United States Patent (15) Batchelor et USOOS9984278 (54) 75] 73] ANDROSTENONES Inventors: Kenneth William Batchelor; Stephen Vernon Frye, both of Durham, NC. Assignee: Glaxo Welleome Ine., Research Triangle Pars, N.C. Notice: This patent is subject to terminal dis- claimer. [21] Appl. No.: 09/078,468 22] Filed: May 14, 1998 Related US. Ap [60] Division of apiction No, (617,859, filed as application No, PCTYUSD4/10479, Sep. 16, 1994, Pal. No, 2817818, hich isa continuation-inrpat of application No, (8/123 23aU, Sep. 17,1903, abandoned, anda Gominsaionia-partof {pplication No, 0813515, Dee. 10, 1993, abandoned [51] Int. cL? AGIK 31/58; CO7D 221/18 [52] US. Ch 514/284; 54077 [58] Field of Seareh 514,284; 54677 [56] References Cited US. PATENT DOCUMENTS 4.377;584 3/1985 Rasmosson etal sparse 4760071 7/1985. Rasmusson eta. S1284 S.O17-S68 5/1991 Holt eta SL4173 5.084'574 1/1992 Bhattacharya e 546077 5.00808 3/1992. Steinberg eta. 540966 5,215,804 5/1993 Arison ct al 235353 51565;457 10/1996. Batchelor et S124 S[603810 121997 Resmasson eta 54677 5.846.976. 1211998. Batchelor eta S424 FOREIGN PATENT DOCUMENTS 04949 A1 4/1979 European Pat. Of. 271219 AL 11/1987 European Pat. Of 2712201 11/1987 European Pat. Of. 277002. A2 1/1988 Bropean Pat. Of. 285383 A2 3/1988 Furopean Pat Of 4144902811990 uropean Pat. Of. 414491 A) $1199 Buropean Pat Of 428306 2. 11/1990 European Pat. Of. ‘402682. A2 6/1991 European Pat. Of 462664 A2 61901 Furopean Pat. Of "484094 A2_ 10/1991 European Pat. Of 538192 AL 811992 Furopean Pal. Of 547687 A2 6/1993 European Pat Of. 5170789 12/1991 Japan woo26213 311992 WIPO woo216233 31902 WIPO woo2I8i32 41992 WIPO WO93/23088 11/1993 WIPO woos23089 11/1993 WIPO woos/23080 11/1993 WIPO woos/23041 11/1993 WIPO woos/23042 11/1993 WIPO woo3/25018 11/1993 WIPO ‘woo3/23050 11/1993 WIPO woos/2a0st 11/1903 WIPO woo3/250s3 11/1993 WIPO woos/23419 11/1993 WIPO [1] Patent Number: 5,998,427 (35) Date of Patent: Dec. 7, 1999 wons/23420 11/193 WiRO Wootorsst 4004 WIRO OTHER PUBLICATIONS McGinley, et al. 1979, pp. 1233. Robuaice, et al.,J. Steroid Biochem., 8, 1977, pp. 307-310. Petrow, ot al, Sterpids, 38, 1981, p. 121 Liang, et sl J. Steroid Biochem, 19, 1983, pp. 385-390 Holt, etal, J. Med, Chem., 33, 1990, 937-982 “Steeoidal A Ring Aryl Cusboxylic Acids: A New Class of Steroid 5-Reductase Inhibitors” Stoner, et al J. Steroid Biochem, Molec, Biol, vol. 37, 1990, pp. 373-378 Russell, D.W., et al, J. Clin, Invest, 89, 1992, p. 293, Russell, DLW, et al, Nature, 354, 1991, p. 139, Russell, D.W, etal New England J. of Med., 327, 1992, p. 1216. Russell, D.W,, et al, J. Clin, Invest, 90, 1992, p. 799, Brooks, et al, Steroids, 47, 1986, p. 1, “Sa-Reductase Inhibitory and Anti-Androgenic Activities of Some 4—Aza- steroids in the Rat” Rasmusson, etal, Med. Chem.,29, 1986, pp. 2208-2315, Steroids: Siructure~Activity Relationships for Inhibition of| Sa-Reductase and Androgen Receptor Binding” New England Journal of Medicine, 300, 237 (List continued on next page.) Primary Exaniner—Iobn Kight Assistant Examiner-—Charanjit S. Avlakh ‘Attorney, Agent, or Firm-—Robert H. Brink [57 ABSTRACT The present invention relates to compounds of formula (I), wherein carbons 1 and 2 are joined by either a single or 2 double bond R? is hydrogen or methyl; R° is hydrogen or methyl; R® is (B) wherein X, R°, R” and R® are various ‘eroups, and. pharmaceutically’ acceplable solvates thereof tod their use in the teatment of androgen responsive and mediated diseases. 19 Claims, No Drawings5,998,427 Page 2 OTHER PUBLICATIONS Rasmusson, et aly J. of Med. Chem, 27, 1984, pp. 1690-1701, “Azasieroids « Inhibitor. of Rat Prostatic Sa-Recictse” Imperator, ct al, 1G, 1986, 130-133, “Inerited 5/-Reduc- tase Deficiency in Man" Jones, etal, British J. of Urology, 66, 1990, pp. 506-508, “Origin and Structure of Benign Prostatic Hyperplasia”. Blaktnyi etal, J. of Organic: Chem, wo. 10,0. 