CA2199979A1 - Combination method for acne treatment - Google Patents

Abstract

Described is a combination method using selective inhibitors of 5.alpha.reductase 1 and/or 2 including 7.beta.-substituted 4-aza-5.alpha.-cholestan-3-ones and related 4-aza-5.alpha.-androstan-3-one compounds which are useful in the treatment of acne vulgaris in combination with a retinoid, e.g., tretinoin or isotretinoin, and at least one agent selected from an antibacterial, keratolytic, and/or an anti-inflammatory.

Description

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WO 96/12487 PCI'IUS95/13305 TITLE OF THE INVENTION
COMB~ATION METHOD FOR ACNE TREATMENT

BACKGROUND OF THE INVENTION
The present invention is directed to a combination method for treating acne using selective 50c-reductase 1 inhibitors, 5O~-reductase 2 inhibitors, combination.s thereof, or dual inhibitors, including but not limited to; 7,B-substituted-4-aza-Scx-cholestan-3-ones and related 4-aza-Soc-androstan-3-one compounds, together with a retinoid agent, e.g., 10 tretinoin or isotretinoin, and at least one agent selected from an antibacterial, a keratolytic, an anti-inflammatory agent. or mixture thereof.

DESCRIPTION OF THE PRIOR ART
Acne vulgari,s is the mo.st comrnon ~kin condition evaluated and managed by phy,~;ician,s in the United State.~. It is estimated that more than 17 million people have some degree of acne. While it i,s most prevalent in adole.scents, nearly g5% of 12-24 ye~r old~ % of 25-34 year old.s, and 3% of 35-55 year olds have acne. ln 1990. nearly 4.~
20 million patient vi,sit.s to dermatologi.st~ were for acne-related problems; an additional 500,000 visits were to primary care providers.
Acne is basically an androgen dependent di.sorder. Its peal;
incidence is at age 1 X, and it is more prevalent in men than in women. ln ,some case,s, it can be severe enough to call~e ~ignificant .scarring that 25 does not resolve. In many patients, its presence is p,sychologically distre,ssing. While it is not a life-threatening condition, it can have ,~ignificant psychosocial effects on those who suffer with it. Acne has also been shown to be associated with impaired academic and social functioning, a,s well as to affect employment .status. Thus, the accurate 30 assessment and appropriate m;~n;lgement of acne can have important consequences on the overall well-being and ~luality of life of the patient with acne.
Sebum is one of the major factors, along with abnormal ker~tini7~tion of the follicular epithelium, infl~mm~tion and colonization WO 96/12487 PCT/US95113305~

by the bacterium P. acnes, that causes acne. Since all of these factor~s are inter-related, affecting just one, e.g., sebum production, can have a profound influence on acne.
The hormonal milieu plays an important role in modulating S sebum production in males and females. In children, on~;et of acne and sebum secretion occur coincident with the increasing androgen,s that accompany adrenarche and pubarche. Administration of androgens worsens acne and increases sebum production, while ~lmininstration of estrogens decrease,s sebum production and is associated with an 10 improvement in acne. Antiandrogen~, such as cyproterone and ,spironolactone, are sometime~s used for the treatment of acne in women.
Although these clinical observations provided convincing evidence that androgens modulate sebum production, it had been uncertain which of the androgens plays the mo,st important role.
It is now known in the art that the principal mediator of androgenic activity in some target organs is S~-dihydrotesto.sterone (DHT), and that it is formed locally in the target organ by the action of testosterone-50c-reductase. It is al~o known that inhibitors of te~tosterone-50~-reducta~e will ~erve to prevent or le~,~en ~ymptom~i of 20 hyperandrogenic stimulation.
A number of 4-aza steroid compound~ are known in the art.
For example, See U.S. Patent Nos. 2,227,~76, 3,239,417, 3,264,301 and 3,2~SS,9lg; French Patent No. 1,465,544; Doorenbos and Solomon~, J.
Pha~ nZ. Sci., ~2, 4, pp. 63~-640 (1973); Doorenbo~ and Brown, J. Pha~ m.
25 Sci., 6û, ~, pp. 1234-1235 (1971); and Doorenbo~; and Kim, J. Pharm.
Sci., ~3, 4, pp. 620-622 (1974).
In addition, U.S. Patent No.s. 4,377,5~4, 4,220,775, 4,~59,6g 1, 4,760,071 and the article.s "J. Med. Chem. " 2 7, p. 1690- 1701 (19~4) and "J. Med. Chem." 29, 299~-2315 (19g6) of Rasmusson, et 30 U.S. Patent 4,g45,104 to Carlin, et al., and U.S. Patent 4,732,~97 to Cainelli, etal. describe 4-aza-17~-substituted-50~-andro.stan-3-ones which are said to be useful in the treatment of DHT-related hyperandrogenic conditions.

~ 7 9 However, despite the suggestion in the prior art that hyperandrogenetic diseases are the result of a single 50~-reductase, there are reports regarding the presence of other 5Oc-reductase isozymes in both rats and humans. For example, in human prostate, Bruchovsky, et al.
(See J. Clin. Endocrinol. Metab. 67, ~06-816, l 9~Sg) and Hudson (see J.
Ste7 oid Biochenz. 26, p 349-353, 19~7) found different 5cc-reductase activities in the stromal and epithelial fractions. Additionally, Moore and Wilson described two distinct human reductase.s with peaks of activitie~s at either pH 5.5 or pH 7-9. (See J. Biol. Chem. 251, 19, p. 5~95-5900, 1976).
Recently, Ander~sson and Russell isolated a cDNA which encodes a rat liver S(x-reductase (see J. Biol. ChenZ. 2 f)4 pp. 16249-55 (l 9~S9). They found a single mRNA which encode~ both the liver and prostatic reductases of rats. The sequence of this rat gene was later used to ,select a human prostatic cDNA encoding a 5a-reductase termed "5a-reductase 1 ". (See Proc. Nat'l. Acad. Sci. 87, p. 3640-3644, 1990).
More recently, a second, human prostatic reducta.se (5a-reductase 2) has been cloned with properties identified with the more abundant form found in crude human prostatic extracts. (See Nature, 354, p. 159-161, 1991).
Further, "Syndromes of Androgen Re.sistance"- The Biology of Reproduction, Vol. 46, p. 16~- 173 (1992) by Jean O. Wil.son indicates that the 5(x-reductase 1 enzyme may be associated with hair follicles.
Thus, the art supports the existence of at least two genes for Soc-reductase and two distinct isozymes of 5a-reducta.se in humans. The isozyme that principally interacts in certain skin tissue.s, e.g., skin or .scalp, is conventionally designated as Soc-reducta,se I (or Soc-reductase type 1), while the isozyme that principally interacts within the pro.static 7 tissues is designated a.s 5(x-reducta.se 2 (or Soc-reductase type 2). See.
e.g., G. Harris, et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 107~S7-10791 (Nov. 1992).
Local dihydrotesterone (DHT) formation via 5 alpha reductase (5 alphaR) plays a major role in sebum production and the pathophysiology of acne since it is known that the sebaceous gland is rich WO96/12487 ~ 9 9 7 Q PCI-/US95/13305 in 5 alpha reductase and that acne prone skin contains excessive 5 alphaR
activity. On thi.s basis, local DHT formation is responsible for increased sebum production in sebaceous follicles of acne prone tissue and 5 alpha R 1 or R2 inhibition, or combination thereof, can be useful in the 5 treatment of acne.
As described above, acne is a disea~e with multifactorial pathogene,si,s including the factors of: (a) increased sebum production, (b) follicular keratinization, (c) Propionibacte7 ium acnes proliferation and (d) infl~mm~tion. On this basi~s, we believe that it,s 10 effective m~n~gement can best be brought about through combination therapy that concurrently addre~sses more than one of these pathogenic factor,s in a therapeutic protocol. In the treatment of acne vulgaris, it would be desirable to employ a 5(x-reductase 1 or 2 inhibitor, combination thereof, or a dual inhibitor, which decreases sebum 15 production, in combination with another agent to amplify the therapy against the other above-described pathogenic factors in the treatment.
Therefore it is an object of this invention to provide a combination method of agents that ha,s sufficient activity in the inhibition of 5cc-reductase isozyme 1, 5c~-reducta,se isozyme 2, 20 combination thereof, or the use of a dual inhibitor, in combination with another agent that will enhance the effectiveness of the 5cc-reductase 1 or 2 inhibitor, or combination thereof, in the treatment of acne vulgarls.

By this invention there is provided a combination method involving the use of a 50~-reductase 1 and/or 2 inhibitor, in combination with a retinoid agent, including but not limited to, e.g., tretinoin (all-trans-retinoic acid, RETIN A) and i,sotretinoin ( 1 3-ci,s-retinoic acid, 30 ACCUTANE), and at least one agent selected from: an antibacterial, an anti-inflammatory, and a keratolytic, or combination thereof, in the treatment of acne vulgaris by topical and/or systemic ~lministration.
The 5 alpha reducta,se 1 or 2 inhibitor inhibits the production of sebum while concurrently: the retinoid norm~li7es des~luamation of the 7 ~

follicular epithelium, promotes drainage of preexisting comedones, inhibits the formation of new one~ and can decrease the production of sebum, especially isotretinoin; the antibacterial improves both inflammatory and non-inflammatory lesions by reducing the population 5 of Propionibacterium acnes and other Gram-negative and Gram-positive bacteria on the skin surface and within the follicles; the keratolytic, decreases follicular ker:~tini7.~tion; and the anti-inflammatory decrease infl~mm~tion and can lead to a mild drying and peeling of the skin. This combination of agents leads to a more effective method of treatment than 10 use of either agent alone.
The invention i.s still further concerned with pharmaceutical folmulations comprising one or more inhibitors of 50c-reductase 1 or 2, or combination thereof, or a dual inhibitor, in combination with a retinoid agent, e.g., tretinoin or isotretinoin, and at lea,~t one agent ~selected from 15 an antibacterial, a keratolytic, and an anti-inflammatory, or combination thereof.
In one embodiment of this invention, is a method of treating acne employing Sa reductase 1 inhibitors, i.e., 7,B-sub,stituted-~-aza-Sa-cholestan-3-ones and 5a-androstan-3-one compound,~i, which are ,~;elected 20 from the group con.sisting of the generic Formulae (I.):
~'~

0~

or a pharmaceutically acceptable salt or ester thereof, wherein for Structure I:
25 R is .selected from hydrogen, methyl, ethyl, -OH, -NH2, and -SCH3;
the dashed lines " - - - " _ and b independently represent a single bond or a double bond providing that when _ is a double bond, the Sa hydrogen~ Ha, is absent;

WO96/12487 ~ a I ~ ~ 9 7 ~ PCT/US95/13305-=Z is selected from: ~
1 ) oxo, 2) (x-hydrogen and a ,B-substituent selected from:
a) Cl-C4 alkyl, S b) C2-C4 alkenyl, c) CH2COOH, d) -OH, e) -COOH, f) -COO(C1-C4 alkyl), g) -OCONR1R2 wherein Rl and R2 independently are selected from:
i) H, ii) Cl-C4 aIkyl, iii) phenyl, and iv) benzyl, or R 1 and R2 together with the nitrogen atom to which they are attached represent a 5-6 membered saturated heterocycle, optionally containing one other heteratom selected from -O-, -S- and -N(R')- wherein R' is -H or methyl;
h) Cl-C4 alkoxy, i) C3-C6 cycloalkoxy, j) -OC(O)-C 1-4 alkyl, k) halo, 1) hydroxy -C1-C2 alkyl, m) halo-C1-C2 alkyl, n) -CF3, and o) C3-C6 cycloalkyl;

