Patent EA-002189-B1 (EA)
Title: Diazepino-indoles as phosphodiesterase iv inhibitors
Inventor: PASCAL YVES
IPC: A61P11/06
Filed: 1997-03-27
Abstract: 1. A use of diazepine-indole of formula (I)   wherein A is phenyl, naphthyl or nitrogen-containing heteroaryl, each optionally being substituted with one to three groups chosen independently from halogen, C1-4 alkyl, haloalkyl, C1-4 alkoxy, cycloalkyloxy, amino, C1-4 alkylcarbonylamino or C1-4 alkyloxycarbonylanino; B is: 1) -OR1, wherein R1 is -H or R4, 2) -NR2R3, wherein R2 is -C(NH)NH2 and R3 is -H, 3) -NR2R3, wherein R2 is R4 and R3 is -H, 4) -NR2R3, wherein R2 and R3 are independently -H or C1-4alkyl or 5) -N-R2-R3, wherein R2 and R3 forming, together with the nitrogen atom to which they are attached, a saturated five- to seven-membered heterocycle which may comprise, as second hetero atom not attached directly to the nitrogen atom, an oxygen, a sulfur or a nitrogen; R4 is: 1) -CH2-COH, 2) -CO-(CH2)p-CO2H, 3) -CO-A, wherein A is determined above, 4) -CO-CH = CH-CO2H, 5) -CO-(CH2)n-CH3, n is integer from 0 to 18 inclusive, 6) -CO-(CH2-O-CH2)p-CH2-O-CH3, 7) -CO-(CH2-O-CH2)p-CO2H, 8) -(CH2)p-NR5R6, wherein R5 and R6 independently being -H or C1-4alkyl or 9) -(CH2)p-N-R5-R6, R5 and R6 forming, together with the nitrogen atom to which they are attached, a saturated five- to seven-membered heterocycle which may comprise, as second hetero atom not attached directly to the nitrogen atom, an oxygen, a sulfur or a nitrogen; p is an integer equal to 2, 3 or 4; the racemic forms and isomers thereof of configuration determined in particular by carbon 3 of the diazepinoindol-4-one ring, as well as the pharmaceutically acceptable salts thereof for preparation of a medicinal product for treatment of complaints that respond to administration of a phosphodiesterase 4 inhibitor. 2. A use of diazepine-indole of formula (I) according to Claim 1, characterized in that their absolute configuration is R according to the Cahn-Igold-Prelog rule, considering the asymmetric carbon atom in an alpha position relative to the carbonyl of the diazepine ring. 3. A use of diazepine-indole of formula (I) according to Claim 1 or 2, characterized in that B is OR1 or NR2 R3 where R1 R2 R3 are hydrogen. 4. A use of diazepine-indole of formula (I) according to any of Claims 1-3, in which A is phenyl or naphthyl substituted with one to 3 groups independently chosen from halogen, amino and C1-4 alkoxy. 5. A use of diazepine-indole of formula (I) according to any of Claims 1-4, in which A is monocyclic nitrogen-containing heteroaryl comprising from 1 to 2 nitrogen atoms or bicyclic nitrogen-containing heteroaryl comprising from 1 to 4 nitrogen atoms. 6. A use of diazepine-indole of formula (I) according to any of Claims 1-5, in which A is heteroaryl substituted with amino, C1-4 alkyl, C1-4 alkyloxycarbonylamino or alkylcarbonylamino groups. 7. A use according to any of Claims 1-6, wherein diazepine-indoles of formula (I), are selected from the group: (3R)-isoquinoline-3-carboxylic acid (9-hydroxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)amide; (3R)-4-tert-butyloxycarbonylamino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7,-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-benzamide; (3R)-4-amino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1-hi]indol-3-yl)benzamide; (3R)-4-amino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1-hi]indol-3-yl)-3,5-dichlorobenzamide; (3R)-4-amino-N-[9-(4-amino-3,5-dichlorobenzamido)-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl]-3,5-dichlorobenzamide; (3R)-2-acetylamino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide; (3R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-2-methoxybenzamide; (3R)-4-amino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino 6,7,1-hi]indol-3-yl)-5-chloro-2-methoxybenzamide; (3R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-3-cyclopentyloxy-4-methoxybenzamide; (3R)-pyridine-2-carboxylic acid (9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino[6,7,1-hi]indol-3-yl)amide; (3R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1,-hi]indol-3-yl-isonicotinamide; (3R)-3-tert-butyloxycarbonylamino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)isonicotinamide; (3R)-3-amino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1-hi]indol-3-yl)isonicotinamide; (3R)-3-acetylamino-N-(9-acetylamino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino-[6,7,1-hi]indol-3-yl)isonicotinamide; (3R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl-)-3,5-dichloroisonicotinamide; (3R)-pyrazine-2-carboxylic