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
3.211.7233.148.198 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. See, Schwartz, “Inhibition of spontaneous breast 65 cancer formation in female C3H-A‘T/a mice by long term treatment with dehydroepiandrosterone, Cancer F Res, 39, 1129-1132 (1979); and Schwartz, et al., “Dehy 5,175,154 3 4 US. Pat. No. 3.471.480 to Fritsch. et a1. discloses the one. epiandrosterone, 3/3-hydroxy-5a-pregnan-20-one, following compounds which are useful as progesta ' 5a-androstan- l 7-one and 5a-androstan-3B,l6a-diol tional agents: 17-one are inhibitors of glucose 6-phosphate dehydro (a) 3B-iodo-A5-6-methyl-l7-oxoandrostene genase. Furthermore. said reference discloses that tes (b) 3B-chloro-A5-6-methyl-l7-oxoandrostene 5 tosterone, 17B-Estradiol. 5-androstene-3B,17Bdiol, (c) 3B-hydroxy-A5-6-methyl-l7-oxoandrostene dehydroepiandrosterone-3-sulfate and 5a—androstan Hanson, et al. in Perkin Transactions 1. 1977. pp. 178-01 are noninhibitors of glucose-o-phosphate dehy 499-501, disclose 313,4B-dihydroxyandrost-5-en-l7-one. drogenase. The reference suggests that there is a gen No utility is disclosed. eral correlation between the structure requirements for Chemical Abstract 89:105866b discloses that 38 blocking differentiation to adipocytes and inhibiting hydroxy-Sa-androstan-17-one can be hydroxylated in glucose-6-phosphate dehydrogenase. the lSa-position. Furthermore. said reference teaches Julian, et al. in JACS, 70, 3872-3876 (1948) discloses that hydroxylation of 38-hydroxy-5aandrosten-l7-one the preparation of 16-dimethylaminomethyldehy gave both the 7a and 7B-hydroxyisoandrosterones. droisoandrosterone and 16-methylenedehydroisoan Numazawa, et al. in Steroids, 32. 519-527 disclose 5 3B,16a-dihydroxyandrost-S-en-l7-one. No utility is drosterone acetate. disclosed. Ross. et al. in J. Chem. Soc., 25, (1945) disclose the DE-A- 2,035,738 discloses 7a-Methyl-3B-hydroxy-5 synthesis of lé-isopropylidene-S-androstene-17-one. androsten-17-one and 6,7a-dimethyl-3B-hydroxy-5~ Peat in US. Pat. No. 4,628,052 disclose compositions androsten-17-one. 20 containing the following compound as the active ingre DE-A2 705917 discloses 313,16B-dihydroxy-5-andros dient: ten-17-one. The Annual Report of the Fels Research Institute, pp. 32-33, (1979-1980) discloses the following com pounds as having tumor-preventive. anti-obesity and - anti-aging qualities: 3B-hydroxy-16a-bromo-5a-androstan-l 7-one 3B-hydroxy-16a-chloro-5a-androstan-17-one 3B-hydroxy-l6a-?uoro-5a-androstan-17-one 3B-hydroxy-16a-iodo-5a-androstan-l7-one 3B-hydroxy-16a-bromoandrost-5-ene-17-one 16abromoandrostan-17-one wherein R1 is O or OH and R3 is O. or OH; and which Abou-Gharbia. et al. in Journal of Pharmaceutical may contain one double bond in ring A and/or ring B or Sciences, 70, 1154-1156 (1981) disclose the syntheses of: tocopherol. 3B-hydroxy-16a-chloro-5a-androstan-l7-one. 35 The compounds are alleged to be useful in treating 3B-hydroxy-16ot-flu0ro-5a-androstan-17-one. rheumatoid arthritis. osteoarthritis and arthritis associ 3B-hydroxy-l6a-bromo-5a-androstan-l7-one. ated with psoriasis and with lupus and other auto 3,8-hydroxy-16a-iodo-5a-androstan-17-0ne. immune diseases and also for treating non-speci?c joint Pashko, et al. in Carcinogenesis, 2, 717-721 (1981) pain associated with stress. disclose that l6a-Br-epiandrosterone is more active than DHEA in inhibiting G6PDH and in reducing the ' SUMMARY OF THE INVENTION rate of [3H] thymidine incorporation into mouse breast The present invention relates to novel steroids which epithilum and epidermis. The authors suggest that this are useful as anti-obesity agents. anti-hyperglycemic compound may be useful in suppressing breast cancer agents, anti-hypercholesterolemic agents and anti development. 45 autoimmune agents. Neef, et al. in Journal of Org. Chem., 43, 4679-4680 Moreover, the present invention is directed to novel disclose the syntheses of 3B-hydroxy-l6a-methyl-5 steroids, useful as anti-obesity, anti-hyperglycemic, and andr0sten-l7-one and 3B-hydroxy-l6B-methyl-5 anti-hypercholesterolemic agents, which do not evi androsten-l7-one. dence estrogenic effects. Robinson, et al. in Journal ofOrg. Chem., 28, 975-980 50 Finally, the present invention is directed to the pro (1963) disclose the synthesis of 3B-hydroxy-l6ot, 16B cess for the treatment and/or prevention of obesity, di?uoro-S-androsten-17-0ne, and 16-f0rmyl-5-andros diabetes and hyperlipidemia. tene-3Bol-l7-one. Therefore, the present invention provides novel ste Ranier, et al. in Biochemistry, 9, 2233-2243 (1970) roids of the general