3, 1974, pp. 512-316, “Synthesis of the Analogs of 3-p-Menthanol Wil & Fluorinated Methyl Group.” Reet etal Angew: Chem. In Fd. Engl, vol. 19, No. 11, 1980, pp. 960-001, “Geminal Dialkyation of Ketones with Grignard Compounds and Methyhitaaium (IV) Chlorides. Davies, HLW,, et al, Terrahedron Letters, vol. 30, No. 38, 1989, pp. 5057-5060, “Stereoselective Cyclopropanations with Vinylearbenoids.” Baum, et al, Synuhetic Communications, vol. 17, No. 14, 1987, pp. 1709-1716, “Diazotransfer Reactions with p-Ac~ cetamidobenzenesulfonyl Azide. He, et al, J. Med. Chem., 36, 1993, pp. 1188-1193, Sya- thesis and Biological Evaluation of 1-{1-(2-Benzof}]thie~ nyl)eyelobexyl}piperidine Homologues at Dopamine-Uptake and Pheneyclidine- and o-Binding Sites.5,998,427 1 ANDROSTENONES ‘This application is « divisional of application Ses. No. (08/617,859 filed Mar. 14, 1996 and now US. Pat. No. 5817,818, which is a 35 US.C. § 371 of PCT US94/10479 filed Sep. 16, 1994, which isa continuation in part of US. ‘Ser, No. G8/123,280, fled Sep. 17, 1993 now abandoned and US. Ser. No. 08/136,515, filed Bec. 10, 1993, now aban- ddoned, “The present invention relates to certain substituted 17B- anilide-4-aza-Secandrostan-3-ones, in particular as surpris- ingly potent and selective dual inhibitors of type 1 and 2 human S-reduetase BACKGROUND OF THE INVENTION Andeogeas are responsible for many physiological fune= tions in both males and females, Androgen action is medi= ated by specific intracellular hormone receptors expressed in landrogen responsive cells Testosterone, the major circulat- ing androgen, is secreted by Leydig cells ofthe testes under the stimulation of pititary-derived luteinizing hormone (LH). However, reduction of the 4, 5 double bond of testosterone 10 dihydrotestosterone (DHT) is requited in some target tissues, such as prostate andl skin, for androgen action. Steroid Sc-teductases in arget tissues catalyze con- version of testosterone to DHT in an NADPH dependent 25 Tashion as shown in Scheme A, “HEME A ‘Tetnteone A ‘The requirement for DHT to act a8 an agonist in these target tissues has been highlighted by studies of steroid Sacreductase deficient individuals who have vestigial peos- fate glands and do not suifer fiom acne vulgaris or male paltern baldpess (see McGinley, Jet al., The New England J. of Medicine, 300, 1233 (1979)). Thus, of the ‘conversion of testosterone to DHT in these target tissues is Anticipated to he useful in the treatment of a variety of androgen responsive diseases, eg, benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness and hirsutism. Additionally, it has recently been discovered that two isozymes of Scereductase exist in humans which differ in 2 tir tssie distribution, affinity for testosterone, pH profile and sensitivity to inbibitors (see Russell, D. Wea. J. Clin. Invest, 89, 293 (1992), Russel, D. W. etal, Nature, 354, 159 (1991)). The steroid Saereductse deficient individuals studied by Imperato-MeGinley are deficient in the type 2, Secreductase enzyme (Russell, D. W. et al, J. Clin. hnest, ‘90, 79 (1992); Russell, D. W. etal, New England J. Med. 327, 1216 (1992), which is the’ predominaat isozyme prescat in the prostate, while the type 1 isozyme is predomi nant in the skin. The relative value of isozyme specific and dual inhibitors of the two isozymes of Sc-reductase will depend upoa the type of disease tated! (benign prostatic hyperplasia, prostate cancer acne, male pattern baldness oF hirsutism) as well as the slage of the disease (prevention versus teatmen!) and the anticipated side-ifects i the intended patents (Tor example treatment of aene vulgaris in pubescent males). Because of their valuable therapeutic potential, testester- fone Sc-reductase inhibitors [hereinafier “Seceeductase inhibitors") have been the subject of active research