Patent EA-004500-B1 (EA)
Title: Antihistaminic spiro compounds
Inventor: JANSSENS FRANS EDUARD
IPC: C07D495/22
Filed: 1999-12-15
Abstract: 1. A compound of formula a prodrug, a N-oxide, an addition salt, a quaternary amine or a stereochemically isomeric form thereof wherein R<1> is hydrogen, C1-6alkyl, halo, formyl, carboxyl, C1-6alkyloxycarbonyl, C1-6alkyl-carbonyl, N(R<3>R<4>)C(=O)-, N(R<3>R<4>)C(=O)N(R<5>)-, ethenyl substituted with carboxyl or C1-6alkyloxycarbonyl, or C1-6alkyl substituted with hydroxy, carboxyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, N(R<3>R<4>)C(=O)-, C1-6alkylC(=O))N(R<5>)-, C1-6alkyl S(=O)2N(R<5>)-or N(R<3>R<4>)C(=O)N(R<5>)-; wherein each R<3> and each R<4> independently are hydrogen or C1-4alkyl; R<5> is hydrogen or hydroxy; R<2> is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl; N(R<3>R<4>)C(=O)-, aryl or halo; n is 1 or 2; -A-B- represents a bivalent radical of formula -Y-CH=CH-  (a-1); CH=CH-Y-  (a-2); or -CH=CH-CH=CH-  (a-3); wherein ch hydrogen atom in the radicals (a-1) to (a-3) may independently be replaced by R<6> wherein R<6> is selected from C1-6alkyl, halo, hydroxy, C1-6alkyloxy, ethenyl substituted with carboxyl or C1-6alkyloxycarbonyl, hydroxyC1-6alkyl, formyl, carboxyl and hydroxycarbonylC1-6alkyl; each Y independently is a bivalent radical of formula -O-, -S- or -NR<7>-; wherein R<7> is hydrogen, C1-6alkyl or C1-6alkylcarbonyl; Z is a bivalent radical of formula -(CH2)p  (b-1), -CH=CH-  (b-2), -CH2-CHOH-  (b-3), --O-  (b-4), -CH2-C(=O)-  (b-5), or -CH2-C(=NOH)-  6), provided that the bivalent radicals (b-3), (b-4), (b-5) and (b-6) are connected to the nitrogen of the imidazole ring via their -CH2- moiety; wherein p is 1, 2, 3 or 4; L is hydrogen; C1-6alkyl; C2-6alkenyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C1-6alkyl substituted with one or more substituents each independently selected from hydroxy, carboxyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, aryl, aryloxy, cyano or R<8>HN-wherein R<8> is hydrogen, C1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl; or L represents a radical of formula -Alk-Y-Het<1>  (c-1), -Alk-NH-CO-Het<2>  (c-2) or -Alk-Het<3>c-3); wherein Alk represents C1-4alkanediyl; Y represents O, S or NH; Het<1>, Het<2> and Het<3> each represent furanyl, tetrahydrofuranyl; thienyl; oxazolyl, thiazolyl or imidazolyl each optionally substituted with one or two C1-4alkyl substituents; pyrrolyl or pyrazolyl optionally substituted with formyl, hydroxyC1-4alkyl, hydroxycarbonyl, C1-4alkyloxycarbonyl or with one or two C1-4alkyl substituents; thiadiazolyl or oxadiazolyl optionally substituted with amino or C1-4alkyl; pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl each optionally substituted with C1-4alkyl, C1-4alkyloxy, amino, hydroxy or halo; and Het<3> may also represent 4,5-dihydro-5-oxo-1H-tetrazolyl substituted with C1-4alkyl, 2-oxo-3-oxazolidinyl, 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl or a radical of formula wherein A-Z represents S-CH=CH, S-CH2-CH2, S-CH2-CH2-CH2, CH=CH-CH=CH, or CH2-CH2-CH2-CH2; aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C1-4alkyl, polyhaloC1-4alkyl, cyano, aminocarbonyl, C1-4alkyloxy or polyhaloC1-4alkyloxy; provided that 5,6-dihydrospiro[imidazo[1,2-b][3]benzazepine-11[11H],4'-piperidine] and pharmaceutically acceptable addition salts thereof are not included. 