Patent EA-005071-B1 (EA)
Title: NOVEL SUBSTITUTED PYRAZOLO[4,3-e]DIAZEPINES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, USE AS MEDICAL PRODUCTS AND PROCESSES FOR PREPARING THEM
Inventor: BURNOUF CATHERINE
IPC: C07D487/04
Filed: 2000-12-27
Abstract: 1. A compound of formula I below: in which: R1 is chosen from the following groups: linear or branched alkyl containing from 1 to 6 carbon atoms; cycloalkyl containing from 3 to 6 carbon atoms; cycloalkylalkyl comprising an alkyl group containing from 1 to 6 carbon atoms and a cycloalkyl group containing from 3 to 6 carbon atoms; aryl containing from 5 to 10 carbon atoms; arylalkyl containing from 6 to 10 carbon atoms; the groups (CH2)nORB, (CH2)nCOORB, (CH2)nC(O)NRBRC in which RB and RC, which may be identical or different, are chosen from: hydrogen; linear or branched alkyl containing from 1 to 6 carbon atoms; aryl containing from 5 to 10 carbon atoms; it being possible for RB and RC to form a ring containing from 5 to 7 atoms; Z is a halogen; and n is an integer from 0 to 4 inclusive; R2 is chosen from the following groups: linear or branched alkyl containing from 1 to 6 carbon atoms; cycloalkylalkyl comprising an alkyl group containing from 1 to 6 carbon atoms and a cycloalkyl group containing from 3 to 6 carbon atoms; cycloalkyl containing from 3 to 6 carbon atoms; aryl containing from 5 to 10 carbon atoms; linear or branched alkenyl containing from 2 to 6 carbon atoms; the groups (CH2)mORB, (CH2)nCF3 or (CH2)mZ, in which RB and Z are as defined above, and m is an integer from 1 to 4 inclusive; R3 is chosen from the following groups: hydrogen; linear or branched alkyl containing from 1 to 6 carbon atoms; cycloalkyl containing from 3 to 6 carbon atoms; aryl containing from 5 to 10 carbon atoms, optionally interrupted with a hetero atom chosen from nitrogen, oxygen and sulphur; arylalkyl containing from 6 to 10 carbon atoms, optionally interrupted with a hetero atom chosen from nitrogen, oxygen and sulphur; alkylaryl containing from 6 to 10 carbon atoms, optionally interrupted with a hetero atom chosen from nitrogen, oxygen and sulphur; the group (CH2)nCOORB, in which RB and n are as defined above; the aryl, arylalkyl and alkylaryl groups defined above being unsubstituted or substituted on the aryl group with 1, 2 or 3 groups chosen from: halogen, hydroxyl, CN, alkoxy containing from 1 to 4 carbon atoms, (CH2)nORB, (CH2)nNRBRC, (CH2)nNC(O)RB, (CH2)nHNSO2RB, (CH2)nN(SO2RB)2, CO2RB, CF3 and in which RB, RC and n are as defined above; and the dotted line present in formula I indicates that the bond between W and the carbon in position 5 may be: -a single bond, in which case W represents a nitrogen atom substituted with a hydrogen atom, -a double bond, and in this case W represents an unsubstituted nitrogen atom; X is S, O or NCN; as well as the oxides, the tautomeric forms and the corresponding opticals isomers or the pharmaceutically acceptable derivatives of the compounds of formula I, with the proviso that when R1 represents a methyl group, R2 an ethyl group, W is N, X is an oxygen atom and the bond between W and the carbon in position 5 is a double bond, then R3 is neither an unsubstituted phenyl group nor a phenyl group bearing a fluorine atom in an ortho position as sole substituent. 2. The compound according to Claim 1 of the formula I below: in which R1 is linear or branched alkyl containing from 1 to 6 carbon atoms; cycloalkyl containing from 3 to 6 carbon atoms; cycloalkylalkyl comprising an alkyl group containing from 1 to 6 carbon atoms and a cycloalkyl group containing from 3 to 6 carbon atoms; aryl containing from 5 to 10 carbon atoms; arylalkyl containing from 6 to 10 carbon atoms; the groups (CH2)nORB, (CH2)nCOORB, (CH2)nC(O)NRBRC in which RB and RC, which may be identical or different, are chosen from: hydrogen; linear or branched alkyl containing from 1 to 6 carbon atoms; aryl containing from 5 to 10 carbon atoms; it being possible for RB and RC to form a ring containing from 5 to 7 atoms; Z is a halogen; and n is an integer from 0 to 4 inclusive; R2 is linear or branched alkyl containing from 1 to 6 carbon atoms; (CH2)nCF3, where n is an integer from 0 to 4 inclusive; cyclopropylmethyl; linear or branched alkenyl containing from 2 to 6 carbon atoms; or the group (CH2)mORB where m is an integer from 1 to 4 inclusive; and RB is as defined above; R3 is linear or branched alkyl containing from 1 to 6 carbon atoms; cycloalkyl containing from 3 to 6 carbon atoms; aryl containing from 5 to 10 carbon atoms, optionally interrupted with a hetero atom chosen from nitrogen, oxygen and sulphur; arylalkyl containing from 6 to 10 carbon atoms, optionally interrupted with a hetero atom chosen from nitrogen, oxygen and sulphur; alkylaryl containing from 6 to 10 carbon atoms, optionally interrupted with a hetero atom chosen from nitrogen, oxygen and sulphur; the group (CH2)nCOORB, in which RB and n are as defined above; the