Semicarbazones having CNS activity and pharmaceutical preparations containing same

a technology of central nervous system and semicarbazone, which is applied in the direction of biocide, animal repellents, drug compositions, etc., can solve the problems of low protection index, namely the ratio td.sub.50/ed.sub.50, of compounds displaying neurotoxicity, etc., and achieves good anticonvulsive activity and acceptable neurotoxicity

Inactive Publication Date: 2004-02-10
UNIV OF SASKATCHEWAN TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

Another object of the invention is to provide pharmaceutical compositions that have good anticonvulsive activity and acceptable neurotoxicity.
Yet ano

Problems solved by technology

Nevertheless, the compounds of formula A displayed neurotoxicity when administered by this route and the

Method used

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  • Semicarbazones having CNS activity and pharmaceutical preparations containing same
  • Semicarbazones having CNS activity and pharmaceutical preparations containing same
  • Semicarbazones having CNS activity and pharmaceutical preparations containing same

Examples

Experimental program
Comparison scheme
Effect test

example 1

The compounds 2a to 5v shown in Table 1 below were synthesized by the method previously mentioned. The structures of the listed compounds correspond to those shown in FIG. 2 identified by the same first number (2, 3, 4 or 5), with only the substituents being identified in Table 1.

TABLE 1 Aryl Substituents, Physical Data and Anticonvulsant Evaluation after Intraperitoneal Injection into Mice and Oral Administration to Rats of the Compounds in Series 2-5 intraperitoneal injection in mice.sup.a MES acPTZ toxicity oral administration to rats.sup.b aryl yield screen screen screen dose MES screen compound substituents m.p.(.degree. C.) % 0.5 h 4 h 0.5 h 4 h 0.5 h 4 h (mg / kg) 0.25 h 0.5 h 1 h 2 h 4 h 2a H 198-199 40 -- -- -- -- -- -- 50 -- -- 2 1 1 2b 4-F 210-212 48 -- -- -- -- -- -- 30 0 0 1 2 4 3 H 224-225 70 -- 300 -- -- -- -- 50 -- -- -- -- -- 4a H 224-225 60 100 300 -- -- -- -- 50 -- 3 4 4 4 4b 4-F 233-234 65 30 100 -- -- -- -- 50 2 4 4 4 4 4c 4-Cl 225-226 40 30 30 30 -- 300 30 50 4 4...

example 2

An initial anticonvulsant evaluation of the compounds prepared according to Example 1 was undertaken by administering the compounds by the intraperitoneal route to mice. Protection and / or neurotoxicity was noted 0.5 and 4 hours after administering doses of 30, 100 and 300 mg / kg of each semicarbazone to the animals. These results are presented in Table 1 above.

All of the compounds were active in the MES screen except compounds 2a,b,5t,v and protection was afforded by 60% of the compounds in the scPTZ test. Neurotoxicity was displayed by approximately 70% of the semicarbazones. Bioactivity was quantitated for selected compounds and these data are given in Table 2 below:

TABLE 2 Evaluation of Selected Compounds in the MES, acPTZ and Neurotoxicity Screens after Intraperitoneal Injection in Mice MES screen acPTZ screen neurotoxicity screen PI Com- pound t (h) ED.sub.50 (mg / kg) (95% CI) slope (SE) t (h) ED.sub.50 (mg / kg) (95% CI) slope (SE) t (h) TD.sub.50 (mg / kg) (95% CI) slope (SE) ##EQU...

example 3

The compounds having the structures shown in Table 4 were prepared. The structures of the listed compounds correspond to those shown in FIG. 3 identified by the same first number (12, 13, 14, 15, 16, 17 or 18), with only the substituents being identified in Table 4.

TABLE 4 Aryl Substituents, Physical Data and Anticonvulsant Evaluation after Intraperitoneal Injection into Mice and Oral Administration to Rats of the Compounds in Series 12-18.sup.a intraperitoneal injection in mice.sup.b MES acPTZ toxicity oral administration to rats.sup.c m.p. yield screen screen screen dose MES screen compound R.sup.1 R.sup.2 (.degree. C.) % 0.5 h 4 h 0.5 h 4 h 0.5 h 4 h (mg / kg) 0.25 h 0.5 h 1 h 2 h 4 h 12a H F 240.sup.a 65 30 100 -- -- -- -- 50 2 4 4 4 4 12b H H 224-225 60 100 300 -- -- -- -- 50 -- 3 4 4 4 12c H Cl 225-226 40 30 30 30 -- 300 30 50 4 4 4 4 4 12d H Br 225-226 60 30 30 -- -- 300 30 50 1 4 4 4 4 12e H CH.sub.3 219-221 50 30 100 -- -- -- -- 50 3 4 4 4 4 13a CH.sub.3 H 169-171 60 30 100 -...

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Abstract

A compound of general formula I below useful as an anticonvulsant for disorders of the central nervous system: ##STR1## wherein: R.sup.1, R.sup.2, R.sup.3 and R.sup.4 may be the same or different and each represents a hydrogen or halogen atom, or a C.sub.1-9 alkyl, C.sub.3-9 cycloalkyl, cyano, C.sub.1-9 alkoxy or C.sub.6-10 aryloxy group; R.sup.5 represents a hydrogen atom or a C.sub.1-9 alkyl, C.sub.3-9 cycloalkyl or C.sub.6-10 aryl group; and X is oxygen or sulfur; or a pharmaceutically-acceptable salt thereof. The compound may be adimistered orally for treating convulsions in humans or animals.

Description

BACKGROUND OF THE INVENTIONI. Field of the InventionThis invention relates to semicarbazone compounds having central nervous system (CNS) activity and to pharmaceutical preparations containing such compounds. More particularly, the invention relates to semicarbazones having anticonvulsant properties and to the use of such semicarbazones for the treatment or prevention of convulsions and seizures in humans and animals.II. Description of the Prior ArtThere has been a great deal of interest for many years in the identification of drugs that exhibit central nervous system activity in humans and animals and that are, in particular, anticonvulsants used for the treatment or prevention of epileptic seizures and other central nervous system disorders.A previous study carried out by one of the inventors of the present invention (Dimmock et al., J. Med. Chem., 1993, 36, pp. 2243-2252) revealed that a number of aryl semicarbazones of the general formula A ##STR2##possess anticonvulsant activit...

Claims

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Application Information

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IPC IPC(8): C07C281/00C07C281/14A61P25/00A61P25/08A61K31/175
CPCC07C281/14A61P25/00A61P25/08A61K31/175
Inventor DIMMOCK, JONATHAN RICHARDPUTHUCODE, RAMANAN NARAYAN
Owner UNIV OF SASKATCHEWAN TECH
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