Patent EA-004536-B1 (EA)
Title: New imidazoline compounds, method of preparation thereof and pharmaceutical compositions comprising them
Inventor: CORDI ALEX
IPC: C07D233/10
Filed: 1999-12-17
Abstract: 1. A compound selected from those of formula (I): wherein: A represents a benzene ring unsubstituted or substituted by from 1 to 4 identical or different groups selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, hydroxy, polyhalo-(C1-C6)alkyl in which the alkyl moiety is linear or branched, cyano, nitro, amino, alkylamino, dialkylamino, thioalkyl, sulphonylalkyl, sulphinylalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, formyl, carbamoyl, carboxamide, phenyl, benzyl, and halogen, B represents an imidazoline ring as represented in formula (Ia) or (Ib): X represents - CR<6> or CR<6>R<7> (wherein R<6> and R<7>, which may be the same or different, each represent hydrogen or linear or branched (C1-C6)alkyl), - nitrogen or NR<8> (wherein R<8> represents hydrogen or linear or branched (C1-C6)alkyl or benzyl), - oxygen, sulphur or SO or SO2, Y represents CH or CH2 or a single bond (and, in that case, the ring containing X, Y and Z is represented by the formula (1c); Z represents carbon or CR<4> wherein R<4> represents hydrogen or linear or branched (C1-C6)alkyl, R<1>, R<2>, R<3>, which may be the same or different, each represent hydrogen or linear or branched (C1-C6)alkyl, optionally (R<2> and R<4>) or (R<1> and R<4>) form cyclopropane, R<5> represents hydrogen, linear or branched (C1-C6)alkyl or benzyl, the symbol means that the bonds can be single or double, it being understood that the valency of the atoms is respected, wherein alkyl is understood to mean linear or branched alkyl containing 1 to 6 carbon atoms, its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 2. A compound of formula (I) according to claim 1, wherein R<5> represents hydrogen, its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 3. A compound of formula (I) according to claim 1, wherein R<1>, R<2>, R<3> each simultaneously represent hydrogen and Z represents carbon or CH, its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 4. A compound of formula (I) according to claim 1, wherein R<1> and R<2> each simultaneously represent hydrogen and R<3> or R<4> represents methyl, its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 5. A compound of formula (I) according to claim 1, wherein (R<1> and R<4>) or (R<2> and R<4>) represent cyclopropane, their tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 6. A compound of formula (I) according to claim 1, wherein the ring system represents 3,4-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, indane, indene, or benzofuran, its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 7. A compound of formula (I) according to claim 1, wherein the ring system represents 3,4-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, indane, indene, or benzofuran, those ring systems being unsubstituted, their tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 8. A compound of formula (I) according to claim 1, wherein the ring system represents 3,4-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, indane, indene, or benzofuran, those ring systems being substituted by one or more identical or different substituents selected from halogen and methyl, methoxy and CF3, their tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 9. A compound of formula (I) according to claim 1 which is selected from 4-(3,4-dihydro-2-naphthylmethyl)-4,5-dihydro-1H-imidazole, their tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 10. A compound of formula (I) according to claim 1 which is selected from 4-[(8-chloro-3,4-dihydro-2-naphthyl)methyl]-4,5-dihydro-1H-imidazole, its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 11. A compound of formula (I) according to claim 1 which is selected from 4-[(8-methoxy-3,4-dihydro-2-naphthyl)methyl]-4,5-dihydro-1H-imidazole, its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 12. A compound of formula (I) according to claim 1 which is 4-(benzo[b]furan-2-ylmethyl)-4,5-dihydro-1H-imidazole, its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 13. A compound of formula (I) according to claim 1 which is selected from 4-{spiro[cyclopropan-2:2'-(1',2',3',4'-tetrahydronaphth)]-1-yl}-4,5-dihydro-1H-imidazole (isomer 1) and 4-{spiro [cyclopropan-2:2'-(1',2',3',4'-tetrahydronaphth)]-1-yl}-4,5-dihydro-1H-imidazole (isomer 2), its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 14. A compound of formula (I) according to claim 1 which is selected from 4-[1,2,3,4-tetrahydro-2-naphthylmethyl]-4,5-dihydro-1H-imidazole (isomer 1), 4-[1,2,3,4-tetrahydro-2-naphthyl-methyl]-4,5-dihydro-1H-imidazole (isomer 2), 4-[1,2,3,4-tetrahydro-2-naphthylmethyl]-4,5-dihydro-1H-imidazole (isomer 3), and 4-[1,2,3,4-tetrahydro-2-naphthylmethyl]-4,5-dihydro-1H-imidazole (isomer 4), its tautomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 15. A compound of formula (I) according to claim 1, which is selected from 4-(1,3-dihydro-1H-2-indenylmethyl)-4,5-dihydro-1H-imidazole, its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 16. A compound of formula (I) according to claim 1, which is selected from 4-[(3,4-dihydro-4,4-dimethyl-2-naphthyl)methyl]-4,5-dihydro-1H-imidazole, its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 17. A compound of formula (I) according to claim 1, which is selected from 4-[(7-fluoro-3,4-dihydro-2-naphthyl)methyl]-4,5-dihydro-1H-imidazole, its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 18. A compound of formula (I) according to claim 1 which is selected from 4-[(8-chloro-2-naphthyl) methyl]-4,5-dihydro-1H-imidazole, its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 19. Compounds of formula (I) according to claim 1, which is selected from 4-{spiro[cyclopropan-2':2"-(5",6"-difluoro-indan)]-1'-yl}-4,5-dihydro-1H-imidazole (diastereoisomer 1), 4-{spiro[cyclopropan-2':2"-(5",6"-difluoro-indan)]-1"-yl }-4,5-dihydro-1H-imidazole (diastereoisomer 2), its tautomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 20. A compound of formula (I) according to claim 1, which is selected from 4-[(5-Fluoro-2,3-dihydro-1H-inden-2-yl)methyl]-4,5-dihydro-1H-imidazole, its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 21. A compound of formula (I) according to claim 1, which is selected from 4-[(5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)methyl]-4,5-dihydro-1H-imidazol e, its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 22. A process for the preparation of compounds of formula (I), characterized in that there is used as starting material a compound of formula (II): wherein A, X, Y, Z, R<1>, R<2>, R<3> and the symbol ---- are as defined hereinbefore, which is subjected either to the conditions of a Strecker reaction (KCN, NH4Cl) or to the action of an amine RaNH2 (wherein Ra represents a hydrogen atom or a hindered protecting group allowing better separation, where applicable, of the diastereoisomers formed) and of trimethylsilyl cyanide to yield a compound of formula (III): wherein A, X, Y, Z, R<1>, R<2>, R<3>, Ra and the symbol ---- are as defined hereinbefore, which compound of formula (III), when Ra represents a hydrogen atom, may alternatively be obtained starting from a compound of formula (IV): wherein A, X, Y, Z, R<1>, R<2> and the symbol ---- are as defined hereinbefore, which is subjected to a halogenating agent to yield a compound of formula (V): wherein A, X, Y, Z, R<1>, R<2>, and the symbol ---- are as defined hereinbefore and Hal represents a halogen atom, with which there is condensed a compound of formula (VI): wherein R<3> is as defined hereinbefore, to yield a compound of formula (VII): wherein A, X, Y, Z, R<1>, R<2>, R<3> and the symbol ---- are as defined hereinbefore, which is subjected to acid hydrolysis to yield a compound of formula (III/a), a particular case of the compounds of formula (III): wherein A, X, Y, Z, R<1>, R<2>, R<3> and the symbol ---- are as defined hereinbefore, which compound of formula (III) is subjected to the action of a reducing agent such as LiAlH4, AlH3 or a catalytic hydrogenation, for example, to obtain a compound of formula (VIII): wherein A, X, Y, Z, R<1>, R<2>, R<3>, Ra and the symbol ---- are as defined hereinbefore, which, in the case where Ra is other than a hydrogen atom, is deprotected in an acidic or reductive medium, for example, to yield a compound of formula (IX): wherein A, X, Y, Z, R<1>, R<2>, R<3> and the symbol ---- are as defined hereinbefore, which is reacted with formamidine acetate or methyl orthoformate to give a compound of formula (I/a), a particular case of the compounds of formula (I): wherein A, X, Y, Z, R<1>, R<2>, R<3> and the symbol ---- are as defined hereinbefore and B' represents an unsubstituted imidazoline ring as represent