Alpha-fluoro alkynoic acids with anticonvulsant activity

Details Alpha-fluoro alkynoic acids with anticonvulsant activity Alpha-fluoro alkynoic acids with anticonvulsant activity

1999-06-22

2001-02-06

Carr, Deborah D. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Fatty compounds having an acid moiety which contains the...

C554S150000, C514S557000

Reexamination Certificate

active

06184401

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to fluorinated alkynoic acids, to the preparation thereof, and to the use thereof as anti-convulsive therapeutic agents. The fluorinated alkynoic acids of the invention are comparable to valproic acid in their utility for the prevention of seizures, but have reduced teratogenic potential. Consequently, this invention provides effective anti-epileptic agents with a greater margin of safety than valproic acid with respect to teratogenic potential. Certain compounds of this invention also exhibit comparable or reduced sedative effects relative to valproic acid, and certain compounds of the invention exhibit a longer duration of activity than valproic acid.
BACKGROUND OF THE INVENTION
Epilepsy affects roughly 1% of the world'population. Among the drugs employed for control of epileptic seizures is valproic acid. Valproic acid (also referred to as VPA, valproate, or 2-propylpentanoic acid) is an effective anticonvulsant, but it has a short duration of action. More seriously, VPA suffers from serious side effects, among them sedation, potentially fatal hepatotoxicity, and teratogenicity. Hepatotoxicity is particularly a problem in young children, especially children on polytherapy. The VPA-induced hepatic fatality rate among the latter patient category is reported to be 1/500 (F. E. Dreifuiss et al., Neurology (1987), 37, 379-385). Valproic acid has been shown to induce neural tube defects in mice, and it is estimated that the risk of spina bifida among newborns of women taking VPA during pregnancy is 1-2% (Centers for Disease Control, Morbidity and Mortality Weekly Report (1983), 32(33), 438-439).
There has been a considerable effort to discover analogues of valproic acid that are equally effective, but that have a greater margin of safety. See, for example, H. Nau et al., PCT application WO 94/06743, wherein a variety of modifications to the alkyl chains of valproic acid are made, and the related U.S. Pat. No. 5,786,380, which is hereby incorporated in its entirety by reference.
With regard to teratogenicity, it has been reported that introduction of a triple bond into the 4-position of valproic acid greatly increases teratogenicity, but that this effect is largely confined to the S-(−) enantiomer. Addition of a methyl group to the end of the triple bond abolished teratogenicity, while maintaining anticonvulsant activity (H. Nau, R.-S. Hauck, K. Ehlers,
Pharmacology & Toxicology
(1991), 69, 310-321.) These results indicated that separation of teratogenicity and anticonvulsive activity was possible. Sedative side effects were also separated from anticonvulsant activity in some analogues (M. Elmazar, R.-S. Hauck, H. Nau,
J. Pharm. Sci
. (1993), 82, 1255-1288.)
Alpha-branched carboxylic acids with an alpha-fluorine are little known. P. Crowley et al., in European patent application EP 468681, refers to 2-ethyl-2-fluorobutanoic acid as a fungicide intermediate, and a method for its preparation. Takeuchi refers to several examples of this class of compound in a publication relating to methods of preparing tertiary alkyl fluorides (Y. Takeuchi et al.,
J. Org. Chem
. (1993), 58(13), 3483-3485).
The valproic acid analogue 2-fluoro-2-propyl-4-pentenoic acid has also been reported. The compound was used as a probe for studies of valproic acid hepatotoxicity and metabolism. (W. Tang et al.,
Chem. Res. Toxicol
. (1995), 8(5), 671-682; M. Jurima-Romet et al.,
Toxicology
(1996), 112(1), 69-85; W. Tang and F. Abbott,
Drug Metab. Dispos
. (1997), 25(2), 219-227.) In the above references, the presence of the 2-fluoro substituent was reported to reduce hepatotoxicity relative to 2-propyl-4-pentenoic acid. Anticonvulsant, sedative or teratogenic properties of the fluorinated compound were not disclosed.