world ‘wide. For example, see: Hsia, S. and Voight, W,, J. Invest Derm, 62, 224 (1973); Robaire, B. et al, J. Steroid Biochem, 8, 307 (197); Petrow, V. et al, Steroids, 38, 121 (1981; Liang, Tet al, J. Steroid Biochem, 19, 385 (1983); Holt, D-etal,J. Med. Chem, 33,937 (1990); U.S. Pat. Nos. 4.377.584, 4,760,071 and 5,017,568. Two particularly prom- ining Sa-reductase inhibitors are MK-906 (Merck), known by the generic name, finasteride, and marketed under the trademark, Proscar; and SKF-105657 (SmithKline Beecham), shown in Scheme B. a A « — ona wx s ‘The potent inhibition of bovine adrenal and porcine granulosa cell 3f-hydroxy-A°-steroid debydrogenase/3- eo Keto-A*-steroid isomerase (3BHSD) by the 4-zasteroid derivative, 4-MA, shown ia Scheme C and aot by the drug finasteride5,998,427 3 Ma (Fao, C. Hs Fong, C. Ys Chan, W. K. Biociem. Biophys. Res. Comm. 144, 166 (1987) and Brandl, Ms Levy, M.A. Biochemistry, 8, 140 (1989)) along with ie exitical role of SBHSD in steroid biosynthesis Pots, G.O. etal, Steroids, 32, 257 (1978), sugaess that optimal inhibitors of type 1 land 2 Scoreductase should also be selective versus human adrenal 3BHSD. The importance of selectivity in Secedvctase inhibitors hss bec emphasized by reports of hepatotoxicity in certain. 4-azasteroids such as +MA (MeConnell, 1. D. The Prostate Suppl, 3, 49 (1990) and Rasmusson, G. Het al J Med. Chem, 27, 1690 (1984)) ‘SUMMARY OF THE INVENTION One aspect of the present invention provides compounds of formula (D, © wherein ‘carbons | and 2 are joined by either a single or a double bond, R’ is hydrogen or methyl, R° is hydrogen or methyl, Ris (A) o y) 2 phe oes \ wherein, R° and R® are independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, eyano, halogen, phenyl (optionally substituted with one oF more halogens), oF 0 6 s 6 4 ‘when Rand R® are on adjacent carbons, taken together form a fused 5, 6 or 7 member ting optionally coxtain- ing one or more oxygen or sulfur atoms; W and Z are methylene groups which taken together with the carbon to which they ate attached form a saturated, 3 10 12 member ring system optionally: 1) substituted independently with one or more lower alkyl groups, 2) containing an oxygen or sulfur atom, 3) two said methylene groups of suid 3 to 12 member ing are joined with a (C,.<) alkylene group to form a bieyelie ring system, and X is hydrogen or halogen; or (B) % at wherein, R® is trifluoromethyl, phenyl optionally substituted with ‘one or more halogens or branched (C..) alkyl groups, or branched (C,.,) alkyls either of R? or R® is trifluoromethyl, halogen, phenyl ‘optionally substinted with one or more halogens of branched (C,.,)alky! groups, or branched (C,,,) alkyl, while the other is hydrogen or halogen; and X is hydrogen or halogen, and pharmaceutically acceptable solvates thercof. Other aspects of the invention are 1. A method of inhibiting. testosterone-Sa-reductases ‘comprising contacting testosterone-Secreductases with «compound of formula (I), ‘A method of treatment of androgen responsive or mediated disease comprising administering an effective amount of a compound of formula (I) 10 patient in need of suet treatment 3, Pharmaceutical formulations containing a compound of formula (1) as an active ingredient, 4. A method of treatment of androgen responsive or mediated disease comprising administering an effective lamouat of a compound of formula (I) to a patient in need of such tceatment ia combination with an antian- drogen such as fluamide ‘method of treatment of benign prostatic hyperplasia ‘comprising administering an effective amount of a ‘compound of Formula (1) to a patient in need of such leeaiment in combination with aa alpha 1 adrenergic receptor blocker (e.g. terazosin). 6, A metbod of treatment of benign prostatic hyperplasia ‘comprising administering an effective amount of a ‘compound of formula (1) to a patient in need of such treatment in combination with an anti-esirogen. 