formula: tested the inhibitory activity of the following steroids 55 on NADP and NAD linked activity of glucose 6-ph0s phate dehydrogenase: 3B-Hydroxy-S-pregnen-ZO-one 3B, 17a-Dihydroxy-Sa-pregnan-ZO-one 38-1-1ydroxy-Sa-pregnan-ZO-one 60 3B-Hydroxy-SB-pregnan-ZO-one 4-Pregnene-3,2O -dione 3B, 21-Dihydroxy-S-pregnen-ZO-one 3B-Hydroxy-16a,17a-epoxy-5-pregnen-20-one 3B-Hydroxy-6-methyl-S-pregnen-ZO-one 65 3B-Hydroxy-16a-bromo-5-pregnen-20-one Gordon, et al. in Cancer Research 46, 3389-3395 (1986) disclose that DHEA, léa-bromoepiandroster wherein 5,175,154 5 6 R1. R3. R3. R4. R5. Rh. RT. R» R1]. R13. R13. R14and structure. described hereinafter in more detail. are char Ri5 are each independently hydrogen. lower alkyl. acterized with signi?cant pharmacological properties halogen. hydroxy or lower alkoxy: without toxic or undesirable estrogenic effects. That is. Rs 15 hydrogen. lower alkyl or halogen: ithas been quite unexpectedly discovered that the ste RH, and Rnare independently hydrogen. lower alkyl, 5 roids of the present invention are useful as anti-obesity, halogen. hydroxy or lower alkoxy: anti-diabetic, and anti-hypercholesterolemic agents. but Rn; is hydrogen. lower alkyl. halogen or lower alk unlike DHEA are more potent and exhibit very little or oxy; or R“, and Rig taken together with the carbon to which no estrogenic effects. they are attached form an epoxide ring; and More particularly, the steroids of the present inven R19 is hydrogen. lower alkyl. tri-haloloweralkyl, di tion have the general formulae: haloloweralkyl or mono-halolowerall-zyl. with the pro viso that when Riqis methyl and R1, R3, R3. R4, R7. R5. RQ. R1]. R13. R13, R14. R15, R10, R17 and R13 are hydro gen or when Riq is methyl. R15, and R18 taken together with the carbon to which they are attached form an epoxide ring and R1. R3. R3. R4. R7, R3. R9. R11, R13. R13, R14. R15 and R11 are hydrogen, or when R10 and R9 are methyl and R1, R1, R3, R4. R7, R5. R11, R13. R13, R14. R15. R16. R17 or R13 are hydrogen or when R16 is bromo.R1<;is methyl and R1. R3. R3. R4. R5. R7. R3. Rq, R11. R13. R13. R14. R15. R17 and R13 are hydrogen, then neither R5 nor R6 is hydroxy. Further objectives are accomplished herein by pro viding novel steroids of the formula:
wherein R1—R1<> are as de?ned hereinbefore. The wherein R1—R1g substituents are designated as being in the a R1, R3. R3. R4,. R5. Rh. R7. Rx. R1]. R13, R13. R14and position by means ofa broken line (---) joining the sub R15 are each independently hydrogen. lower alkyl. stituent to the steroid nucleus, the substituents are desig halogen. hydroxy or lower alkoxy; nated as being in the B~position by means of a solid line R9 and R10 are each independently hydrogen. lower (—) joining the substituent to the steroid nucleus and in alkyl or halogen: those cases in which the substituent may be either in the Rlband R17 are independently hydrogen, lower alkyl, 45 a- or B-posi'tion the substituents are indicated as being halogen, hydroxy or lower alkoxy; joined to the steroid nucleus by a wavy line. Further‘ R15 is hydrogen. lower alkyl. halogen or lower alk more, in accordance with I.U.P.A.C. nomenclature, the oxy: or R16 and R18 taken together with the carbon to which carbon atoms of the steroids of the present invention are they are attached form an epoxide ring: and numbered as follows and the steroids have the desig R19 is hydrogen, lower alkyl. tri-haloloweralkyl, di nated I.U.P.A.C. stereochemistry: haloloweralkyl or mono-haloloweralkyl, with the pro viso that when R19 is methyl and R1, R3, R3, R4, R7, R3, R9, RlO- R11, R12, R13, R14, R15. R16, R17 and R18 are hydrogen or when R19 is methyl, R13 is hydroxy, and R1, R2, R3, R4, R7, R8, R9, R11, R12, R13‘ R14, R15, Rio and R17 are hydrogen, then neither R5 nor R6 is hy droxy. The present invention is also directed to processes for the prophylaxis of obesity, diabetes and hyperlipidemia and autoimmune diseases, such as lupus erthematosus or Coomb’s positive hemolytic anemia, by administering to a host, e.g., mammals, a therapeutically effective amount of the afore-identi?ed steroids. The present invention provides processes for the prophylaxis of obesity, diabetes, and hyperlipidemia DETAILED DESCRIPTION OF THE 65 and autoimmune diseases, such as lupus erythematosus INVENTION or Coomb’s positive hemolytic anemia comprising ad In accordance with the present invention, it has been ministering to a host, e.g., mammals, a therapeutically surprisingly discovered that steroids having a certain effective amount of the present new steroids. 