AU666177B2 - Process of preparing 3-carbonylandrostadiene 17-carboxamides - Google Patents

Description

OPI DATE 03/09/93 AOJP DATE 11/11/93 APPLN. ID 36126/93 PCT NUMBER PCT/US93/01068 11111 111111111111111111 li AU9336126 i (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 93/16097 C07J 75/00, 3/00, 43/00 Al (43) International Publication Date: 19 August 1993 (19.08.93) (21) International Application Number: PCT/US93/01068 (72) Inventors; and Inventors/Applicants (for US onl) BAINE, Neil, Howard (22) International Filing Date: 5 February 1993 (05.02.93) [US/US]; 216 Edgehill Road, Merion, PA 19066 (US).

OWINGS, Franklin, Fell [US/US]; 5030 Copley Road, Philadelphia, PA 19144 (US).

Priority data: 07/832,280 7 February 1992 (07.02.92) US (74) Agents: DUSTMAN, Wayne, J. et al.; SmithKline Beecham Corporation, Corporate Patents U.S. UW2220, 709 Swedeland Road, P.O. Box 1538, King of Prussia, Parent Application or Grant PA 19406-0939 (US).

(63) Related by Continuation US 07/832,280 (CIP) Filed on 7 February 1992 (07.02.92) (81) Designated States: AT, AU, BB, BG, BR, CA, CH, CZ, DE, DK, ES, Fl, GB, HU, JP, KP, KR, LK, LU, MG, MN, MW, NL, NO, NZ, PL, RO, RU, SD, SE, SK, UA, (71) Applicant (for all designated States except US): SMITH- US, European patent (AT, BE, CH, DE, DK, ES, FR, KLINE BEECHAM CORPORATION [US/US]; One GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent Franklin Plaza, P.O. Box 7929, Philadelphia, PA 19101 (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, SN, TD,

TG).

Published With international search report.

666177 (54)Title: PROCESS OF PREPARING 3-CARBONYLANDROSTADIENE 17-CARBOXAMIDES (57) Abstract Invented is an improved process for the preparation of substituted steroidal dienes. Also invented are novel intermediates used in said process.

WO 93/16097 PCT/US93/01068 Process of Preparing 3-Carbonylandrostadiene 17-Carboxamides The present invention relates to an improved process for the conversion of substituted steroidal 3halogen 3,5 diene derivatives to subscituted steroidal 3,5-diene-3-carboxylic acid derivatives. Such compounds are described in U.S. Patent No. 5,017,568, issued on May 21, 1991 to Holt, et al. as being useful in inhibiting steroid Background of the Invention Processes for the preparation of substituted steroidal 3,5-diene-3-carboxylic acid derivatives from substituted steroidal 3-halogen 3,5 diene intermediates have previously been described. In particular the use of catalytic or alkyllithium mediated carboxylation of steroidal 3-bromo-3,5 diene intermediates to yield steroidal-3,5-diene-3-carboxylic acid derivatives (in yield when N-butyl lithium was used) is reported in U.S. Patent No. 5,017,568. The use of a basic medium, when applicable, to selectively deprotonate acidic hydrogen atoms of the brominated intermediate in the above reaction prior to the addition of a dehalogenating reagent has been shown to increase the yield of the resulting steroidal 3,5 diene-3-carboxylic acid derivative in U.S. Application No. 07/817,179 filed on January 6, 1992 (63% for the preparation of N-t-butylandrost-3,5-diene-178-carboxamide-3-carboxylic acid from N-t-butyl-androst-3,5-diene-3-bromo-178-carboxamide).

Disclosed therein as preferred bases utilized in preparing said basic medium are ethylmagnesium bromide and ethylmagnesium chloride.

In addition to a low overall yield, the principle shortcoming of these disclosures is that N-butyl lithium and ethylmagnesium bromide and ethylmagnesium chloride are expensive reagents adding significant cost to an industrial process. Further, N-butyl lithium is flammable and the carboxylation reaction is performed at 1 I I WO 93/16097 PCT/US93/01068 dilute concentrations. Thus, there is a need in the art for a safe, economical and reliable method to convert substituted steroidal 3-halogen 3,5 diene derivatives to substituted steroidal 3,5-diene-3-carboxylic acid derivatives.