7. Certain chemical intermediates used in the preparation ‘of compounds of formula5,998,427 5 DETAILED DESCRIPTION OF THE INVENTION Compounds ‘Those skied in the at of organic chemistry will appre= ate that many organie compounds can form complexes with solvents in which they ate reacted or from which they ate precipitated or erystallized. These complexes are known, as “solvates”. For example, a complex with waters known, as a “hydrate”, Solvatesof the compound of formula (I) are within the scope of the invention It will also be appreciated by those skilled in organic chemistry that many’ organic compounds can exist in more thao one erysalline form. For example, crystalline form may vary from solvate to solvate. Thus, all erysialline forms of the’ compounds of formula (I) oe the pharmaccutically acceptable solvates thereof are within the scope of the present invention, ‘As used herein the term “lower” in relation to alkyl and. alkoxy means 1 t0 6 carbons, especially 1 10 4, straight or branched. As used herein the term “branched (C,.) alkyl” means 3-6 carbons altached via a quaternary catbon, ¢ t-butyl, amyl, ete. The term “halogen” means thuoro, coro, bromo, acl iodo moieties. Examples ofthe ring systems formed by W and Z. include, bot are not limited to: cyclopropyl, eyclobuty cyclopentyl, cyclohexyl, eycloheptyl, eycloociyl, eyclodo-decyl, eles norbornyi, bicyelo[3.3.1Jnonyl, tetrahydrofuryl, tettahydropyranyl, oF teleahydrothiopyranyl. Ring systems of 3 to 8 members are preferred. Examples of bicyclic ring systems formed when one of the W methylene groups is joined 10 one of the Z methylene sroups by a (Ci) alkvlene group inelude, but are not OO LY > 2 As DD. Examples of fused 5, 6 or 7 member rings formed by R* and R® include but are’ not Limited to: 4 ~ "D> 6 -coatinued twill be appreciated by those skilled inthe art of organic chemistry that the “quaternary carbon” of substituent (A), ice, the carhon upon which —NH—, the phenyl group, W: ‘and Z are attached, may be asymmetric. This asymmetry sbout the quaternary catbon wives rise to a pair of stereos Somers (sce March, J., Advanced Organic Chemistry, 3” Ed., Chap. 4, "Stereoctemisiry”, John Wiley an Sons, New ‘York (1985)). Further, when W and Z. are substituted with alkyl groups or are joined with an alkylene group, other asymmetric carbons may be established also resulting in ‘lhe puis of stereoisomers. All stereoisomers of the novel ‘compounds laught herein are within the scope of the present invention. ‘As used herein the rippled lines representing single bonds ‘connecting the quaternary carbon to W and to Z indicate that 25 nose two bonds can be of either an «of relationship with respect to the quaternary carbon, ‘The term “ce” means the ‘hon andl corresponding substituent extends helow the plane of the page while the term ,“B" means the bond and corresponding substituent extends above the plane of the page and is depicted herein by a solid wedge shape bond. ‘The use of these terms is consistent with standard chemical terminology ‘In a particular group of the compounds of formula (I), X is hydrogen, In another particular group of the compounds of formula (2), R® is bydiogen, In yet another group of the compounds of formula (D, R® is tiluoromethyl, phenyl optionally substituted. with one or more. halogens, or branched (C,.,) alkyl, and cither of R” or R® is trifluoromethyl, halogen, phenyl optionally substituted with fone or more halogens, or branehed (C,..) alkyl, while the other is hydrogen or halogen. In another particular group of the compounds of formula (1), carbons 1 and 2 are joined by 4 doubie bond! ‘A particular group ofthe compounds of formula (I) are the ‘compounds of formula (IA) w a) 2 Ao wherein carbons 1 and 2 are joined by either a single or a