3) =CHR3; wherein R3 is selected from -H and Cl-C4 alkyl; "
and 4) spirocyclopropane-R3 of structure: "
~/ R3 ; and ~ ~ 2 ~ 7 9 (II.) F~
o N R5 l 4 H 11 R

or a pharmaceutically acceptable salt or ester thereof wherein:
the C1-C2 carbon-carbon bond may be a ~ingle bond, or a double bond as indicated by the dashed line;
R4 is ~selected from the group consisting of hydrogen and Cl lo alkyl;
10 R5 i,s selected from the group consisting of hydrogen and C1-10 alkyl;
one of R6 and R7 is selected from the group con,sisting of hydrogen and methyl, and the other is selected from the group consisting of:
(a) amino;
(b) cyano;
(c) fluoro;
(d) methyl;
(e) OH;
(f) -C(O)NRbRC, where Rb and Rc are independently H, C1 6 alkyl, aryl, or arylCl 6alkyl; wherein the alkyl moiety can be substituted with 1-3 of: halo; Cl 4alkoxy;
or trifluoromethyl; and the aryl moiety can be substituted with 1-3 of: halo; Cl 4alkyl; Cl 4 alkoxy; or trifluoromethyl;
~ (g? Cl-10 alkyl-X-;
(h) C2 l0alkenyl-X-;
wherein the Cl lo alkyl in (g) and C2 l0 alkenyl in (h) can be unsubstituted or substituted with one to three of:

i) halo; hydroxy; cyano; nitro; mono-, di- or trihalomethyl; oxo; hydroxysulfonyl; carboxy;
ii) hydroxycl-6alkyl; Cl-6alkyloxy; Cl-6 alkylthio; C l 6alkylsulfonyl; C 1 6 S alkyloxycarbonyl; in which the C1 6 alkyl moiety can be further substituted with 1-3 of:
halo; Cl 4 alkoxy; or trifluoromethyl;
iii) arylthio; aryl; aryloxy; arylsulfonyl;
aryloxycarbonyl; in which the aryl moiety can be further .substituted with 1-3 of: halo; C1-4 alkyl; C 1-4 alkoxy; or trifluoromethyl;
iv) -C(O)NRbRc; -N(Rb)-C(O)-RC; -NRbRc;
where Rb and Rc are defined above;
(i) aryl-X-;
(j) heteroaryl-X-, wherein heteroaryl is a 5, 6 or 7 membered heteroaromatic ring containing at least one member.selected from the group consisting of: one ring oxygen atom, one ring sulfur atom, 1-4 ring nitrogen atoms, or combinations thereof; in which the heteroaromatic ring can also be fused with one benzo or heteroaromatic ring;
wherein the aryl in (i) and heteroaryl in (j) can be unsubstituted or substituted with one to three of:
v ) halo; hydroxy; cyano; nitro; mono-, di- or trihalomethyl; mono-, di- or trihalomethoxy;
C2 6 alkenyl; C3-6 cycloalkyl; formyl;
hydrosulfonyl; carboxy; ureido;
vi) C 1 6 alkyl; hydroxy C1 6 alkyl; C1 6 alkyloxy;
C 1 6 alkyloxy C 1 6alkyl; C 1 6 alkylcarbonyl;
C1 6 alkylsulfonyl; C1 6 alkylthio; Cl-6 alkylsulfinyl; Cl 6 alkylsulfonamido; Cl-6 alkylarylsulfonamido; C 1 6 alkyloxy-carbonyl;
C1 6 alkyloxycarbonyl C1 6alkyl; RbRCN-C(O)-Cl 6alkyl; Cl-6 alkanoylamino C1-6 alkyl; aroylamino Cl-6 alkyl; wherein the C1-6 W096/12487 ~ 2 ~ ~ ~ 9 7 9 P~ S113305 alkyl moiety can be substituted with 1-3 of:
halo; Cl 4alkoxy; ortrifluoromethyl;
n vii) aryl; aryloxy; arylcarbonyl; arylthio;
arylsulfonyl: arylsulfinyl; arylsulfonamido;
S aryloxycarbonyl; wherein the aryl moiety can be substituted with 1-3 of: halo; cl-4alkyl; Cl-4alkoxy; or trifluoromethyl;
viii) -C(O)NRbRC; -O-C(O)-NRbRC; -N(Rb)-C(O)-Rc; -NRbRC; Rb-C(O)-N(RC)-; where Rb and Rc are defined in (f) above; and -N(Rb)-C(O)-ORg, wherein Rg i~ Cl 6alkyl or aryl, in which the alkyl moiety can be substituted with 1-3 of:
halo; Cl 4alkoxy; or trifluoromethyl, and the aryl moiety can be ~ub~tituted with 1-3 of: halo;
C l 4alkyl; C l 4 alkoxy, or trifluoromethyl;
-N(Rb)-C(O) NRCRd~ wherein Rd i.~ ~elected from H, C1 6 alkyl, and aryl; in which said Cl 6alkyl and aryl can be Isub,stituted a,s described above in (f) for Rb and Rc;
i.x) a heterocyclic group, which is a 5, 6 or 7 membered ring, containing at least one member ~elected from the group con.si,sting of: one ring oxygen atom, one ring sulfur atom, 1-4 ring nitrogen atom.s, or combination~ thereof; in which the heterocyclic ring can be aromatic, unsaturated, or ~saturated, wherein the heterocyclic ring can be fused with a benzo ring, and wherein ~aid heterocyclic ring can be substituted with one to three substituent~, as ~ defined above for v), vi), vii) and viii), excluding ix) a heterocyclic group; and (k) R6 and R7 taken together can be carbonyl oxygen;

7~ ' (I) R6 and R7 taken together can be =CH-Rg, wherein Rg is defined in viii); and wherein:

X i~s selected from the group consisting of:
-O-; -S(O)n-; -C(O)-; -CH(Re)-; -C(O)-O-*; -C(O)-N(Re)-*;
-N(Re)-C(O)-O-*; -o-c(o)-N(Re)-*; -N(Re)c(o)-N(Re)-;
-O-CH(Re)-*; -N(Re)-; wherein Re is H, C1 3 alkyl, aryl, aryl-C1 3 alkyl, or unsubstituted or substituted heteroaryl, a.s defined above in (j);
wherein the asterisk (*) denote.s the bond which is attached to the 16-position in Structure II; and n is zero, 1 or 2.
DETAILE~) DESCRIPTION OF THE INVENTION
The present invention has the objective of providing a combination method of treating the hyperandrogenic conditions of acne, which can be comedonal, papulopustular, nodular or cystic, including acne vulgaris, seborrhea, neonatal acne, infantile acne, adolescent acne, adult acne, postmenopausal acne, acne conglobata, hidradeniti.s suppurativa, acne mechanica, perioral dermatitis, acne fulmin~n.s, pyoderma faciale, acne excoriée de.s jeunes fille.s, acne tropicalis, acne e.stivalis, Favre-Racouchot Syndrome, or acne venenata. The method involves the oral, systemic, parenteral or topical ~lministration of a therapeutically effective amount of one or more 5 alpha reductase 1 inhibitor compounds of Formula I or II, or a 5Oc-reductase 2 inhibitor, or combination thereof, or a dual inhibitor, in combination with tretinoin or isotretinoin, and at lea~st one agent selected from an antibacterial, a keratolytic, an anti-infl~mm~tory, or mixture thereof.
By the term "Soc-reductase 1 inhibitor" as used herein, is meant a compound which .selectively interferes with the phy.siological action of the enzyme Soc-reductase I on human tissue. An example is 4,7,13-dimethyl-4-aza-Soc-cholestan-3-one, and related analogue.s, de.scribed herein.

WO96/12487 6~ 9 7 9 PCIIUS95/1330S

By the term "5Oc-reductase 2 inhibitor" as used herein, is meant a compound which selectively interferels with the physiological action of the enzyme Soc-reductase 2 on human tissue. An example i~
finasteride, described in U.S. Patent 4,760,071 (to Merck & Co., Inc.) and 5 related analogues.
By the term "dual 50c-reductase 1 and 2 inhibitor" a,s used herein, is meant a compound which interferes with the physiological action of the enzymes, So~-reductase 1 and 5cc-reductase 2, on human ti.ssue. Examples of these type of compound.s are the 6-azaandrost-4-en-3-ones, described in "J. Med Chem.", 1993, Vol 3~, pagels 4313-4315, and related analogues, and aryl esters in U.S. Patent 5,27fs,159.
In the treatment of acne, a.s described herein, the above described Soc-reducta,se can be used individually or in combination with one or more of the others.
1~
DISCUSSION OF FORMULA I (STRUCTURE I) The 17-substituent cholestane side chain in Formula I is in the beta configuration. Combinationls of substituents and/or variables are pe~nissible only if such combinations result in stable 20 compounds.
The term "C1-C4 alkyl" als used herein, is meant to include methyl (Me), ethyl (Et), propyl (Pr), ilso-propyl (i-Pr), n-butyl (n-Bu)?
~sec-butyl (s-Bu), iso-butyl (i-Bu) and tert-butyl (t-Bu).
The term "C2-C4 alkenyl" a,s ulsed herein ils meant to include 25 vinyl, allyl, l-propen-l-yl, 1-propen-2-yl, l-buten-l-yl, 1-buten-2-yl, and the like. Included in this invention are all E, Z diastereomers.
The term "C3-C6 cycloalkyl" als u.sed herein is meant to include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term "halo" as used herein ils meant to include ~luoro, 30 chloro, bromo, and iodo.
The term "OC1-C4 alkyl" or "C1-C4 alkoxy" as used herein ~. .
is meant to include methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

~ ~ ~ 9 9 9 7 Q ,~

The term "OC3-C6 cycloalkyl" or "C3-C6 cycloalkoxy" a~
used herein is meant to include: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.
Representative examples of =Z are where the oc-sub,stituent 5 (dashed lines) is hydrogen and the ,3-substituent (wedge) is e.g. methyl, ethyl, propyl, allyl, carboxymethyl, hydroxy, methoxy, ethoxy, cyclopropyloxy, cyclopentyloxy, acetoxy, fluoro, chloro, bromo, trifluoromethyl, fluoromethyl, chloromethyl, carboxy, N,N-dimethylcarbamate, hydroxymethyl, and the like.
Repre,sentative examples where =Z i~ an alkenyl .substituent, =CH-R3, includes =CH2, =CH-CH3, =CH-CH2CH3, and the like.
Representative example.s wherein =Z is the spirocyclopropyl substituent:

R3 includes, e.g., >~ H

~ C H3 >~ C H2C H3 ,stereoisomer.s thereof and the like.
Representative examples wherein -NR I R2 represent a heterocycle include: N-piperidinyl, N-morpholinyl, N-piperazinyl. N-(4-methyl)piperazinyl, N-thiomorpholinyl~ N-pyrrolidinyl, N-imidazolidinyl and the like.
Representative compounds of Formula I included in the invention wherein all of the 17-substituent~i are in the beta configuration are:
7~B-ethyl-4-methyl-4-aza-cholest-5 -en-3-one .
7,13 -ethyl -4-methyl -4-aza-cholestane -3 -one, 2~ 7~-ethyl-4-aza-cholest-5-en-3-one, 7~-ethyl-4-aza-50l-cholestan-3 -one, 7~ -carboxymethyl-4-aza-cholest-5-en-3-one, 7,~ -carboxymethyl-4-aza-cholestan-3-one, 7,B-propyl-4-methyl-4-aza-chole,st-5-en-3 -one, WO96/12487 ~ 9 ~ 7 - PCTIUS95/13305 7~13-propyl-4-methyl-4-aza-50~-cholestan-3-one, 7~ -propyl-4-aza-cholest-5 -en-3 -one, 7,B-propyl-4-aza-S(x-cholestan-3-one, 7,B -methyl-4-aza-cholest-S -en-3 -one, 7,~-methyl-4-aza-cholestan-3-one, 4,7,(~-dimethyl-4-aza-cholest-S-en-3-one, 4,7,B-dimethyl-4-aza-So~-cholestan-3-one, 4-methyl -4-aza-5cc-cholestan-3 ,7-dione, 7,13-acetoxy-4-methyl-4-aza-50~-cholestan-3-one, 1 0 4-methyl-4-aza-cholest-S-en-3,7-dione, 7~ -hydroxy-4-methyl-4-aza-5(x-chole.stane-3 -one, 7~-methoxy-4-methyl-4-aza-Sol-cholestane-3-one, 7,B-hydroxymethyl-4-aza-50~-cholestane-3-one, 7~-bromomethyl-4-aza-5O~-cholestane-3-one, 1 5 7~-chloromethyl-4-aza-Soc-cholestane-3-one, 7~-fluoromethyl -4-aza-50~-cholestane-3-one, 7~-carboxy-4-aza-5Oc-cholestane-3-one, 7,B -trifluoromethyl-4-aza-chole,st-5-en-3-one, 7,7 -dimethoxy-4-methyl-4-aza-So~-cholestane-3-one, 7,B-methoxy-4-methyl-4-aza-cholesta-5-en-3-one, 7~-methoxy-4-methyl-4-aza-cholesta-6-en-3-one, 7,~ -cyclopropyloxy-4-methyl-4-aza-50~-cholestane-3 -one, 7~3-cyclopropyloxy-4-methyl-4-aza-cholesta-S ,7-dien-3 -one, 7,(3-propylidene-4-methyl-4-aza-50c-cholestane-3 -one, 7~-(2-ethyl)spiroethylene-4-methyl-4-aza-5a-cholestane-3-one~
7~-methyl-4-aza-5a-cholest- 1 -en-3-one, 7,(3-methyl-5-oxo-A-nor-3,5-seco-cholestanoic acid, 7~(~-ethyl-5-oxo-A-nor-3,5-seco-chole.stanoic acid, 7~-propyl-5-oxo-A-nor-3,5-seco-cholestanoic acid, 7,B-i-propyl-5-oxo-A-nor-3.5-seco-chole.stanoic acid, 7~-n-butyl-5-oxo-A-nor-3,5-seco-cholestanoic acid, 7(3-i-butyl-5-oxo-A-nor-3,5-seco-cholestanoic acid, 7~-s-butyl-5-oxo-A-nor-3,5-seco-cholestanoic acid, 7,B-t-butyl-5-oxo-A-nor-3,5-seco-cholestanoic acid, 7 ~

7~-n-pentyl-5-oxo-A-nor-3,5-seco-cholestanoic acid, and 7,~-n-hexyl-5-oxo-A-nor-3,5-seco-cholestanoic acid.

DISCUSSION OF FORMULA II (STRUCTURE II) In one embodiment of the instant invention are compounds of Formula II wherein R4 is hydrogen or methyl and R5 is hydrogen or methyl.
A further embodiment of the in,stant invention are compounds of Forrnula II wherein:
10 one of R6 and R7 i,s selected from the group consisting of hydrogen and methyl, and the other i.s selected from the group consisting of:
(b) cyano;
(c) fluoro;
(e) OH;
(g) C 1-10 alkyl-X-; or C I -10 alkyl-X-, where alkyl can be substituted with aryl, and wherein aryl in turn can be sub,stituted with 1-2 of halo or C 1 -6alkyl;
(h) C2 l0alkenyl-X-;
(i) aryl-X-;
(j) heteroaryl-X-, wherein heteroaryl is a 5 or 6 membered heteroaromatic ring containing 1-2 ring nitrogen atoms;
wherein the aryl in (i) and heteroaryl in (j) can be unsubstituted or substituted with one to two of:
x) halo; cyano; nitro; trihalomethyl; trihalomethoxy; C

6 alkyl; aryl; Cl-6 alkylsulfonyl; C1 6 alkyl-arylsulfonamino;
xi) -NRbRC; Rb-C(O)-N(RC)-; wherein Rb and Rc are independently H, Cl -6 alkyl, aryl, or arylC 1 -6alkyl;
wherein the alkyl moiety can be .substituted with 1-3 of: halo; Cl 4alkoxy; or trifluoromethyl; and the aryl moiety can be substituted with 1-3 of: halo; C
4alkyl; Cl 4 alkoxy; or trifluoromethyl;

7 q~ 2 ~ 9 ~ ~ 7 9 PCT/US95113305 xii) a heterocyclic group~ which i.~ a S membered aromatic ring, cont~ining one ring nitrogen atom, or one ring oxygen and one ring nitrogen atom; and (k) wherein R6 and R7 taken together can be carbonyl oxygen;
and wherein:

X is selected from the group consisting of:
-0-; -S(O)n-; -CH(Re)-; -C(O)-N(Re)-*;
-O-C(O)-N(Re)-*;
wherein Re is H, C1 3 alkyl, aryl, aryl Cl 3 alkyl;
wherein the asterisk (*) denotes the bond which i.s attached to the 16-position in Structure II; and n is zero or 2.

Novel compounds of the present invention exemplified by this embodiment include but are not limited to the following compounds:
4-aza-4,7,13-dimethyl-5Oc-androstane-3, 1 6-dione;
4-aza-4-methyl-Soc-androstan-3, 1 6-dione;
3-oxo-4-aza-4-methyl- 1 6~-hydroxy-So~-androstane;
3-oxo-4-aza-4-methyl- 1 6~-(benzylaminocarbonyloxy)-50~-andro.stane;
3-oxo-4-aza-4-methyl- 1 6,B-benzoylamino-Soc-androstane;
3-oxo-4-aza-4-methyl- 1 6,B-methoxy-So~-androstane;
3-oxo-4-aza-4-methyl- 1 6~-allyloxy-5cl-andro.stane;
3-oxo-4-aza-4-methyl- 1 6~-(n-propyloxy)-Soc-androstane;
3-oxo-4-aza-4-methyl- 1 60c-hydroxy-50~-andro,stane;
3-oxo-4-aza-4-methyl-1 6,B-(phenoxy)-Soc-androstane;
3-oxo-4-aza-7~B-methyl- 1 6,1~-(phenoxy)-So~-androst- 1 -ene;
3-oxo-4-aza-4-methyl- 1 60c-methoxy-Soc-androstane;
3-oxo-4-aza-4-methyl- 1 6,13-(4-chlorophenoxy)-So~-androstane;
3-oxo-4-aza-7,~-methyl- 1 6,B-(4-chlorophenoxy)-Soc-androst- 1 -ene;
3-oxo-4-aza-7,(3-methyl- 1 6,(~-(4-chlorophenoxy)-Soc-androstane;
3-oxo-4-aza-7,(~-methyl- 1 6~-(3-chloro-4-methylphenoxy)-S~x-androstane;
3-oxo-4-aza-7~-methyl- 1 6~-(4-methylphenoxy)-Sol-androstane;
3-oxo-4-aza-7,B-methyl- 1 6,B-(4-methylphenoxy)-Soc-androst- 1 -ene;
3-oxo-4-aza-7,~-methyl- 1 6,B-[4-( 1 -pyrrolyl)phenoxy]-Soc-androst- 1 -ene;

9 ~

3-oxo-4-aza-4,7,~-dimethyl- 1 6~-hydroxy-Soc-androstane;
3-oxo-4-aza-4,7,B-dimethyl- 1 6~-methoxy-Sa-androstane;
3-oxo-4-aza-4,7,(~-dimethyl- 1 6,B-allyloxy-Soc-androstane; e 3-oxo-4-aza-4,7,13-dimethyl- 16~-(3 ,3-dimethylallyloxy)-Soc-androstane;
3-oxo-4-aza-4,7,B-dimethyl- 1 6,~-(n-propyloxy)-5Oc-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6,13-(i.so-pentoxy)-Soc-androstane;
3-oxo-4-aza-4, 1 6cc-dimethyl- 1 6,B-hydroxy-5cc-androstane;
3-oxo-4-aza-4,7,~-dimethyl- 1 6~-ethyloxy-So~-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-benzyloxy-Soc-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6O~-hydroxy-Soc-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-methylthio-Soc-androstane;
3-oxo-4-aza-4,7,~-dimethyl- 1 6,~-(n-propylthio)-Soc-androstane;
3-oxo-4-aza-4,7,13-dimethyl- 1 6~-fluoro-Soc-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-cyano-Soc-andro.stane;
3-oxo-4-aza-4-methyl-16,~-(1-hexyl)-So~-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-(n-propyl)-S(x-androstane;
3-oxo-4-aza-4,7,B-dimethyl- 1 6,B-benzyl-Soc-androstane;
3 -oxo-4-aza-4,7~-dimethyl- 1 6~-(4-chlorobenzyl )-Soc-androstane;
3-oxo-4-aza-4, 1 6O~-dimethyl- 1 6~-methoxy-So~-androstane;
3-oxo-4-aza-4,7,~-dimethyl- 1 6,B-(4-cyanophenoxy)-Soc-androstane;
3-oxo-4-aza-4,7,~-dimethyl- 1 6,(~-(3-cyanophenoxy)-Soc-androstane;
3-oxo-4-aza-4,7,(~-dimethyl- 1 6~-(4-nitrophenoxy)-5~-androstane;
3-oxo-4-aza-4,7~-dimethyl- 16~-(1 -naphthyloxy )- 5a-andro.stane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-(3-chlorl -$-methylphenoxy)-5a-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-(4-methylphenoxy)-5Oc-andro.stane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-(tert-butyloxy) -51x-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-(3-methyl- 1 -butyloxy)-5Oc-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6O~-(n-propyloxy)-5a-androstane;
3-oxo-4-aza-4,7,B-dimethyl- 1 6~-(4-trifluoromethylphenoxy)-So~-andro,stane;
3-oxo-4-aza-4,7,B-dimethyl- 1 6,~-(4-trifluoromethoxyphenoxy)-S(x-androstane;
3-oxo-4-aza-4,7~B-dimethyl- 1 6,B-ethylthio-Soc-androstane;