5,175,154 7 8 In accordance with the present invention. it has been The most preferred embodiment of Formula I has the surprisingly discovered that steroids having a certain structure. described hereinabove and hereinafter in formula: more detail. are characterized with signi?cant pharma cological properties without toxic or undesirable estro genic effects. That is, it has been quite unexpectedly discovered that the steroids of the present invention are useful as. anti-obesity. anti-diabetic, anti-autoimmune and anti-hypercholesterolemic agents, but unlike DHEA are more potent and exhibit very little or no estrogenic effect. Furthermore, unlike DHEA, com pounds of the present invention do not induce liver enlargement and increased catalase activity. Preferred embodiments of the compounds of For R5 mula I have the formula: wherein III R5 is hydrogen or lower alkyl; Rl?and R17 are independently hydrogen, lower alkyl, halogen. hydroxy or lower alkoxy; or R18 is hydrogen, lower alkyl, halogen or lower alk oxy: RH, and R18 taken together with the carbon to which they are attached form an epoxide ring; and Rs Ra R10 is hydrogen, lower alkyl, tri-haloloweralkyl, di haloloweralkyl or mono-haloloweralkyl. wherein Preferred compounds of Formula II have the for R], R3. R3. R4, R7, R3. R11, R13, R13, R14 and R15 are 30 each independently hydrogen, lower alkyl, halogen, mula: hydroxy or lower alkoxy: R5 and R6 are independently hydrogen, lower alkyl, halogen or lower alkoxy; Re is hydrogen. lower alkyl or halogen; Riband R17 are independently hydrogen, lower alkyl, halogen, hydroxy or lower alkoxy; R15 is hydrogen, lower alkyl, halogen or lower alk oxy: or R“' and R13 taken together with the carbon to which they are attached form an epoxide ring: and R19 is hydrogen, lower alkyl, tri-haloloweralkyl, di haloloweralkyl or mono-haloloweralkyl. Especially preferred compounds of Formula I have the formula: 45 wherein
W R1, R3, R3, R4, R7. R3, R11, R13, R13, R14and R15 are each independently hydrogen, lower alkyl, halogen hydroxy or lower alkoxy; 50 R5 and R6 are independently hydrogen, lower alkyl, halogen or lower alkoxy; R9 and R10 are each independently hydrogen, lower alkyl or halogen; R5 55 .R16and R17are independently hydrogen, lower alkyl, wherein halogen, hydroxy or lower alkoxy; R5 and R6 are independently hydrogen or lower al R13 is hydrogen, lower alkyl, halogen or lower alk kyl; oxy; or R16J and Rnare independently hydrogen, lower alkyl, halogen, hydroxy or lower alkoxy; R16 and R13 taken together with the carbon to which R13 is hydrogen, lower alkyl, halogen or lower alk they are attached form an epoxide ring; and oxy; or R19 is hydrogen, lower alkyl, tri-haloloweralkyl, di R“, and R18 taken together with the carbon to which 65 haloloweralkyl or mono-haloloweralkyl. they are attached form an epoxide ring; and R19 is hydrogen, lower alkyl, tri-haloloweralkyl, di Especially preferred embodiments of Formula II haloloweralkyl or mono-haloloweralkyl. have the formula: 5,175,154 10 the carbon to which they are attached form an epoxide ring. The most preferred Rio is hydrogen, triiluoro methyl. difluoromethyl, mono?uoromethyl or methyl, Additional variations in the structural formula repre senting the instant compounds can be effected without significantly altering the therapeutic properties. For example, the alkyl moieties can be substituted by one or more of a variety of substituents, such as hydroxy, halo gen. alkyl and the like. R5 t 10 The procedures described hereinbelow are represen Re tative of the processes for preparing compounds of the present invention. For example, even though the proce wherein dures are shown for the preparation of compounds R5 and R6 are independently hydrogen or lower al kyl; wherein R19 is CH3, the procedures are also applicable Rwand R17 are independently hydrogen. lower alkyl, for the preparation of other compounds within the halogen, hydroxy or lower alkoxy: scope of the present invention. Furthermore, the proce R13 is hydrogen, lower alkyl, halogen or lower alk dures described hereinbelow are also applicable to those oxy; or steroids which have additional substituents than those Ru, and R18 taken together with the carbon to which _ depicted hereinbelow. If substituents on the steroidal they are attached form an epoxide ring: and ring are themselves reactive under the reaction condi R19 is hydrogen, lower alkyl, tri-haloloweralkyl. di tions then these substituents can themselves be pro haloloweralkyl or mono-haloloweralkyl. tected according to chemical techniques known in the The most preferred embodiment of Formula ll has art. A variety of protecting groups known in