double ‘ond; Ris hydrogen or methyl Rand R® are independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, eyano, halogen, phenyl5,998,427 7 optionally substituted with one or more halogens), or when Rand R® are on adjacent carbons, taken together form a fused 5,6 or 7 member ring optionally contain- ing one or more oxygen or sulfur atoms; ‘W and Z are methylene groups which taken together with the carbon to which they are attached form a saturated, 3 to 12 member ring system optionally 1) substituted with one or more lower alkyl groups, 2) containing an oxygen or sulfur atom, and 3) two said methylene groups of said 3 10 12 member sing ae joined wit a (C,.9) alkylene group to form 4 bieyelie ring system; and X is hydrogen or halogen. Ina paniculac group of the compounds of formula LA); R" apd R° are independently hydrogen, lower alk, lower alkoxy, trilluoromethyl, eyano, balogen, or phenyl (optionally substituted with one Or more halogens); and Xis hydrogen; ‘Compounds of formula (IA) wherein at least one of X, R* and R? is other than hydrogen are preferred, Substituents in the para (4) position of the phenyl ring are expecially preferred, Tn particular group of the compounds of formula (1A) at least one of RY and R? is lower alkyl, lower alkoxy, trifluoromethyl, halogen or phenyl, especially. branched alkyl, e-, rbutyl, tfluoromethyl, or halogen. Tn four other particular groups of the compounds of formula (1A) 1) W and Z are methylene groups which taken together with the carbon to which they are attiched form a saturated, 3 10 12 member ring system containing only carbon atoms and which may be substituted indepen dently with one or more lower alkyl groups; or 2) W and Z are methylene groups which taken together with the carbon to which they are attached form a saturated, 3 to 12 member ring system containing an Oxygen oF sulfur atom and which may be substituted independently with one or more lower alkyl groups; or 3) W and Z are methylene groups which taken together with the carbon to which they are attached form a saturated, 3 to 12 member ring system containing only carbon atoms and which may be substituted indepen- dently with one or more lower alkyl groups and two said methylene groups are joined with a(C,,) alkylene group to form ab 1g system; oF| 4) W and Z. are methylene groups whieh taken together with the carbon to which they are atticbed form a saturated, 310 12 member ring system containing an ‘oxygen or sulfur atom and which may be substituted independently with one or more lower alkyl groups and 0 6 8 two said methylene groups are joined with a (C,.) alkylene group to form a bieyelie ring system. Another particular group of the compounds of formula (1) are the compounds of formula (IB); we wherein ceabons 1 and 2 are joined by either a single or a double ‘bond: Ris hydrogen or methyl; R° is trifluoromethyl, phenyl optionally substituted with ‘one or more halogens, or branched (C:,..) alkyl, either of R” or Ris trifluoromethyl, halogen, phenyl optionally. substituted with one or more. halogens, or branched (C,.,) alkyl, while the other is hydrogen or halo gen; X is hydrogen or halogen. {In a paticular sroup of the compounds of formula (1B) ‘when R” or Ris branched (C,.,) alkyl and X is hydrogen, R° is trifluoromethyl or phenyl optionally substituted with ‘one or more halogens In another particular group of the compounds of formula (By R° is trifluoromethyl or branched (C;..) alkyl cither of R” of R® is trifluoromethyl, halogen, or phenyl substituted with one or more halogens, while the other is hydrogen or halogen. In another particular group of the compounds of formula, (By; R° is trifluoromethyl or branched (C,.,) alkyl either of R” oF R® is trifluoromethyl while the other is, hydrogens X is hydrogen {In another particular group of the compounds of fo (1B) R® and R® ace independently