Patent EA-005159-B1 (EA)
Title: Aminothiazole derivatives and their use as crf receptor ligands
Inventor: FONTAINE EVELYNE
IPC: A61P25/00
Filed: 2000-07-11
Abstract: 1. A compound of formula (I): in which R1 and R2, which may be identical or different, each independently represent a halogen atom; a hydroxy (C1-C5)alkyl; a (C1-C5)alkyl; an aralkyl in which the aryl portion is (C6-C8) and the alkyl portion is (C1-C4); a (C1-C5)alkoxy; a trifluoromethyl group; a nitro group; a nitrile group; a group -SR in which R represents hydrogen, a (C1-C5)alkyl or an aralkyl in which the aryl portion is (C6-C8) and the alkyl portion is (C1-C4); a group -S-CO-R in which R represents a (C1-C5)alkyl or an aralkyl radical in which the aryl portion is (C6-C8) and the alkyl portion is (C1-C4); a group -COORa in which Ra represents hydrogen or a (C1-C5)alkyl; a group -CONRaRb with Ra and Rb as defined above for Ra; a group -NRaRb with Ra and Rb as defined above for Ra; a group -CONRcRd or -NRcRd in which Rc and Rd constitute, with the nitrogen atom to which they are attached, a 5- to 7-membered heterocycle; or a group -NHCO-NRaRb with Ra and Rb as defined above for Ra; R3 represents hydrogen or is as defined above for R1 and R2; or alternatively R2 constitutes with R3, when the latter substitutes the phenyl in position 5, a represents a (C1-C6)alkyl; a (C1-C6)alkoxy(C1-C3)alkyl; a (C3-C5)cycloalkyl; a (C3-C6) group -X-CH2-X- in which X independently represents a CH2 or an oxygen or sulphur atom; R6 cycloalkyl(C1-C6)alkyl; a (C1-C6)alkylthio(C1-C3)alkyl; a (C1-C6)alkylsulphoxy(C1-C3)alkyl; or a (C1-C6)alkylsulphodioxy(C1-C3)alkyl; R7 represents a phenyl which is unsubstituted, mono-, di- or trisubstituted in position 3, 4 or 5 with a halogen, with a (C1-C5)alkyl, with an -O-CH2-O- group on two neighbouring carbon atoms of the phenyl, with a -CF3, -NO2 or -CN, with a group -COOR8 or -CONR8R9 or with a group CH2OR8 in which R8 and R9 represent a (C1-C3)alkyl, OR10 in which R<10> represents a (C1-C5)alkyl; or alternatively R7 represents a pyridyl, thiophene, pyrazolyl, imidazolyl, (C3-C5)cycloalkyl or (C3-C6)cycloalkyl(C1-C6)alkyl group; or the acid or base addition salts thereof, the hydrates thereof and/or the solvates thereof. 2. A compound according to claim 1 wherein: R1 and R2, which may be identical or different, each independently represent a halogen atom; a (C1-C5)alkyl; or a (C1-C5)alkoxy; R3 represents hydrogen or is as defined above for R1 and R2; R6 represents a (C1-C6)alkyl; a (C1-C6)alkoxy(C1-C3)alkyl; a (C3-C5)cycloalkyl; or a (C3-C6)cycloalkyl(C1-C6)alkyl; R7 represents a phenyl which is unsubstituted or mono- or disubstituted in position 3 or 4 with a halogen, a (C1-C5)alkyl group, a group -CH2OR8 in which R8 represents a (C1-C3)alkyl or with an -O-CH2-O- group in position 3, 4; or alternatively R7 represents a (C3-C5)cycloalkyl group. 3. A compound according to claim 4 wherein R3 is in position 5 of the phenyl. 4. A compound according to claim 1 selected from the group consisting of: [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1R)-(1-(3-fluoro-4-methylphenyl)-2-methoxyethyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-phenylbutyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-phenylethyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxyphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-phenylethyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-4-fluorophenyl)ethyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-phenylpentyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1R)-(2-methoxy-1-(4-methoxymethylphenyl)ethyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(4-methoxymethylphenyl)pentyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(4-fluorophenyl)pentyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(cyclopropylphenylmethyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(3-fluoro-4-methylphenyl)pentyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(4-fluorophenyl)butyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(3-fluoro-4-methoxymethylphenyl)butyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(4-chlorophenyl)ethyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(4-methylphenyl)ethyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclobutyl-1-(4-fluorophenyl)ethyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(4-bromophenyl)ethyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3,4-methylenedioxyphenyl)ethyl)]prop-2-ynylamine; [4-(2-chloro-4-methoxyphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylamine; [4-(2,4-dimethoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylamine; [4-(4-methoxy-2,5-dimethylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylamine; and [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(3,4-methylenedioxyphenyl)butyl)]prop-2-ynylamine; or the acid or base addition salts, solvates or hydrates thereof. 5. A process for preparing a compound according to claim 1 which comprises reacting a compound of formula (II): in order then to subject it to an alkylation reaction to give the compound (I), wherein R4 is methyl, and R1, R2, R3, R4, R5, R6 and R7 are as defined for (I). 6. A pharmaceutical composition containing a compound according to claim 1 as an active principle. 7. Use a compound according to claim 1 for manufacturing a medicament for preventing or treating CRF-dependent conditions. 8. Use a compound according to claim 1 for manufacturing a medicament for preventing or curative treating stress-related conditions and more generally in the treatment of any pathology involving CRF, such as, Cushing's disease, neuropsychiatric disorders such as depression, anxiety, panic, obsessive compulsive disorders, mood disorders, post-traumatic stress, behavioural disorders, aggressiveness, anorexia, bulimia, hyperglycaemia, premature labour, at-risk pregnancy, retarded growth, sleeping disorders, epilepsy, and all types of depression; Alzheimer's disease, Parkinson's disease, Huntington's chorea; amyotrophic lateral sclerosis; vascular, cardiac and cerebral disorders; sexual activity disorders and fertility disorders; immunodepression, immunosuppression, inflammatory processes, multiple infections, rheumatoid arthritis, osteoarthritis, uveitis, psoriasis and diabetes; cancers; gastrointestinal functional disorders and inflammations arising therefrom (irritable and inflammatory bowel, diarrhoea); pain-perception disorders, fibromyalgias which may or may not be associated with sleeping disorders, fatigue or migraine; symptoms associated with (alcohol) dependency and withdrawal from drugs.