the art the formula: may be employed. Examples of many of these possible groups may be found in “Protective Groups in Organic Synthesis,” by J. W. Green, John Wiley and Sons, 1981. If more than one substituent is to be added to the steroidal ring, the substituents can be added in any or der, except it is preferred that halogens are added last. _Finally. the procedures described hereinbelow are applicable to all the steroids of the present invention, regardless of whether a double bond is present in the 5,6 position of the steroidal ring. Moreover, those steroids of Formula II can be prepared from the corresponding steroids of Formula I by techniques known to one skilled in the art, e.g., by catalytic hydrogenation using, wherein €.g., Hg/Pd, Hg/Pt Or HZ/Ni. R5 is hydrogen or lower alkyl: Ru3 and R17 are independently hydrogen, lower alkyl. The steroids of the present invention may be pre halogen, hydroxy or lower alkoxy; pared in accordance with conventional organic synthe R13 is hydrogen. lower alkyl, halogen or lower alk sis from known compounds or readily preparable inter oxy; or mediates. R16 and Rig taken together with the carbon to which The Pregnanes and Pregnenes can be prepared by they are attached form an epoxide ring; and techniques known in the art. An exemplary procedure is R19 is hydrogen, lower alkyl, tri-haloloweralkyl, di 45 as follows: haloloweralkyl or mono-haloloweralkyl. In the present invention, the alkyl groups are prefera bly lower alkyl, which may be straight or branched chain, and which contain up to 6 carbon atoms. Exam ples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, amyl and the like. A preferred alkyl group contains l-3 carbons. The most preferred alkyl group is methyl. The halo atoms are preferably Br, F or Cl, especially F. 55 HO Moreover, it is preferred that at most one of the sub stituents, R1, R2, R3, R4, R7, R3, R9, R10, R11, R13, R13, R14 or R15 is other than hydrogen. In the most preferred CH3 embodiment, R1, R2, R3, R4, R7, R3, R9, R10, R11, R12, R13, R14 and R15 are hydrogen. In all of the compounds described hereinabove, it is preferred that R5 and R6 are independently hydrogen or lower alkyl. In the most preferred embodiment R5 is hydrogen or lower alkyl and R6 is hydrogen. The most preferred alkyl group of R5 is methyl. 65 In addition, it is preferred that R13 is hydrogen or ?uorine; R16J is hydrogen, fluorine or methyl: R17 is hydrogen or methyl or R16 and R13 taken together to 5,175, 154 11 12 -continued 2 is placed in methanol and reacted with potassium acetate to form the methoxy substituent (3). Hydrogen 16”‘ iodide addition to 3 produces the 3B-iodide derivative C=O (4). Reaction of4 with Zn/AcOH produces the desoxy 5 derivative 5. Catalytic hydrogenation of 5 produces 6. Hl/ACOH ; Preparation of 3-Desoxy Compounds The 3-desoxy compounds are prepared from the cor responding 3-hydroxy compounds by techniques ' l0 known in the art. For example,
OCH; ‘Flu O 3 (‘=0 \ l. P-Cl. Pyridine. THF / O 2. lj/CHjCl: 3r Zn/ACOH
l
25
fH; c=o 3O In other words, the 3,8-OH compound, such as 38 hydroxy-Sa-pregnan-ZO-one, is dissolved in an inert Zn/AeOH ; solvent, such as methylene chloride and reacted with O-phenylene phosphorohloroidite. The resulting prod 35 uct was reacted with iodine to form the 3-i0do deriva tive which in turn is reached with a Lewis acid, such as l zinc in acetic acid, to form the corresponding 3-desoxy compound. 4 ALKYLATION CH: 40 I . CARBON-l-ALKYLATION C=O A representative procedure for alkylation at carbon-1 is given in Scheme 1. Hg/l’d _> 45 Scheme 1 RI‘) H H 5 50
2.l. ZnNBS;
6
The A5-3B-ol is placed in a suitable solvent, such as pyridine with p-toluene sulfonyl chloride and reacted at room temperature. Approximately 2 liter of ice and O {1;93 MegCuLi water is added to quench the reaction. The product is ?ltered off and washed, and the tosylate product (2) is 9 isolated. 5,175,154 13 14 -continued tion of 2 with an acetylating agent. such as acetic anhy Scheme 1 dride (AcgO) and p-toluenesulfonic acid (p-TSA) in RN toluene affords the ZcI-methyl 3.20 dihydroxy-3,5-preg HC-OAc nadien-3.20-diacetate (4). Treatment of the diacetate (4) with sodium borohydride in 95% ethanol yields 2a methyl-3B,20,8-dihydroxy-5~pregnene-20-acetate (5). l,- NagCOg/MeOH Protection of the S-hydroxy group as a tetrahydropyra 3%-. CrOg/pyr nyl ether followed by hydrolysis ofthe ZO-acetate yields Za-methyl-3B,20B-dihydroxy-5-pregnene-3-tetrahy dropyranyl ether 7. Oxidation of the C-20 hydroxy group in 7 followed by hydrolysis of the tetrahydro pyranyl ether with hydrochloric acid and aqueous ace tone yielded 38-hydroxy-Za-methyl-S-pregnen-l7-one. (9). reduction E Scheme 2
