Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – N-c doai
Reissue Patent
2000-04-20
2004-02-10
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
N-c doai
C564S036000
Reissue Patent
active
RE038425
ABSTRACT:
BACKGROUND OF THE INVENTION
I. Field of the Invention
This 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 Art
There 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
possess anticonvulsant activity in the maximal electroshock (MES) screen and the subcutaneous pentylenetetrazole (scPTZ) screen when administered by the intraperitoneal route to mice. These screens are test systems developed to detect compounds which will afford protection to generalized tonic-clonic seizures and generalized absence convulsions, respectively. The MES screen and the scPTZ screen have been discussed by Krall, et al. in “Antiepileptic drug development:II. Anticonvulsant drug screening”, Epilepsia, 1978, 19, pp. 409-428; the disclosure of which is incorporated herein by reference.
Nevertheless, the compounds of formula A displayed neurotoxicity when administered by this route and the protection indices (PI, namely the ratio TD
50
/ED
50
) of ten representative compounds were low.
There is accordingly a need for compounds showing much improved anticonvulsive effects with reduced toxicity.
SUMMARY OF THE INVENTION
An object of the invention is to provide compounds having central nervous system activity.
Another object of the invention is to provide pharmaceutical compositions that have good anticonvulsive activity and acceptable neurotoxicity.
Yet another object of the invention is to provide methods of treating convulsions in humans and animal patients without producing unacceptable side effects.
According to one aspect of the invention, there is provided a compound of the general formula I
wherein: R
1
, R
2
, R
3
and R
4
may be the same or different and each represents a hydrogen or halogen atom, or a C
1-9
alkyl, C
5-9
cycloaliphatic, cyano, C
1-9
alkoxy or C
6-10
aryloxy group; R
5
represents a hydrogen atom or a C
1-9
alkyl, C
3-9
cycloalkyl or C
6-10
aryl group; and X is oxygen or sulfur. In the compounds of the invention, the alkyl substituents, when present, may be straight-chained or branched.
It should be noted, however, that the compound of Formula I above in which R
1
, R
2
, R
3
, R
4
and R
5
are all hydrogen is known from Tomita et. al., “Synthesis of Aldehyde Derivatives Containing a Diphenyl Ether Nucleus”, J. Pharm. Soc. Japan, 1955, 75, 1021-1023, but this reference does not disclose the anticonvulsive property of the compound.
According to another aspect of the invention, there is provided a composition comprising a compound of general formula I and a pharmaceutically acceptable diluent, excipient or carrier.
According to yet another aspect of the invention, there is provided a method of treating diseases of the central nervous system of a human or animal patient, which comprises administering to said patient an effective amount of a compound of general formula I.
The compounds of the invention may be administered orally and may exhibit very high potencies against CNS convulsions, e.g. they may possess ED
50
figures (for the maximal electroshock screen in rats) in the 1-5 mg/kg range (more usually the 2-3 mg/kg range) while exhibiting an absence of neurotoxicity at the maximum dose utilized (e.g. 500 mg/kg), thus leading to extremely favourable protection index (PI) values.
The compounds of the invention appear to act by one or more mechanisms which are different from those of conventional anticonvulsant drugs. Moreover, the compounds of the invention may be free from some of the disadvantages of conventional anticonvulsant drugs since proconvulsant properties and effects on the activities of certain hepatic enzymes are absent in at least some of the compounds of the invention.
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Memorandum from
Dimmock Jonathan Richard
Puthucode Ramanan Narayan
Lambkin Deborah C.
Sterne Kessler Goldstein & Fox P.L.L.C.
University of Saskatchewan Technologies Inc.
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