Claims for Patent: 5,468,743

Summary for Patent: 5,468,743

Title:	Imidazo[2,1-b]benzazepine derivatives, compositions and method of use
Abstract:	The present invention is concerned with novel imidazo[2, 1-b][3]benzazepines of formula ##STR1## the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein each of the dotted lines independently represents an optional bond; R1 represents hydrogen, halo, C1-4 alkyl or C1-4 alkyloxy; R2 represents hydrogen, halo, C1-4 alkyl or C1-4 alkyloxy; R3 represents hydrogen, C1-4 alkyl, ethenyl substituted with hydroxycarbonyl or C1-4 alkyloxycarbonyl, C1-4 alkyl substituted with hydroxycarbonyl or C1-4 alkyloxycarbonyl, hydroxyC1-4 alkyl, formyl or hydroxycarbonyl; R4 represents hydrogen, C1-4 alkyl, hydroxyC1-4 alkyl, phenyl or halo; R5 represents hydrogen, C1-4 alkyl or halo; L represents hydrogen; C1-6 alkyl; C1-6 alkyl substituted with one substituent selected from the group consisting of hydroxy, halo, C1-4 alkyloxy, hydroxycarbonyl, C1-4 alkyloxycarbonyl, C1-4 alkyloxycarbonyl-C1-4 alkyloxy, hydroxycarbonylC1-4 alkyloxy, C1-4 alkyloxycarbonylamino, C1-4 alkylaminocarbonyl, C1-4 alkylaminocarbonylamino, C1-4 alkylaminothiocarbonylamino, aryl, aryloxy and arylcarbonyl; C1-6 alkyl substituted with both hydroxy and aryloxy; C3-6 alkenyl; C3-6 alkenyl substituted with aryl; or, L represents a radical of formula --Alk--Y--Het1 (a-1),--Alk--NH--CO--Het2 (a-2)or --Alk--Het3 (a-3); provided that 6,11-dihydro-11-(4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine is ecxluded, which are useful antiallergic compounds.Compositions comprising said compounds, methods of using and processes for preparing the same.
Inventor(s):	Frans E. Janssens, Gaston S. M. Diels, Joseph E. Leenaerts
Assignee:	Janssen Pharmaceutica NV
Application Number:	US08/142,474
Patent Claims:	1. A compound of the formula: ##STR159## a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein:each of the dotted lines independently represents an optional bond; R1 represents hydrogen, halo, C1-4 alkyl, or C1-4 alkyloxy; R2 represents hydrogen, halo, C1-4 alkyl, or C1-4 alkyloxy; R3 represents hydrogen, C1-4 alkyl, ethenyl substituted with hydroxycarbonyl or C1-4 alkyloxycarbonyl, C1-4 alkyl substituted with hydroxycarbonyl or C1-4 alkyloxycarbonyl, hydroxyC1-4 alkyl, formyl or hydroxycarbonyl; R4 represents hydrogen, C1-4 alkyl, hydroxyC1-4 alkyl, phenyl or halo; R5 represents hydrogen, C1-4 alkyl or halo; L represents C1-6 alkyl; C1-6 alkyl substituted with one substituent selected from the group consisting of hydroxy, halo, C1-4 alkyloxy, hydroxycarbonyl, C1-4 alkyloxycarbonyl, C1-4 alkyloxycarbonylC1-4 alkyloxy, hydroxycarbonylC1-4 alkyloxy, C1-4 alkyloxycarbonylamino, C1-4 alkylaminocarbonyl, C1-4 alkylaminocarbonylamino, C1-4 alkylaminothiocarbonylamino, aryl, aryloxy and arylcarbonyl; C1-6 alkyl substituted with both hydroxy and aryloxy; C3-6 alkenyl; C3-6 alkenyl substituted with aryl; wherein each aryl is phenyl or phenyl substituted with halo, cyano, hydroxy, C1-4 alkyl, C1-4 alkyloxy, aminocarbonyl or phenyl substituted with C1-4 alkyloxycarbonyl or hydroxycarbonyl; or L represents a radical of the formula: --Alk--Y--Het.sup.1 (a- 1), --Alk--NH--CO--Het.sup.2 (a- 2), or --Alk--Y--Het.sup.3 (a- 3); wherein Alk represents C1-4 alkanediyl; Y represents O, S or NH; Het1, Het2 and Het3 each represent:furanyl, thienyl, oxazolyl, thiazolyl or imidazolyl each optionally substituted with one or two C1-4 alkyl substituents; pyrrolyl or pyrazolyl optionally substituted with formyl, hydroxyC1-4 alkyl, hydroxycarbonyl, C1-4 alkyloxycarbonyl or with one or two C1-4 alkyl substituents; thiadiazolyl or oxadiazolyl optionally substituted with amino or C1-4 alkyl; pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl each optionally substituted with C1-4 alkyl, C1-4 alkyloxy, amino, hydroxy or halo; or imidazo[4,5-c]pyridin-2-yl; and Het3 may also represent a member selected from the group consisting of:(a) 4,5-dihydro-5-oxo-1H-tetrazolyl substituted with C1-4 alkyl; (b) 2-oxo-3-oxazolidinyl; (c) 2,3-dihydro-2-oxo-1H-benzimidazol1-yl; and (d) a radical of the formula: ##STR160## wherein: R6 represents hydrogen or C1-4 alkyl; and A-Z represents --S--CH═CH--, --S--CH2 --CH2 --, --S--CH2 --CH2 --CH2 --, --CH═CH--CH═CH--, --CH2 --CH2 --CH2 --CH2 --, --N(CH3)--C(CH3)═CH-- or --CH═C (CH3)--O--. 2. A compound according to claim 1 wherein L is C1-4 alkyl or C1-4 alkyl substituted with hydroxycarbonyl or C1-4 alkyloxycarbonyl. 