3a Allylic bromination (eg with N-bromosuccinimide (NBS)) of ZOB-acetoxypregn-1,4-dien-3-one, for exam ple. followed by treatment with zinc affords the non conjugated enone 9. 1,4-Alkylation with lithiodimethyl cuprate provides the lot-methyl ketone 1021. At this stage the 10a may be converted to a methylene by Wolff-Kishner reduction or the Huang Minlon modifi 2 8i 3 cation thereof. These vigorous reaction conditions re sult in hydrolysis of the resulting carbon-20-acetate 45 thereby yielding the hydroxy derivative, SB-hydroxya l‘“ methyl-S-pregnene-ZO-one (3b). Both 10a and its desoxy HC-OH derivative can be converted via standard reactions, i.e., hydrolysis of the ZO-acetate with sodium carbonate and methanol followed by chromium trioxide oxidation of 50 Ac3O the resulting ZO-alcohol to the carbon-20 ketone. Selec CHIK~ pTSA E tive reduction of the carbon-3 ketone, 3,20-diketone 3c C6H5CH3 using sodium borohydride pyridine (pyr) yields the la-methyl derivative 3a. O 55 CARBON-Z-ALKYLATIONS 2
The following procedures are illustrative for alkyla R19 0 tion at carbon-2 and are ?guratively illustrated in Scheme 2 below. ' HCO'-C-CH3 Alkylation of (1), such as 20-hydroxy-4-pregnen 3-one, with'an alkylating agent, such as methyl iodide, in the presence of a strong base, such as t-BuOK, so NaBl-Li dium t-pentoxide, lithium diisopropylamide (LDA), Na CHR 95% EtOH > NI-lg, EtZNi, n-butyl lithium and the like gives a mixture of the 2a- and 2B-alkyl-20-B-hydroxy derivatives (2 and 65 CHgCO 3). Treatment of the mixture with a strong base, such as ll sodium methoxide in methanol, epimerizes the ZB-axial 4 alkyl to the Z-a-equitorial con?guration (2). Acetyla 5,175,154 15 16 -continued Scheme 2 Scheme 3 R10 0 0 l ll HCO-C-CH; C—R1Q
cmx ' ,T>DHP EtgO
HO HO
CrO; CH3\._ ipyridine (CHzOHh pTSA E THPO
II OCH;
Rm | C=O
THPOClix/(?g 35
8
W
CH 45 HO : { l-lgO/acetone pTSA 9
50 CH3 CARBON 3-ALKYLATIONS The schematic for carbon 3-alkylations are shown ?guratively in scheme 3 below. Synthesis of 3-alkyl-S-pregnene-ZO-one, e.g., with a 55 methyl group replacing the hydroxyl group at carbon-3 is shown below in scheme 3. The methyl con?guration at carbon-3 is B, as determined by X-ray analysis. 38 Hydroxy-5-pregnen-l7-one (10) is iodinated at carbon-3 with O-phenylenephosphorochloridite followed by de 60 composition of the resulting phosphite ester with io CH; dine. 3B-lodo-5-pregnen-l7-one (11) is ketalized, then alkylated with a mixture of methyl lithium and cuprous cyanide in tetrahydrofuran to yield 3B-methyl-5-pregn 65 en-ZO-ethylene ketal (l3). Hydrolysis of the ketal af ALKYLATION AT CARBON-4 fords BB-methyl-S-pregnen-l7-one (14). A procedure for carbon-4 alkylation is given in Scheme 4. 5,175,154 17 18
-continued
Scheme 4 Scheme 4
R]\: I l” HC-OH HC-OH
NBS CCl4 > CrOg/pyr E o THPO ‘
R la R = H CH3 6 R = CH). Rio l l‘“ =0 HC-OH
| ClS'i-l DMF 9 THPO H305" imidazolu 0 CH3 7 CH; Br 2 llliq C: R]u HC-OS|i+I l
LAH % HO CH3 8 0 A CH5 Br With reference to Scheme 4, alkylation of la, such as 2 20-hydroxy-4-pregnen-3-one, using potassium t-butox
R10 ide and methyl iodide yields 4-methyl-20-hydroxy-4 1 I pregnen-3-one 1b. Allylic bromination of N-bromosuo HC—OS|i+ cinimide in carbon tetrachloride yields the 6B-bromo derivative. Protection of the C-20 alcohol as its t-butyl DHP ; pTSA dimethyl silyl derivative yields 3. Lithium aluminum hydride reduction of the ketone in 3 with concomitant HO , double bond migration and loss of bromide should yield 6H; 4 55 4. Protection of the C-3 alcohol as a'tetrahydropyranyl ether, followed by deprotection and oxidation of the R10 G17 alcohol should yield the C-17 ketone 7. Removal HC--OSIi+ of the C-3 tetrahydropyranyl ether yields 4a-methyl-5 pregnen-ZO-one. nBu4N~a5F9 ALKYLATION AT CARBON-6
THPO 65 Steroids may be alkylated at carbon-6 using the CH3 5 method of U. Stache and W. Fritsch, Liebigs Analen 1966, 697,204. 5,175,154 19 20 -continued R RluI O I inO / C C \ O
Phi-.P' "'C‘HR While a
ll 0 l
R|u O / C \ 0
%LAH H1O pTSA E kl 'JI II CHR 2
O //
35
HO
R 3