trifluoromethyl ort while R” and X are hydrogen, Specific compounels of formula (1) ar: T7BN-1a-Choropbenybeylopenyleamey-tazn Sarandon Fone EN. G-cherpaeyhoeopentenaney met aS TUN I-G.Chloepteny)yclopenycuhamoylareSe-andet ee rp 1444 yphenpysopentfcarbamoyt-t-anSe-aneor n-ne 178-144 DatyphenDoyloexylntamos-tazn Sanden -er Fone 1 N14}Chlorpbenyfeohenlcatemoyl-bazsSa-andost-l-an Sone 1-¢-iuoromehypenyeelopenslcbemoyl-+zeSeeanes5,998,427 9 10 continued ‘Compounr sample Compound Sumer _ Nene BPN Methonphenybeyeepenientamnyaa Sa antares 5, bX etharophenlicplopentyetbmoy- tar Secaadoat Len Sone 10, 11BN-14FhmoephenDeylohesylaxbanoy- ten Sandon enone 1. Lyp¥-(e-Metnyphenydejcohey erry ta-Seandron- enone 12 MBG, Mabyeeedompenyhqeohnlevbamayl sty Sasa 13. 1BN-1-(44-BuylphenyDeyelobeptylebamoyl-taze-Sa-androstl-e0-300e 1a LipN-ecsipeny eiahyaopyanyetomayt zn So-ndrn ene 1 TPN-1-@.4Diehlophensoycloprepylerbunay-taza-Seandest ens 16 Tp-N-1-4-tritaoromeypbeny)-2.2 dehy eylopopyenbanoy ‘Hien Seranlos- en -one 1 FEN Rus iene 16 TENS Gaepsea 4 eaneydohaykaunoyt-tae Sando 19, TBN"/-@-Tituoromethiphenybeylopentyaibamoyl- dm Sande cto 2a, HpNE(4ensiphensteianttiopmeyloriamnyltene San 21, TpnCiseiptenh-22-deseytapoploutumoyltazn Sa oen-g suchtacrometyptryntenoy-tara Saantounn 08 TpN-@-statieronehs pteeyeaatylny ane Se 24 TENE ay Saitommabyptesenanoy-+ac Sad no a Bisco titoormay ipesletamas-tazs-sasndes- 5 25 TIBN-Ce-Buyl-iteorometbyipheaskatumayl-tmethy-tarsSa 27, TBN-ASresetspbeascatanoyl daze Sandon en Sone 28 7BN-ASDetbetgpheaycartnnoyl-4azs Seandonten bone 22 LIBN-'s-Detetghphenycntnnay-tnethy acy Seeanlota-Sope io MPNCG's.ha(tetaocmethy pengcainmoy an N-methyl Sear Ker sone 31 T7PN-2e-Buy--iteorometbyiphenkatemay-tazs Tmt Sa TPN I-choropeasieyslpenycnanoy-+-ze Teeth Se-andost lee booe 38 1B BuylpbenyDhicyl 3. onsartamoy- tae Sean A particular specific compound of formula (1) is: and 2 are joined by a single bond may be prepared by the 17P-N-1-(4-Chloropbenyleyclopentylearbamoyl-4-aza- 45 procedure shown in Scheme I. Sa-androst-l-en-s-one Specific intermediate compounds of formulas (II), (IV) and (IVa) are: yDeyelopeatylearbamoyl- androst-4-en-3-one; so 17f-N-1-(4-chlorophenyeyelopentyleartamoyl ‘Acnor3 S-sccoandrostan-Soie acid and 17f-N-1-(4-chlorophenyl)eyelopentylearbamoyl-4-aza- androst-5-en-3-one, Preparation of Compounds a ‘The compounds of the present invention may be prepared x by the methods taught in U.S. Pat, No. 4,377,584 (hereinafter, “'584") and U.S. Pat. No. 4,760,071 (hereinafter, '071") both incorporated herein by reference. For example, compounds of formula (1) wherein earboos 1 ws5,998,427 iw -coatinued 0 o In Scheme I, the 4-12a-androst-5-¢n-3-0ne compound of formula (IVa) is converted to the corresponding 4-aza-5a- androstan-3-one of formula (I) by hydrogenation. For ‘example the hydrogenation may be carried out in acetic acid at 60 to 70° C. and 40-60 psi hydrogen pressure in the presence of eatalytic platinum oxide. ‘Compounds of formula (IVa) may be prepared by the procedure of Scheme LA: 12 ‘The compounds of formula (la) wherein R* is (A) i, cyclouikylbeczylarines are prepared By Cuts rearrage” ment ofthe comresponding seid, whee available, or by the thd of i Rta Med Chem 3611881993}, reeling the corresponding eycloalKanoge With the appro= plate aryl Grignard Feaget followed by conversion ofthe eillingalcolol to te amine by teatocat with sodiusa de and iifvoroscetie acid followed by reduction of the fide with tim alumioum hydride. Substituted eyclopeo= Pylbeazylamioee of formula (Ha) are prepared by fodiusa Edlalyzcd ‘incertion of the appropiac.try-a-claza-eater (repared by the method of Baum, 1.8. cl aly Sytic Comm, 17, 1709 (1987) into the appropriate’ olin (as described by Davies, H, W.ct ily Terahedron Lett, 30, S057 (1989}) followeal by saponiication ofthe este and Garis rearrangement ofthe