Summary of the Invention This invention relates to an improved process for converting steroidal 3-halogen 3,5 diene derivatives to steroidal 3,5-diene-3-carboxylic acid derivatives.

This invention specifically relates to an improved process for the preparation of diene-178-carboxamide-3-carboxylic acid.

In a further a'-pect of the invention there are provided novel intermediates useful in the presently invented process.

Detailed Description of the Invention As used above and throughout the remainder of the specification and claims the carbons of the steroid nucleus are numbered and the rings are lettered as follows: /12 17 11 13 I I /16 J IA B I 3\ /-7 4 6 Pharmaceutically acceptable salts hydrates and solvates of Formula compounds are formed where appropriate by methods well known to those of skill in the art.

Unless otherwise specified the term "halogen" as used herein and in the claims means chlorine, bromine or iodine.

Preferably the term "halogen" as used herein means bromine or iodine.

2 WO 93/16097 PCT/US93/01068 The present invention provides a process for the production of a compound of Formula (I)

R

H

HO-C

(I)

in which

R

1 is

CONR

2

R

3 where R 2 and R 3 are each independently selected from hydrogen, C 1 8 alkyl,

C

3 -6cycloalkyl and phenyl; or R 2 and R 3 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or (ii) moieties which are chemically convertible to moieties of such as N, -COOH or -COOC 1 6 alkyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises cyanation of a compound of Formula (II)

R

X (II) in which R 1 is as defined above and X is halogen; in the presence of a cyanating reagent and an appropriate solvent, preferably dimethylformamide, to form a compound of Formula (III) 3 WO 93/16097 PCT/US93/01068 N- v- V (III) in which R 1 is as defined above and subsequently saponifying the compound of Formula (III) to form a compound of Formula and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

Preferably R 1 as used in the above process, is;

CONR

2

R

3 where R 2 and R 3 are each independently selected from hydrogen, Cl- 8 alkyl,

C

3 -6cycloalkyl and phenyl; or (ii) -CQN,-COOH or -COOCI-6alkyl.

Most, preferably R 1 as used in the above process, is B-CONR 2

R

3 where R 2 and R 3 are each independently selected from hydrogen, C1-8alkyl, C 3 -6cycloalkyl and phenyl.

Compounds of Formula I comprise R 1 or moieties which can be chemically converted to those of R 1 by known chemical reactions such as described in Derek Barton and U.D. Ollis, Comprehensive Organic Chemistry: The Synthesis and Reactions of Orgainc Compounds. Pub: Pergamon Press (1979) provided that R 1 does not include any such moieties that render inoperative the presently invented process. Reactions to convert said moieties to

R

1 are performed on products of the synthetic pathways disclosed or claimed herein or, where appropriate or preferable on certain intermediates in these synthetic pathways. For example, carboxylic acid substituents can be converted to the carboxamide by conversion to the acid halide followed by reacting the same with an amine.

Esters can be converted to the acid and treated as above. Nitriles can be converted to carboxamides by 4 WO 93/16097 PCT/US93/01068 reaction with an alkylating agent, such as tbutylacetate or t-butanol, under acidic catalysis.

In utilizing the presently invented process to prepare compounds of Formula novel intermediates of the following Formula (IV) are synthesized;

R

NfC

(IV)

in which:

R

1 is

CONR

2

R

3 where R 2 and R 3 are each independently selected from hydrogen, Cl- 8 alkyl, C 3 -6cycloalkyl and phenyl; or R 2 and R 3 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or (ii) moieties which are chemically convertible to moieties of such as -COOH or -COOCl-6alkyl; Preferably R 1 as used in the above compound of formula is;

CONR

2

R

3 where R 2 and R 3 are each independently selected from hydrogen, Cl-galkyl,

C

3 -6cycloalkyl and phenyl; or (ii) -CEN,-COOH or -COOCl-6alkyl.

