lllllllllllllllllllllllllllIlllllllllllllllllllllllllllllllllllllllllllllll 0500517515411 United States Patent [191 [11] Patent Number: 5,175,154 Schwartz et a1. [45] Date of Patent: Dec. 29, 1992 [54] 5 a-PREGNAN-ZO-ONES AND Malloux. et al., in Bulletin de la Societe Chemique de S-PREGNEN-ZO-ONES AND RELATED France. 617 (1969). COMPOUNDS Pouzar et a1. Chem. Abstracts 94:103670p ( 1980) “Ste [75] Inventors: Arthur G. Schwartz, Philadelphia; roids. Part CCXXXIV, Absolute Con?guration at C30 Marvin L. Lewbart, Media. both of of the Derivatives of 21-Nor-52-Cho1one-20,~ Pa. 24-Dio1“. Danilewicz et al., CA 62: 91936 1965. [73] Assignee: Research Corporation Technologies, Gravestock et a1. CA 92: 2156245 1980. Inc. Hanson, et al., Perkin Transactions 1, (1977), pp. [21] Appl. No; 126,310 499-501. Chemical Abstracts, 89. 1058656, (1978). [22] Filed: Nov. 25, 1987 Numazawa, et al., Steroids, 32. 519-527 (1978). [51] Int. C1.5 .................... .. A61K 31/58; A61K 31/56 (List continued on next page.) [52] 13.8. Cl. .................................. .. 514/172; 514/182; 514/909 [58] Field of Search ........................... .. 260/397, 397.5; Primary Examiner-Frederick E. Waddell 552/541-544, 546. 551-552. 554-556, 559-560, Assistant Examiner-Raymond J. Henley, Ill 562. 564. 565. 567-568. 582-583. 585, 589, 599, Attorney, Agent, or Firm—Scully, Scott, Murphy & 603-606, 609-616, 623-624, 650-652, 514. 536, Presser 537-539. 548: G23/182, 172 [56] References Cited [57] ABSTRACT US. PATENT DOCUMENTS Compounds of the formulae: 2.833.793 5/1958 Dodson et a1. ................... .. 514/178 2.911.418 11/1959 Johns et al. ....... .. 514/178 3.131.125 4/1964 Wettstein et a1. .. 514/182 3.148.1983.211.723 10/19659/1964 GoldkampKagan ............................ et a1. .. 260/3973 3.318.789 5/1967 3.391.166 7/1968 3.471.480 10/1969 Fritsch et a1. ..... .. 3.471.5263.639.598 10/19692/1972 Klimstra et............ a1. .. 3.836.629 9/1974 Klimstra ............ .. 3.890.3563.914.265 10/19756/1975 GrunwellMiddleton et......... al. .. 3.976.691 8/1976 Middleton et a1. 4.029.777 6/1977 Engelfried et a1. .. 4,628,052 12/1986 Peat et a1. ......................... .. 514/171 FOREIGN PATENT DOCUMENTS 133995 3/1985 European Pat. Off. 210665 2/1987 European Pat. Off. 1239306 4/1964 Fed. Rep. of Germany . 2035738 6/1970 Fed. Rep. of Germany‘. 2705917 2/1977 Fed. Rep. of Germany . 2317934 2/1977 France . 989503 8/1963 United Kingdom . OTHER PUBLICATIONS Remington's Pharmaceutical Sciences (16th edition) 1980; pp. 420-435. Bishop et al., J. Chem. Soc., Chem. Commun. (1983), pp. 123-124. Pouzar et al., Collection Czech. Chem. Commun. (1981) 46, pp. 917-925. Pouzar et al., Collection Czech. Chem. Commun. (1980) 45, pp. 2443-2451. useful as anti-obesity, anti-diabetic, anti-coronary and Gravestock eta1., J. Amer. Chem. Soc., 102:2 (1980) pp. hypolipidemic agents. 800-807, Bull et al., S.-Afr. Tydskr. Chem, (1979) 32(1) pp. 17-22. Danilewicz et al., J. Chem. Soc. 1965 (Feb.) 1306-1319. 