acd to give the desired amine, The compounds of formula (Hla) wherein Re is (B), Le Stbuted soins, ar commercially wallable or coave niently prepared by methods Known inthe at (ee Blakithyi etal, J. Org. Chem. USSR (Eosish tansltion)10, 312 (1974) apsieacted in CA 80 23). [4623F an Reet, MT. et M1, Angew Chem. Ina. Engl, 19, 900 and 901 (1580). in Stop 2, the compound of formula (Il) converted 10 the 5-ox0-Artor.3,>-secoandrosian oie acid derivative of w aw wave In Step 1 of Scheme IA, 3-oxo-4-androstene-17f- carboxylic acid (II) is converied to the corresponding amide ff formula (Il). This may be accomplished by activation of ss the acid and reaction with a compound of formula (Ila). For feximple, the reaction sequence cin be conversion of ‘compound of formula (If) to the corresponding acid halide bby treatment with a halogenating agen such 2s oxalyl chloride of thionyl chloride in an aprotic solvent sch as toluene, methylene chloride or tetabydrofuran at ~3 0 10" C. in the presence of a base such as pyridine, The interme diate acid halide, e., an acid chloride, may be reacted with aan amine of formula (Ila) (wherein the substituents are as defined for formula (1), optionally in the presence of a catalyst such as 4-N.N-limelhylaminopyridine, at 25 10 70° Cin an aprotic solvent such as tetrahydrofuran to give the amide of formula (U1), w formula (IV) by oxidation, e-g. by treatment with aqueous sodium permanganate and sodium periodate under basic ‘conditions at rellux in butanol In Step 3, the compound of formula (IV) is converted to the corresponding compound of formula (IVa) by treatment ‘with a compound of the formula NHR, e.g., ammonia (R11) or methylamine (R"=methyl), at elevated tempera- tures in a protic or aprotic solvent, eat reflux in ethylene slycol Compounds of formula (I) may also be prepared by interconversion from other compounds of formula (I). For ‘example, the progese of Scheme IB may be used to prepare 4 compound of formula (I) where there is a double bond between carbons 1 and 2, and where R’ is hydrogen, ie. the5,998,427 13 ‘compound of formula (Ib) from the corresponding com- pound of formula (0, ie., the compound of formula (I). m 1B wo » In Scheme IB, a compound of formula (Ia) is dehydro- genated to give the corresponding 4-aza-Se-androst-L-en-3- One of formula (Ib) by treatment with a dehydrogenating system, eg. 2,3dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and’ bis(ri-methylsiy!eifluoroacetamide in dry dioxane at zoom temperature for 2-5 bes followed by heating at rellux for 10-20 hrs (see Bhattacharya, A. et al, J. Am. Chem. Soc., 110, 3318 (1988), te? wo a wun 0 14 step BN a o Alternatively, in Scheme II compounds of formula (1, ‘wherein carbon 1 and 2 are joined by a double bond, may be prepared from 3-oxo-4-aza-Sc-androst-1-ene-17B- carboxylic acids of formula (V) by reaction with & come pound of formula (ls) as described in Scheme 1A, stop 1. ‘Compounds of formula (V) whereia Ris hydrogen may be prepared by the method of Rasmussoo, G. H. et al, J- Med. CChem., 29, 2298 (1980). The compounds of formula (V) ‘wherein Ris methyl may be prepared according to Scheme Mh, Ole Ole sep Ale 03, a ©5,998,427 15 continued ‘Opal ste Hoe o rc, o © oat Y , I, (vp wherein RE CH In Step 1, a compound of formula (VI), wherein JO is a protected hydroxy group, eg. tiisopropylsilyloxy group, and CO,Alk isa earboxylie atid ester group, eg, methyl ester, is reacted with a strong, heavy metal ‘oxidizing complex, eg, chromic acid/3,5-dimelbyl pyrazole in an protic salvent, eg, dichloromethane, to yield the corre- sponding compounc! of formula (VID). Compounds of for- ‘mula (VI may be prepared from a 3f.