Alpha-fluoro alkynoic acids with anticonvulsant activity
OwnerHeinz Nauinventor
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Abstract
Alpha-fluorinated alkynoic acids and pharmaceutical compositions containing these compounds are provided, which are useful for the treatment and prevention of seizures such as are associated with epilepsy. The compounds of the invention exhibit reduced side effects, relative to valproic acid, with regard to sedation and teratogenic potential.
Claims23
A compound of structure
- wherein R1 is selected from the group consisting of C3 to C10 alkyl, C3-C6 cycloalkyl, and cyclopropylmethyl, and R2 is selected from the group consisting of C1 to C3 alkyl and cyclopropyl;
- and pharmaceutically acceptable salts, esters, and amides thereof.
A compound selected from the group consisting of 2-ethyl-2-fluoro-4-hexynoic acid, 2-cyclopropyl-2-fluoro-4-hexynoic acid, 2-fluoro-2-n-propyl-4-hexynoic acid, 2-n-butyl-2-fluoro-4-hexynoic acid, 2-fluoro-2-n-pentyl-4-hexynoic acid, 2-fluoro-2-n-hexyl-4-hexynoic acid, 2-fluoro-2-n-heptyl-4-hexynoic acid, 2-fluoro-2-n-octyl-4-hexynoic acid, 2-ethyl-2-fluoro-4-heptynoic acid, 2-fluoro-2-n-propyl-4-heptynoic acid, 2-n-butyl-2-fluoro-4-heptynoic acid, 2-fluoro-2-n-pentyl-4-heptynoic acid, 2-fluoro-2-n-hexyl-4-heptynoic acid, 2-fluoro-2-n-heptyl-4-heptynoic acid, 2-fluoro-2-n-octyl-4-heptynoic acid, 2-fluoro-2-n-propyl-4-cyclopropyl-4-pentynoic acid, and 2-cyclopropylmethyl-2-fluoro-4-hexynoic acid;
- and pharmaceutically acceptable salts, esters, and amides thereof.
The compound 2-fluoro-2-n-pentyl-4-hexynoic acid.
A pharmaceutical composition comprising the compound 2-fluoro-2-n-pentyl-4-hexynoic acid, in combination with at least one pharmaceutically acceptable additive.
A process for preparing a compound of structure
- wherein R1 is selected from the group consisting of C3 to C10 alkyl, C3-C6 cycloalkyl, and cyclopropylmethyl, and R2 is selected from the group consisting of C1 to C3 alkyl and cyclopropyl, comprising the steps of:
- (a) alkylating a compound of structure
- wherein R3 is lower alkyl or benzyl and R4 is H, lower alkyl, lower alkoxy, or benzyloxy, with an alkylating reagent of structure
- R2—C≡C—CH2—X (III)
- wherein X is a suitable leaving group, in the presence of a suitable base, so as to obtain a compound of structure
- (b) where R4 is lower alkoxy or benzyloxy, hydrolysis, decarboxylation, and re-esterification of compound IV, or where R4 is H or lower alkyl, deacylation of compound IV, so as to obtain a compound of structure
- (c) enolization of compound V with a suitable base, in an inert solvent;
- (d) addition of a fluorinating reagent, so as to obtain a compound of structure
- and
- (e) hydrolysis of the ester moiety.
A process for preparing a compound of structure
- wherein R1 is selected from the group consisting of C3 to C10 alkyl, C3-C6 cycloalkyl, and cyclopropylmethyl, and R2 is selected from the group consisting of C1 to C3 alkyl and cyclopropyl, comprising the steps of:
- a) alkylating a compound of structure
- wherein R3 is lower alkyl or benzyl with an alkylating reagent of structure
- R2—C≡C—CH2—X (III)
- wherein X is a suitable leaving group, in the presence of a suitable base, so as to obtain a compound of structure
- (b) enolization of compound V with a suitable base, in an inert solvent;
- (c) addition of a fluorinating reagent, so as to obtain a compound of structure
- and
- (d) hydrolysis of the ester moiety.
Dependencies are inferred from the claim text.