Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-05-31
1998-02-17
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, A61K 3158, C07D22102
Patent
active
057191590
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel 4-azasteroids with side-chain fluoroketones, to a process for their preparation, and to pharmaceutical compositions containing them. These compounds are 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 catalysed 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 hyperptasia 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-21hydroxy-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 moiethy into substrates type 3-keto-D.sup.4 -progestins and androgens (Petrow et al., Steroids 38, 352-53 (1981); U.S. Pat. No. 4,396,615)).
Later on unsaturated derivatives of 3-carboxy steroids have been reported as uncompetitive 5.alpha.-reductase inhibitors versus testosterone (Biorg. Chem. 17, 372-376 (1989); Eur. Pat. Appln. No. 0289327; 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. The compounds known in the art 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. 200859; Eur. Pat. Appln. 0155096; U.S. Pat. No. 4,845,104; Eur. Pat. Appln. 0462662; Eur. Pat. Appln. 0484094 A2; U.S. Pat. No. 4,859,681; WO 91/12261; 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.
The invention provides compounds of the following formula (I) ##STR2## wherein
the symbol - - - represents a single or a double bond
R is a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group;
A is a single bond or a straight or branched C.sub.1 -C.sub.6 alkylene chain;
B is a straight or branched C.sub.1 -C.sub.12 alkylene group optionally substituted by one or more aryl groups or fluorine atoms;
W is a group R.sub.1 or ##STR3## wherein R.sub.1 is a straight or branched C.sub.1 -C.sub.6 alkyl group unsubstituted or substituted by one or more fluorine atoms, provided that at least one fluorine atom is present in B or W.
In the formulae of this specification the dot
REFERENCES:
patent: 5155107 (1992-10-01), Panzeri et al.
patent: 5342948 (1994-08-01), Panzeri et al.
patent: 5407939 (1995-04-01), Panzeri et al.
patent: 5418238 (1995-05-01), Panzeri et al.
Di Salle Enrico
Nesi Marcella
Panzeri Achille
Pharmacia S.p.A.
Shah Mukund J.
Wong King Lit
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