~ 9 7 9 3-oxo-4-aza-4,7~-dimethyl- 1 6,B-ethylsulfonyl-Soc-androstane;
3-oxo-4-aza-4,7,~-dimethyl- 1 6,B-(4-methylsulfonylphenoxy)-Soc-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-[4-(4-tolylsulfonylamino)phenoxy] -So~-S androstane;3-oxo-4-aza-4,7~-dimethyl- 16~-(3 -pyridyloxy)-5c~-androstane;
3-oxo-4-aza-4,7,(~-dimethyl- 1 6,B-[(4-phenyl)phenoxy)-Soc-androstane;
3-oxo-4-aza-4,7,B-dimethyl- 1 6~-(4-fluorophenoxy)-S(x-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6,B-(2-pyrazinyloxy)-5O~-androstane;
3-oxo-4-aza-4,7,~-dimethyl- 1 6~-[4-(5-oxazolyl)phenoxy]-5Oc-andro~tane;
3-oxo-4-aza-4,7,(~-dimethyl- 1 6,~-(2-pyrimidinyloxy)-Soc-androstane;
3-oxo-4-aza-4,7,(~-dimethyl- 16~-[4-(1 -pyrryl)phenoxy]-5Oc-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6,(~-(4-aminophenoxy)-So~-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-(4-acetylaminophenoxy)-Soc-androstane:
3-oxo-4-aza-4,713-dimethyl- 1 6,13-(4-benzoylaminophenoxy)-Soc-androstane;
3-oxo-4-aza-4,7,3-dimethyl- 1 6,(~-(4-chlorophenoxy)-S(x-androstane;
3-oxo-4-aza-4,7,B-dimethyl- 1 6~-(phenoxy)-Sa-andro~tane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-(2-chlorophenoxy)-Soc-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6,B-(3-chlorophenoxy)-50l-androstane;
3-oxo-4-aza-4,7,13-dimethyl- 1 6,B-(4-chlorophenoxy)-Sol-androst- 1 -ene;
3-oxo-4-aza-4,7,(3-dimethyl- 1 6-(4-chlorobenzylidene)-5~x-androstane;
3-oxo-4-aza-4,7,3-dimethyl- 1 6-benzylidene-5cc-androstane;
3-oxo-4-aza-4,7,B-dimethyl- 1 6-(4-methylbenzylidene)-Soc-andro~;tane;
3-oxo-4-aza-4,7,B-dimethyl- 1 6-(4-chlorobenzyl)-50c-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6-(4-methylbenzyl)-50c-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6-(3-pyridylmethyl)-50~-androstane;
3-oxo-4-aza-4,7,~3-dimethyl- 1 6cc-methanesulfonyl-5cx-androstane;
3-oxo-4-aza-4,7,3-dimethyl- 1 6,B-thiophenoxy-5O~-androstane;
3-oxo-4-aza-4,7,(~-dimethyl- 1 6~-(4-chlorothiophenoxy)-50c-androstane;
3-oxo-4-aza-4,7,3-dimethyl- 1 6~-(4-fluorothiophenoxy)-50~-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-(4-methylthiophenoxy)-Soc-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-(4-methoxythiophenoxy)-Slx-androstane;
3-oxo-4-aza-4,7,~3-dimethyl- 1 6,3-phenylsulfinyl-Soc-androstane;

7 9 f~

3-oxo-4-aza-4,7~-dimethyl- 1 6,13-phenylsulfonyl-5a-androstane;
3-oxo-4-aza-4,7,(~, 1 6O~-trimethyl- 1 6~-(4-trifluoromethylphenoxy)-5Oc-androstane;
3-oxo-4-aza-4,7~, 1 6(x-trimethyl-1 6~-hydroxy-Soc-androstane;
5 3-oxo-4-aza-4,7,B,16cc-trimethyl-16,(~-methoxy-Soc-androstane;
pharmaceutically acceptable salts thereof, and analogs of the above-described compounds wherein the C 1-( 2 carbon-carbon bond i.s a double bond, and/or R4 is -H, and/or R5 is -H or methyl, where appropriate.
In another embodiment of thi,s invention are compounds of 10 Formula II further limited to those wherein the C1-C2 carbon-carbon bond is a single bond, R4 is methyl, R5 i.~ methyl, R7 is selected from unsubstituted or substituted aryloxy, and R6 is hydrogen.
Some non-limiting examples of compounds within thi.s embodiment are:
3-oxo-4-aza-4,7,B-dimethyl- 1 6,B-(4-cyanophenoxy)-5Ol-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-(3-cyanophenoxy)-So~-androstane;
3-oxo-4-aza-4,7,B-dimethyl- 1 6,B-(4-nitrophenoxy)-5(x-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6,B-( l -naphthyloxy)-Soc-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-(3-chloro-4-methylphenoxy)-Sa-20 androstane;
3-oxo-4-aza-4,7,(~-dimethyl- 1 6~-(4-methylphenoxy)-5a-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6~-(4-trifluoromethylphenoxy)-5Oc-androstane;
3-oxo-4-aza-4,7,(~-dimethyl- 1 6~-(4-trifluoromethoxyphenoxy)-5(x-25 androstane;3-oxo-4-aza-4,7~-dimethyl- 1 6,~-(4-methylsulfonylphenoxy)-5(x-androstane;
3-oxo-4-aza-4,7,~-dimethyl- 1 6~-[4-(4-tolylsulfonylamino)phenoxy]-5O~-androstane;
30 3-oxo-4-aza-4,7,~-dimethyl- 1 6~-[(4-phenyl)phenoxy)-5O~-androstane;
3-oxo-4-aza-4,7,(~-dimethyl- 1 6~-(4-fluorophenoxy)-5Oc-androstane;
3-oxo-4-aza-4,7~-dimethyl- 1 6,B-[4-(5-oxazolyl)phenoxy]-So~-androstane;
3-oxo-4-aza-4,7~-dimethyl- 16~-[4-(1 -pyrryl)phenoxy]-5Oc-androstane;
3-oxo-4-aza-4,7~B-dimethyl- 1 6~-(4-aminophenoxy)-5O~-androstane;

~2 ~9 97~

3-oxo-4-aza-4,7~-dimethyl- 1 6,13-(4-acetylaminophenoxy)-~o~-;androstane;
3-oxo-4-aza-4,7,3-dimethyl- 1 6~-(4-benzoylaminophenoxy)-So~-androstane;
3-oxo-4-aza-4,7~3-dimethyl- 1 6,13-(4-chlorophenoxy)-5a-androstane;
5 3-oxo-4-aza-4,7~-dimethyl- 1 6,~-(phenoxy)-5(x-androstane;
3-oxo-4-aza-4,7,(3-dimethyl- 1 6~-(2-chlorophenoxy)-5O~-androstane;
3-oxo-4-aza-4,7,B-dimethyl- 1 6~-(3-chlorophenoxy)-5a-androstane;
and the phalmaceutically acceptable salts thereof.
A useful compound of the present invention is 3-oxo-4-aza-10 4,7~-dimethyl-1 6~3-(4-chlorophenoxy)-50~-androstane, or a pharmaceutically acceptable salt thereof.

The following discussion applie.s to terms u.sed in both Formulae I and ~I.
As used herein "alkyl" is intended to include both branched-and straight-chain saturated aliphatic hydrocarbon group.s having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, iso-propyl (i-Pr), iso-butyl (i-Bu), tert-butyl (t-Bu), sec-butyl (s-Bu), iso-pentyl, and the like.
20 "Alkyloxy" (or "alkoxy") represents an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, e.g., methoxy, ethoxy, propyloxy, and the like. "Alkenyl" is intended to include hydrocarbon groups of either a straight or branched configuration with one or more carbon-carbon double bonds which may occur in any 25 stable point along the chain, such as ethenyl, propenyl or allyl, butenyl, pentenyl, and the like. Included in this invention are all E, Z
diastereomers.
The alkyl and aL~cenyl group.s can be unsubstituted or .substituted with one or more, and preferably 1-3, 30 i) halo; hydroxy; cyano; nitro; mono-, di- or trihalomethyl;
oxo; hydroxysulfonyl; carboxy;
ii) hydroxyC1 6alkyl; Cl 6alkyloxy; C 1 6 alkylthio; C l 6alkylsulfonyl; C1 6 alkyloxycarbonyl; in which the C1 6 alkyl moiety WO 96/12487 ~ PCT/US95/13305 can be further substituted with 1-3 of: halo; C1 4 alkoxy; or trifluoromethyl;
iii) arylthio; aryl; aryloxy; arylsulfonyl; aryloxycarbonyl; in which the aryl moiety can be further substituted with 1-3 of: halo; C 1-4 5 alkyl; C 1-4 alkoxy; or trifluoromethyl;
iv) -C(O)NRbRC; -N(Rb)-c(o)-Rc; -NRbRc; where Rb and Rc are defined above, and where halo is F, Cl, Br or I as used herein.
The term "oxo", as used herein, indicates an oxo radical which can occur in any stable point along the carbon chain resulting in a 10 formyl group, if at the end of the chain, or an acyl or aroyl group at other point,~ along the carbon chain.
A,s used herein the term "aryl" i~ intended to mean phenyl or naphthyl, including 1-naphthyl or 2-naphthyl, either unsub~tituted or substituted as de,scribed below.
The term "heteroaryl" as used herein, is intended to include a 5, 6 or 7 membered heteroaromatic radical containing at lea,st one member selected from the group consisting of: one ring oxygen atom. one ring sulfur atom, 1-4 ring nitrogen atom,~;, or combinations thereof; in which the heteroaryl ring can al~o be fused with one benzo or 20 heteroaromatic ring. Thi,s category includes the following either unsubstituted or substituted heteroaromatic ring~(a~ de~cribed below):
pyridyl, furyl, pyrryl, thienyl, isothiazolyl. imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidv], quinolyl quinazvlinyl. i,soquinolyl, benzofuryl, i,sobenzofuryl. benzothienyl. pyrazolyl. indolyl, i~;oindolyl, 25 purinyl, carbazolyl, i,soxazolyl, thiazolyl, i~othiazolyl, oxazolyl, benzthiazolyl, and benzoxazolyl. The heteroaryl ring may be attached within structural Formula II or sub~;tituted at any heteroatom or carbon atom in the ring. However, the attachment to -X- has to be through a ring atom which affords a stable structure. The heteroaryl ring can also be 30 fused to a benzo ring.
The one or more, preferably one to three, ,substituents which can be on the aryl and heteroaryl groups named above are independently selected from:

WO96tl2487 ~ 3 7 9 PCI/US95/13305 v ) halo; hydroxy; cyano; nitro; mono-, di- or trihalomethyl;
mono-, di- or trihalomethoxy, C2 6 alkenyl; C3 6 cycloalkyl; formyl;
hydrosulfonyl; carboxy; ureido;
vi) C1 6 alkyl; hydroxy Cl-6 alkyl; Cl-6 alkyloxy; C1-6 S alkyloxy Cl 6alkyl; Cl-6 alkylcarbonyl; Cl 6 alkylsulfonyl; C1 6 alkylthio; C1 6 alkylsulfinyl; C1-6 alkylsulfonamido; C1 6 alkylarylsulfonamido; C1 6 alkyloxy-carbonyl; C1 6 alkyloxycarbonyl C1 6alkyl, RbRcN-C(O)-Cl 6alkyl; C1 6 alkanoylamino C 1 6 alkyl;
aroylamino C1 6 alkyl; wherein the C1 6 alkyl moiety can be ~substituted 10 with 1-3 of: halo; Cl 4alkoxy; or trifluoromethyl;
vii) aryl; aryloxy; arylcarbonyl; arylthio; arylsulfonyl;
arylsulfinyl; arylsulfonamido; aryloxycarbonyl; wherein the aryl moiety can be substituted with 1-3 of: halo; Cl 4alkyl; Cl 4alkoxy; or trifluoromethyl;
15 viii) -C(O)NRbRC;-O-c(o)-NRbRc;-N(Rb)-c(o)-Rc;-NRbRc;
Rb-C(O)-N(RC)-; where Rb and Rc are defined in (f) above; and -N(Rb)-C(O)-ORg, wherein Rg is Cl -6alkYI or aryl, in which the alkyl moiety can be substituted with 1-3 of: halo; Cl 4alkoxy; or trifluoromethyl, and the aryl moiety can be substituted with 1-3 of: halo; Cl 4alkyl; Cl 4 20 alkoxy, or trifluoromethyl; -N(Rb)-C(O) NRCRd~ wherein Rd is selected from H, C1 6 alkyl, and aryl; in which said C1 6alkyl and aryl can be ,substituted as described above in (f) for Rb and Rc;
ix) a heterocyclic group, which is a 5. 6 or 7 membered ring, containing at least one member,selected from the group consisting of:
25 one ring oxygen atom, one ring sulfur atom, 1-4 ring nitrogen atoms, or combinations thereof; in which the heterocyclic ring can be aromatic, un.saturated, or saturated, wherein the heterocyclic ring can be fu~sed with a benzo ring, and wherein said heterocyclic ring can be .substituted with one to 30 three substituents, as defined above for v), vi), vii) and viii), excluding i~-) a heterocyclic group.
The fused heteroaromatic ring systems include: purine.
imidazoimidazole, imidazothiazole, pyridopyrimidine, pyridopyridazine~

