Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-10-11
1995-10-31
McKane, Joseph K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D20904
Patent
active
054630770
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR93/00351 filed Apr. 8, 1993.
1. Field of the Invention
The present invention relates to new perhydroisoindole derivatives of the general formula: ##STR2## in which: the symbols R are identical and represent phenyl radicals which are optionally substituted by a halogen atom or by a methyl radical in position 2 or 3, in position 2 by an alkyl or alkyloxy radical containing 1 or 2 carbon atoms, symbol R'" represents a hydrogen atom, or radical, and to their salts, where these exist, which are synthesis intermediates for the preparation of derivatives having an antagonistic activity against substance P.
2. BACKGROUND OF THE INVENTION
European Patent Application EP 430 771 has described perhydroisoindolone derivatives having the structure: ##STR3## in which the symbols R are hydrogen or together form a bond and the symbols R' are phenyl radicals which are optionally substituted, which are intermediates for the preparation of perhydroisoindolone antagonists of substance P described in European Application EP 429 366. However, these perhydroisoindolone derivatives have been found to be active mainly in binding tests using homogenates of the rat brain, and show less activity in binding tests using cultured human lymphoblast cells.
U.S. Pat. No. 4,042,707 has described products derived from isoindole of the general formula: ##STR4## having an opiate activity. These products do not have any activity against substance P, and neither are they useful as intermediates.
In the general formula (I), if R carries a halogen substituent, this can be chosen from chlorine or fluorine.
The protective radical R.sup.o can be any compatible amino-protective group, the introduction and elimination of which does not change the remainder of the molecule. Examples which may be mentioned are the optionally substituted alkyloxycarbonyl, benzyloxycarbonyl and benzyl groups, and the formyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, vinyloxycarbonyl, phenoxycarbonyl, 1-chloroethoxycarbonyl or chlorocarbonyl groups.
In addition, the products of the general formula (I) have different stereoisomeric forms, and it is understood that the racemic forms and the stereoisomeric forms having the structure: ##STR5## as well as their mixtures fall within the context of the present invention. More specifically, the present invention relates to the perhydroisoindole derivatives in which R" is hydroxyl or fluorine and R'" is hydrogen in the (3aS,4S,7aS) form in the pure state, or in the form of the racemic mixture (3aRS,4RS,7aRS), the perhydroisoindole derivatives in which R" and R'" are hydroxyl in the (3aS,4S,5S,7aS) form in the pure state or in the form of the racemic mixture (3aRS,4RS,SRS,7aRS) and the perhydroisoindole derivatives in which R" forms a bond with R'" in the (3aS,7aR) form in the pure state, or in the form of the racemic mixture (3aRS,7aSR).
DESCRIPTION OF THE INVENTION
According to the invention, the perhydroisoindole derivative of the general formula (I) may be obtained by the action of an organometallic compound of the general formula: CeX.sub.2 radical, in which X is a halogen atom, on the corresponding perhydroisoindolone derivative of the general formula: ##STR6## in which R is as defined above, R'" is a hydrogen atom or a hydroxyl radical, which is protected if appropriate, and R.sup.o is a protective radical as defined above, followed by liberation, where appropriate, of the protective radical of R'", then by conversion, where appropriate, of the product obtained in which R" is a hydroxyl radical and R'" is a hydrogen atom into a product in which R" is a fluorine atom and R'" is a hydrogen atom or into a product in which R" and R'" together form a bond, and, where appropriate, removal of the protective radical R.sup.o.
The protection of the radical R'" and the removal of the protective radical are carried out by the usual methods of protection and/or removal of hydroxyl radicals which do not change the remainder of the molecule.
The reaction is carried out in an anhydrous medium under t
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Achard Daniel
Grisoni Serge
Malleron Jean-luc
Peyronel Jean-Francois
Tabart Michel
McKane Joseph K.
Rhone-Poulenc Rorer S.A.
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