Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-03-23
1996-12-10
Daus, Donald G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514183, 514212, 540597, 540481, 546 77, A61K 3158
Patent
active
055831389
DESCRIPTION:
BRIEF SUMMARY
SPECIFICATION
The invention relates to novel 17.beta.-substituted 4-azaandrostane derivatives of formula (I), ##STR2## wherein R means hydrogen or a C.sub.1-3 alkyl group; C.sub.1-4 alkyl group with the proviso that both can mean hydrogen only in the case when n is higher than 5; or containing 5 to 7 carbon atoms, the terminal carbon atoms of said alkylene group being bound to the same ring carbon atom;
Furthermore, the invention relates to a process for the preparation of the above compounds and compositions.
The compounds of the formula (I) according to the invention are new and possess a valuable biological activity namely, by inhibiting the function of the 5.alpha.-reductase enzyme, they impede the transformation of testosterone to dihydrotestosterone.
Accordingly, the invention relates also to a method of treatment, which comprises administering a therapeutically effective amount of a compound of the formula (I) to a patient to be treated including humans for inhibiting the 5.alpha.-reductase enzyme.
BACKGROUND OF THE INVENTION
Among the steroid hormones, the androgens are reponsible for all the physical characteristics distinguishing male individuals from the female ones. In male individuals two steroids, testosterone and its reduced metabolite, i.e. dihydrotestosterone (abbreviated: DHT) are primarily responsible for the androgenic effects. In the tissues of mammals, the transformation of testosterone into DHT is catalyzed by the steroid 5.alpha.-reductase enzyme in the presence of nicotinamide adenine dinucleotide phosphate (NADPH). In male individuals, testosterone is predominantly synthetized by the testicles, wherefrom it is carried to the various tissues by the blood flow. In a part of the androgen-sensitive tissues where a significant activity of the steroid 5.alpha.-reductase enzyme can be detected, e.g. in the prostatic and skin tissues, the direct mediator of the androgenic effect is dihydrotestosterone which is synthetized in situ from testosterone taken up from the blood flow.
The increase of the DHT concentration in the tissues plays a role in the development and persistence of a number of androgen-dependent diseases, such as e.g. benign prostatic hyperplasia, acne, seborrhea, female hirsutism and androgenic alopecia [J. Clin. Invest. 49, 1737 (1970); J. Invest. Dermatol. 56, 366 (1971); J. Endocr. 75, 83 (1977); as well as Clin. in Dermatol. 6, 122 (1988)]. All substances inhibiting the steroid 5.alpha.-reductase enzyme and thereby diminishing the concentration of DHT in the tissues, may be useful for the treatment of the above DHT-dependent diseases.
Based on this recognition, research was directed to the synthesis of 5.alpha.-reductase enzyme inhibitors. In the last fifteen years many 5.alpha.-reductase enzyme inhibitors containing the steroid skeleton have been described in the literature.
The largest group of 5.alpha.-reductase inhibitors known until now is represented by the 4-aza-17-carbamoyl steroids.
A compound containing the 4-aza structural moiety is described in the U.S. Pat. No. 4,377,584 and in J. Steroid Biochem. 19, pages 385 to 390 (1983).
The synthesis of 17.beta.-(N,N-diethylcarbamoyl)-4-methyl-4-aza-5.alpha.-androstan-3-one is emphasized in the U.S. Pat. No. 4,220,775. On the basis of literature data this compound was subjected to a comprehensive biological study.
The synthesis of novel 17.beta.-(N-monosubstituted carbamoyl)-4-aza-5.alpha.-androstenones, e.g. 17.beta.-[N-(1,1-dimethylethyl)carbamoyl]-3-oxo-4-aza-5.alpha.-androst-1-e ne [compound of code No. MK-906, named Finasteride] is described in the European patent specification No. 155,096. Nowadays, the above compound has been accepted for therapeutical use.
The synthesis of oxidized analogues of 17.beta.-(N-monosubstituted carbamoyl)-4-aza-5.alpha.-androstan-3-one derivatives are published in the European patent specification No. 271,220. It is characteristic of the compounds described that the alkyl substituent of the 17.beta.-(N-monosubstituted carbamoyl) moiety may bear a hydroxyl, carboxyl or alkoxycarb
REFERENCES:
patent: 4220775 (1980-02-01), Rasmussen et al.
patent: 4377584 (1983-03-01), Rasmussan et al.
patent: 4885289 (1989-12-01), Breuer
patent: 5304562 (1994-04-01), Biogaz
patent: 5312984 (1994-05-01), Nicholas
patent: 5410040 (1995-04-01), Tuba et al.
patent: 5418238 (1995-05-01), Panzeri
Stinson, Chem & Eng News 29 Jun. 1992 pp. 7-8.
Hellikeer, Wall St. Jour. 7 Jun. 1991 pp. A1, A7.
Diani et al. Jour. Clin. Endo. & Metab., vol. 74, pp. 345-350 (1992).
Frye, et al. J. Med Chem vol. 36 pp. 4313-4315 (1993).
Kuttenn et al. J. Endocr. (1977), vol. 75, 83 to 91.
Sansong et al. J. Invest. Dermatol, vol. 56, 366-372, (1971).
Siiteri et al. J. Clin. Invest., vol. 49, 1737-1745, (1970).
Rittmaster Clin. In. Dermatol, vol. 6, 122-128, (1988).
Liang et al. J. Steroid Biochem., vol. 19, 385-390 (1983).
Rasmusson, Jour. Med. Chem. vol. 29 pp. 2298-2315 (1986).
Back, J. Org. Chem., 1981, 46, 1442 to 1446.
Rasmusson J. Med. Chem., 1984, 27, 1690 to 1701.
Solomons J. Pharm. Sci., 63, 1974, 19 to 23.
Battacharya Synthetic Communications, 30(17), 2683 to 2690 (1990).
Brooks Steroids 47/1, Jan. 1986, 1 to 19.
Winslow, Wall St. Jour., May 7, 1996 p. B4.
Balogh G abor
Csehi Attila
Hajo os Gy orgy
Horv ath Judit
J avor Andr as
Daus Donald G.
Dubno Herbert
Myers Jonathan
Richter Gedeon Vegyeszeti Gyar Rt.
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