Patent FR-2895407-A1 (FR)
Title: New 2-hydrazono-pyrimidine derivatives are useful as neuroprotective agents for treatment of e.g. Huntington's disease
Inventor: COMPAGNONE NATHALIE
IPC: C07D239/42
Filed: 2005-12-28
Abstract: 2-Hydrazono-pyrimidine derivatives (I) and their acid addition salts are new. 2-hydrazono-pyrimidine derivatives of formula (I) and their acid addition salts are new. Either R 2>phenyl; R 3>and R 4>H; R 5>2-hydroxyphenyl; and R 1>phenyl (optionally substituted by 3- or 4-chloro, 4-methoxy, 2-, 3- or 4-trifluoromethyl, 3-methyl or 3- or 4-hydroxy) or 4-pyridyl. Or R 2>phenyl; R 3>and R 4>H; R 1>4-methylphenyl; and R 5>phenyl (ortho-substituted by chloro, methyl or hydroxy) or 4-methyl-2-hydroxyphenyl. Or R 2>phenyl; R 3>H; R 4>methyl; R 5>4-hydroxyphenyl; and R 1>4-methylphenyl. Or R 2>4-methylphenyl; R 3>and R 4>H; R 5>4-hydroxyphenyl; and R 1>4-methylphenyl. Or R 2>3-methylphenyl; R 3>and R 4>H; R 5>4-hydroxyphenyl; and R 1>4-methylphenyl. Independent claims are included for the following: (1) preparation of (I) by reacting pyrimidine derivatives of formula (II) with ketones of formula R 4>COR 3>(III); (2) new compounds (II) provided that when R 2>is phenyl R 1>is not phenyl or 4-methylphenyl; (3) preparation of (II) (with no proviso) by reacting 2-methylsulfonyl-pyrimidine derivatives of formula (IV) with hydrazine; (4) new compounds (IV); (5) preparation of (IV) by reacting 2-methylthio-pyrimidine derivatives of formula (V) with m-chloroperbenzoic acid; (6) new compounds (V) provided that when R 2>is phenyl R 1>is not 3- or 4-chlorophenyl, 4-methoxy-phenyl or 4-trifluoromethyl (sic); (7) preparation of (V) by reacting 2-mercapto-pyrimidine derivatives of formula (VI) with 1.1-3 equivalents of methyl sulfate and 2-10 equivalents of potassium carbonate at reflux in e.g. anhydrous dimethylformamide for 6-24 hours; (8) new compounds (VI) provided that when R 1>is 4-hydroxyphenyl R 2>is not phenyl; (9) preparation of (VI) by reacting ketones of formula R 1>C(O)-Ctriple boundCR 2>(VII) with 0.8-1.5 equivalents thiourea, in presence of 0.8-3 equivalents of sodium ethoxide, in e.g. refluxing anhydrous methanol, for 0.5-24 hours; and (10) use of compounds (I) and their acid addition salts, with the following definitions, as drugs. R 1>and R 2>(hetero)aryl; R 3>and R 4>H or alkyl; and R 5>(hetero)aryl or cycloalkyl. Provided that compounds with the following sets of definitions are excluded: (i) R 1>is 4-F-phenyl, R 2>is phenyl, R 3>and R 4>are H and R 5>is 2-nitrophenyl; (ii) R 1>is 2-methoxy-4-ethoxy-phenyl, R 2>is 2,4-dimethoxy-phenyl, R 3>and R 4>are H and R 5>is 4-methoxy-phenyl; (iii) R 1>and R 2>are phenyl, R 3>and R 4>are H and R 5>is 3,5-di-tert-butyl-4-hydroxyphenyl; (iv) R 1>is 2,4-diethoxyphenyl, R 2>is phenyl, R 3>and R 4>are H and R 5>is 4-methoxyphenyl; (v) R 1>is 3,4-dimethylphenyl, R 2>is 4-chlorophenyl, R 3>and R 4>are H and R 5>is 4-chlorophenyl; (vi) R 1>is 2,4-diethoxyphenyl, R 2>is 4-methoxyphenyl, R 3>and R 4>are H and R 5>is phenyl; (vii) R 1>is 2,4-dimethoxyphenyl, R 2>is phenyl, R 3>and R 4>are H and R 5>is 4-methoxy-phenyl; (viii) R 1>is 2,4-diethoxyphenyl, R 2>is 2,4-dimethoxyphenyl, R 3>and R 4>are H and R 5>is 4-methoxyphenyl; (ix) R 1>is 2,4-dimethoxyphenyl, R 2>is 4-methoxyphenyl, R 3>and R 4>are H and R 5>is phenyl; (x) R 1>is 2,4-diethoxyphenyl, R 2>is 2-methoxy-4-ethoxyphenyl, R 3>and R 4>are H and R 5>is 4-methoxyphenyl; and (xi) R 1>and R 2>are 2,4-dimethoxyphenyl, R 3>and R 4>are H and R 5>is 4-methoxyphenyl. [Image] [Image] ACTIVITY : Anticonvulsant; Nootropic; Neuroprotective; Antiparkinsonian; Neuroleptic; Anti-HIV; Nephrotropic; Antidiabetic; Vasotropic; Ophthalmological; Auditory. In tests on isolated neurons from the striatum of rats, (I) protected these cells against death induced by overexpression of a mutant form of huntingtin. MECHANISM OF ACTION : None given.