acid (9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino[6,7,1-hi]indol-3-yl)amide; (3R)-isoquinoline-3-carboxylic acid (9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]-diazepino[6,7,1-hi]indol-3-yl)amide; (3R)-quinoline-3-carboxylic acid (9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino[6,7,1-hi]indol-3-yl)amide; (3R)-4,7-dimethylpyrazolo[5,1-c][1,2,4]triazine-3-carboxylic acid (9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)amide; (3R)-4-amino-3,5-dichloro-N-(9-dimethylamino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide; (3R)-4-amino-3,5-dichloro-N-(4-oxo-1-phenyl-9-pyrrolidin-1-yl-3,4,6,7-tetrahydro[1,4]-diazepino[6,7,1-hi]indol-3-yl)benzamide; (3R)-4-amino-3,5-dichloro-N-(4-oxo-1-phenyl-9-morpholin-1-yl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide; (3R)-4-amino-3,5-dichloro-N-(9-quanidino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]-diazepino[6,7,1-hi]indol-3-yl)benzamide; (3R)-N-(9-acetylamino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1-hi]indol-3-yl)-4-amino-3,5-dichlorobenzamide; (3R)-4-amino-3,5-dichloro-N-(9-{2-[2-(2-methoxyethoxy)ethoxy]acetylamino}-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino-[6,7,1-hi]indol-3-yl)benzamide; (3R)-(2-{2-[3-(4-amino-3,5-dichlorobenzoylamino)-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-9-ylcarbamoylmethoxy]ethoxy}ethoxy) acetic acid; (3R)-hexadecanoic acid [3-(4-amino-3,5-dichlorobenzoylamino)-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-9-yl]amide; (3R)-isoquinoline-3-carboxylic acid (9-acetylamino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-9-yl)amide; (3R)N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-2-benzofuranecarboxamide; (3R)N-[4-oxo-1-phenyl-9-(pyrrolidin-1-yl)-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1-hi]indol-3-yl)-isonicotinamide; or (3R)4,7-dimethyl-pyrazolo[5,1-c][1,2,4]triazine-3-carboxylic acid [4-oxo-1-phenyl-9-(pyrrolidin-1-yl)-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl]-amide. 8. A use according to any of Claims 1-7, for preparing medical product for the treatment of inflammatory pathologies such as asthma or rheumatic arthritis. 9. A use of (3R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1-hi]indol-3-yl)nicotinamide for preparation of a medicinal product for treatment of complaints that respond to administration of a phosphodiesterase 4 inhibitor. 10. A use of (3R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1-hi]indol-3-yl)nicotinamide for preparation of a medicinal product for treatment of inflammatory pathologies such as asthma or rheumatic arthritis. 11. A use of (3R)-4-amino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1-hi]indol-3-yl)benzamide for preparation of a medicinal product for treatment of complaints that respond to administration of a phosphodiesterase 4 inhibitor. 12. A use of (3R)-4-amino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1-hi]indol-3-yl)benzamide for preparation of a medicinal product for treatment of inflammatory pathologies such as asthma or rheumatic arthritis. 13. A use of a compound selected from the group consisting from: (3R)-4-tert-butyloxycarbonylamino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl) benzamide; (3R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)isonicotinamide; (3R)-3-tert-butyloxycarbonylamino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl) isonicotinamide; and (3R)-3-amino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1-hi]indol-3-yl) isonicotinamide for preparation of a medicinal product for treatment of complaints that respond to administration of a phosphodiesterase 4 inhibitor. 14. A use of a compound selected from the group consisting from: (3R)-4-tert-butyloxycarbonylamino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl) benzamide; (3R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)isonicotinamide; (3R)-3-tert-butyloxycarbonylamino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl) isonicotinamide; and (3R)-3-amino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1-hi]indol-3-yl) isonicotinamide for preparation of a medicinal product for treatment of inflammatory pathologies such as asthma or rheumatic arthritis.