Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-08-03
1995-07-18
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546198, A61K 31445, C07D41712
Patent
active
054341680
DESCRIPTION:
BRIEF SUMMARY
This application is based upon PCT Application No. PCT/EP 92/00356filed Feb. 14, 1992, which claims priority from U.S. patent application Ser. No. 695,645, filed Feb. 25, 1991, now abandoned.
BACKGROUND OF THE INVENTION
In U.S. Pat. No. 4,861,785 there are described benzoxazol- and benzothiazolamine derivatives having anti-anoxic activity. The benzothiazole compounds of the present invention show unexpected anti-stroke activity when compared to the structurally related compound sabeluzole.
DESCRIPTION OF THE INVENTION
The present invention is concerned with the racemic mixture and the (S)-form of 4-[(2-benzothiazolyl)methylamino]-.alpha.-[(3,4-difluorophenoxy)methyl]- 1-piperidine-ethanol which may be represented by the formula ##STR2##
and the pharmaceutically acceptable acid addition salts thereof.
The acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compound of formula (I) is able to form. The latter can conveniently be obtained by treating the base form with appropriate acids, such as, for example, inorganic acids, such as hydrohalic acid, e.g. hydrochloric, hydrobromic acid and the like, sulfuric acid, nitric acid, phosphoric acid and the like: or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy- 1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2hydroxybenzoic, 7,7-dimethyl-2-oxobicyclo[2,2,1 ]heptane- 1-methanesulfonic, 2-[(4methylphenyl)sulfonylamino]pentanedioic and the like acids. Conversely the salt form can be converted into the free base form by treatment with alkali.
The term acid addition salt as used hereinabove also comprises the solvales which the compounds of formula (I) are able to form and said solvates are meant to be included within the scope of the present invention. Examples of such solvales are e.g., the hydrates, alcoholates and the like.
The compounds of this invention have an asymnetric carbon atom and the absolute configuration of this asymmetric centre may be indicated by the stereochemical descriptors R and S. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms.
Hereinafter the term "enantiomerically" pure concerns compounds having an enantiomeric excess of at least 94% (i.e. minimum 97% of one enantiomer and maximum 3% of the other enantiomer) up to an enantiomeric excess of 100% (i.e. 100% of one enantiomer and none of the other), in particular compounds having an enantiomeric excess of 96% up to 100%, more in particular having an enantiomeric excess of 98% up to 100%.
Preferred compounds within the invention are: -1-piperidine ethanol and its dihydrochloride salt.
The compounds of formula (I) can generally be prepared by N-alkylating a piperidine of formula (II) with an alkylating reagent of formula (III) following an-known N-alkylation procedures. ##STR3##
In formula (III) W.sup.1 represents an appropriate reactive leaving group such as, for example, halo, e.g. chloro, bromo or iodo; sulfonyloxy, e.g. methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, 4-methylbenzenesulfonyloxy and the like leaving groups. Said N-alkylation reaction can conveniently be carried out by mixing the reactants, optionally in a reaction-inert solvent such as, for example, an aromatic solvent, e.g. benzene, methylbenzene, dimethylbenzene and the like; a C.sub.1-6 alkanol, e.g. methanol, ethanol, 1-butanol and the like; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone and the like; an ester, e.g ethyl acetate, .gamma.-buryrolactone and the like; a dipolar ether, e.g. 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like; a dipolar aprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide
REFERENCES:
patent: 3963732 (1976-06-01), Bruzzese
patent: 4310658 (1982-01-01), Lazarus
patent: 4689330 (1987-08-01), Janssens
patent: 4749702 (1988-06-01), Janssens et al.
patent: 4808596 (1989-02-01), Matsuishi
patent: 4861785 (1989-08-01), Stokbroekx et al.
Cecil "Medical textbook" Saunders Co. pp. 2051-2054 (1983).
Van Reempts "Structural cell damage and regional blood flow in the hypoxic brain" CA 107: 51799c (1987).
Grauwels Gilbert A. J.
Stokbroekx Raymond A.
Chang Ceila
Janssen Pharmaceutica N.V.
Metz Charles J.
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