Perhydroisoindole derivatives as substance P antagonists

Details Perhydroisoindole derivatives as substance P antagonists Perhydroisoindole derivatives as substance P antagonists

1997-05-30

1998-04-14

Ivy, C. Warren

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

514414, C07D20944, A61K 3140

Patent

active

057393516

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/FR95/015777 which is now published as WO 95/16939 on Jun. 6, 1996.
The present invention relates to novel perhydroisoindole derivatives of general formula: ##STR2## in which R, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are defined as below, and to their salts when they exist, which antagonize the effects of substance P and are, as a result, particularly advantageous in the therapeutic fields in which this substance is known to be involved.
European Patent Application EP 429 366 and the International Application WO 93 21155, both incorporated herein by reference, have described substance P antagonists of structure: ##STR3## in which the symbols R are hydrogen or together form a bond, the symbols R' are optionally substituted. phenyl radicals, the symbols R" and R"' together form an oxo radical, or else one represents an optionally substituted phenyl radical and the other represents a hydroxyl radical, and the symbols R.sub.1 and R.sub.2 represent various substituents. Some of these products display little activity in binding tests using human lymphoblast cells in culture.
American U.S. Pat. No. 4,042,707 incorporated herein by reference, has described products derived from isoindole, of general formula: ##STR4## having an opiate activity. These products have no activity towards substance P.
In the general formula (I): substituted with one or more halogen atoms or hydroxyl radicals, alkyl radicals which may be optionally substituted (with halogen atoms or with amino, alkylamino or dialkylamino radicals), alkyloxy or alkylthio alkylamino or dialkylamino radicals which are optionally substituted (with phenyl, hydroxyl or amino radicals), or dialkylamino radicals in which the alkyl moieties form, with the nitrogen atom to which they are attached, a 5- to 6-membered heterocycle which can contain another heteroatom chosen from oxygen, sulphur and nitrogen, which is optionally substituted with an alkyl, hydroxyl or hydroxyalkyl radical)!, or substituted with amino radicals or with alkylamino or dialkylamino radicals in which the alkyl moieties can form, together with the nitrogen atom to which they are attached, a heterocycle as defined above, or represents a cyclohexadienyl, naphthyl or indenyl radical or a saturated or unsaturated, mono- or polycyclic heterocyclic radical containing 5 to 9 carbon atoms and one or more heteroatoms chosen from oxygen, nitrogen and sulphur, and optionally substituted with a halogen atom or with an alkyl or alkyloxy radical, alkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxyl, alkyloxycarbonyl, dialkylaminoalkyloxycarbonyl, benzyloxycarbonyl or acylamino radical, substituted in position 2 with an alkyl or alkyloxy radical containing 1 or 2 carbon atoms, a hydroxyl radical or a fluorine atom, or is disubstituted with trifluoromethyl radicals, and atoms which is substituted with a halogen atom or with a cyano, azido or cyanamido radical, and an alkyl or phenyl radical.
It is understood that the abovementioned alkyl or acyl radicals contain (unless mentioned otherwise) 1 to 4 carbon atoms in a straight or branched chain.
When R.sub.1 or R.sub.4 contains a halogen atom, the latter can be chosen from chlorine, bromine, fluorine and iodine.
When R.sub.1 represents a saturated or unsaturated, mono- or polycyclic heterocyclic radical it may, by way of example, be chosen from thienyl, furyl, pyridyl, dithiinyl, indolyl, isoindolyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrrolyl, triazolyl, thiadiazolyl, quinolyl, isoquinolyl and naphthyridinyl.
When R.sub.1 represents phenyl which is substituted with a chain carrying a heterocycle, the latter may be chosen from pyrrolidinyl, morpholino, piperidyl, tetrahydropyridyl, piperazinyl and thiomorpholino.
Moreover, the products of general formula (I) have different stereoisomeric forms, and it is understood that the racemic forms and the stereoisomeric forms of structure: ##STR5## and their mixtures are within the scope of the present invention. More

REFERENCES:
patent: 5451601 (1995-09-01), Archard et al.

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