3a,5~cyclosteroids, such as 3a,5-cyclo-5a-pregnan 6,20-dione-20-ketal 1 are readily available by solvolysis of steroidal 5-ene-3B~tosylates and mesylates followed by oxidation of the C-6 hydroxyl group. Methylenation of 1 affords 6-methylene-3a,5-cyclo~5a-pregnan ZO-one-ZO-ketal l7-ketal 2 (RzH). Treatment of 2 with aqueous acid results in the addition of water and the formation of 35-hydroxy-é-methyl-S-pregnen-ZO-one, 3 HO (RIH). 5 ALKYLATION AT C-7 Alkylation of, e.g., pregna-4,6-dien-3,20-dione-20 ketal with methyl magnesium bromide in the presence 55 19 of cuprous chloride, proceeds via conjugate addition to O yield 7a-methyl-S-pregnen-3,20-dione-20-ketal 2. Al lylic bromination of 2 using N-bromosuccinimide in carbon tetrachloride yields the 6B-bromo-7a-methyl-5 pregnen-3,20-dione 2O ketal 3. Lithium aluminum hy dride reduction of the ketone in 3 with concomitant double bond migration and loss of bromide should yield CHgMgBr 4. Deprotection of the C-20 ketone with aqueous acid CuCl 5 yields 3B-hydroxy-7a-methyl-5-pregnen-20-one, 5. Higher homologues may be synthesized using the sub stituted Grignard reagent, i.e., R=CH3, C2H5, C3H7. The 7B-epimer can be synthesized by treatment of 2 with DDQ--dich1orodicyanoquinone to generate an 5,175,154 21 22 other ole?n at C-7. Catalytic reduction of this ole?n -continued should occur from the a face of the steroid to yield the Rm 7,8-methyl steroid, i.e., 7,8-methyl-5-pregnen-3.20 dione~20-ketal. Following the same sequence as above yields 3B-hydroxy-7B-methy]~5-pregnen-20-one
ALKYLATION AT CARBON-ll ll base 9 KgCOyx/MeOl-l I 2‘ Bu4N+F l0 - Rio +?‘O c1 6
// Rio l5 CHOH
l. hydride reduction 9 l o ' l 2. ClS'i+. imidazole. DMF +SliCl 1 70 imidazole E
R10 7
CH—OS.i+ 25 RI“) 0% CHOH HCl CHClz/HOAe 9
I 3O CrOg/pyr E —SiO + 2
Km 35 Rio CH—()5['i+ l O§ =0
MeLi 9 40 i) +50|1 a' 1 3 —SiO 45 + R10 9 fits C=O Me 50
55 no
10
Due to the hindered nature of the C-ll ketone, selec 60 tive reduction of the steroid of Formula I, such as 5 pregnen-3,ll,20-trione with hydride should yield the C-3, C-20 dihydroxy steroid 2a, R=H which is pro tected as its bis(dimethyl-tertbutylsilyl)ether 2b R Si(Cl-I3)3t-Bu. Addition of hydrogen chloride across the 65 C-5 ole?n affords Sol-chloro-3B,2OB-dihydroxy-5 pregnen-l 1-one-3,20-bis(dimethyl-t-butylsilyDether 3. Alkylation with methyl lithium proceeds from the less hindered a face to yield 5a-chloro-lla-methyl pregn 5,175,154 23 24 en-3B.l lB.2OB-triol-3.20-bis(dimethyl-t-butylsilyl)ether Alkaline hydrogen peroxide epoxidation of a com 4. Dehydration of the methylcarbinol 4 with thionyl pound of Formula I. such as pregna-l.4.6-triene-3.20 chloride in pyridine provides the olefin 5. Catalytic dione-ZO-ketal l with basic hydrogen peroxide yields hydrogenation of 5 gives the saturated Ila-methyl the la,2a-epoxide 2. Treatment of la,2a-epoxypregna Sach'loro-bis (silyl) ether 6. Treatment of the chloro 4,6-dien-3,ZO-dione-ZO-ketal with a large excess each silyl ether 6 with base followed by tetrabutyl ammo of lithium metal and ammonium chloride in ammonia nium ?uoride affords lla-methyl-5-pregnen-3B,20B tetrahydrofuran (1:1) under re?ux leads to 1:1,3B-dihy dial 7. Selective silylation yields lla-methyl-S-pregnen droxy-S-pregnen-ZO-one ZO-ketal. Hydrolysis of the 38,20/3-diol 3-dimethyl t-butylsilyl ether 8. Oxidation of ketal affords 1a,3B-dihydroxy-S-pregnen-ZO-one (4). the C-20 alcohol in 8 yields 9 and deprotection of the 3-alcohol yields l la-methyl-5-pregnen-3B-ol-20-one C-2 Hydroxylation 10. 2a,3B-dihydroxyandrost-S-en-l7-one The following procedures illustrate hydroxylation at Carbon-l. 2, 4, 7, 11 or 16. W 10 Cl HYDROXYLATION O
NaBH4
HO
HO__
HO
55
HO
4
65 Reduction of pregna-1,5-dien-3,20-dione-20-ketal l with sodium borohydride yields 3B-hydroxy 1,5-preg nadien-ZO-one-ZO-ketal 2. Hydroxylation of the C-1 double bond by hydroboration followed by oxidation 5,175,154 25 26 with alkaline hydrogen peroxide affords 2a,3,8-dihy drOXy-S‘pregnen-l7-one-l7-ketal 3. Deprotection ofthe -continued
C-ZO ketone with aqueous acid yields 2a,3B-dihydroxy R ]u l 5-pregnene-17-one. 4. C=O Carbon-4 Hydroxylation
CHCI3 5 Rio lo I LL C: HO 0\ /H
1 SeOgHOAc 15 90= 9 HO T” C=O 1 20 T“ c=o Zn/AcOH
Z5 HO OOH
NaOEl/EtOH 9 3
H0 30 R11; OH l 2 C:
T" 35 c=0
HO \OH
40 4
HO 3B-Hydroxy-5-pregnen-20-one 1 reacts with singlet OH 3 45 oxygen to yield Sa-hydroperoxy-3B-hydroxy-6-preg
Selenium dioxide oxidation of 3B-hydroxy-5-pregn nene-ZO-one 2. This hydroperoxide undergoes a rear en-ZO-one yields 3/3,4B-dihydroxy-S-pregnen»20-one 2. rangement when in chloroform solution to yield 7a The axial C-4 alcohol may be epimerized to the equato hyclroperoxy-3B-hydroxy-S-pregnene-l7-one, 3. Treat rial position by reaction with sodium ethoxide in etha nol to yield 3B,4a-dihydroxy-S-pregnen~20-one, 3. ment of the hydroperoxide with zinc and acetic acid Carbon-7 Hydroxylation yields 3B,7a-dihydroxy-S-pregnen-ZO-one 4. 55
T19 Rio C=O l 60
102 ——> NBS/n-hexanol ; hv (GE 500 wall HO 65 pholospot B20 bulb 2-3" from ?ash 15 min.) 5,175,154 27 28 -continued -continued Rm R w |
HO I j; Onpenauer ;
1320 \Br O
