Derivatives of 4-amino-1-trifluoromethyltetralines their prepara

Details Derivatives of 4-amino-1-trifluoromethyltetralines their prepara Derivatives of 4-amino-1-trifluoromethyltetralines their prepara

1989-07-22

1992-02-25

Shen, Cecilia

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

544401, 544403, A61K 31495, A61K 31135, C07D29508, C07C 8740

Patent

active

050914294

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The present invention relates to derivatives of 4-amino-1-trifluoromethyltetraline, the process for their preparation and their therapeutic application.


DESCRIPTION OF THE PRIOR ART

Aminotetralines having an antidepressant activity have already been described, this is the case for example, in European patent applications N.sup.o 30081 and 28901.
These actively studied compounds do not appear to have the unwanted side effects, particularly at the cardiovascular level, of other antidepressants, such as the tricyclic compounds.


SUMMARY OF THE INVENTION

The applicant has now found aminotetralines, and acid addition salts thereof, having a trifluoromethyl group on an alicyclic carbon in place of a hydrogen atom and having antidepressant and analgesic activities.
Introduction of a trifluoromethyl group into a molecule increases its lipophilic properties and reinforces or creates pharmacological activity by facilitating cellular penetration and crossing of the hematoencephalic barrier.
But known techniques of trifluoromethylation of the aliphatic carbon still present enormous difficulties.
The applicant has developed new processes for the preparation of trifluoromethylated tetralines useful, in particular, in the synthesis of trifluoromethylated aminotetralines.
Consequently, the object of the present invention is the derivatives of 4-amino-1-trifluoromethyltetralines of general formula: ##STR2## wherein: X represents an aromatic nucleus, namely phenyl, naphthyl .alpha. or .beta. thienyl able to carry one to two substituents chosen from halogeno, hydroxy, C.sub.1 to C.sub.8 alkoxy, trifluoromethyl; to C.sub.8 alkoxy group, in one of positions 5, 6 or 7, or even a methylenedioxy group in positions 5 and 6 or 6 and 7; to C.sub.8 alkoxy group in one of the other positions 5, 6 or 7, and C.sub.1 to C.sub.n alkyl group, n being 2 or more, possibly halogenated, hydroxylated or aminated, or R.sub.3 and R.sub.4 together with the nitrogen atom to which they are linked form a saturated heterocyclic compound, possibly substituted, with five or six atoms of which one or two are heteroatoms chosen from nitrogen, oxygen or sulfur.
Among the compounds of formula I defined hereinabove, a preferred class of compounds comprises the derivatives wherein X is a phenyl ring able to carry one to two substituents chosen from halogeno, hydroxy, C.sub.1 to C.sub.8 alkoxy or trifluoromethyl.
The compounds of formula I wherein X represents a phenyl ring carrying 1 to 2 halogen atoms appear to be particularly advantageous.
The compounds of formula I have an amine function on carbon number 4; depending on the nature of R.sub.3 and R.sub.4, the compounds of the invention can thus be primary amines, secondary amines or tertiary amines; the following can be given as examples: represents a methyl group or a group of formula --(CH.sub.2).sub.n --OH in which n is 2 or more; or R.sub.3 and R.sub.4 together with the nitrogen atom to which they are linked form a group of formula: ##STR3## wherein n=2 or more. As halogens, chlorine and fluorine are particularly preferred.
The following derivatives and their hydrochlorates, given in the tables below, can be cited as non limiting examples of compounds of formula I which are useful according to the present invention.
The syntheses described hereinafter lead to a mixture of two racemic diastereoisomers a and b which can be separated by conventional chromatography or fractional crystallization processes and each diastereoisomer is likely to be divided into two optic isomers.
All these compounds fall within the scope of the present invention.
The compounds of formula I which can form salts also constitute part of the invention. Conventionally formed salts comprise acid addition salts which are formed with various mineral and organic acids, for example, halohydrates, sulfates, nitrates, tartrates, mandelates, acetates, succinates, benzenesulfonates.
The compounds of the present invention can be prepared using the various processes described hereinafter.
The compounds of form

REFERENCES:
patent: 4536518 (1985-08-01), Welch, Jr. et al.
patent: 4556676 (1985-12-01), Welch, Jr. et al.

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