 15. A pharmaceutical composition in which 0.1 to 1000 mg of a compound according to claim 1 is present in association with a tranquilizer. 1. A compound of the formula ##STR43## in which: R.sub.1 and R.sub.2 are similar or different and are each independently hydrogen or a group selected from a C.sub.1 -C.sub.6 alkyl, a C.sub.1 -C.sub.4 alkoxy, an amino, an aminomethyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is C.sub.1 -C.sub.4, a cyano, a tetrazolyl, a methyltetrazolyl, a methylsulfonylamino, a trifluoromethylsulfonylamino, a trifluoromethylsulfonylaminomethyl, an N-cyanoacetamide, an N-hydroxyacetamide, an N-(4-carboxy-1,3-thiazol-2-yl)acetamide, a ureido, a 2-cyanoguanidinocarbonyl, a 2-cyanoguanidinomethyl, an imidazol-1-ylcarbonyl and a 3-cyano-2-methylisothioureidomethyl, with the proviso that at least one of the substituents R.sub.1 or R.sub.2 is other than hydrogen; R.sub.3 is a hydrogen, a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C.sub.2 -C.sub.6 alkenyl, a C.sub.3 -C.sub.7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, or a phenylalkenyl in which the alkenyl is C.sub.2 -C.sub.3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C.sub.1 -C.sub.4 alkyl, a C.sub.1 -C.sub.4 halogenoalkyl, a C.sub.1 -C.sub.4 polyhalogenoalkyl, a hydroxyl or a C.sub.1 -C.sub.4 alkoxy; and either R.sub.4 and R.sub.5 are each independently a C.sub.1 -C.sub.6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a C.sub.1 -C.sub.4 perfluoroalkyl, a hydroxyl and a C.sub.1 -C.sub.4 alkoxy; or R.sub.4 and R.sub.5 together form a group of the formula .dbd.CR.sub.7 R.sub.8, in which R.sub.7 is hydrogen, a C.sub.1 -C.sub.4 alkyl or a phenyl and R.sub.8 is a C.sub.1 -C.sub.4 alkyl or a phenyl; or else R.sub.4 and R.sub.5 together are either a group of the formula (CH.sub.2).sub.n or a group of the formula (CH.sub.2).sub.p Y-(CH.sub.2).sub.q, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a C.sub.1 -C.sub.4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, or a group N--R.sub.6, in which R.sub.6 is a hydrogen, a C.sub.1 -C.sub.4 alkyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, a C.sub.1 -C.sub.4 alkylcarbonyl, a C.sub.1 -C.sub.4 halogenoalkylcarbonyl, a C.sub.1 -C.sub.4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R.sub.4 and R.sub.5, together with the carbon atom to which they are bonded, form an indane or an adamantane; p+q=m; n is an integer between 2 and 11; and m is an integer between 2 and 5; or R.sub.4 is a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms; and R.sub.5 is a cycloalkyl or a cycloalkylmethyl, the cycloalkyl being C.sub.3 -C.sub.7, which is unsubstituted or substituted by one or more halogen atoms; or R.sub.4 and R.sub.5 are each a cyclopropyl; X is an oxygen atom or sulfur atom; and z and t are zero or one is zero and the other is one; and its salts. 2. A compound according to claim 1 wherein R.sub.1 is in the ortho position and is a carboxyl or tetrazolyl group and R.sub.2 is hydrogen. 3. A compound according to claim 1 wherein R.sub.4 and R.sub.5 form a cyclopentane or a cyclohexane with the carbon to which they are bonded. 4. A compound according to claim 1 wherein R.sub.4 is methyl and R.sub.5 is cyclohexyl. 5. A compound according to claim 1 wherein R.sub.3 is a linear C.sub.1 -C.sub.6 alkyl group. 6. A compound according to claim 1 wherein X is oxygen. 7. A compound according to claim 1 wherein z=t=0. 8. A compound according to claim 1 which is 2-n-butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]- 2-imidazolin-5-one or one of its salts with acids or bases. 9. A compound according to claim 1 which is 2-n-butyl-4-methyl-4-cyclohexyl-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl ]-2-imidazolin-5-one or one of its salts with acids or bases. 10. A pharmaceutical composition in which a compound according to claim 1 is present as the active principle. 11. A pharmaceutical composition in which 0.1 to 1000 mg of a compound according to claim 1 is present in associated with a beta-blocking compound. 12. A pharmaceutical composition in which 0.1 to 1000 mg of a compound according to claim 1 is present in associated with a diuretic. 13. A pharmaceutical composition in which 0.1 to 1000 mg of a compound according to claim 1 is present in association with a non-steroidal antiinflammatory. 14. A pharmaceutical composition in which 0.1 to 1000 mg of a compound according to claim 1 is present in association with a calcium antagonist. 15. A pharmaceutical composition in which 0.1 to 1000 mg of a compound according to claim 1 is present in association with a tranquilizer.