Derivatives of perhydroisoindole and preparation thereof

Details Derivatives of perhydroisoindole and preparation thereof Derivatives of perhydroisoindole and preparation thereof

1993-11-17

1996-04-16

Haley, Jacqueline

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D20948

Patent

active

055084338

DESCRIPTION:

BRIEF SUMMARY
This is a National Stage application of PCT/FR92/00430 filed May 15, 1992,
published as WO/92/20654 on Nov. 26, 1992.


FIELD OF THE INVENTION

The present invention relates to new perhydroisoindole derivatives of general formula: ##STR2## and their salts, which are intermediates in the preparation of perhydroisoindoles which antagonize the effects of substance P and are useful in the therapeutic sectors where this substance is known to play a role.


BACKGROUND OF THE INVENTION

Products derived from isoindole of general formula: ##STR3## which exhibit opium activity, have been described in U.S. Pat. No. 4,042,707.
These products exhibit no activity towards substance P and neither can they be used as intermediates leading to such products.
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): form a bond, optionally substituted by a halogen atom or by a methyl radical in position 2 or 3, represents a halogen atom.
When R.sub.2 carries a halogen substituent, or when R.sub.3 is a halogen atom, the latter may be chosen from chlorine or fluorine.
Moreover, the products of general formula (I) having various stereoisomeric forms, it is understood that the isoindole derivatives of the (3aR, 7aR) form, in a 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 R.sub.3 may be in an axial or equatorial position and therefore that the R and S derivatives as well as mixtures thereof, are also included within the scope of the present invention.
According to the invention, the isoindole derivative of general formula (I) for which R.sub.3 represents a halogen atom and R.sub.4 represents a hydrogen or halogen atom, may be obtained by halogenation of the isoindole derivative of general formula: ##STR4## for which R.sub.1 and R.sub.2 are defined as above, R'.sub.3 is a hydroxyl radical, R'.sub.4 is a hydrogen atom if it is desired to obtain a monohalogenated derivative, or R'.sub.3 and R'.sub.4 together form an oxo radical if it is desired to obtain a dihalogenated derivative, followed by the removal of the protective radical R.sub.5.
The protective radical R.sub.5 may be any aminoprotecting group which is compatible with the reaction and whose introduction and removal does not affect the rest of the molecule. Alkoxycarbonyl groups, benzyloxycarbonyl groups, optionally substituted benzyl groups, formyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, vinyloxycarbonyl, phenoxycarbonyl, 1-chloroethoxycarbonyl or chlorocarbonyl groups, may be mentioned by way of example.
When it is desired to obtain a product for which R.sub.3 represents a fluorine atom, the reaction is advantageously carried out using a fluorinating agent such as sulphur fluoride (morpholinosulphur trifluoride, sulphur tetrafluoride (J. Org. Chem., 40, 3808 (1975)), diethylaminosulphur trifluoride (Tetrahedron, 44, 2875 (1988)), phenylsulphur trifluoride (J. Am. Chem. Soc., 84, 3058 (1962)], such as hexafluoropropyldiethylamine (Japanese Patent 2,039,546) or N-(2-chloro-1,1,2-trifluoroethyl)diethylamine, or selenium tetrafluoride (J. Am. Chem. Soc., 96, 925 (1974) or such as tetrafluorophenylphosphorane (Tet. Let., 907 (1973), by carrying out a procedure in an organic solvent such as a chlorine-containing solvent (for example dichloromethane, dichloroethane) at a temperature between -30 and +30.degree. C. It is understood that the use of an alcohol of the (S) configuration leads to the fluorine-containing derivative of the (R) configuration and that the use of an alcohol of the (R) configuration leads to the fluorine-containing derivative of the (S) configuration. It

REFERENCES:
patent: 4042707 (1977-08-01), Ripka
patent: 5102667 (1992-04-01), Dubroeucq et al.

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