3. A compound according to claim 1 wherein:R3 represents hydrogen, C1-4 alkyl, formyl, hydroxyC1-4 alkyl or hydroxycarbonyl; R4 represents hydrogen, halo or hydroxyC1-4 alkyl; and L represents C1-4 alkyl, haloC1-4 alkyl, hydroxycarbonylC1-4 alkyl, C1-4 alkyloxycarbonylC1-4 alkyl, C1-4 alkyloxycarbonylaminoC1-4 alkyl, arylC1-4 alkyl, propenyl, or L is a radical of the formula: --Alk--Y--Het.sup.1 (a- 1), --Alk--NH--CO--Het.sup.2 (a- 2), or --Alk--Y--Het.sup.3 (a- 3); wherein Het1, Het2 and Het3 each represent furanyl oxazolyl, or thiazolyl each optionally substituted with C1-4 alkyl; thiadiazolyl optionally substituted with amino; pyridinyl; pyrimidinyl optionally substituted with hydroxy; or imidazo[4,5-c]pyridin-2-yl; or Het3 may also represent a radical of the formula (b-2): ##STR161## 4. A compound according to claim 3 whereinR1 represents hydrogen or halo; R2 represents hydrogen, halo or C1-4 alkyloxy; and L represents hydrogen, C1-4 alkyl, haloC1-4 alkyl, hydroxycarbonylC1-4 alkyl, C1-4 alkyloxycarbonylC1-4 alkyl, or a radical of formula (a-1), wherein Y represents NH. 5. A compound according to claim 1 wherein said compound is selected from the group consisting of5,6-dihydro-11-(1-methyl-4-piperidinylidene)-11H-imidazo[2,1-b][3 ]benzazepine; 9-fluoro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine; 11-(1-methyl-4-piperidinylidene)-11H-imidazo[2,1-b][3]benzazepine; 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine-3-methanol; 8-fluoro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine; 6,11-dihydro-11-(1-methyl-4-piperidinylidene)- 5H-imidazo[2,1-b][3]benzazepine-3-carboxaldehyde; 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine-3carboxylic acid; 7-fluoro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine; and 4-(8-fluoro-5,6-dihydro-11H-imidazo[2,1-b][3]benzazepin-11-ylidene)-1-piperidinepropanoic acid dihydrate. 6. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound as defined in claim 1 and a pharmaceutically acceptable carrier. 7. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound as defined in claim 2 and a pharmaceutically acceptable carrier. 8. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound as defined in claim 3 and a pharmaceutically acceptable carrier. 9. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound as defined in claim 4 and a pharmaceutically acceptable carrier. 10. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound as defined in claim 5 and a pharmaceutically acceptable carrier. 11. A method of treating allergic conditions in warm blooded animals which comprises administering to warm blooded animals suffering from allergic conditions an effective anti-allergic amount of a compound as defined in claim 1. 12. A method of treating allergic conditions in warm blooded animals which comprises administering to warm blooded animals suffering from allergic conditions an effective anti-allergic amount of a compound as defined in claim 2. 13. A method of treating allergic conditions in warm blooded animals which comprises administering to warm blooded animals suffering from allergic conditions an effective anti-allergic amount of a compound as defined in claim 3. 14. A method of treating allergic conditions in warm blooded animals which comprises administering to warm blooded animals suffering from allergic conditions an effective anti-allergic amount of a compound as defined in claim 4. 15. A method of treating allergic conditions in warm blooded animals which comprises administering to warm blooded animals suffering from allergic conditions an effective anti-allergic amount of a compound as defined in claim 5. 16. A compound of the formula: ##STR162## an acid addition salt thereof or a stereochemically isomeric form thereof, wherein each of the dotted lines independently represents an optional bond, and wherein:R1 represents hydrogen, halo, C1-4 alkyl or C1-4 alkyloxy; R2 represents hydrogen, halo, C1-4 alkyl or C1-4 alkyloxy; R3 represents hydrogen, C1-4 alkyl, ethenyl substituted with hydroxycarbonyl or C1-4 alkyloxycarbonyl, C1-4 alkyl substituted with hydroxycarbonyl or C1-4 alkyloxycarbonyl, hydroxyC1-4 alkyl, formyl or hydroxycarbonyl; R4 represents hydrogen, C1-4 alkyl, hydroxyC1-4 alkyl, phenyl or halo; R5 represents hydrogen, C1-4 alkyl or halo; and Q represents phenyloxycarbonyl, or C1-6 alkyl substituted with a member selected from the group consisting of halo, cyano, amino, isothiocyanato, (4-amino-3-pyridinyl)aminothiocarbonylamino, (CH3 O)2 CH--CH2 --NH--C(═NCH3)--NH--, and methylsulfonyloxy.