Thiopyranopyrrole derivatives

Details Thiopyranopyrrole derivatives Thiopyranopyrrole derivatives

1993-11-17

1996-01-16

Springer, David B.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D49504

Patent

active

054849420

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to new thiopyranopyrrole derivatives of general formula: ##STR2## as well as their salts, when these exist, useful as intermediates in the preparation of thiopyranopyrrole derivatives, which are antagonists of the effects of substance P.


BACKGROUND OF THE INVENTION

Products derived from the isoindole of general formula: ##STR3## which exhibit an opium activity, have been described in American U.S. Pat. No. 4,042,707.
These products exhibit no activity towards substance P and nor are they used in the synthesis of such products.
Herbicides of the general formula: ##STR4## in which X may be a sulphur atom, R.sub.1 and R.sub.2 are hydrogen or alkyl and R is a substituted phenyl, have been described in European Application 0,068,822.
In spite of the research activities carried out and in spite of the interest created [M. R. Hanley, TINS, (5) 139 (1982)], practically no product has been discovered so far which acts specifically on substance P and has a nonpeptide structure, accordingly, the thiopyranopyrrole derivatives of general formula (I) are of great interest in so far as they make it possible to obtain such products.


DESCRIPTION OF THE INVENTION

In the general formula (I), the symbol R represents a hydrogen atom, an allyl radical or a radical of the structure: are optionally substituted (by a halogen atom, an alkyl, alkoxy or nitro radical), and R.sub.c is defined as R.sub.a and R.sub.b or represents an alkyl or alkoxyalkyl radical, at least one of R.sub.a, R.sub.b and R.sub.c being a substituted or unsubstituted phenyl radical, and the symbol n represents an integer from 0 to 2.
It is understood that the abovementioned alkyl radicals contain 1 to 4 carbon atoms in a linear or branched chain.
The products of general formula (I) possess various stereoisomeric forms; it is understood that the thiopyranopyrrole derivatives of the (4aR,7aR) form or of the (4aS,7aS) form in a pure state, or in the form of a mixture of the cis- (4aRS,7aRS) forms are included within the scope of the present invention.
Furthermore, the products of general formula (I) for which n=1 also have axial or equatorial stereoisomers at the level of the S-oxide. It is understood that the position-1 R and S derivatives and mixtures thereof are also included within the scope of the present invention.
According to the invention, the thiopyranopyrrole derivative of general formula (I) may be obtained by treating the derivative of general formula: ##STR5## in which R' is defined as R except for representing a hydrogen atom, successively with a phenylmagnesium halide, and then with benzene in the presence of zirconium tetrachloride, followed optionally by removal of the protective radical R' if it is desired to obtain a product for which R is a hydrogen atom, and/or followed, where appropriate, by oxidation of the product obtained, in order to obtain a thiopyranopyrrole derivative for which n=1 or 2.
The treatment of the thiopyranopyrrole derivative of general formula (II) is carried out according to the usual methods. The treatment with a phenylmagnesium halide is advantageously carried out using phenylmagnesium bromide in an ether (for example ethyl ether), at a temperature between 20.degree. C. and the reflux temperature of the reaction mixture. The treatment with benzene in the presence of zirconium tetrachloride is carried out at a temperature of between 20.degree. C. and the reflux temperature of the reaction mixture.
Where appropriate, when it is desired to remove the radical R', the procedure is carried out using any known method which does not affect the rest of the molecule.
In particular, when R' is other than an allyl radical, the group R' may be removed by catalytic hydrogenation in the presence of palladium. Generally, the reaction is carried out in an acidic medium in a solvent such as an alcohol (methanol, ethanol), in water or directly in acetic acid or formic acid, at a temperature between 20.degree. and 60.degree. C.
When R' is a benzhydryl or trityl radical, the remov

REFERENCES:
patent: 4042707 (1977-08-01), Ripka
patent: 4503043 (1985-03-01), Blankley
patent: 5017708 (1991-05-01), Ogata et al.

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