Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1986-03-21
1989-03-07
Schenkman, Leonard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
26039747, A61K 3156, C07J 100
Patent
active
048107018
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the bio-organic chemistry and, more particularly, to novel 11-desoxy-17.alpha.-hydroxycorticosterone deivatives (hormonocytostatics) exhibiting both antitumor and hormonal activity and useful in medicine as cancer treatment agents and immunodepressants.
BACKGROUND OF THE INVENTION
Known in the art are esters of corticoids, intermediate products of their biosynthesis and cytotoxic acids of different structure.
They can be exemplified by esters of pregnenolone and p-di-(2-chloroethyl)aminophenylacetic acid (chlorophenacyl):
3.beta.-hydroxy-5-pregnen-20-one-3.alpha.-p-di(2-chloroethyl)aminophenylace tate ##STR2## and desoxycorticosterone and chlorophenacyl-21-hydroxy-4-pregnen-3,20-dione-21-[p-di(2-chloroethyl)amin ophenylacetate]: ##STR3##
The antitumor properties of these compounds have been studied but insufficiently. There has been established their antitumor activity against Walker carcino-sarcoma W-256, chronic leukemia of rats and certain tumors originating from hormone-depending tissues-cervical carcinoma RShm-S, mammary carcinoma R-13762. However, these compounds have not revealed any activity in respect of lymphoid leukemia L 1210 (cf. Z. P. Sof'ina, N. D. Lagova, I. M. Valueva, Z. V. Kuz'mina, E. N. Shkodinskaya, A. M. Khaletsky. Proceedings of I All-Union Conference on Chemiotherapy of Malignant Tumors, Riga, 1968, p. 441-443; M. Wall. G. Abernethy, F. Carrol, D. Taylor, J. Med. Chem., 1969, 12, No. 5, pp. 810-818; N. D. Lagova. Experimental Oncology 1982, vol. 4, No. 5, p. 38-42).
Known are esters of corticoids, more particularly esters of hydrocortisone and .beta.-chloroethylcarbamic acid; 9.alpha.F,11.beta.,16.alpha.,17.alpha.,26-tetraoxypregna-1,4-diene-3,20-di one-21-[bis-(2-chloroethyl)carbamate], 16,17-acetonide ##STR4## and esters of triamcinolone-acetonide and .beta.-chloroethylcarbamic acid: 11.beta.,17.alpha.,21-trihydroxy-pregnene-4-3,20-dione-21-[bis(2-chloroeth yl)carbamate]: ##STR5## The compounds are biologically active. They inhibit growth of cultures of mice fibroblasts L-929 and react with cell receptors. However, these biological effects are reversible (cf. A. Masry, V. Braun, C. Nielsen, W. Pratt, J. Med. Chem., 1977, vol. 20, No. 9, pp. 1134-1139).
Known in the art is an ester of a synthetic corticoidprednisolone and p-di-(2-chloroethyl)aminophenylbutyric acid (chlorambucyl): pregna-1,4-diene-3,20-dione, 11.beta.17,21-trihydroxy-21-[p-di(2-chloroethyl)aminophenylbutyrate] of the formula: ##STR6## which was give the tradename "Prednimustine" (D. Alftchew, I. Rush. Ann. Chir, Gynaecol. Fenw., 1969, vol. 58, p. 234; J. Kaufmann, G. Hunjura, A. Mittelmann, C. Arengsta, G. Murphy, Cancer. Treat. Rep. 1976, vol. 60, No. 3, pp. 277-279).
The preparation "Prednimustine" is useful in oncological clinic for the treatment of systemic blood diseases and, to a lesser extent--breast cancer. Side effects of "Prednimustine" are associated mainly with hematotoxicity.
Disclosure of the Invention
The present invention is directed to the provision of novel 11-desoxy-17.alpha.-oxycorticosterone derivatives exhibiting a wide range of an antitumoral effect and hormonal activity.
The 11-desoxy-17.alpha.-oxycorticosterone derivatives are novel and hitherto unknown from the literature.
The object of the present invention is accomplished by providing the derivatives of 11-desoxy-17.alpha.-hydroxycorticosterone comprise compounds of the general formula: ##STR7## wherein R is --CO(CH.sub.2).sub.n C.sub.6 H.sub.4 N(CH.sub.2 CH.sub.2 Cl).sub.2 ; n=1, 3.
In the compounds according to the present invention as the steroid use is made of 11-desoxy-17.alpha.-oxycorticosterone which is a hormone-mediator in the biosynthesis of mineralo- and glucocorticoids and is also capable of metabolizing according to the estrogen type.
The compounds according to the present invention comprise esters of 11-desoxy-17.alpha.-hydroxycorticosterone and p-di(2-chloroethyl)aminophenylalkane acids.
Examples of the compounds according to the present invention are 11-desox
REFERENCES:
patent: 3657434 (1972-04-01), Radscheit et al.
patent: 4261910 (1981-04-01), Asano et al.
J. Med. Chem., vol. 12, No. 5, (1969), pp. 810-818; Wall et al.
Annales Chirurgiae et Gynaecologiae Fenniae, 1969, pp. 234-240.
Cancer Treatment Reports, vol. 60, No. 3, 3/76, pp. 277-279.
Effects of Steroidal Alkylating Agents, Wall et al., vol. 12, pp. 810-818.
Synthesis and Biological Action of two Glucocorticoid Alkylating agents, asry, J. Medicinal Chem., 1877, vol. 20, No. 9, pp. 1134-1139.
Experimental Oncology, 1982, No. 5, vol. 4, pp. 38-42.
First All-Union Conference on Chemotherapy of Malignant Tumors, Oct. 7-11, 1968.
Krasnova Margarita A.
Kurdjumova Kira N.
Lagova Nina D.
Lopatin Petr V.
Mikhailova Ljudmila M.
Lipovsky Joseph A.
Schenkman Leonard
Vsesojuzny Onkologichesky Nauchny Tsentr Akademii Meditsinskikh
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