98 Claims, No Drawings 5,175,154 Page 2 OTHER PUBLICATIONS Denny, et al., in J. C.S. Perkin I, 486 (1972). Bridgeman. et al., in J. Chem. Soc. C. 250 (1970). Swern, Fels Report, pp. 32-33 (date unknown). Chemical Abstracts 67, 54331k (1967). Abou-Gharbia, et 21]., Journal of Pharmaceutical Sci Catsoulacos, Yet 21., in J. Org. Chem, 32, 3723—3724 ences, 70, 1154 (1981). (1967). Pashko, et al., Carcinogenesis, 2, 717-721 (1981). Sheppard, et al., in Some Chemistry of i3-Iso-Steroids, Pashko, et a1.. Carcingenesis, 5, 463-466 (1984). 2551 (1977). Raineri and Levy, Biochemistry, 9, 2233 (1970). Pelc, et al., in Collection Czechoslov. Chem. Commun. 31, Robinson, st 211.. J. Org. Chem, 28. 975 (1963). 1064 (1966). Neef, et al., J. afOrg. Chem, 43, 4679-4680 (1978). Klimstra, et al., in Journal ofMed. Chem. 9, 924 (1966). Gordon, et al., Cancer Research 46, 3389-3395 (1986). Bishop et 211., CA 99:88445e 1983. Julian, et al., in JACS, 70, 3872-3876 (1948). Pouzar et al., CA 95:1875162 1981. Ross, et al., in J. Chem. Soc, 25 (1945). Pradhan et 211., CA 95:62499q 1981. Crabb, et al., in J.C.S. Perkin 1, 1041 (1981). Bull et al., CA 92:111221s 1980. Chemical Abstracts 92, 215616v (1980). Kocovsky et 211., CA 90:204358r 1979. Bird. et al., in J.C.S. Perkin I, 750 (1980). Allinger, CA 65:5504d 1966. Kirk. et 211., in J. CS. Perkin I, 762 (1976). Scherico, CA 69:97013s 1968. Chemical Abstracts 79, 42723 (1973). Vandcnheuvcl, CA 85:59846t 1975. 5,175,154 1 2 droepiandrosterone: an anti-obesity and anti-carcino 5 ot-PREGNAN-ZO-ONES AND genic agent." Nut. Cancer 3. 46-53 (1981). 5-PREGNEN-20-ONES AND RELATED Ben-David. et al.. “Anti-hypercholesterolemic effect COMPOUNDS of dehydroepiandrosterone in rats.“ Proc. Soc. Expt. Biol. Med, 125, 1136-1140 (1967) have observed that BACKGROUND OF THE INVENTION DHEA treatment has an anti-hypercholesterolemic This invention relates to novel steroids and more effect in mice. while Coleman, et al. (Diabetes 31, 830. particularly to 17-formyl and 17-alkanoyl derivatives of 1982) report that administration of DHEA produces a Sa-androstanes and S-androstenes useful as anti-obesity, marked hypoglycemic effect in C57BL/KsJ-db/db anti-diabetic, anti-coronary and hypolipidemic agents. mice. The latter authors suggest that the therapeutic Dehydroepiandrosterone (DHEA) and DHEA-sul effect of DHEA might result from its metabolism to fate are major adrenal secretory products in humans, estrogens. The plasma concentration of DHEA-sulfate, which It is further known that DHEA and l6c1-bromoepian drosterone are inhibitors of Epstein-Barr virus-induced next to cholesterol, is the most abundant steroid in hu transformation of human lymphocytes and that 16a mans, undergoes the most marked age-related decline of any known steroid. bromoepiandrosterone is a more potent inhibitor of Although DHEA-sulfate is the main precursor of mammalian G6PDl-I than DHEA. See, Schwartz, et a1. placental estrogen and may be converted intoactive Carcinogensis, Vol. 2 No. 7, 683-686 (1981). While DHEA has been found effective in the afore androgens in peripheral tissue, there is no obvious bio 20 described manners, there is however, evidence of an logical role for either DHEA or DHEA-sulfate in the estrogenic effect after prolonged administration. normal individual. Several retrospective and prospec DHEA is not an estrogen per se but is well known to be tive studies suggest that women with sub-normal levels convertible into estrogens. In addition, the therapeutic of these steroids may be predisposed to develop breast dose of DHEA is rather high. It would therefore be cancer. For example, see Brownsey, et al., "Plasma 25 highly desirable to provide steroids. which while hav dehydroepiandrosterone sulfate levels in patients with ing the same afore-described advantage of DHEA are benign and malignant breast disease," Eur. J. Cancer, 8, more potent and do not produce an estrogenic effect. 