7 2 Methyl t-butyl HCOOH ether HCOONu D. R. Brannon, J. Martin, A. C. Ochlschlager, N. N. Durham. and L. H. Zalkow, J. Org. Chem. 1965 30, 760. i‘“ C:
20
B20 \CCHO
3 dimune aq. OH 1?“: C=()
HO \OH
Alternatively, irradiation for approximately 15 min utes of 3B-benzyloxy-5-pregner1-20-one l in the pres ence of NBS produces the 7-aBromo-3B-benzyloxy-5 pregnen-ZO-one 2. The light source is provided by a SE. 500 watt photospot bulb, which is placed 2-3" from the ?ask. Reaction of2 with sodium formate in the presence of methyl 7-butyl ether produces the formate ester 3. Substitution with aqueous base, such as OH—, results in the 3,7-dihydroxy-S-pregnen-ZO-one 4. 5 Carbon-ll Hydroxylation 55 Hydroxylation of 1, such as 20~hydroxy-5-pregnen 3-one, at Carbon-ll using Aspergillus tamarii affords 1l[3,20B-dihydroxy-S-pregnen-S-one 2. Oppenauer oxi dation of 2 oxidizes the ZOB-aleohol in the presence of the hindered llB-hydroxyl group to yield 118 Mramarii hydroxy-S-pregnen-3,20-dione 3. Migration of the dou ble bond out of conjunction by treatment with potas sium t-butoxide followed by protonation with acetic acid yields llB-hydroxy-5-pregnen-3,ZO-dione 4. Selec tive reduction of 4 yields 3B,l IB-dihydroxy-S-pregnen l7-one 5. 5,175,154 29 30 Halogenation at Carbon-l Halogenation at Carbon-2
C=O
HO 5
HO HO 1 TM C=O
OH SOClg or PBr; 5
R0 HO
, 2 Rlu Addition of HX across the C-1 double bond in BB C=O hydroxy-l,5-pregnadien-20-one, 1, yields a mixture of the O1 and C-2 haloenated steroids. Separation affords X P; a 2-halo-3B-hydroxy-S-pregnen-ZO-one (2, RzF, Cl, Br, I). Halogenation at Carbon-3 l +510 l 35 3 ‘RN l C=O
X
HO
HO
4
X = Cl. Br. 1
Selective protection of the Carbon-3 hydroxyl in the presence of the 1a~hydroxyl group should yield 2. For example, let, -3,8-dihydroxy-S-pregnen-ZO-one 1 reacts with t-butyl-dimethyl silyl chloride in the presence of imidazole using dimethylformamide as a solvent to 55 yield la,SB-dihydroxy-5-pregnene-20-one 3t-butyl N dimethylsilyl ether, 2. Reaction of 2 with thionyl chlo ride, or phosphorous tribromide or catechol phospho nIIu|| chloridate followed by iodine yields the corresponding CLOO'N 2:21:02: IB-chloro, bromo or iodo derivatives 3. Reaction of 3 60 (RzCl, Br, I) with tetrabutyl ammonium ?uoride Reaction of 3B-hydroxy-5-pregnen-20-one 1 with yields lB-halo-3B-hydroxy-5-pregnen-17-one, 4 diethyl (2-chloro-l,1,Z-tri?uoroethyl) amine yields 38 (R—_—Cl, Br or I). The ?uoride (4, R_—_F) may be synthe ?uoro-S-pregnen-ZO-one 1. Reaction of l with thionyl sized via a similar route using an ester as the protecting chloride yields 3B~chloro-5-pregnen-ZO-one. Reaction group at C-3 and reacting the la-hydroxyl group with 65 of 1 with phosphorus tribromide yields 3B-bromo-5 diethyl (Z-chloro-1,l,2-tri?uoroethyl)amine. Hydrolysis pregnen-17-one, 20. Reaction of l with catechol phos should yield 1-/3-?uoro-38-hydroxy-S-pregnen-ZO-one, phochloridate followed by iodine yields 3B-iod0-5 4, RzF. - pregnen-17-one 2d. 5,175,154 31 32 Halogenation at Carbon-4 -continued
Rm 0 \ ll H-COCCH3
AcgO E
O
ZaX bX Cl cX Br dX
R10 0 \ ll H-COCCH;
3O
With the 3B-hydroxyl group protected as its t-butyl dimethylsilyl ether the C-4 hydroxyl may be chlori nated using thionyl chloride. Treatment with ?uoride 35 ion cleaves the silyl ether to yield 4?chloro-3B hydroxy-S-pregnen-ZO-one 2b. Reaction of 3,4-dihy droxy-S-pregnen-ZO-one S-t-butyldimethylsilyl ether 1 with O-phenylene phosphochloridite, followed by dis placement with bromide ion and cleavage of the silyl ether with ?uoride ion yields 4?bromo-3B-hydroxy-5 pregnen-ZO-one 20. Reaction of l with catechol phos 45 phochloridate, followed by iodine and cleavage of the silyl ether with ?uoride yields 4?iodo-3B-hydroxy-5 pregnen-ZO-one 2d. Fluorination of 3B,4§dihydroxy-5 pregnen-20-one-3-acetate with diethyl (2-chloro-1,l,2 tri?uoroethyl) amine followed by hydrolysis of the ester yields 4??uoro-3B-hydroxy-S-pregnen-ZO-one 2a. Halogenation at Carbon-6 55
allvlic ; halogenation
65 5,175,154 34 -continued -continued R|o I l‘“ C=O C=O