Alpha-fluorinated valproic acid, 2-fluoro-2-propylpentanoic acid, has also been reported (Ph.D. thesis of Wei Tang, University of British Columbia, 1996). The anticonvulsant activity and pharmacokinetics of this compound were studied, and its pharmaceutical potential was speculated upon (F. Abbott, W. Tang, J. Palaty,
J. Pharmacol. Exp. Ther
. (1997), 282, 1163-1172). The compound was reported to be less potent than VPA, and the hepatotoxic, sedative, or teratogenic properties were not disclosed.
Valproic acid analogues with terminal trifluoromethyl groups have been reported: 5,5,5-trifluoro-2-(3,3,3-trifluoropropyl) pentanoic acid (K. Yamaguchi and M. Taninaka, Japanese patent Application 4-21652 (1992), and 5,5,5-trifluoro-2-n-propyl pentanoic acid (Hiroshima et al.,
Japan. J. Psychopharmacol
. (1992) 12, 427). These compounds, too, are less potent than VPA.
SUMMARY OF THE INVENTION
This invention relates to 2-fluoro-2-alkyl-4-alkynoic acid compounds, pharmaceutical compositions containing them, and their use to treat or prevent convulsions. This invention also provides processes for the preparation of these compounds. The preferred 2-fluorinated carboxylic acids of the invention possess anticonvulsant activity comparable or superior to that of valproic acid, but exhibit reduced teratogenicity, and a longer duration of activity as well.
The compounds of this invention may also be used to treat and/or prevent affective disorders such as for example bipolar depression, especially the manic phase; and migraine, especially for prophylaxis of attacks.
The compounds of the invention have the following structure:
wherein R
1
is C
3
to C
10
alkyl, C
3
to C
6
cycloalkyl, or cyclopropylmethyl, and R
2
is C
1
to C
3
alkyl or cyclopropyl, and the pharmaceutically acceptable salts, esters, and amides thereof. The term alkyl as used herein refers to both branched and straight-chain alkyl groups. Preferred embodiments of this invention are those wherein R
2
is methyl. R
1
is preferably C
3
to C
8
alkyl, and more preferably C
3
to C
5
alkyl. In the most preferred embodiments, R
2
is methyl and R
1
is C
3
to C
5
alkyl.
The invention also provides a method of treating and/or preventing convulsions due to a variety of causes, by administering to an individual in need of such treatment a therapeutically or prophylactically effective amount of at least one of the compounds of the invention.
An object of this invention is to provide compounds useful for preventing or reducing seizure activity.
Another object of this invention is to provide anticonvulsant pharmaceutical compositions comprising at least one compound of this invention.
Yet another object of this invention is to provide methods of preventing or reducing seizure activity by administering to an individual in need of such treatment a pharmaceutical composition of this invention.


REFERENCES:
Tang, et al., 1997, “Time Course of &agr;-Fluorinated Valproic Acid in Mouse Brain and Serum and its Effect on Synaptosomal &ggr;-Aminobutyric Acid Levels in Comparison to Valproic Acid ”,Journal of Pharmacology and Experimental Therapeutics,282: 1163-1172.
Michel, et al., 1997, “No Evidence For Intramolecular Hydrogen Bonds in &agr;-Fluorocarboxamides,”Liebigs Ann./Recueil,517-519.
Marie-Gabrielle Le Pironee, et al., 1997, “General and Simple Synthesis of &agr;-Halo Amides via &agr;, &agr;-Dicyano Expoxides,”(Synthesis)229-232.
Wei Tang, 1995, “Fluorinated Analogues As Mechanistic Probes In Valproic Acid Hepatotoxicity: Comparative Metabolic And Pharmacokinetic Studies,”The University of British Columbia, Thesispp. ii-v, 31-45, 181-191, 236-241.

Affiliated with

Also associated with

Rating

Alpha-fluoro alkynoic acids with anticonvulsant activity does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Alpha-fluoro alkynoic acids with anticonvulsant activity, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Alpha-fluoro alkynoic acids with anticonvulsant activity will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2614423