-bydroxyetienic acid fester UJ. Med, Chen. 27, 1690) by the method taught in PCT patent application WO 94/1483. For example, ‘Bhydroxyeticnic acid methyl ester may be reacted with & hhydroxy group protecting reagent such 3s uiisopropylsily1- chloride in the presence of a base, eg., imidazole ia an aprotic solvent, ¢g., dimethyl formamide or dichloromethane, at moderate temperatures ranging from 25 to 55°C, In Step 2, the 7-ox0 moiety of the compound of formula (VID) is converted 10 « corresponding alkyl group, ¢., ‘methyl group, by tweatmeat with a Wittig reagent followed by catalytic’ hydrogenation and deprotection of the S-hydroxy group to yield the corresponding compound of | ormula (Vil1) For example, the compound of formula (VID) ‘may be reacted with methyl tiphenylphosphonium iodide and a-butyl lithium in an aprotic solvent, such as tetraby- ‘rofuran in the temperature range of about 5° t0 10° C., 8. a1 0 C. to yield the corresponding 7-alkylidene deriva tive. The exocyelic double bond may then be reduced selectively by treatment with tris(iriphenylphosphine) shodium chloride under a hydrogen atmosphere 10 yield predominately the 7ealkyl substituted compound. The pro= {ecting group on the 3-hydroxy is then removed to yield the compound of formula VILL. For example, if the protecting group is triisopropylsily, it may be removed by treatment ‘with tetrabutyl-ammonium fluoride in tetrahydrofuran In Step 3, the 3-hydroxy group of the compound of formula (Vill) is oxidized 16 yield the corresponding 3-0x0 moiety with migration of the double bond to yield the ‘compound of formula (IX). For example, the oxidation may be accomplished with Jones’ reagent nan alkyl Ketone, such as acetone, at about oom temperature In Step 4, the compound of formula (IX) is oxidized in an analogous manner to that described in Step 2 of Scheme 1A. 6 s 16 Al 1o yield the corresponding 5-on0-A-nor-3.5-secoandrestan- 3oie acid derivative of formula (X). In Step 5, the compound! of formuis (X) is converted to the ‘corresponding compound of formula (XI) in aa analogous manner to that described in Scheme I Tn Step 6, the compound of formula (XI) is debydroge- nated in an analogous manner to that deseribed in Scheme IB. to yield the comresponding 4-aza-Sa-androst-1-en-3-one derivative. The 17-carhoxylic acid ester group is then con ‘verted by saponification to the corresponding 17-carboxylic acid group yielding the compound of formula (V). For ‘example, the carboxylic acid ester group may be converted to the carboxylic group by treatment with a moderate 10 strong base in aprotic or aprotie solvent, e.g treatment with ‘4 metal hydroxide, such as litbium hydroxide, in dioxane! ‘water a about room temperature, “Those skilled in the art will appreciate that at an earlier stage in the preparation of compound of formula (I) or & solvate thereof it may have been necessary and/or desirable lo protect one or more sensitive groups in the molecule 10 prevent undesirable side reactions. “The protecting groups used in the preparation of com- pounds of formula (I) may be used in a conventional manner. ‘See for example Protective Groups in Organic Chemistry, Ed. J. F. W. McOmie, Plenum Press, London (1973) or Protective Groups in Orgsnic Synthesis, Theodora Green, John Wiley and Sons, New York (1981). Removal of any protecting groups present may be eved by conventional procedures. An arylalkyl group such as benzyl, may be cleaved by hydrogenolysis in the presence of a catalyst, eg, palladium on charcoal; an acyl ‘group such as N-benzyloxyearbonyl may be removed by hycrolysis with, for example, hydrogen bromide in acetic acid of by reduction, for example by catalytic hydrogena- tioa, ‘AS will be appreciated, ia any of the general processes described above it may be desirable or even necessary 10 protect any sensitive groups in the molecule as just described, Thus, a reaction step involving deprotection of protected derivative of general formula (I) of a salt thereof may be carried out subsequent to any of the above described processes,