WO1998006690B1

WO1998006690B1 - USE OF η-HYDROXYBUTYRIC ACID AMIDES IN THE TREATMENT OF DRUG ADDICTION AND IN PARTICULAR OF ALCOHOLISM

Info

Publication number: WO1998006690B1
Application number: PCT/EP1997/004309
Authority: WO
Filing date: 1997-08-07
Publication date: 1998-04-16

Abstract

The present invention relates to the use of η-hydroxybutyric acid amides, herein referred to as GHB, in the treatment of drug addiction, such as heroin, morphine and psychoactive substances and in the treatment of alcoholism, more particularly in reducing chronic alcoholics' desire for and habit of consuming alcoholic drinks and in the treatment of the syndrome of abstinence from alcohol.

Claims

AMENDED CLAIMS

[received by the International Bureau on 9 March 1998 (09.03.98); original claims 24-33 replaced by amended claims 24-32; remaining claims unchanged (3 pages)]

- and the amide of group c) is compound 16) of formula (I), in which Q=CH₃, T^T^H, n=1 , R^phenyl, R₂=H. 24. The composition as claimed in claim 23, wherein the amide is selected from compound 5), 7), 14) and compound 15). 25. The composition as claimed in claim 18 to be administered by the oral or parenteral way. 26. Amide of formula (I) Q I R₂0-(CH₂),-CO-N-CCT₁TJ_π-R₁ (I) where Q=H, T^T^H, n=1 , R^ethyl, R₂=H compound 2); where Q=H, T^T^H, n=1 , R₁=4-methylphenyl, R₂=CH₃ compound 7) where Q=H, T₁=T₂=H, n=1 , R^S.δ-dimethoxyphenyl, R₂=H compound 8); where Q=H, T,=T₂=H, n=1 , R^-pyridyl, R₂=H compound 9); where Q=H, T^T^H, n=1 , R^phenyl, R₂=CH₃ compound 10); where Q=H, T₁=T₂=H, n=1 , R₁=4-chlorophenyl, R₂=CH₃ compound 11 ); where Q=H, T^T^H, n=1 , R₁=4-methylphenyl, R₂=CH₃CH₂- compound 12); where Q=H, T^T^H, n=1 , R₁=4-methylphenyl, R₂=CH₃CH₂CH₂- compound 13); where Q=H, T^T^H, n=1 , R^l-naphthyl, R₂=CH₃ compound 14); where Q=H, T₁=T₂=H_f n=1 , R₁=4-CF₃-phenyl, R₂=CH₃ compound 15); where Q=CH₃, T^T^H, n=1 , R^phenyl, R₂=H compound 16). 27. The amide as claimed in claim 26, selected from compound 7) and compound 14). 28. Process for the preparation of an amide of formula (I) Q

where R₂ is an alkyl and the other substituents are as defined in claim 1 , comprising the following steps: a) treating γ-butyrolactone with an alcohol of formula R₂OH (III) in which R₂ is an alkyl, in the presence of an ortho-formiate of formula (IV) 34

H-C(OR₂)₃ (IV) in which R₂ is as defined above for the alcohol of formula (III), in the presence of an acid catalyst, to give an ester of formula (V) R₂0-(CH₂)₃-COOR₂ (V) in which R₂ is as defined above for the alcohol of formula (III); b) treating the ester of formula (V) obtained in a) with an amine of formula (VI) Q I H-N-tCT ^-R, (VI) where R_{1 f} Q, T_{1 (} T₂, and n are as defined above for formula (I), in the presence of an ammonium halide. 29. The process as claimed in claim 28, wherein R₂ is C1-C3 alkyl. 30. The process as claimed in claim 28, wherein step a) utilizes ortho-formiate in a quantity of 1.5-2 mol per mol γ-butyrolactone, an alcohol of formula (III) as solvent; an acid catalyst consisting of an inorganic acid in a quantity of 0.05-0.5 equivalent in respect of γ-butyrolactone, a reaction temperature ranging from 30°C to 100°C; step b) is carried out in the absence of solvent, at a temperature ranging from 100°C to 200°C, at a pressure ranging from atmospheric to autogenous pressure (obtained by operating in a bomb), with ammonium halide in a quantity ranging from 0.01 to 0.1 equivalent in respect of the substrate. 31. The process as claimed in claim 28, wherein step a) is carried out with a catalyst consisting of sulphuric acid in a quantity of 0.1 equivalent, at a temperature ranging from +50°C to +80°C; in step b) the catalyst is NH₄CI, the temperature is 160°C to 170°C, and the reaction is carried out in a bomb. 32. Process for the preparation of an amide of formula (l)B Q I HO-(CH₂)₃-CO-N-[CT₁T₂]_n-R₁ (l)B in which R, is an aromatic heterocycle, and Q, T_{1 f} T₂ and n are as defined for formula (I) in claim 1 , in which γ-butyrolactone reacted with the corresponding amine of formula (II) Q I H-N-fCT J_n-R, (II)

in which R₁₍ Q, T_1t T₂ and n are as defined above, by contacting the reagents in equimolar amounts in the absence of solvent at a temperature ranging from 100°C to 200°C, at atmospheric pressure.