Indeno(1,2-b)pyrrole derivatives

Details Indeno(1,2-b)pyrrole derivatives Indeno(1,2-b)pyrrole derivatives

1984-05-07

1986-03-25

Daus, Donald G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548450, A61K 3140, C07D20970

Patent

active

045783977

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD AND DISCLOSURE OF THE INVENTION

This invention relates to novel and therapeutically valuable hexahydro-indeno[1,2-b]pyrrole derivatives which are represented by the formula: ##STR2## wherein R.sup.1 is hydrogen, lower alkyl (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) or carbamoylmethyl, R.sup.2 is halogen (fluorine, chlorine, bromine or iodine) or trifluoromethyl, R.sup.3 is hydrogen or halogen (the same as mentioned above), and X is oxygen or sulfur.
The compound of formula: ##STR3## which is useful as an intermediate for the synthesis of compounds having blood sugar lowering action is described in J. Pharm. Sci., 62, 1363 (1973).
The present inventors have synthesized various compounds having a structure containing a 5-membered ring lactam which is formed by intramolecular cyclization of gamma-aminobutyric acid (hereinafter "GABA"), and investigated their utility. As a result, it has been found that compounds of the invention have the potent antagonistic activities against toxicity and convulsion induced by GABA antagonists such as picrotoxin or bicuculline, therefore they have GABA-like activities. Since GABA in itself, when administered peripherally, is said to be hard to transmit through the blood-brain barrier, GABA is not expected to exhibit its effects on the central nervous system. However, the compounds of the invention even when administered orally show the effects mentioned above, and so they are highly useful as medicines.
Moreover, the compounds of formula (I) have also antielectroshock and antimetrazole actions or electrocorticogram-improving action in a temporary cerebral ischemia model, antihypoxia effect and the like, and they are useful as medicines for treating cerebral dysfunction, anticonvulsants, antiepileptics and antianxiety drugs.
On the other hand, the known compounds mentioned above are extremely weak in such actions in comparison to the compounds of the invention or do not practically exhibit said activities.
The compounds of formula (I) can be produced in accordance with the conventional methods, for example, by the following reaction scheme: ##STR4##
In the above reaction scheme, R.sup.1, R.sup.2 and R.sup.3 are as defined above, R is --CH.sub.2 COOR.sup.4 in addition to R.sup.1, R.sup.4 is lower alkyl, R.sup.5 is lower alkyl or carbamoylmethyl, Y is a leaving reactive group such as halogen, --SO.sub.3 H, methylsulfonyloxy or p-tolylsulfonyloxy.
The objective compounds of the invention are the compounds of formula (I-a) wherein R is R.sup.1, and compounds of formulas (I-b), (I-c) and (I-d).
In accordance with the reaction scheme, the methods for the production of the compounds of the invention will be explained more concretely.
The oxime derivative (III) which is obtained by the reaction of the compound (II) with hydroxylamine is subjected to catalytic reduction in the presence of a catalyst such as Raney nickel, platinum oxide or palladium carbon, preferably at 40-60 atm of hydrogen under heating to give the compound (I-b).
The compound (I-b) is allowed to react with an alkylating agent of the formula: R.sup.5 --Y is an aprotic solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or dioxane, or in a hydrocarbon solvent such as benzene or toluene, in the presence of sodium hydride or sodium alkoxide, at a temperature of from 0.degree. C.to the boiling point of the solvent employed for several hours to give the compound (I-a). The compound (I-a) is also obtained by reacting the compound (II) in the presence of an amine of the formula: R.sup.1 NH.sub.2 under the same reduction conditions mentioned above.
The compound (I-a) or (I-b) is allowed to react with diphosphorus pentasulfide in pyridine at 70.degree.-100.degree. C. for 4-5 hours to give the compound (I-c).
The compound of formula (I-a) wherein R is --CH.sub.2 COOR.sup.4 is allowed to react with ammonia in a lower alkanol to give the compound (I-d).
The pharmacological properties of the compounds of the invention are shown below.


METHODS



1. Anti-picrotoxin Effect

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