Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-04-18
1997-09-02
Morris, Patricia L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D40306
Patent
active
056633548
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is based upon PCT application Ser. No. PCT/EP 93/03066, filed Nov. 2, 1993, published as WO94/11364, May 26, 1994, which claims priority from European Application Ser. No. 92.203.443.4, filed on Nov. 10, 1992.
BACKGROUND OF THE INVENTION
In U.S. Pat. No. 4,943,574 there are described 1H-azol-1 -ylmethyl substituted benzotriazole derivatives which are potent aromatase inhibitors. These compounds are useful in treating estrogen hormone dependent disorders in mammals. 6-[(4-chlorophenyl) (1H-1,2,4-triazol-1-yl)methyl]-1-methyl]1H-benzotriazole in particular is a highly potent and selective inhibitor of the human aromatase. Most of its activity and selectivity, however, originates from its dextrorotatory (S)-enantiomer. Resolution of the racemic benzotriazole compound by selective crystallization of its diastereomeric salts proved impractical.
The present invention is concerned with a process for separating the enantiomers of a hydrazinc intermediate. Said separation is obtained by the selective crystallization of the diastereomeric salts of said intermediate with chiral acids or by chromatographically separating diastereomeric covalent compounds derived from said hydrazine derivative and a chiral acid. The enantiomerically pure intermediate then is further converted into the desired dextrorotatory (S)-benzotriazole end product.
DESCRIPTION OF THE INVENTION
The present invention is concerned with a process of preparing enantiomerically pure 6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]1-methyl-1H-benzotriazole having the formula ##STR1## and the pharmaceutically acceptable acid addition salt forms thereof.
In the foregoing definitions and hereinafter the term `enantiomerically pure` concerns compounds having an enantiomeric excess of at least 80% (i.e. minimum 90% of one enantiomer and maximum 10% 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 90% up to 100%, more in particular having an enantiomeric excess of 94% up to 100% and most in particular having an enantiomeric excess of 97% up to 100%. The term `enantiomerically enriched` concerns compounds having an enantiomeric excess of up to 80%. The terms `diastereomerically pure` and `diastereomerically enriched` as used hereinafter should be understood in a similar way, but then having regard to the diastereomeric excess of the mixture in question.
The compound of formula (I) has weak basic properties and, consequently, it may be converted into a therapeutically active non-toxic acid addition salt form by treatment with an appropriate acid. Conversely the salt form can be converted by treatment with alkali into the free base form. The term pharmaceutically acceptable acid addition salts also comprises the solvates which the compound of formula (I) may form. Examples of such solvates are hydrates and alcoholates.
As used hereinafter halo represents fluoro, chloro, bromo and iodo, in particular bromo; C.sub.1-4 alkyl defines straight and branch chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1,1-dimethylethyl, 1-methylpropyl and 2-methylpropyl; C.sub.1-6 alkyl defines C.sub.1-4 alkyl radicals as defined hereinabove and the higher homologs thereof having 5 or 6 carbon atoms, e.g. pentyl or hexyl; C.sub.5-7 cycloalkyl is generic to cyclopentyl, cyclohexyl and cycloheptyl.
Each Aryl is phenyl optionally substituted with 1 or 2 substituents each independently selected from halo, hydroxy, nitro, cyano, trifluoromethyl, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, C.sub.1-6 alkylthio, mercapto, amino, mono- and di(C.sub.1-6 alkyl)amino and C.sub.1-6 alkylcarbonyl.
Hereinafter, the notation (.+-.) denotes the racemic mixtures, whereas (A) denotes an enantiomerically or diastereomerically enriched or pure fraction of the intermediate which yields upon further reaction the desired dextrorotatory (S)-e
REFERENCES:
Wouters et al., "Comparative Effects of the Aromatase Inhibitor R76713 and of its Enantiomers R83839 and R83842 on Steroid Biosynthesis in Vitro and in Vivo", J. Steroid Biochem. Molec. Biol., vol. 37, No. 6, pp. 1049-1054, 1990.
Vanden Bossche et al., "R 76713 and Enentiomers: Selective, Nonsteroidal Inhibitors of the Cytochrome P450-Dependent Oestrogen Synthesis", Biochemical Pharmacology, vol. 40, No. 8, pp. 1797-1718, 1990.
Copmans Alex Herman
De Knaep Alfons Gaston Maria
Vandendriessche Anna Maria Jozefa
Venet Marc Gaston
Verstappen Walter Louis Antoine
Janssen Pharmaceutica N.V.
Metz Charles J.
Morris Patricia L.
LandOfFree
Process for preparing enantiomerically pure 6-[(4-chlorophenyl) does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for preparing enantiomerically pure 6-[(4-chlorophenyl) , we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing enantiomerically pure 6-[(4-chlorophenyl) will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-309799