Most preferably R 1 as used in the above compound of formula is; B-CONR 2

R

3 where R 2 and R 3 are each independently selected from hydrogen, C-g 8 alkyl,

C

3 -6cycloalkyl and phenyl.

The presently invented process discloses several advantages over the cited references. Specifically, reagents and conditions used to convert 3-halogen to steroidal-3,5-diene 3-carboxylic acids are safe, inexpensive, can be reacted in high concentrations and result in high yields of the desired 5 WO 93/16097 PCT/US93/01068 compound thereby rendering said processes appropriate for industrial scale utilization.

As used herein and in the claims, unless otherwise specified, Cl-nalkyl means a straight or branched hydrocarbon chain having C1-n carbons.

By the term "cyanating reagent" as used herein and in the claims is meant reagents which are capable of reacting, under certain conditions, with a halogenated moiety to form a cyanated moiety. Preferably said cyanated moiety is prepared by reacting the corresponding halogenated moiety with a cyanating reagent in an appropriate solvent, such as N,N-dimethyl- N,N-propylene urea (DMPU), N,N-dimethylformamide (DMF) or N-methyl-2-pyrrolidinone (NMP), preferably DMF, at increased temperatures.

By the term "saponifying" as used herein and in the claims is meant a compound or reagent or a series of reagents which are capable of reacting with a nitrile to form a carboxylic acid substituted moiety under appropriate conditions. Preferably said carboxylic acid substituted moiety is prepared by reacting the corresponding cyanated moiety with a hydroxide base, preferably aqueous sodium hydroxide, in an appropriate solvent, such as; ethylene glycol, isopropyl alcohol or ethanol, preferably ethanol, at increased temperatures with subsequent acidification.

By the term "increased temperatures" as used herein and in the claims is meant above 25 0 C, preferably at reflux temperatures.

Preferably cyanating reagents for use in the presently invented process utilize cyanide complexes such as described in Richard C. Larock, Comphrehensive Organic Transformations: A Guide to Functional Group Preparations. Pub: VCH Publishers, Inc. (1989) P. 861.

An example of a cyanide complex as used herein is the in situ co-mixture of KCN, NiBr 2 (PPh 3 2 Zn, PPh 3 Other 3examples include: Co examples include: Co(CN) 4

K

4 Ni 2

(CH)

6 KCN; KCN, cat 6 WO 93/16097 PCT/US93/01068 3- Pd(PPh 3 4 Co(CN) 5 CuCN and NaCu(CN) 2 As used herein the term "NaCu(CN) 2 refers to the reagent formed by comixing CuCN and NaCN in situ.

Preferred among the above cyanating complexes are CuCN and NaCu(CN) 2 Particularly preferred among the above cyanating complexes is NaCu(CN) 2 Preferably said NaCu(CN) 2 complex is prepared by adding 1 molar equivalent of sodium cyanide to cuprous cyanide in situ.

By the term "solvent" or "appropriate solvent" as used herein and in the claims is meant a solvent such as methylene chloride, ethylene chloride, chloroform, ethylene glycol, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, dimethylsulfoxide, N,N'-dimethyl-N,N'-propylene urea, Nmethyl-2-pyrrolidinone, methanol, isopropylalcohol, dimethylformamide, water, pyridine, quinoline or ethanol.

Preferably, therefore, the process of the present invention is particularly useful for preparing a compound of structure (IIIA) O

N

1IIIH

H

N v (IIIA) and converting the same into the following compound of structure (IA) 7 WO 93/16097 PCT/US93/01068 I 111H H HO-C

(IA)

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

EXAMPLES

Dimethylformamide, and cuprous cyanide are available from Aldrich Chemical Co. (Milwaukee, WI) androst-4-en-3-one-178-carboxylic acid is available from Berlichem, Inc. (Wayne, NJ).

