Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-11-17
1995-09-19
Haley, Jacqueline
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514323, 546200, 546201, 548465, 548470, 548515, A61K 3140, C07D20908
Patent
active
054516013
DESCRIPTION:
BRIEF SUMMARY
This application is a National Stage Application of PCT/FR92/00429, filed May 15, 1992, now WO 92/20653, published Nov. 26, 1992.
FIELD OF THE INVENTION
The present invention relates to new perhydroisoindole derivatives of the general formula: ##STR2## and their salts when these exist, which antogonise the effects of the substance P and are as a result particularly useful in the therapeutic sectors where this substance is known to play a role.
BACKGROUND OF THE INVENTION
Products derived from the isoindole of the general formula: ##STR3## which exhibit opium activity, had been described in U.S. Pat. No. 4,042,707.
These products exhibit no activity towards substance P.
In spite of the research carried out and in spite of the interest created [M. R. Hanley, TINS, (5) 139 (1982)], practically no product had been discovered so far which acts specifically on substance P and which has a nonpeptide structure; accordingly, the isoindole derivatives of general formula (I) are of great interest.
DESCRIPTION OF THE INVENTION
In the general formula (I): a bond, optionally substituted in position 2 or 3 by a halogen atom or by a methyl radical, substituted by one or more halogen atoms or hydroxyl or alkyl radicals which may be optionally substituted (by halogen atoms or amino, alkylamino or dialkylamino radicals) alkoxy or alkylthio radicals which may be optionally substituted [by hydroxyl, amino, alkylamino or dialkylamino radicals optionally substituted (by phenyl, hydroxyl or amino radicals) or by dialkylamino radicals whose alkyl parts form with the nitrogen atom to which they are attached, a heterocycle with 5 to 6 members which may contain another heteroatom chosen from oxygen, sulphur or nitrogen, optionally substituted by an alkyl, hydroxyl or hydroxyalkyl radical)], or which is substituted by amino, alkylamino or dialkylamino radicals whose alkyl parts may form with the nitrogen atom to which they are attached, a heterocycle as defined above, or represents a cyclohexadienyl, naphthyl 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 or sulphur, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, alkylthio, acyloxy, carboxyl, alkoxycarbonyl, dialkylaminoalkoxycarbonyl, benzyloxycarbonyl, amino, acylamino or alkoxycarbonylamino radical, represents a halogen atom.
It is understood that the abovementioned alkyl or acyl radicals contain 1 to 4 carbon atoms in a linear or branched chain.
When R' carries a halogen substituent, the latter may be chosen from chlorine or fluorine.
When R.sub.1 contains a halogen atom, the latter may be chosen from chlorine, bromine, fluorine or iodine.
When R.sub.1 represents a saturated or unsaturated, mono- or polycyclic heterocyclic radical, it may for example be chosen from thienyl, furyl, pyridyl, dithiinyl, indolyl, isoindolyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrrolyl, triazolyl, thiadiazolyl, quinolyl, isoquinolyl or naphthyridinyl.
When R.sub.1 represents a phenyl which is substituted by a chain carrying a heterocycle, the latter may be chosen from pyrrolidinyl, morpholino, piperidinyl, tetrahydropyridinyl, piperazinyl or thiomorpholino.
When R.sub.3 is a halogen atom, it may be advantageously chosen from fluorine or chlorine.
Moreover, the products of general formula (I) have various stereoisomeric forms, it is understood that the isoindole derivatives of the (3aR,7aR) form, in the pure state, or in the form of a mixture of the cis-(3aRS,7aRS) forms, are included within the scope of the present invention. When the radicals R.sub.3 and R.sub.4 are different, it is also understood that the substituent R3 may be in the axial or equatorial position and, therefore, that the R and S derivatives and mixtures thereof are also included within the scope of the present invention. Furthermore, when the symbol R.sub.2 is other than the hydrogen atom, the substituted chain on the isoindole has a chiral centre, it is understood that the stereoisomer
REFERENCES:
patent: 5102667 (1992-04-01), Dubroeucq et al.
patent: 5112988 (1992-05-01), Dubroeucq et al.
Lotz, M. et al, "Effect of Neuropeptides on Production of Inflammatory Cytokines by Human Monocytes," Science, vol. 241, p. 1218, Sep. 1988.
Achard Daniel
Grisoni Serge
Hanessian Stephen
Moutonnier Claude
Peyronel Jean-Francois
Haley Jacqueline
Rhone-Poulenc Rorer S.A.
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