Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-05-13
1999-07-13
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 77, C07D22118, A61K 3158
Patent
active
059227281
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to phenylsubstituted 4-azasteroid fluoroderivatives and to a process for their preparation. Moreover, the present invention relates to pharmaceutical compositions containing said phenylsubstituted 4-azasteroid fluoroderivatives and to their use as inhibitors of androgen action, by means of testosterone 5.alpha.-reductase inhibition.
In certain androgen responsive tissues the action of testosterone is mediated primarily through its 5.alpha.-reduced metabolite, dihydrotestosterone (DHT) (Bruchowsky N., Wilson J. D.; J. Biol. Chem. 243, 5953, 1968). The conversion of testosterone to dihydrotestosterone is catalyzed by the enzyme 5.alpha.-reductase and if 5.alpha.-reductase is inhibited, the formation of dihydrotestosterone is reduced and its specific androgenic effect is attenuated or prevented.
The 5.alpha.-reductase inhibitors may find medical application for the treatment of hyperandrogenic conditions, e.g. certain prostatic diseases, such as benign prostatic hyperplasia and prostatic cancer, and certain skin-hair conditions, such as acne, seborrhoea, female hirsutism and male pattern baldness (Siiteri P. K., Wilson J. D., J. Clin. Invest. 49, 1737, 1970; Price V. H., Arch. Dermatol. III, 1496, 1975; Sandberg A. A., Urology 17, 34, 1981). Also breast cancer treatment can take advantage from use of 5.alpha.-reductase inhibitors as the said tumour is known to be aggravated by presence of androgens. Androst-4-en-3-one-17.beta.-carboxylic acid and its methyl ester (Voigt and Hsia, Endocrinology, 92, 1216 (1973); Canadian Patent No. 970,692) are among the first steroidic compounds described as 5.alpha.-reductase inhibitors.
Two 5,10-secosteroids having a 3-keto-4,5-diene system in the expanded ring have been found to be selective inhibitors of rat epididymal 5.alpha.-reductase (Robaire et al., J. Steroid Biochem. 8, 307-310 (1977)).
The (20R)-4-diazo-21-hydroxy-20-methyl-5.alpha.-pregnan-3-one and its analogs are reported to be enzyme activated inhibitors of testosterone 5.alpha.-reductase (Blohm et al., Biochem. Biophys. Res. Comm. 95, 273-80 (1980); U.S. Pat. No. 4,317,817).
Another series of enzyme-directed irreversible inhibitors of 5.alpha.-reductase have been prepared by introducing a 6-methylene moiety into substrates such as 3-keto-D.sup.4 -progestins and androgens (Petrow et al., Steroids 38, 352-53 (1981); U.S. Pat. No. 4,396,615).
More recently, on unsaturated derivatives of 3-carboxy steroids have been reported as non-competitive 5.alpha.-reductase inhibitors versus testosterone (Biorg. Chem. 17, 372-376 (1989); Eur. Pat. Appln. No. 0289327; Int. Pat. Appln. WO92/20700; Eur. Pat. Appln. No. 0465123; Eur. Pat. Appln. No. 0528485; Eur. Pat. Appln. No. 0567271).
4-Aza steroids are by far the most studied steroid 5.alpha.-reductase inhibitors. These compounds are reported in a very large number of publications and patents. In particular the 17.beta.-acylamides and their metabolites are described in: J. Med. Chem. 27, 1690-1701 (1984); J. Med. Chem. 29, 2298-2315 (1986); Eur. Pat. Appln. No. 0004949; U.S. Pat. No. 4,377,584; Eur. Pat. Appln. No. 0155096; U.S. Pat. No. 4,845,104; Eur. Pat. Appln. No. 200859; Eur. Pat. Appln. No. 0462662; Eur. Pat. Appln. No. 484094; U.S. Pat. No. 4,859,681; Int. Pat. Applns. WO91/12261, WO 94/03474, WO 94/03475, WO 94/034476.
The 17.beta.-alkanoyl derivatives are described in J. Med. Chem. 29, 2298-2315 (1986), Eur. Pat. Appln. No. 314119, Eur. Pat. Appln. No. 367502, U.S. Pat. No. 5,061,803, Eur. Pat. Appln. No. 478066.
In Int. Pat. Appln. WO94/03475 fluorinated 17.beta.-substituted-4-aza-5.alpha.-androstan-3-one derivatives are disclosed.
We have now found that new di(fluoroalkyl)phenyl-17.beta.-substituted-4-aza-5.alpha.-androstan-3-one derivatives as described hereinunder, which fall within the scope of the general formula of WO94/03475, but which are not specifically disclosed therein, are endowed with valuable pharmacological properties.
The present invention provides compounds of formula (I) ##STR1## wherein: the symbol represents a si
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di Salle et al., "PNU 157706, a NOvel Dual Type 1 and II 5-alpha-reductase inhibitor," J. Steroid Biochem. Molec. Biol., vol. 64, No. 3-4, pp. 179-186, 1998.
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Di Salle Enrico
Nesi Marcella
Panzeri Achille
Kessinger Ann M.
Pharmacia & Upjohn S.p.A.
Shah Mukund J.
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