Example 1 N-t-butyl-androst-3.5-diene-17R-carboxamide-.3carboxylic acid N-t-butyl-androst-3,5-diene-3-bromo-178carboxamide A flask under nitrogen atmosphere was charged with 100 mL of methylene chloride and 6.12 mL (2.5 molar equivalents) of dimethylformamide. The solution was cooled to 0-5 0 C, and was treated with 6.9 mL (2.5 molar equivalents) of oxalyl chloride while maintaining the temperature between 0-10 0 C. A white precipitate formed.

After stirring for one hour, 50.1 grams (19.6 molar equivalents) of hydrogen bromide gas were bubbled through the solution while maintaining the temperature between 0-10 0 C. The suspension became a clear colorless solution. The solution was degassed by reducing the solution volume by about one-half by vacuum distillation and restoring to its original volume with methylene 8 WO 93/16097 PCT/US93/01068 chloride. This concentration/refill procedure was repeated. Androst-4-en-3-one-17p-carboxylic acid, 10.0 grams (1 molar equivalent), was added to the resulting white suspension and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched into a vessel containing 100 mL of methylene chloride and 23.1 grams (10 molar equivalents) of tert-butylamine while maintaining the temperature between 0-10 0 C. The mixture was stirred for 30 minutes.

About 100 mL of water were added and the biphase mixture was filtered through a pad of Celite. The organic phase was separated and reduced to about half its volume by vacuum distillation. The solution was restored to its original volume with acetone. This concentration/fill procedure was repeated twice more. The resulting acetone solution (about 300 mL) was warmed to about 50 0 C and was treated with about 100 mL of water to precipitate the product. The suspension was cooled, and the product, Nt-butyl-androst-3,5-diene-3-bromo-17B-carboxamide, was isolated by filtration and dried. Yield 89%, mp 181- 183"C.

(ii) N-t-butyl-androst-3. 5-diene-3-cyano-178carboxamide A stirred mixture of N-t-butyl-androst-3,5-diene-3bromo-178-carboxamide (50 grams, 1 molar equivalent), cuprous cyanide (11.0 grams, 1.1 molar equivalents), and dimethylformamide (200 mL) was heated to reflux for hours. The reaction was cooled to 90-100 0 C and quenched with stirring into a solution of 100 mL of conc. aqueous ammonia and 200 mL of water. The reaction flask was rinsed out with 25 mL of dimethylformamide, which was also added to the quench solution. The resulting suspension was extracted twice with 200 mL portions of methylene chloride, and the organic extracts were filtered through a pad of celite. The organic phase was 9 WO 93/16097 PCT/US93/01068 washed with three 200 mL portions of 50/50 v/v conc.

aqueous ammonia/water, followed by two 200 mL portions of water. The organic phase was concentrated under vacuum to 150 mL and 250 mL of ethanol were added. The solution was again concentrated under vacuum to 150 mL, and 250 mL of ethanol were added. The solution was concentrated under vacuum to 300 mL, and 30 mL of water were added to induce crystallization. The resulting suspension was chilled for 2 hours at 0-5 0 C. The solid product was collected by filtration and was dried at under vacuum to afford 37.0 grams of N-t-butylandrost-3,5-diene-3-cyano-178-carboxamide as yellow crystals in 85% yield. mp 195-197 0

C.

(iii) N-t-butvl-androst-3.5-diene-178-carboxamide- 3-carboxylic acid.

A mixture of N-t-butyl-androst-3,5-diene-3-cyano- 17B-carboxamide (20.0 grams, 1 molar equivalent), aqueous sodium hydroxide (80 mL, 30 molar equivalents), and ethanol (200 mL) was heated to reflux for 18 hours.

