Process for preparation of enantiomerically pure polysubstituted

Details Process for preparation of enantiomerically pure polysubstituted Process for preparation of enantiomerically pure polysubstituted

1991-08-14

1993-09-14

Fan, Jane T.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546323, 546318, 546 21, 546286, 546257, 546270, 546283, 546284, 546278, 544333, C07D21186

Patent

active

052450392

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

A large number of drugs, currently in clinical use, are chiral molecules containing one or more asymmetric centers; in many cases these drugs are used as racemic mixtures even if the therapeutic effect is sometimes due to only one of the isomers forming the racemic mixture.
A great attention is recently directed to the role of stereoselectivity principles in the design of biologically active molecules.
Since the stereoselectivity principle is a general rule in biology rather than an exception, often only one of the components of a racemic mixture (the "eutomer") is the active drug while the other one, that is not complementary to the receptor (the "distomer"), is poorly active, or inactive if not even an antagonist.
Except for a few cases when a racemate is more active, less toxic or of longer (or shorter) duration of action then the single components of the racemic mixture, the use of pure enantiomers instead of racemates is today preferred, in order to reduce the xenobiotic load in the living organism, and to avoid risks of toxic side-effects due to the distomer or tis metabolites (see for example E. J. Ariens, "Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology", Eur. J. Clin. Pharmacol., 26, 663, 1984).
The increasing use of "eutomers" in therapy instead of racemates requires, or course, the development of effective, economic and industrially applicable methods of stereoselective synthesis and/or separation and resolution of diastereoisomers and racemates. Optical resolution is often an expensive process and the majority of the methods involves the loss of 50% of the starting racemic material, at least.
The above considerations apply also to the 1,4-dihydropyridine Ca-antagonist family of drugs, that in the last ten years have been introduced in the market for treatment of several cardiovascular diseases, including hypertension, angina of different aetiologies and different types of arrythmias.
The C-4 carbons atom of 1,4-dihydropyridines (see FIG. 1) is a prochiral atom. When at lest one of the substituents, bound to the C.sub.2 and C.sub.3 carbon atoms, is different form those on the symmetric C.sub.6 and C.sub.5 positions of the ring, the C-4 carbon atom is chiral and the compounds are racemates. Nifedipine, (dimethyl, 2,6-dimethyl-4-(2-nitrophenyl) 1,4dihydropyridine-3,5-dicarboxylate) is a symmetrical molecule while many other drugs (for ex. nitrendipine, nimodipine, nisoldipine, nicardipine, niludipine, felodipine, isradipine, ryodipine, Fr 24235, amlodipine and nivaldipine) are chiral 1,4-dihydropyridines that have been used in mammalians and humans as racemates; some of them are already marketed.
Only few dihydropyridines are available for investigation as pure enantiomers, even if it is by now well established that the principles of stereoselectivity apply also to this family of drugs.
Qualitative and quantitative differences between enantiomers of 1,4-dihydropyridines may be shown by "in vitro" studies on tissue preparations or on "in toto" organs (see for example H. Glossmann et al., Arzeneim. Forsch./Drug. Res. 35 (12a), 1917, 1985).
More recently, a report by T. Kazuharu (J. Med. Chem., 29 2504, 1986) point out the importance of stereoselectivity: of the four possible diastereoisomers the S,S enantiomers [(S,S)-YM-09730)] proved to have the greatest potency and the longer duration of action.
The use of enantiomerically pure 1,4-dihydropyridines was recently claims in Ep 0240828 and 0273344.
At present, few and very complex methods are available for preparing enantiomerically pure dihydropyridines.
In absence of basic groups (that could then be salified with optically active acids), the known methods required the selective cleavage of an ester group to form a racemic monocarboxylic acid that is salified with optically pure bases. The mixture of diasteroisomeric salts is separated to recover enantiomerically pure acids that are then esterified with chiral and achiral alcohols to give the desired pure enantiomers. The

REFERENCES:
Klotzer, Monatsh, Chem. 87, pp. 346-353, 1956.

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