9 9 ~ ~ ~

pyrimidopyrimidine, imidazopyridazine, pyrrolopyridine, imidazopyridine, and the like.
The "heterocyclic" group include~s the aromatic heteroaryl rings described above and also their respective dihydro, tetrahydro, 5 hexahydro and fully saturated ring systems. Examples include:
dihydroimidazolyl, dihydrooxazolyl, dihydropyridyl, tetrahydrofuryl, dihydropyrryl, tetrahydrothienyl, dihydroisothiazolyl, 1,2-dihydrobenzimida~olyl, 1,2-dihydrotetrazolyl, 1,2-dihydropyrazinyl, 1,2-dihydropyrimidyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydroi,soquinolyl, 1,2,3,4-tetrahydrobenzofuryl, 1,2,3,4-tetrahydroisobenzofuryl, 1,2,3,4-tetrahydrobenzothienyl, 1,2,3,4-tetrahydropyrazolyl, 1,2,3,4-tetrahydroindolyl, 1,2,3,4-tetrahydroi~soindolyl, 1,2,3,4-tetrahydropurinyl.
1,2,3,4-tetrahydrocarbazolyl, 1,2,3,4-tetrahydroisoxazolyl, 1,2,3,4-tetrahydrothiazolyl, 1,2,3,4-tetrahydrooxazolyl, 1,2,3,4-15 tetrahydrobenzthiazolyl, and 1,2,3,4-tetrahydrobenzoxazolyl and the like.
The heterocyclic group can be substituted in the .same fashion as described above for heteraryl.
Whenever the terms "alkyl", "alkenyl", "alkyloxy (or alkoxy)", "aryl" or "heteroaryl", or one of their prefix roots, appear in a 20 name of a substituent in Formula 1 and Il, (e.g.~ aralkoxyaryloxy) they shall have the ,same definition,s a,s tho~e described above for "alkyl"~
"alkenyl", "alkyloxy (or alkoxy)", "aryl" and "heteroaryl", respectively.
Designated number.s of carbon atom,s (e.g., C I l o) shall refer independently to the number of carbon atoms in an alkyl or alkenyl 25 moiety or to the alkyl or alkenyl portion of a larger substituent in which alkyl or alkenyl appears as its prefix root.
Also included within the ,scope of thi.s invention are pharmaceutically acceptable ~salts of the compounds of Formula I and Il, where a basic or acidic group i~s present on the structure. When an acidic 30 substituent is pre.sent, i.e., -COOH, there can be formed the ammonium, ~sodium, potas,sium, calcium salt, and the like, for use as the dosage form.
Where a basic group is present, i.e., amino or a basic heteroaryl radical such as, e.g., 4-pyridyl, an acidic salt, i.e., hydrochloride, hydrobromide, acetate, pamoate, and the like, can be used a~s the dosage form.

.

WO 96112487 PCr/US95/13305 ~ 2 ~ 9 ~ 9 7 9 Also, in the case of the -COOH group being present, pharmaceutically acceptable esters can be employed, e.g., acetate, r maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteri~tic~ for use as 5 su~tained relea,se or prodrug formulations.
Representative salts include the following ,salts:
acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, 10 cam~sylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, 15 glycollylars~nil~te, sulfate, hexylresorcinate, ~ubacetate, hydrabamine, succinate, hydrobromide, t~nn~te, hydrochloride, tartrate, hydroxynaphthoate, teoclate, Iodide, tosylate, isothionate, triethiodide, lactate, and valerate.
In addition, some of the compounds of the in,stant invention 20 may form .solvates with water or common organic ,solvent~. Such ,solvates are encompassed within the scope of this invention.
The compounds of Formula I and Il of the pre.sent invention have asymmetric centers and may occur a,s racemate,s, racemic mixture.s and as individual enantiomers or diastereomers, with all isomeric form,s 25 being included in the present invention a.s well a~i mixtures thereof.
Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and a.s such are intended to be included in the present invention.
The term "therapeutically effective amount" shall mean that 30 amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

WO96112487 ~ ~ ~ 9 ~ 9 7 ~ PCTJUS95/13305 Fo~nula I
The compounds of this invention can be made by procedures outlined in the following Flowsheets. All temperatures are in degrees Celsius.
GENERAL FLOWSHEET

,~ Cr(CO)6/t-BuOOH

AcO CH3CN/ 24h ~~ <

~ AlkMgCI

AcO"'--~O THF/24h ~~Y

Al(Oi Pr)3/C6H1 o~

HO ~OH Toluene/24h ~/' Li/TH F/N H3/Toluene/-78~

O~Alk lV

WO 96/12487 ~ ~ 1 9 ~ 9 7 9 PCT/US95/1330S

GENERAL FLOWSHEET (CONT'D) y ~ THF/DBU/1 h O~Alk y ~ / KMnO4/NalO4t-Bu-OH/

O~Alk 80~/H20/2 h Vl ~<
NaOAc ~, / CH3NH3CI/
HOOC oD Alk CH20HCH20H/~
Vll Y~
~~

O~ ,N~Alk Vlll 0 ~ 9~Q ~

GENERAL FLOWSHEET (CONT'D) ~~
~ PtO2/HOAclH2 O~N~Alk Vlll ,~
O~N~~Alk CH3 ~<
lX ~ ~

,~ ~
Vll NH40Ac/HOAc O~N~Alk X, ~y / J~ ,_~
X Pt~2/H2. O~N~Alk HOAc H H
Xl 7 ~

7-Beta Alkyl Series The compounds of the instant invention comprising Z a~ a 7,13 alkyl group, e.g., methyl, ethyl, isopropyl, allyl, can be prepared by the procedure outlined in The General Flowsheet.
As seen in the Flowsheet, the ~tarting 3-acetoxy-cholest-5-ene 1 (see Example l for synthesis) is oxidized to the corresponding 5-en-7-one II by treatment with hydrogen t-butyl peroxide and chromium hexacarbonyl in e.g., acetonitrile, at reflux. The C 1 -C4 alkyl group, de.signated Alk, e.g., methyl, can be introduced at this point by a Grignard reaction using e.g., alkyl magnesium chloride in e.g., anhydrous tetrahydrofuran (THF) at 0-23~C to produce the 7-alkyl-7-hydroxy adduct III. This is then oxidized with e.g., aluminum isopropoxide and cyclohexanone (Oppenauer oxidation condition.~) in refluxing toluene solvent to produce the 7-alkyl-4,6-dien-3-one IV. This in turn is reduced via a e.g., metal-ammonia reduction, using lithium, liquid ammonia, THF
and toluene at -7~~C, quenching the reaction with dibromoethane and arnmonium chloride, to selectively yield the 7-beta-alkyl-5-en-3-one V.
In the next step the delta-5 double bond i~ omerized to the 4-ene by use of DBU ( 1 ,~s-diazabicyclo-[5.4.0]undec-7-ene) in, e.g., refluxing THF to produce the 7-beta-alkyl 4-en-3-one, VI. The A Ring is next cleaved by treatment with e.g., potassium permanganate, .sodium periodate in t-butyl alcohol at ~0~C to produce the corre.sponding seco-acid VII. Treatment of the seco-acid with an appropriate amine e.g.~ methylamine hydrochloride and .sodium acetate in ethylene glycol at l ~0~C, yields e.g., the 4-methyl-4-aza-cholest-5-en-3-one VIII. This in turn is selectively reduced with e.g., PtO2 catalyst in a hydrogen atmosphere, to remove the 5-position double bond to produce the Soc-hydrogen compound IX. The seco-acid vn can be similarly treated with ammonium acetate in acetic acid (HOAc) to produce the corresponding N-H compound, X, which can then be analogously treated with PtO2 in a catalytic hydrogenation to produce the corresponding 50c-4N-H compound XI. Similarly, use of hydroxylamine or hydrazine for ring A closure of the seco acid will afford the corresponding delta-5-4N-X compounds where -X can be -OH
or -NH2, respectively. Reaction of the anion of saturated 4N-compound 9 7 ~ ~

- 2~ -(generated from the NH precursor by NaH treatment) with methylsulfenyl chloride can provide the corresponding 4N-X compound where -X is -SCH3. Thus, R can also be -OH, -NH2 or SCH3 in the Formula.

FLOWSHEET A

~' ~ Cr(CO)6/t-BuOOH

AcO CH3CN/24h CA
~ ~, ~ / EtMgCI(5 eq.) AcO ~~O TH F/24h l= Y
~ Al(Oi Pr)3/C6H1 0~

HO J~ 2 EtOH Toluene/24h ., ~\f / Li/THF/NH3/Toluene/-78~

O~Et WO 96tl2487 PCI~/US9S113305 FLOWSHEET A (CONT'D) ~ ~ THF/DBU/1 h O Et ~ KMnO4iNalO4/t-Bu-OH

O Et 80~/H20/2h .~

~ ~ CH3NH3CI
HOOC O Et CH20HCH20H

~<
~X ' O N Et F;LOWSHEET B

~<
~> PtO2 O N~Et I IOAc, H2 ~ <
f~

0~ N~H--~ Et CH3 8 - ' Ammonium Acetate ~ /
Acetic Acid O~ N ~ Et WO96/12487 ~ ~ q ~ 9 ~ 7 9 PCI'IUS9S/13305 FLOWSHEET B (CONT'D) g PtO2 HoAc~ H2 ~~ H ~~Et .~
o~N----~Ph ~Y

O~N~Ph I

~79997~ --7-Beta-~thyl-Cholestane Analoguels The 7-ethyl substituent i,s introduced into the cholestane .series as illustrated in Flowsheet~ C and D by the same analogous procedure as described in the General Flowsheets.
The starting cholesteryl acetate CA is available commercially (Aldrich). Thils ils treated using the analogous chromium hexacarbonyl/hydrogen t-butylperoxide!acetonitrile oxidation procedure (described in JCS Perkin Trans. 1985, p. 267 by A. J. Pearson) to yield the 3-acetoxy-cholest-5-en-7-one 1. This can be reacted with an alkyl Grignard reagent, e.g., ethyl magnesium chloride to form the adduct _.
This is oxidized under Oppenauer conditions to yield the dienone 3, which then can undergo metal-ammonia reduction to yield the 7~B-ethyl-5-en-3-one, 4. This is isomerized using DBU to the 4-en-3-one, _, which i~s oxidized to open Ring A to yield the ,seco-acid 6. This can be treated with amines, e.g. methylamine, to yield the A-ring clo.sed 4-methyl-4-aza compound 7. Thi,s in turn can be catalytically hydrogenated to yield the 7-ethyl-5-alpha-4-methyl-4-aza-chole~stan-3-one, ~.
Similarly, by treatment of the seco-acid 6 with ammonium acetate/acetic acid, the corresponding 4-NH ~n~log 9, is produced which can be catalytically hydrogenated to yield the 7-beta-ethyl-5Oc-4-az~-cholestan-3-one, 10.
Following the same procedure but using phenylmagnesium chloride as the Grignard reagent, the corresponding compounds 50 and 51 are produced ("Ph" represents phenyl).