The reaction suspension was cooled to 50°C and was added to a stirred mixture of 6N hydrochloric acid (300 mL) and methylene chloride (200 mL). The final pH of the aqueous phase was 1.5-2.0. The organic phase was separated and the aqueous phase was reextracted with 250 mL of methylene chloride. The combined organic phases were stirred with 2 grams of decolorizing charcoal for one hour and were filtered through a pad of celite. The organic phase was concentrated under vacuum to 120 mL and 200 mL of ethyl acetate were added. The suspension was again concentrated under vacuum to 120 mL and 200 mL of ethyl acetate were added. The resulting suspension was concentrated under vacuum to a final volume of 120 mL and was heated at reflux for 2 hours. The suspension was chilled at 0-5 0 C for two hours and filtered. The solid product was dried under vacuum at 65 0 C to afford 14.8 grams, 71% yield, of 10 WO 93/16097 PCT/US93/01068 17B-carboxamide-3-carboxylic acid. Recrystalization of the mother liquors afforded an additional 3.14 grams yield) of product. 86% total yield for reaction.

mp 250-251 0

C.

Example 2 N-t-butvyl-androst-3.5-diene-3-cyano-17f-carboxamide A 5 L 3-neck flask (Morton) equipped with a mechanical stirrer, thermometer, and reflux condenser was charged with 250 grams of diene-3-bromo-17B-carboxamide (prepared as in Example 1 55 grams of cuprous cyanide, 29 grams of sodium cyanide, and 1 ''ter of dimethylformamide. The reaction mixture was heated to reflux (152-153 0 C) for at least 12 hours. The reaction mixture was slowly cooled to 30 0 C with a cold water bath, and was quenched with one liter of 50% aqueous ammonium hydroxide (50/50 v/v conc.

ammonia/water) with rapid stirring. After stirring minutes, one liter of methylene chloride was charged, and the two phase system was allowed to separate. The phases were separated and the aqueous phase was reextracted with 2 x 500 mL of methylene chloride. The combined methylene chloride extracts were passed through a celite filter pad to remove insoluble copper salts.

The celite pad was washed with 150 mL of methylene chloride. The combined methylene chloride phases were washed with 3 x 500 mL ammonium hydroxide to remove last traces of copper salts. The organic phase was concentrated by atmospheric distillation, removing approximately 1.5 liters of methylene chloride. A 600 mL portion of ethanol was charged to the reactor and the concentration/displacement of methylene chloride was continued by distilling a second 500 mL portion of solvent. A second 600 mL portion of ethanol was charged to the reactor and the atmospheric distillation was continued until the vapor temperature reached 82-840C.

A 60 mL portion of water was charged to the reactor and the resulting suspension was chilled at 0-5 0 C for at 11 1V I r l 12- 0 0I least two hours. The solid was collec' washed with 75 mL aqueous alcohol and dried at 60- under vacuum to yield 191.3 grams of the title compound. 88% yield; mp=190- 192 0

C.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

While the preferred embodiments of the invention are illustrated by the above, it is understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the S 15 scope of the following claims is reserved.

e 951129,p:\ol rAdab,36126.spc,12 e r^* eW 5 19p\prdb3 16sc1

Claims (17)

1. A process for the preparation of a compound of Formula (I) H O HO-C (I) in which and R 1 is CONR 3 R 4 where R 3 and R 4 are each independently selected from hydrogen, Cl- 8 alkyl, C 3 6cycloalkyl, phenyl; or R 3 and R 4 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or (ii) moieties which are chemically convertible to moieties of or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises cyanation of a compound of Formula (II) R X (II) in which R 1 is as defined above and X is halogen, in the presence of a cyanating reagent and an appropriate solvent to form a compound of Formula (III) 13 WO 93/16097 PCT/US93/01068 R N=-C in which R 1 is as defined above and subsequently saponifying the compound of Formula (III) to form a compound of Formula and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate.

2. A process according to claim 1 in which the cyanating reagent comprises a cyanide complex of the formula CuCN and NaCu(CN) 2

3. A process according to claim 2 in which the cyanating reagent consists of a cyanide complex of the formula NaCu(CN) 2

4. A process according to claim 3 in which the cyanide complex of the formula NaCu(CN) 2 is prepared by adding 1 molar equivalent of sodium cyanide to cuprous cyanide il .itul.

A process according to claim 2 in which the cyanide complex is cuprous cyanide.