2. A compound according to claim 1 wherein L is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl or C1-6alkyl substituted with hydroxy, carboxyl, C1-6alkyloxy or C1-6alkyloxycarbonyl. 3. A compound according to claim 1 wherein L is C1-6alkyl substituted with aryl and C1-6alkyloxycarbonyl. 4. A compound according to any one of the preceding claims wherein -A-B- is a bivalent radical of formula -CH=CH-CH=CH- (a-3) or -CH=CH-Y- (a-2). 5. A compound according to any one of the preceding claims wherein Z is (CH2)p- (b-1), -CH=CH- (b-2), or -CH2-O- (b-4). 6. A compound according to claims 1, 2, 4 or 5 wherein L is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, carboxyC1-6alkyl, C1-6alkyloxycarbonyl, or C1-6alkyloxycarbonylC1-6alkyl. 7. A compound according to any one of the preceding claims wherein R<1> is hydroxyC1-6alkyl, formyl, C1-6alkyloxycarbonyl, C1-6alkyloxyC1-6alkyl, N(R<3>R<4>)C(=O)-, halo or hydrogen. 8. A compound according to claim 1 wherein the compound 17 is 5,6-dihydrospiro[11H-imidazo[2,1-b][3]benzazepine-11,4'-piperidine]-3-carboxamide dihydrochloride; the compound 3 is 1'-butyl-5,6-dihydrospiro[imidazo[2,1-b] [3] benzazepine-11-[11H];4'-piperidine]; the compound 1 is 6,11-dihydro-1'-methylspiro[5H-imidazo[2,1-b][3]benzazepine-11,4'-piperidine] cyclohexylsulfamate (1:2); the compound 18a is 6,11-dihydrospiro[5-imidazo[2,1-b][3]benzazepine-11,4'-piperidine]-3-methanol] (E)-2-butenedioate (2:1); the compound 20 is 3-chloro-6,11-dihydrospiro[5H-imidazo[2,1-b][3]benzazepine-11,4'-piperidine] (E)-2-butenedioate (1:1); the compound 58 is 6,11-dihydro-3-(methoxymethyl)spiro[5H-imidazo[2,1-b][3]benzazepine-11,4'-piperidine] (E)-2-butenedioate (1:1); the compound 62 is 6,11-dihydro-1'-(2-hydroxyethyl)spiro[5H-imidazo[2,1-b][3]benzazepine-11,4'-piperidine]-3-carboxamide; the compound 80 is 6,11-dihydro-1'-methylspiro[5H-imidazo[2,1-b][3]benzazepine-11,4'-piperidine]-3-carboxamide monohydrate; the compound 64 is ethyl 3-(aminocarbonyl)-6,11-dihydro-alpha-phenylspiro[5H-imidazo[2,1-b][3]-benzazepine-11,4'-piperidine]-1'-propanoate monohydrochloride; the compound 79 is 3-(aminocarbonyl)-6,11-dihydrospiro[5H-imidazo[2,1-b][3]-benzazepine-11,4'-piperidine]-1'-carboxylate; the compound 56a is spiro[10H-imidazo[1,2-a]thieno[3,2-d]azepine-10,4'-piperidine]; the compound 53 is 6,11-dihydrospiro[5H-imidazo[2,1-b][3]benzazepine-11,4'-piperidine]-2,3-dicarboxamide dihydrochloride monohydrate; a prodrug, a N-oxide, an addition salt, a quaternary amine or a stereochemically isomeric form thereof. 9. A compound of formula wherein R<1> is hydrogen, C1-6alkyl, halo, formyl, carboxyl, C1-6alkyloxycarbonyl, C1-6alkyl-carbonyl, N(R<3>R<4>)C(=O)-, N(R<3>R<4>)C(=O)N(R<5>)-, ethenyl substituted with carboxyl or C1-6alkyloxycarbonyl, or C1-6alkyl substituted with hydroxy, carboxyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, N(R<3>R<4>)C(=O)-, C1-6alkylC(=O))N(R<5>)-, C1-6alkyl S(=O)2N(R<5>)-or N(R<3>R<4>)C(=O)N(R<5>)-; wherein each R<3> and each R<4> independently are hydrogen or C1-4alkyl; R<5> is hydrogen or hydroxy; R<2> is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, N(R<3>R<4>)C(=O)-, aryl or halo; n is 1 or 2; -A-B- represents a bivalent radical of formula -Y-CH=CH-  (a-1); -CH=CH-Y-  (a-2); or -CH=CH-CHH-  (a-3); wherein each hydrogen atom in the radicls (a-1) to (a-3) may independently be replaced by R<6> wherein R<6> is selected from C1-6alkyl, halo, hydroxy, C1-6alkyloxy, ethenyl substituted with carboxyl or C1-6alkyloxycarbonyl, hydroxyC1-6alkyl, formyl, carboxyl and hydroxycarbonylC1-6alkyl; each Y independently is a bivalent radical of formula -O-, -S- or -NR<7>-; wherein R<7> is hydrogen, C1-6alkyl or C1-6alkylcarbonyl; Z is a bivalent radical of formula -(CH2)p  (b-1), -CH=CH-  (b-2), H2-CHOH-  (b-3), -CH2-O-  (b-4), -CH2-C(=O)-  (b-5or -CH2-C(=NOH)-  (b-6), provided that the bivalen radicals (b-3), (b-4), (b-5) and (b-6) are connected to the nitrogen of the imidazole ring via their -CH2- moiety; wherein p is 1, 2, 3 or 4; L is hydrogen; C1-6alkyl; C2-6alkenyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C1-6alkyl substituted with one or more substituents each independently selected from hydroxy, carboxyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, aryl, aryloxy, cyano or R<8>HN- wherein R<8> is hydrogen, C1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl; or L represents a radical of formula -Alk-Y-Het<1>  (c-1), -Alk-NH-CO-Het<2> c-2) or -Alk-Het<3>  (c-3); wherein Alk representsC1-4alkanediyl; Y represents O, S or NH; Het<1>, Het<2> and Het<3> each represent furanyl, tetrahydrofuranyl; thienyl; oxazolyl, thiazolyl or imidazolyl each optionally substituted with one or two C1-4alkyl substituents; pyrrolyl or pyrazolyl optionally substituted with formyl, hydroxyC1-4alkyl, hydroxycarbonyl, C1-4alkyloxycarbonyl or with one or two C1-4alkyl substituents; thiadiazolyl or oxadiazolyl optionally substituted with amino or C1-4alkyl; pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl each optionally substituted with C1-4alkyl, C1-4alkyloxy, amino, hydroxy or halo; and Het<3> may also represent 4,5-dihydro-5-oxo-1H-tetrazolyl substituted with C1-4alkyl, 2-oxo-3-oxazolidinyl, 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl or a radical of formula wherein A-Z represents S-CH=CH, S-CH2-CH2, S-CH2-CH2-CH2, CH=CH-CH=CH, or CH2-CH2-CH2-CH2; aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C1-4alkyl, polyhaloC1-4alkyl, cyano, aminocarbonyl, C1-4alkyloxy or polyhaloC1-4alkyloxy; and pharmaceutically acceptable addition salts thereof, a prodrug, a N-oxide, an addition salt, a quaternary amine or a stereochemically isomeric form thereof as a medicament. 10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as described in any one of claims 1 to 9. 11. A process of preparing a composition as claimed in claim 10, characterized in that, a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as described in any one claims 1 to 9. 12. A compound of formula a N-oxide, an addition salt, a quaternary amine or a stereochemically isomeric form thereof wherein P is a protective group and n, -A-B-, Z, R<1> and R<2> are defined as in claim 1, provided that 6,11-dihydro-1'-{phenylmethyl)-5H-spiro[imidazo[1,2-b][3]-benzazepine-11,4'-piperidine] (E)-2-butenedioate(1:2) is not included. 13. A compound according to claim 12 wherein P is benzyl. 14. A process of preparing a compound as claimed in claim 1, characterized by deprotecting an intermediate of formula (II), followed optionally by derivatizing either the piperidine moiety, or the imidazole moiety, or both