1O HO X HO X 2a X = F b X = Cl 6 c X = Br 6a X = F d X = 1 6b X = Br be X = Br 6d X = I Reaction of 3B,7-dihydroxy’5-pregnen-20~one-3-t butyldimethylsilyl ether 1 with thionyl chloride yields Allylic bromination of 2OB-hydroxy-4-pregnen-3-one the C-7 chloro-steroid. Deportection of the 3B hydroxyl group affords 7-chloro-SB-hydroxy-S-pregn ZO-acetate 1 using N-bromosuccinimide together with a en-ZO-one, 2b. Reaction of 1 with catechol phospho radical initiator such as light or benzoyl peroxides or chloridate followed by displacement with bromide ion aliphatic azo compounds [RR’C(CN)—N: and deprotection yields 7-bromo-3B-hydroxy-5-pregm N—C(CN)RR'] e.g. azobisisobutyronitrile yields 65 en-20-one, 2c‘ Similarly reaction of l with catechol phosphochloridate followed by displacement with io bromo-ZOB-hydroxy-4-pregnen-3-one-20-acetate 2. Al 25 dine and deprotection yields 7-iodo-3B-hydroxy-5 lylic chlorination of 1 using sulfuryl chloride together pregnen-ZO-one, 2d. Fluorination of BBJ-dihydroxy-S with a radical initiator such as light or benzoyl peroxide pregnen-ZO-one 3-acetate with diethyl (2-chloro-l,l,2 or aliphatic azo compound yields 6,8-chloro-2OB tri?uoro-ethyl) amine followed by hydrolysis of the ester yields 7-iluoro-3B-hydroxy-S-pregnen-ZO-one, 2a. hydroxy-4-pregnen-3-one-20-acetate. 2c. Allylic iodin 30 ation of 1 using mercuric iodide and light yields 6,8 Halogenation at Carbon-9 iodo-ZOB-hydroxy-4-pregnen-3-one-20-acetate, 2d. Acetylation of 2 with acetic anhydride and p-toluene ‘In; sulfonic acid in toluene yields 6-halo-3, ZOB-dihydroxy C=O 3.5-pregnadien-3,20-diacetate 3. Sodium borohydride HO reduction of 3 followed by basic hydrolysis of the C-20 acetate yields 6-halo-5-pregnen-3B,2OB-diol, 4. Selec tive protection of the C-3 hydroxyl group as its t-butyl dimethylsilyl ether followed by chromium trioxide oxi dation of the C-20 hydroxyl group yields 6-halo-3B hydroxy-S~pregnen-20-one 3-t-butyldimethylsilyl ether 5. Treatment of 5 with ?uoride ion yields 6-halo-3B 45 hydroxy-S-pregnen-ZO-one 6. The C-6 fluoro analogue may be synthesized from the C-6 bromo diacetate, 3c, by treatment with silver fluoride. Following the above sequence, reaction of 6-fluoro-3,20B-dihydroxy 3,5 pregnadien-3,ZO-diacetate, 3a with sodium borohydride yields 6-fluoro-3B-hydroxy-S-pregnen-ZO-one, 6a.
Halogenation at Carbon-7 55
m-chloroper Benzoic acid 9
65 OH 5,175,154 35 36 -continued l-lalogenation at Carbon-ll T‘" c=o HO_' %
+sioI 1 R10 1 =0 HO SOClg/pyr. —+
+sl'o|‘ Br- Br 5 25 2a x = F b = Cl c = Br lilo d = 1 C=O Reaction of 3B,] la-dihydroxy-S-pregnen-20-one 3-t butyldimethylsilyl ether 1 with OPPC followed by l. Hg/Pd chloride yields the G11 chloro steroid. Deprotection of 2. teirabut_\l- E the 3B-hydroxyl group affords ll?-chloro-I’tB-hydroxy ammonium I Fluoride 5-pregnen-20-one, 2b. Reaction of 1 with OPPC fol
S'O ' lowed by displacement with bromide ion and deprotec + [I Br tion yields lltZ-bromo-3B-hydroxy-S-pregnen~20-one, Br 2c. Similarly reaction of l with OPPC followed by (1 displacement with iodine and deprotection yields 11i iodo-3,B,hydroxy-S-pregnen-ZO-one, 2d. Fluorination of Tm 313,1la-dihydroxy-S-pregnen-ZO-one 3-acetate with di C=O ethyl (2-chloro-1,l.2-tri?uoroethyl)amine followed by hydrolysis of the ester yields ll?-?uoro-3/3-hydroxy-5 pregnen-ZO-one, 2a. ALKOXYLATION The alkoxy groups are derived from the correspond HO ing alcohols. The methoxy substituent for example is formed by reacting the corresponding alcohol in methy 7 lene chloride with boron trifluride and etheral diazo methane according to the procedure of Caserio, et al., Bromination of 38,11a-dihydroxy-S-pregnen-ZO-one JACS, 80, 2584 (1958). Similarly, the ethoxy substituent 3-t-butyldimethylsilyl ether 1 yields the dibromide 2. is formed by reacting the corresponding alcohol in Reaction of 2 with thionyl chloride produces the unsat methylene chloride with boron tri?uoride and etheral diazoethane, generated in situ. Alternatively, the alkoxy urated compound, SB-hydroxy-5,6-dibromo~9(ll) 55 substituents can also be added to the steroid ring by pregnen-20-one-3-t-butyl-dimethylsilyl ether 3. 3 is ep reacting the alcohol under Williamson reaction condi oxidized with perbenzoic acid forming 4. Reaction of 4 tions with RX, where X is an organic leaving group with hydrohalic acid, such as HCl, HBr, forms the‘ such as halide tosylate or mesylate and R is loweralkyl. 9a-halo derivative 5. Dehydration of 5 with thionyl Any base normally employed to deprotonate an alcohol may be used, such as sodium hydride, sodium amide, chloride produces the unsaturated compound, the 3B sodium sodium hydroxide, triethylamino or disopropyl hydroxy-5,6-dibromo-l l-pregnen-20-one-3-t-butyl ethylamine. Reaction temperatures are in the range of dimethylsilyl ether 6. Catalytic hydrogenation of 6 fol —78° C. to re?ux. The reaction is carried out in a sol lowed by removal of the protecting group forms the 65 vent that will dissolve both reactants and is inert to both 3-Bhydroxy-9-a-halo-5-pregnen-20-one. reactants and products as well. Solvents include, but are not limited to, diethyl ether, tetrahydrofuran, N,N dimethylformamide, methylene chloride, and the like.