~ ~ 2 ~ 9 9 9 7 9 FLOWSHEET C
.. ~Y

~J~ AllylMgBr(5 eq.) AcO~O 24h ~<
~
Al(oipr)3lc6H1oo HO \~OH
~ Toluene/24h y 1~>

0~~ \ Li/THF/NH3/
Toluene/-78~/2h ~' Y

~ ~/ DBU/THF

0~\

7 ~ --WO 96/12487 PCI~/US95/13305 FLOWSHEET C (CONT'D) ,, ~~y ,~ RuO4/NalO4/CH3CN

o~~ CCI4 NH40Ac/AcOH

Reflux HOOC 0~ CO2H

Y ~

O~N~ CO2H O~N'~--J 2 ~9~ 979 .

WO 96/12487 PCT/US95tl3305 7-Carboxymethyl-Cholestane Series The 7-carboxy substituent is formed through the corresponding 7-allyl group. As seen in Flowsheet C, 7-oxo-cholesteryl acetate 1 is reacted with allyl Grignard reagent to form the adduct 11 5 which is oxidized to the dienone 12 by Oppenauer conditions. Metal-ammonia reduction affords the S-ene analog 13, followed by DBU-catalyzed double bond isomerization to 14. This in turn can be oxidized in a key step to form the 7-carboxymethyl seco-acid lS. Treatment with amines, e.g., ammonia, forms the 4-aza derivative, 16 which is then 10 reduced to the cholestane 17. Use of methylamine in place of ammonia can yield the corresponding 4-methyl analogs of 16 and 17.

02~9~7~ --FLOWSHEET D
'~ ' 0~\

o~ ;~ ~ HOOC

~ , '----Y

O N/~ ~ O~N ~\

~ ~ ~ 11 9 ~ ~ 7 9 WO 96/12487 P~-llU~ /1330S

FLOWSHEET E

~y ( ,~ KMnO4/NalO4/t-BuOH

O

~ <
> N H40Ac/AcOH
~~ .
HOOC 0~ Reflux O' ~ ~
H I H

8~ Q ~ Q PCT/US9S/13305 - 3~ -7-Propyl-Cholestane Series The 7-propyl analogs are made starting with the 7-allyl-4-en-3-one 14, which is reduced by hydrogenation using Wilkinson'~
catalyst to the propyl derivative 1 g, oxidized to the seco-acid 19, then S condensed with amines, e.g., methylamine, to form the 4-methyl analog 20 and then reduced to the cholestane 2E Corresponding treatment with ammonia is shown in Flowsheet E shows the corresponding unsubstituted 4-aza 22 and cholestane 23 analogs.

~ ~ 2 ~ 9 ~ ~ 7 9 WO 96/12487 PCI'IUS9S/13305 FLOWSHEET F

~<
~ ~ Cr(CO)6/t-BuOOH

AcO~J CH3CN/24h CA
,~Y
> MeMgCI
TH F/24h AcO~ O

~ Al(OiPr)3/C6H10O

HO~CH30H Toluene/24h ~/ Li/TH F/N H3/Toluene/-78~
O~C H3 FLOWSHEET F (CONT'D) ~y ~ THF/DBU/1 h .
O~CH3 y _ ¦ ~ KMnO4/NalO4/t-BuOH
~~
80~/H20/2h O~CH3 ~,y ~ N H40Ac HOOC ~ C H3 HOAc y <
\

O~N~CH3 ~ 2 ~9~ 97 Q

FLOWSHEET G
;~ ~
~
HOAc, H2 ¦ l O~H~CH3 O~ IN~cH3 ~ <

28 HOAc Methylamine O~N~CH3 ,~~<

PtO2 ,~--HOAc, H2 ~ N H CH3 9 ~ 9 .

7-Beta Methyl Cholestane Series The 7-beta methyl cholestane series is prepared by the analogously same route as described in Flowsheets A and B for the ethyl derivatives.
The methyl Grignard reagent is used to form the adduct 24, followed by Oppenauer oxidation to form 25, metal-ammonia reduction to form 2G, double bond isomerization to form 27, seco-acid oxidation to form 2~, and treatment by an ammonium salt to form 29, and reduction to form 30. Corresponding treatment with methylamine produces the corresponding 4-methyl-4-aza compound,s, 31 and by reduction, 32.

FLOWSHEET H

oJ 'I o~

~<
~ = catalytic ~<

O~N ~o f ~~
CH3 1~ /
O~N ~O
I H

FLOWSHEET I
,y <

~ ~ AC2O/Py/DMAp/cH2cl2 - O~N~~OH ~~<
CH3 36 ~~

0~ IN~~OAc WO96/12487 ~ 9 9 7 9 PCT/US95/13305--7-Beta Acetoxv Cholestane Series The 7-beta acetoxy serie.s is prepared by the oxidation of .starting 33 to the 5-en-7-one 34 by the chromium hexacarbonyl procedure described for 1, or by pyridine-dichromate/t-butyl hydroperoxide :~ oxidation a,s described in the Examples. Subsequent noble metal, e.g., platinum, ruthenium, catalyzed reduction of 34 yields two product~, the reduced 7-oxo compound 35, and 7-beta hydroxy compound 36.
Acylation of 36 with acetic anhydride (AC2O) yields the 7-beta acetoxy compound 37. DMAP is dimethylaminopyridine; Py is pyridine; Ac is 1 0 acetyl.

FLOWSHEET J

0~

y <

0~ 1 ~0 ~ ~ ~ 9 9 9 7 9 FLOWSHEET J~ CONTINUED

'~
~

0~ 1 ~H\J~O~

The 7-beta ethers in the cholestane series are prepared from 5 the 7-beta-ol (7-beta hydroxy derivative). As illustrated in Flowsheet J, the 4-N-methyl-7-beta ol 36 can be reaçted with e.g., methyl iodide and sodium hydride in e.g., dimethylformamide, to produce the corresponding methyl ether 37. The other Cl -C4 ethers can be prepared in the same manner.
The C3-C6 cycloalkyl ethers can be prepared according to the analogous procedure of Steroids, 1972, vol. 19, pp. 639-647 by R.
Gardi, et al. For example, 36 can be reacted with 1,1-dimethoxy-cyclohexane to produce the enol ether 3~¢, which can be reduced to the corresponding saturated compound by the use of palladium catalyzed 1 5 hydrogenation.

WO96/12487~ ~ ~ Q 9 ~ 7 ~ PCT/US9S/13305 FLOWSHEET K

Y Y
~~

O=COO'H o~ ~

y Y

~~ N~ CO2H 0~ N~- CH2OH

y 41 ~ 0~--/

I H
-9 9 9 ~ 9 ~ s951133Qs wo s6rl24s7 Fl,OWSHEET L

r 7 ~Y ~

o ~; " ~2H ~ I

-~ 0~
~l 44 FLowsHE~T ~l 1~1~ OH C~13 OC~3 C~t3 36 37 WO96/12487 0 ~ 9 ~ ~ PCT/US9S/13305--- 4~S -FLOWSHEET M~ CONT~UED
-36 /~
O N~--O~

S The 7-haloalkyl series is made by the procedure illustrated in Flowsheet K.
Starting with the 7-beta-carboxy, 45, this can be treated under Hunsdiecker reaction conditions, i.e., bromination of a mercury metal salt, to yield the 7-bromo derivative 40. The chloro and iodo derivatives can be made in substantially the same fa.shion.
The haloethyl compounds can be made by starting with the 7-carboxymethyl analog 17 which can be reacted with a reducing agent, e.g., borane, to produce the primary alcohol 41. This in turn can be reacted with triphenylphosphine and carbon tetrabromide to produce the bromoethyl derivative 42.
The halomethyl compoun-ls can be produced starting with the carboxymethyl derivative 17. This is treated with lead tetraacetate under oxidative decarboxylation/halogenation conditions, with a chloride, bromide or iodide salt to yield, e.g., the 7-chloromethyl analog 43. The carboxymethyl compound 17 can be treated with a fluorinating agent (XeF2) to yield the 7-fluoromethyl analog 44.
The 7-trifluoromethyl derivative can be made from the 7-carboxy derivative 45, by conventional Dast halogenation condition~ ~
using SF4 to yield the 7-trifluoromethyl analog 46.

~ 7~9 979 WO 96/12487 P~ 5SI13305 FLOWSHEET N

~ . ~
0~ N ~0 0~ N'--CH-CH2CH3 ~' -- O~ ~H2CH3 S Flowsheet N illustrate,s the 7-methylene ~serie~;. As seen, the Wittig reaction, using e.g., Ph3PCH(CH2CH3), carried out on the 7-oxo compound 35, leads to the 7-(ethyl)methylene compound 47.
Sub.sequent treatment of 47 with the cyclopropyl forming reagents, CH2I2 and zinc, produces the ethyl cyclopropyl spiro compound 4~, which is a mixture of Istereoi.somers.

WO96/12487 2 ~ ~ ~ 9 ~ ~ PCT/US9S11330S ~

FLOWSHEET O

~~
~/(1) DDQ/BSTFA/CF3SO3H

0~ N~~ Toluene/23~/2h H(2) Methylacetoacetate 3023~/1 h, Reflux/24h ~<
~

O~ N ~~~

S Flowsheet O illustrates the .synthe.~ of the l-ene 7-sub~stituted analogs. For example compound 30 is .stirred with DDQ, BSTFA (bis-trimethylsilyltrifluoroacetamide) and trifluoromethyl sulfonic acid in toluene at room temperature for 24 hours, methyl acetoacetate is added and the mixture reluxed for 24 hour.s and purified by preparative thin layer chromatography on silica gel using 3:1 chloroform/acetone to yield 49.