aryl, arylalkyl and alkylaryl groups defined above being unsubstituted or substituted on the aryl group with 1, 2 or 3 groups chosen from: halogen, hydroxyl, CN, alkoxy containing from 1 to 4 carbon atoms, (CH2)nORB, (CH2)nNRBRC, (CH2)nNC(O)RB, (CH2)nHNSO2RB, (CH2)nN(SO2RB)2, CO2RB, CF3 and in which RB, RC and n are as defined above; X is S, O or NCN. 3. A compound according to Claim 1 or 2, in which R1 is linear or branched alkyl containing from 1 to 6 carbon atoms; cycloalkyl containing from 3 to 6 carbon atoms; cycloalkylalkyl comprising an alkyl group containing from 1 to 6 carbon atoms and a cycloalkyl group containing from 3 to 6 carbon atoms; aryl containing from 5 to 10 carbon atoms; the groups (CH2)nORB, (CH2)nCOORB, (CH2)nC(O)NRBRC in which RB and RC, which may be identical or different, are chosen from: hydrogen; linear or branched alkyl containing from 1 to 6 carbon atoms; aryl containing from 5 to 10 carbon atoms; it being possible for RB and RC to form a ring containing from 5 to 7 atoms; n is an integer from 0 to 4 inclusive; R2 is linear or branched alkyl containing from 1 to 4 carbon atoms; or the group (CH2)mOH, where m is an integer from 0 to 4 inclusive; R3 is linear or branched alkyl containing from 1 to 6 carbon atoms; cycloalkyl containing from 3 to 6 carbon atoms; aryl containing from 5 to 10 carbon atoms, optionally interrupted with a hetero atom chosen from nitrogen, oxygen and sulphur; arylalkyl containing from 6 to 10 carbon atoms, optionally interrupted with a hetero atom chosen from nitrogen, oxygen and sulphur; alkylaryl containing from 6 to 10 carbon atoms, optionally interrupted with a hetero atom chosen from nitrogen, oxygen and sulphur; the aryl, arylalkyl and alkylaryl groups defined above being unsubstituted or substituted on the aryl group with 1, 2 or 3 groups chosen from: halogen, hydroxyl, CN, alkoxy containing from 1 to 4 carbon atoms, (CH2)nORB, (CH2)nNRBRC, (CH2)nNC(O)RB, CO2RB, CF3 and in which RB, RC and n are as defined above; X is S, O or NCN. 4. A compound according to Claim 1 or 2, in which: R1 is linear or branched alkyl containing from 1 to 4 carbon atoms; cycloalkyl containing from 3 to 6 carbon atoms; cycloalkylalkyl comprising an alkyl group containing from 1 to 3 carbon atoms and a cycloalkyl group containing from 3 to 6 carbon atoms; R2 is linear or branched alkyl containing from 1 to 4 carbon atoms; R3 is linear or branched alkyl containing from 1 to 4 carbon atoms; aryl containing from 5 to 10 carbon atoms, optionally interrupted with a hetero atom chosen from nitrogen, oxygen and sulphur; arylalkyl containing from 6 to 10 carbon atoms, optionally interrupted with a hetero atom chosen from nitrogen, oxygen and sulphur; preferably phenyl or pyridyl, the aryl groups being unsubstituted or substituted with 1, 2 or 3 groups, which may be identical or different, chosen from NH2, halogen, methoxy, hydroxyl, CN, CH3 and CF3, and X is S, O or NCN. 5. A compound according to Claim 1 or 2, in which: R1 is linear or branched alkyl containing from 1 to 4 carbon atoms; R2 is linear or branched alkyl containing from 1 to 4 carbon atoms; or the group (CH2)nOH, where n is an integer from 0 to 4 inclusive; R3 is linear or branched alkyl containing from 1 to 4 carbon atoms; a cycloalkyl group containing from 3 to 6 carbon atoms, an aryl group chosen from phenyl and thienyl, which may be unsubstituted or substituted with a group chosen from halogen, hydroxyl, methoxy, NH2 and CH3; and X is S or O. 6. A compound according to Claims 1 to 5, chosen from the group consisting of: 1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 5-(4-Bromophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 1,3-Dimethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 5-(4-Methoxyphenyl)-1,3-dimethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 5-(4-Bromophenyl)-1,3-dimethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 1-Ethyl-3-methyl-5-naphth-2-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 5-(3-Chlorothien-2-yl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, Methyl-3-(1-ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)propanoate, 1-Ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 5-(4-Chlorophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 5-(4-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 1-Ethyl-5-(4-fluorophenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 5-(3-Bromophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 3-Methyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 1-Isopropyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, (+-) 1-Ethyl-3-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 1-(2-Hydroxyethyl)-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 1-Ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione, 1-Ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 1-Ethyl-5-(3-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one, 5-(2-Aminophenyl)-1-ethyl-3