Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1996-11-25
1999-03-09
Kumar, Shailendra
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514616, 564138, 564139, 564152, 564155, 564190, A61K 3116, C07C23102, C07C23358
Patent
active
058801570
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US95/01388, filed Feb. 8, 1995, WO95/21814, Aug. 17, 1995.
The present invention relates to derivatives of tetramethyl-cyclopropane carboxylic acid amides, their preparation and pharmaceutical compositions comprising them.
Valporic acid (VPA) and its alkali salts are major drugs in the arsenal of drugs for the treatment of epileptic seizures and convulsions. However, approximately 25% of epileptic patients do not respond to current treatment. Furthermore, VPA has considerable adverse side effects including hepatoxicity and teratogenicity. (See Baille, T. A. et al. In Antiepileptic Drugs, eds. R. H. Levy et al. Raven Press, New York. pp. 641-651 (1989)). One approach to obtain improved antiepileptic agents was to study the primary amide derivatives of VPA and its analogs. (See Bialer, M. Clin. Pharmacokinet. 20:114-122 (1991), Bialer, M. et al. Eur.J.-Clin.Pharmacol. 289-291 (1990), Haj Yehia, A. and Bialer M. J. Pharm.Sci. 79:719-724 (1990)). In addition, glycinamides have been described for this purpose in U.S. Pat. No. 4,639,468. However, these compounds are not generally accepted clinically. Thus, there is still a great need for anticonvulsant agents with an improved efficacy, and agents which give a better margin between the therapeutic dose and the dose which is neurotoxic.
The present invention consists in derivatives of 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA) of general formula I, ##STR3## wherein R is a lower alkyl group (C.sub.1 -.sub.6) an aryl group, an aralkyl group or an amide of general formula II, ##STR4## where R.sub.1 and R.sub.2 are the same or different and may be a hydrogen, a lower alkyl group (C.sub.1 -C.sub.6), an aryl group or an aralkyl group, and n=0-3
Some of the compounds of this invention possess chiral centres. Both the racemic mixtures and the D and L enantiomers are within the scope of the present invention.
The new compounds according to the present invention show improved activity over known antiepileptic agents. Said compounds of the invention are highly effective in at least two generally accepted models of epilepsy: the maximal electroshock test (MES), which is indicative of generalized and partial seizures; and the subcutaneous pentylenetetrazole test (sc Met), which is indicative of absence seizures. Furthermore, the median effective dose (ED.sub.50) of the agents claimed in this disclosure are considerably lower than those required to produce neurological impairment. Our results in animal models indicate that compounds in this group are effective against generalized and partial seizures, in addition to absence seizures and other forms of epilepsy.
The preferred compounds of the present invention are the following:
2,2,3,3-tetramethylcyclopropanecarboxamide
N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide
N-phenyl-2,2,3,3-tetramethylcyclopropanecarboxamide
N-(2,2,3,3-tetramethylcyclopropyl)carbonyl)-alaninamide
N-(2,2,3,3-tetramethylcyclopropyl)carbonyl!-phenylalaninamide
N-(2,2,2,3-tetramethylcyclopropyl)carbonyl!-phenylglycinamicle compounds of general formula I, wherein R has the same meaning as defined above and may also stand for hydrogen, may be prepared, inter alia, as follows: a suitable amine at a temperature range of 0.degree.-60.degree. C. for a period of 1 to 36 hours. CH.sub.2 Cl.sub.2. The amines may be in any form, preferably as an aqueous solution thereof. The temperature is preferably 20.degree.-40.degree. C. and the time of the reaction 4-24 hours. All temperatures are indicated here in degrees Celsius; or This reaction may be performed, for example, with N-hydroxysuccinimide, in the presence of carbodiimides, e.g. dicyclohexylcarbodiimide (DCC) or N-(dimethylaminopropyl)-N'-ethyl (DMAPE) carbodiimide, at a temperature ranging from 0.degree.-50.degree. C., preferably at 0.degree.-25.degree. C., in an inert solvent, e.g. tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, CH.sub.2 Cl.sub.2, dimethyl formamide (DMF); the activated ester, either in its isolated form or in situ, is then reacted with RNH
REFERENCES:
patent: 4291055 (1981-09-01), Chen
patent: 4411925 (1983-10-01), Brennan et al.
patent: 4710518 (1987-12-01), Kurahashi et al.
patent: 4959493 (1990-09-01), Ohfume et al.
Haj-Yehia et al., Journal of Pharmaceutical Sciences, vol. 79, No. 8, pp. 9-724 (1990).
Graham et al., Journal of Medicinal Chemistry, vol. 30, No. 6, pp. 1074-1090 (1987).
Bialer Meir
Haj-Yehia Abdullah
Herzig Yaacov
Sterling Jeff
Yagen Boris
Kumar Shailendra
Yissum Research Development Company of the Hebrew University of
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