Formula II
The compounds of Formula II useful in the present invention l;S can be prepared readily according to the following reaction Schemes and Examples or modifications thereof using readily available starting ~ 7 9 materials, reagents and conventional synthesis procedurels. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Specific definitions of variables in the Schemes are 5 illustrative only, and are not intended to limit the procedure,s described.
Some abbreviations used herein are as follows: Ph is phenyl; Ac is an acyl group; t-Bu is tert-butyl; Et is ethyl; Me is methyl; i-Am i.s iso-amyl;
EtOAc is ethyl acetate.
The inhibitors described in Scheme 1 can be prepared as 10 follows. 4-Aza-4-methyl-50c-androstan-3,17-dione (A) i~s fir.st converted into the isomeric 3,16-dione (52) by the following se(luence of reaction~:
( 1 ) treatment of A with isoamyl nitrite in t-butanol in the presence of potassium t-butoxide to generate the intermediate 16-oximino-17-ketone;
(2) reduction of the 17-keto group with hydrazine hydrate and potas~sium 15 hydroxide in ethylene glycol at elevated temperatures to give 16-oxime (B); and (3) cleavage of the 16-oximino group in B either by hydrolysis with aqueous acetic acid at elevated temperature.s or with .~odium bi~ulfite followed by treatment with aqueous hydrochloric acid to afford (52).
Reduction of the 1 6-ketone (52) to the 1 6,(~-alcohol (53) is carried out 20 with a suitable hydride-based reducing agent, .~uch as sodium borohydride in methanol or lithium tri-sec-butylborohydride in tetrahydrofuran (THF). Alcohol (53) is converted into its alkyl ether derivatives (54) and (55), by first generating the alkoxide anion with potassium hydride in N,N-dimethylformamide (DMF) or potassium 25 hydroxide in dimethyl sulfoxide (DMSO) followed by addition of the appropriate alkyl bromide or iodide. The 1 6~-(n-propyloxy) derivative (56) is obtained from the precursor 16~-(allyloxy) derivative ~55) by catalytic hydrogenation.
The inhibitors described in Scheme 2 can be prepared as 30 follows. 16-Oxime (B) is converted into the 16,B-amine (C) by catalytic hydrogenation in the presence of a heterogeneous catalyst such as pl~tinllm oxide in ayueous acetic acid. Acylation of (C) i,s effected with the appropriate acid anhydride or acid chloride in the presence of an acid acceptor such as pyridine, triethylamine, and 4-dimethylaminopyndine WO96/12487 ~ 7 9 PCI/US9SI13305 (DMAP). In this fashion are obtained Examples 6 and 7. Carbamates, such as (59) depicted in Scheme 3, are made by treatment of alcohol (53) with the appropriate isocyanate in the presence of an organic base, such as triethylamine, pyridine, and 4-dimethylaminopyridine.
The inhibitors described in Scheme 4 can be prepared as follows. The 16,(~-alcohol (53) is converted into the 160~-alcohol (60) by treatment with 4-nitro-benzoic acid in the presence of diethyl azadicarboxylate (DEAD) and triphenylphosphine to generate the intermediate 1 6a-(p-nitrobenzoate) ester (D) followed by hydrolysis in aqueous base in an appropriate alcohol solvent. Alkylation of (60) is carried out in an analogous fashion as described above with alcohol (53) to yield the desired 16a-alkyl ethers, such as the 160~-methoxy derivative (Example 10) shown in Scheme 4.
The 7~-methyl inhibitors described in Scheme 5 are prepared in a similar manner as that described above for the examples in Scheme 1, but using instead as starting material, 4-aza-4,7~B-dimethyl-Sa-androstan-3,17-dione (E).
The 7,~-methyl inhibitors described in Scheme 6 are prepared as follows. Compound (71) is prepared by treatment of alcohol (63) with t-butyl trichloroacetimidate in the presence of an organic sulfonic acid, such as trifluoromethanesulfonic acid. The 1 6,~-aryloxy derivatives, such as Compounds 72-75, are obtained by first generating the alkoxide anion from alcohol (63) with pot~s~ium or sodium hydride in tetrahydrofuran or N,N-dimethylformamide or potassium hydroxide in dimethylsulfoxide and subsequent addition of the appropriately substituted fluorobenzene.
The 7,B-methyl inhibitors described in Scheme 7 are prepared in a similar manner as that described above for the examples in Scheme 4, but using instead as starting material the 7~-methyl-16~-ol intermediate (63). Inversion of configuration at the 1 6-position to form (F) is effected using a Mitsunobu-based transformation as shown in Scheme 7. O-Alkylation to generate 160~-ethers, such as (77), is performed as already described above.

~ 9~ ~7~
WO 96/12487 r~,l/U:,9S113305 - The inhibitors described in Scheme 8 are prepared as follows. Addition of methylmagnesium bromide in tetrahydrofuran to either ketone (52) or (62) affords the corresponding 16Oc-methyl-16,~-alcohol (78) or (79). O-Alkylation or O-arylation is then carried out as S described in the previous Schemes to afford the 16a-methyl-16,B-ether derivatives, Compounds (80) and (81).
The inhibitors described in Scheme 9 are prepared as follow.s. The 7~-methyl-16a-alcohol (76) is converted into the 16~-thiol (H) by treatrnent with thiolacetic acid in the presence of diisopropyl 10 azodicarboxylate (DIAD) and triphenylphosphine to give the intermediate 1 6~-thioacetate (G), which is then hydrolyzed under basic conditions to yield thiol (H). Alkylation is effected by generating the mercaptide anion with sodium hydride or potassium hydride in tertahydrofuran or N,N-dimethylformamide followed by addition of the 15 appropriate alkyl halide. In this fashion are prepared Compound.s 82-84.
The corresponding sulfones, such as Compound 85, are obtained by treatment of the precursor thioethers (X2-84) with an oxidizing agent, such as organic peracid or potassium peroxymonosulfate (OXONE), the latter in a~ueous methanol.
The inhibitors described in Scheme lO are prepared by the following .synthetic pathways. The p-nitrophenoxy derivative (101) is reduced with Pd on carbon at room temperature in a H2 atmosphere to yield the p-amino-phenoxy derivative (102). The amine is then acylated with acetyl chloride in methylene chloride in the presence of pyridine to yield the p-acetylaminophenoxy derivative (103), or likewise treated with benzoyl chloride to yield the corresponding p-benzoylamino analog (104). Alternately, the amino compound (102) is treated with tosyl chloride to yield the p-tosylamino analog (105).
The inhibitors described in Scheme 11 are prepared as follows. The N-2,4-dimethoxybenzyl protected l 6-alcohol (106) is treated with p-fluorochlorobenzene and potassium hydride in dimethylform-amide to yield the p-chlorophenoxy derivative (107), which i~ then treated with trifluoroacetic acid in methylene chloride to remove the N-2,4-dimethoxybenzyl protecting group to yield (108). This 7 ~ --WO 96/12487 PCI~/US9S113305 is treated with hydrogen gas and a palladium on carbon catalyst in methanol to dechlorinate the phenyl ring to yield the phenoxy derivative (109). This compound is treated with methyl iodide and sodium hydride in dimethylformamide to methylate the ring nitrogen to yield (112).
5 Alternately, (109) is treated with DDQ and BSTFA in toluene to introduce a double bond at the l-position to yield (110). Utilizing the same reduction reaction scheme, the 1,2-dihydro androstane (108) yield,s the p-chloroandrost-1-ene (111). This is then methylated at the 1-position by treatment with methyl iodide, sodium hydride in lO dimethylformamide to yield (113).
The inhibitor.s described in Scheme l 2 are prepared via similar reaction pathways as described in Scheme l l. The N-2,4-dimethoxybenzyl protected 16-alcohol (106) is treated with 4-methyl-3-chlorofluorobenzene and potassium hydride in dimethylformamide to 15 yield the 4-methyl-3-chlorophenoxy derivative (114), which is then treated with trifluoroacetic acid in methylene chloride to remove the N-2,4-dimethoxybenzyl protecting group to yield (115). This is treated with hydrogen gas and a palladium on carbon catalyst in methanol to dechlorinate the phenyl ring to yield the p-methylphenoxy derivative 20 (116). This compound is treated with methyl iodide and sodium hydride in dimethylformamide to methylate the ring nitrogen to yield (118).
Alternately, (116) is treated with DDQ and BSTFA in toluene to introduce a double bond at the l-position to yield (117).
The inhibitors in Scheme 13 are prepared as follows.
25 The starting 16-alcohol (76) is treated with methanesulfonic acid in pyridine cont~ining DMAP to yield the mesylate (119). This in turn is treated with an appropriate thiophenol in anhydrous THF cont~ining sodium hydride to yield the thiophenoxy (120), 4-chlorothiophenoxy (121), 4-fluorothiophenoxy (122), 4-methylthiophenoxy (127) and the 4-30 methoxy-thiophenoxy (124) derivatives. Treatment of the thiophenoxy (120) derivative with m-chloroperbenzoic acid in methylene chloride at 0~C for one hour yields the phenylsulfinyl derivative (125). Treatment of the phenylsulfinyl compound (125) under the same reaction conditions ~ 9 7 ~
WO 96/12487 PCI~/US9S/1330S

prolonged however for three hours, yields the phenylsulfonyl derivative (126).
The inhibitors for Scheme 14 are prepared as follows. The 1 6-ketone (62) is treated with an appropriate arylmethyl diethyl-5 phosphonate under Wittig conditions using sodium hydride in DMF atP~0-100~C to yield the corresponding 4-chlorobenzylidene (128), benzylidene (127) and 4-methylbenzylidene (129) analogs. These are reduced in ethanol under a hydrogen atmosphere using a 5% rhodium on carbon catalyst to yield the corresponding 4-chlorobenzyl (130) and 4-methylbenzyl (131) derivatives. The 3-pyridyl-methyl (132) analog is made in the same two step manner.

WO96/12487 ~ jT Q PCI/US95113305--o 1.KOt-Bu,t-BuOH ~~~\
> i-AmONO I ,- NOH
~ ; ,~
2. KOH, ~ Nl 9H8O/(cN2H)4o O~\N/\~
CH3 (A) 1 40~C CH3 (B) 60% AcOH, reflux or NaHSO3, 50% EtOH, then 0.5 N HCI, CH2C12 ~ NaBH4, O N MeOH -1 0~C N
CH (53) CH3 (52) KH, DMF or KOH/DMSO
then R71 or R7Br ~} oR7 G ~ >--oR7 O N H2, PtO~, EtOAc N
CH3 (54): R7 = CH3 CH3 5): R7 = CH2CH=CH2 (56): R7 = C H2C H2C H3 ~ 7 ~

H H20 ~ NH2 CH3 (B) CH3 (C) Ac20 or PhCOCI, ~~\
C H2CI2 ~ --N HCoR3 ~ N
CH (57): R8 = CH3 3 (58): R8= Ph ~ ~ PhCH2NCO, Et3N, O N~ DMAP, CH2C12 (53) ~ H
O N
(59) WO96/12487 ~ 7 ~ PCT/US95/13305 - S~s -,/
~,_ OH 4-No2-C6H4C02H ~
~ ~r DEAD, Ph3P. C6H6 O~N /\/
C H3 (53) ~, NO2 ~ N EtOH
CH3 (D) OH ~ OCH3 KOH, DMSQ~ i ~~ N/~/ then CH31 O~N/\/

CH (60) 1 (61 ) ~ ~199 97~

_ 59 _ 1.KOtBu, > t-BuOH Ijc NOH
~ iAmONO ~ ~l~

~ N/~CH3 980/o~N H O~N--CH3 CH3 HO(CH2)2OH~ CH
(E) 60%AcOH, reflux ~ NaBH4, ~~

~ 1 3 -1 0~C O~N/J~CH3 (63) CH3 (62) KH/ DMF or KOH/DMSO
~r then R91 or R9Br WO96112487 ~ ~ ~ 9 ~ ~ 7 Q PCT/US9S/1330S

SCHEME 5. CONTINUED

~ OR9 (64): R9 = CH3;
r ~' (65): R9 = CH2CH3;
O~N/~CH3 (66) R9 _ CH2CH=CH2;

CH3 (68): R9 = CH2CH=C(CH3)3 for compound (66):
H2, PtO2, EtOAc;
for compound (68):
H2, 10% Pd(C), EtOAc ~