6. A process according to claim 1 in which X is bromine.

7. A process according to claim 1 in which said solvent is dimethylformamide.

8. The process according to claim 1 in which the saponification comprises reacting 14 WO 93/16097 PCT/US93/01068 diene-3-cyano-17B-carboxamide and a hydroxide base in an appropriate solvent with subsequent acidification.

9. The process according to claim 8 in which the appropriate solvent is ethanol.

The process according to claim 9 in which the base is aqueous sodium hydroxide. .0

11. A process according to claim 1 in which the compound prepared is H H HOC (IA) or a pharmaceutically acceptable salt, hydrate or solvate thereof.

12. A compound of the structure R N=C in which R 1 is CONR 2 R 3 where R 2 and R 3 are each independently selected from hydrogen, Cl-8alkyl, C 3 -6cycloalkyl, phenyl; or R 2 and R 3 taken together with the nitrogen to which they are attached represent a 5-6 membered -16- saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or (ii) moieties which are chemically convertible to moieties of

13. A compound of claim 12 wherein R 1 is -CsN, -COOH, -COOC 1 6 alkyl or -CON(H) t-butyl.

14. A compound of claim 13 wherein R 1 is -CON(H) t- butyl.

A compound of claim 13 wherein R 1 is -COOH. 55

16. A compound of claim 13 wherein R 1 is -C=N.

17. A process for the preparation of a compound of Formula substantially as hereinbefore described with reference to the Examples. DATED this 29th day of November, 1995 SmithKline Beecham Corporation By Its Patent Attorneys DAVIES COLLISON CAVE r 951 129,p:\opr\dab,36126spe, 16 INTERNATIONAL SEARCH REPORT PCT/US93/01068 CLASSIFICATION OF SUBJECT MATTER :C07J 75/00,3/00,43/00 US CL :540/108,110; 552/610 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) U.S. 5,o//0o, llb; 5/610 Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) CAS ONLINE-STRUCTURE SEARCH C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. Y Morrison and Boyd, Organic Chemistry 3rd Edition (Boston, Allyn 1-10 and Bacon, 1979) pp. 588-589 Y Fieser and Fieser, reagents for Organic Synthesis, Vol.1 (New 1-10 York, J. Wiley and Sons, 1967) p. 391 X US,A, 5,017,568 (HOLT ET AL)) 11 21 MAY 1991 See example 3 Y Larock, Compreniins;i Organic Transformations (New York, 1-10 VCH, 1989) p. 861 Further documents are listed in the continuation of Box C. O See patent family annex. Special categoriea of cited documents: later document published after the international filing date or pnoriry date and not in conflictwith the application but cited to understand the document definin the eneral state of the art which is not considered principle or theory underlying the invention to be part of particular relevance E earlier document published on or after .he international ling dte X document of paricur relevance; the imed invention cannot b considered novel or cannot be considered to involve an inventive step document which may throw doubts on priority claim(s) or which t when the document is taken alone cited to establiah the publication date of another citation or other special reason (a specified) document of particular relevance; the claimed invention cannot be considcred to involve an inventive step when the document ui document referring to an oral disclosure. use, exhibition or other combined with one or more other such documents. such combinauon means being obvious to a person skilled in the art document published prior to the international filing date but later than document member of the same patent family the priority date claimed Date of the actual completion of the international search Date of mailin in rnational search report 22 MARCH 1993 Name and mailing address of the ISA/US Authorized officer Commissioner of Patents and Trademarks Box PCT EDWARD 'W _D 7 Washington, D.C. 20231 EDWARD Facsimile No. NOT APPLICABLE Telephone No. (703) 308-1235 Form PCT/ISA/210 (second sheet)(July 1992)* I 1. 4 INTERNATIONAL SEARCH REPORT Finternationai application No. IPCTIUS93io 1068 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication. where appropriate, Of the relevant passages Relevant to claim No. X Holt, et al, J. Medicinal Chemist-v 1990 11 33 943-950 "Inhibition of Steroidal 5ce-reductase by Unsaturated 3- CarboxySter0oid. See p. 943, col. 2, schemes VI, VII, and p. 947, column I Form PCT/15A/210 tcontinuation of second sheet)(July 1992)*