131-137 (1972): Bulbrook. et al., “Relation between Besides DHEA. other steroids are known in the art. urinary androgen and corticoid excretion and subse Great Britain Patent No. 989.503 to Burn, et a1. dis quent breast cancer," Lancet. 2, 395-398 (1971); Rose, closes 6, 1 6/3 -dimethy1-3 B-hydroxyandrost-S-en et al.. "Plasma dehydroepiandrosterone sulfate, andro 17-ones. These compounds are disclosed to be useful as stenedione and cortisol, and urinary free cortisol excre possessing pituitary inhibiting action. tion in breast cancer, "Eur. J. Cancer, 13, 43-47 (1977); US. Pat. No. 2,833,793 to Dodson, et al. discloses Wang. et al., "Studies of the sulfate esters of dehydro 35 1B,3B-dihydroxy-5-androsten-l7-one as an androgenic epiandorsterone and androsterone in the blood of and anabolic agent. women with breast cancer," Eur, J. Cancer, 10, 477-482 US Pat. No. 2,911,418 to Johns. et a1. discloses 16a (1974); and Zumoff, et al., “Abnormal 24-hr mean chloro-3B-hydroxyandrost-Sen-17-one and 3,8 plasma concentrations of dehydroisoandrosterone and hydroxy-l6a-iodandrost-5-en-17-one as an anti-andro dehydroisoandrosterone sulfate in women with primary gen. operable breast cancer,“ Cancer Research, 41, Goldkamp, et al. in US. Pat. No. 3,148,198 disclose 3360-3363, September, 1981. that 160.,16B-dif1uoro-3B-hydroxyandrost-S-en-17-one It has also been established that DHEA is a potent possess androgenic properties. non-competitive inhibitor of mammalian glucose-6 French Application No. FR-A 2,317,934 discloses the phosphate dehydrogenase (GéPDl-l). For example, see 45 following compounds: Oertel, et al., "The effects of steroids on glucose-6 3,8-hydroxy-16?-methylandrost-5-en-l7-one phosphate dehydrogenase," J. Steroid Biochem, 3, 3B-hydroxy-16?-ethylandrost-5-en-17-one 493-496 (1972) and Marks, et a1, “Inhibition of mamma 3B-hydroxy-lé?-isopropylandrost-S-en-17-one lian glucose-6-phosphate dehydrogenase by steroids,” US. Pat. No. 3,976,691 discloses the following com Proc. Nat‘l Acad. Sci, USA, 46, 477-452 (1960). More pounds: over, Yen, et al., “Prevention of obesity in Al'y/a mice by' dehydroepiandrosterone,” Lipids, 12, 409-413 (1977), reported that long-term administration of 0 (a) DHEA to VY-A‘Wa mice prevented the development of obesity without suppressing appetite. 55 Furthermore, it is also known that the long-term )W treatment of C3I-I mice with DHEA, in addition to reducing weight gain without suppressing appetite, markedly inhibits spontaneous breast cancer develop HO \ ment and may delay the rate of aging. It has been ob o (b) served that DHEA antagonizes the capacity of the 11 tumor promoter, 1Z-O-tetradecanoylphorbol-13-ace tate, to stimulate 3’I-I-thymidine incorporation in mouse epidermis and in a cultured rat kidney epithelial cell line.