Diastereomerically pure 3-oxo and 3-thioxo-4-aza-androstan deriv

Details Diastereomerically pure 3-oxo and 3-thioxo-4-aza-androstan deriv Diastereomerically pure 3-oxo and 3-thioxo-4-aza-androstan deriv

1997-08-04

2000-11-14

Badio, Barbara

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D22118

Patent

active

061472131

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to azasteroid derivatives, in particular to diastereomerically pure 3-oxo- and 3-thioxo-4-aza-androstans derivatives having, at the 17.beta.-position, a carboxylic group linked with an amido bond to a chiral primary amine with the asymmetric carbon at the .alpha.-position, the use thereof as antiandrogen agents and pharmaceutical compositions containing them.


BACKGROUND OF THE PRIOR ART

Testosterone, the main androgen present in bloodstream, acts directly on many target tissues, as such or as a reduced metabolite, i.e. dihydrotestosterone. The conversion into dihydrotestosterone is mediated by the enzyme 5-.alpha.-reductase, which is present in some target tissues. Dihydrotestosterone has a higher affinity to the androgen receptors than testosterone itself, moreover the hormone-receptor complex is more stable (Kaufman M., Pinsky L. J. Steroid Biochem. 1983, 18, 121-5; Wilbert D. M., Griffin J. E., Wilson J. D. J. Clin. Endocrinol. Metab. 1983, 56, 113-20). The inhibitors of the enzyme 5-.alpha.-reductase strongly bind to the enzyme, thus interfering in the transformation process of testosterone into dihydrotestosterone.
Up to now, a number of examples of inhibitors of the enzyme 5-.alpha.-reductase are known in literature; some having a steroidal structure (Rasmusson, G., H.; Reynolds, G. F.; Steimberg, N. G.; Walton, E.; Patel G. F.; Liang T.; Cacsieri M. A.; Cheung A. H.; Broocks J. R.; Berman C. Azasteroids: Structure-Activity Relationship for Inhibition of 5-.alpha.-Reductase and of Androgen Receptor Binding, J. Med. Chem. 1986, 29, 2298-2315. Holt D. A.; Levy M. A.; Oh H. J.; Erb J. M.; Heaslip J. I.; Brandt M.; Lan-Hargest H. Y.; Metcalf B. W. Inhibition of Steroid 5-.alpha.-Reductase by Unsaturated 3-Carboxysteroids, J. Med. Chem. 1990, 33, 943-950) other being nonsteroidal (EP 0 291 245 A2).
The pathologies connected with hyperandrogenicity conditions, in which these molecules might be used (benign prostatic hyperplasia, acne vulgaris, seborrhea, baldness, female hirsutism) are widespread. Though the therapy with this kind of medicaments proved to be effective, also as far as the life-quality offered to those suffering from said conditions is concerned, nevertheless it is not free from side-effects, therefore the development of novel, more potent inhibitors, which are more selective and better tolerated, is required (Charles D. J. et al. Nonsteroidal Inhibitors of Human Type 1 Steroid 5-.alpha.-Reductase, J. Med. Chem. 1993, 36, 421-423).
A 4-azasteroid conjugated at the 17.beta.-position with a .gamma.-amino acid (.gamma.-aminobutyric acid) is known from EP 0 271 220. In the above cited Patent, a procedure for the preparation of a certain number of compounds oxidized at the carbamoyl branching at the 17-position is claimed.


SUMMARY OF THE INVENTION

Now it has surprisingly been found that, among all of the tested amino acid derivatives, those bearing an asymmetric carbon at the .alpha.-position to the amino acid carboxyl, have a marked inhibitory activity on the enzyme 5-.alpha.-reductase. In fact, for example, whereas the derivative bearing the amino acid glycine at the 17-position (compound Vd) proved to be a mild inhibitor of the above mentioned enzyme, all of the amino acids having an asymmetry centre at the .alpha.-position to the carboxylic group turned out to have a remarkable inhibiting action.


DISCLOSURE OF THE INVENTION

The present invention relates to diastereomerically pure compounds having the following general formula (A) ##STR2## wherein: the carbon-carbon bond at the 1-2 position can be single or double, alkyl residue; ##STR3## wherein T is the --COOH, or a --COOR.sub.3 group, being R.sub.3 a straight or branched C.sub.1 -C.sub.8 alkyl residue; the group --CONHR.sub.4 wherein R.sub.4 is a straight or branched C.sub.1 -C.sub.8 alkyl residue; or T is the group --CH.sub.2 OH; series or of the (D) series; cycloalkyl or C.sub.7 -C.sub.14 arylalkyl group having an asymmetry centre at the .alpha.-position to the amine function;

REFERENCES:
Rasmusson et al., "Azasteroids: Structure-activity relationships for inhibition of 5.alpha.-reductase and or androgen receptor binding", J. Med. Chem., vol. 29, pp. 2296-2315, 1986.

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