~ N~C H3 (69): R9 = CH2CH2CH3;
(70): R9= CH2CH2CH(CH3)~

WO96/12487 ~ 9 7 ~ PCTtUS9S113305 ~

~ J--OH

O~N~~CH3 (63) NH
Cl3C OtBu KH, DMF
CF SO H then R1~-C6H4-F
3 3, CH2cl2 ~~>~ OtBu ~O

o-l~ ~ ~~ R 1 0 3 (71) CH3 (72): R10 = CN;
(73): R10 = CF3 (74): R10= Cl;
(75): R1 0 = F

WO96/12487 ~ 7 Q . PCT/US95/13305 ~ ~OH
~ 4-NO2-C6H4C02H~
O~\N/J~cH3 DEAC, Ph3P, C6H6 (63) 0.4 N aq. NaOH
~~ N/~/ ~ ~ EtOH
3 (F) ~ lOH 1'then CH2-CHCH2Br O N/~CH3 2 H2, 10% Pd(C), (76) WO96/12487 1~ 2 ~ 9 ~ ~ 7 9 PCT/US9S/13305 SCHEME 7. CONTINUED

~ OCH2CH2CH3 O~N/~CH3 (77) SCHEME ~

J ~ I THF ¦ ~ ~,OcH3 ~ I R2 -400C to ~ N R2 CH3 room temp. CH3 R2 = H or CH3 (78): R2 = H
(79): R2 = CH3 ~OC H3 KH, DMF ~/""';~CH3 then CH31 o N/~R2 CH3 (80): R2 = H;
(81): R2= CH3 WO 96/12487 ~ ~ q ~ ~ 9 7 Q PCT/US95113305 OH f--~--SAc ~\/ Ph3P, DIAD, ~/~/
~ IN/--CH3 CH3COSH, ~ h~~CH3 CH3 CH3 (G) (76) 0.4 N NaOH, EtOH

" _"~ ~SR1 1 ~SH

O~\NI/J CH3 then R1 I CH3 CH3 CH3 (H) (82): Rl1 = CH3;
(83): R11 = CH2CH3;
(84): Rll = CH2CH2CH3 for compound (83):
oxone, MeOH/H20 -~ so2c H2c H3 O~N/--~CH3 (85) WO96/12487 ~ 9 9 ~ 7 9 PCT/US95/13305 ~"'~ H2, 1 0% Pd/C
EtOAc:MeOH (1 :1 ) ~o o ~ IH

~~ pyridine CH2C12 ~~X--' NH-Rl2 3 (103) Rl2= CO CH 1~~
(104) R12= -co ph r ~/ ~

~ ~ I----J' N H-Tos (1 05) WO96112487 ~ 9 ~ g ~ ~ PCI'IUS9S/13305 OH F~ Cl, Kl I

O N ~ ~ ~
~, O N (107) Cl H3CO~OCH3 (106) H3CO OCH3 H2, 20%Pd/C
MeOH ~\ o o~NI Cl ~~
H ~ (108) \~ O~N

NaH, C H31 ~10 o~ ~ \
H (110) R10- H CH3 (112) ~ ~~ .
O N (113) Cl WO96/12487 Q ~ 7 ~ PCT/US9S113305 _OH F~CH3, KH

DMF
O~N ~~ f ~

H3CO~OCH3 CH3 ~/'b ~OCH3 (114) ~~ ~ CI H2. 20%Pd/C

H (1 15) ~ ~, ~O ~ ~ CH3 ~--\~0~ CH 1' DMF

0=~/ CH3 H (11 7) o N CH3 CH3 (1 18) WO96/12487 ~ 9 ~ ~ ~ PCT/US9S/13305 - 6~S -~" OH ~I~ OMs '~ Ms20,pyridine /'~~~~
O~N~ DMAP O~N/--~
(1 1 9) (76) ArSNa, THF

~--S(O)Ar SAr O Nl '~/\X
CH3 Ar= phenyl (125) O N
I

mCPBA, CH2C12 phenyl (1 20) 4-chlorophenyl (121 ) 4-fluorophenyl (1 22) 4-methylphenyl (123) ~~~ S(O)2Ar 4-methoxyphenyl (124) ;~~/

O~N~~ Ar= phenyl (126) ' Ar ArCH2P(o)(oEt2) O~N-- NaH, DMF O N
3 (62) H3C
/ Phenyl (127) / 4-chlorophenyl (128) / 4-methylphenyl (129) 3-pyridyl 5%Rh/C, EtOH, H

~\ ~
~~ ~ \Ar Ar 4-chlorophenyl (1 30) O~N~ 4-methylphenyl (131 ) 3-pyridyl (1 32) WO96/12487 ~ Q 7 ~ PCT/US95/13305 In another embodiment of this invention there is provided a combination method involving the use of a 5cx-reductase 1 and/or 2 inhibitor, in combination with a retinoid agent, including but not limited to, e.g., tretinoin (all-trans-retinoic acid, RETIN A) and isotretinoin (13-5 cis-retinoic acid, ACCUTANE), and at least one agent selected from: an antibacterial, an anti-infl~mm~tory, and a keratolytic, or combination thereof, in the prevention of acne vulgaris by topical and/or ,systemic administration.
The activity of the compound.s a~s ,selective Soc-reductase I or 10 2 inhibitor.s, or dual inhibitors, can be determined by the following Biological assays:

BIOLOGICAL ASSAYS

15 Preparation of Human pro,static and ,scalp 5a-reductase,s Samples of human tissue were pulverized using a freezer mill and homogenized in 40 mM pota,ssium phosphate, pH 6.5, 5 mM
magnesium sulfate, 25 mM pota,ssium chloride, I mM phenylmethyl-sulfonyl fluoride, 1 mM dithiothreitol (DTT) containing 0.25 M sucro,se 20 using a Potter-Elvehjem homogenizer. A crude nuclear pellet was prepared by centrifugation of the homogenate at 1~500xg for 15 min. The crude nuclear pellet was washed two times and resu.spended in two volumes of buffer. Glycerol was added to the resuspended pellet to a final concentration of 20%. The enzyme suspension was frozen in 25 ali~luot,s at -~s0~C. The prostatic and .scalp reductase,s were stable for at lea,st 4 month,s when stored under these conditions.

Cloned çnzvme protocol:
For IC50 determinations, the te,st 5~-reducta,se 1 and 2 30 inhibitors were di,ssolved in ethanol and serially diluted to the appropriate concentration. The baculoviru,s-expres,sed recombinant type 1 5OC-reductase wa~s preincubated with inhibitor (0.1-1.000 nM) in 40 mM
sodium phosphate, pH 7.0, 500 !lM NADPH, ImM DTT and 1 mg/ml BSA for 1~ h at 4~C. The reaction was initiated by the addition of 17-a ~ ~ s s 7 s WO g6/12487 PCT/US9S/13305 3H]T (NEN, 20 Ci/mmol) and NADPH to a final concentration of 0.3 ~lM and NADPH and incubated at 37~C for 90 min. Similarly, baculovirus-expressed type 2 5a-reductase was preincubated with inhibitor (1-10,000 nM) in 40 mM sodium citrate, pH 5.5, 500 ~lM
NADPH, lmM DTT and 1 mg/ml BSA for 1~ h at 4~C. The reaction was initiated by the addition of [7-3H]T (NEN, 20 Ci/mmol) and NADPH to a final concentration of 0.3 ~M and 500 ,uM, respectively. The conversion of T to DHT was monitored using a radioflow detector following separation by reverse phase HPLC (Wh~ n RACII C l 8 column, lml/min 0.1% TFA in water;methanol (42:5~); retention time~ T, 6.3 min, DHT, 9.7 min).

50c-reducta,se assay The reaction mixture for the type 1 50c-reductase contained 40 mM potassium phosphate, pH 6.5, 5 !lM [7-3H]-testosterone, 1 mM
dithiothreitol and 500 ,uM NADPH in a final volume of 100 ,ul. The reaction mixture for the type 2 5a-reducta.se contained 40 mM sodium citrate, pH 5.5, 0.3 ~lM [7-3H]-testosterone, I rnM dithiothreitol and 500 !lM NADPH in a final volume of 100 ,ul. Typically, the assay wa.s initiated by the addition of 50-100 ,ug prostatic homogenate or 75-200 llg scalp homogenate and incubated at 37~C. After 10-50 min the reaction was yuenched by extraction with 250 ~1 of a mixture of 70%
cyclohexane: 30% ethyl acetate containing 10 ,ug each DHT and T. The a~lueous and organic layer.s were separated by centrifugation at 14,000 rpm in an Eppendorf microfuge. The organic layer was subjected to normal phase HPLC (10 cm Wh~tm~n partisil 5 silica column equilibrated in 1 ml/min 70% cyclohexane: 30% ethyl acetate; retention times: DHT, 6.~-7.2 min; androstanediol, 7.6-8.0 min; T, 9.1-9.7 min).
The HPLC system consisted of a Waters Model 680 Gradient System e~uipped with a Hitachi Model 655A autosampler, Applied Biosystem.s Model 757 variable UV detector, and a Radiomatic Model A120 radioactivity analyzer. The conversion of T to DHT was monitored u,sing the radioactivity flow detector by mixing the HPLC effluent with one volume of Flo Scint 1 (Radiomatic). Under the conditions described, the WO96/12487 6~ g 7 ~ PCT/US95/13305 production of DHT was linear for at least 25 min. The only steroid,s observed with the human prostate and scalp preparation.s were T, DHT
and androstanediol.

5 lnhibition studies Compounds were dissolved in 100% ethanol. ICso value,s represent the concentration of inhibitor required to decrease enzyme activity to 50% of the control. IC50 values were determined using a 6 point titration where the concentration of the inhibitor was varied from 10 O.ltolOOOnM.
A compound referred to herein as a 50c-reductase 1 inhibitor is a compound that shows inhibition of the Scx-reductase I isozyme in the above-described assay, having an ICso value of about or under 600 nM.
A compound referred to herein a~s a So~-reductase 2 inhibitor 15 i,s a compound that shows inhibition of the So~-reductase 2 isozyme in the above-described assay, having an ICso value of about or under 600 nM.
A compound referred to herein a,~ a dual Sa-reductase I and 2 inhibitor is a compound that shows inhibition of both the So~-reductase 1 and 2 isozyme~ in the above-de,~cribed as,~ay. having an ICso v~lue for 20 each of type 1 and type 2 of about or under 600 nM, and preferably 1 00 nm.

Fuzzy Rat Acne Model Adult fuzzy rats are a varie~y of rat that has ,stunted hair 25 growth, brown colored seborrhea covering their entire back skin and abnormally increased sebum production after puberty that has been demonstrated to be due to circulating androgens. 0.1, 0.05 and 0.025%
,solutions of a selected 50~-reductase inhibitor of interest are prepared in a vehicle of propylene glycol, isopropanol, isopropyl myristate and water 30 (50/30/2/1~%), and is topically applied onto the backs of adult male fuzzy rats, 0.2 ml per ~nim~l daily for 4 weekls. Control.s receive the vehicle alone and S of them are castrated. After 2 week.s seborrhea will be dose-dependently depleted and after 4 weeks bromodeoxyuridine (BrdU, 200 mg/kg) is intraperitoneally injected 2 hours before .sacrifice.

WO 96112487 ~ 9 PCT/US95/13305 The skin tissues are incubated with EDTA (20 mM) in phosphate buffer, 1.5 hours at 37~C. The pilo-sebaceous unit attached to the epidermis is striped from the dermis and fixed with formalin for immllno-staining of BrdU. DNA synthesis cells showing a BrdU-positive nucleus are located in the outer glandular border. The number of S-phase cells per lobe i.s deterrnined with a micro-image apparatus. Using forrnalin fixed skin, frozen serial sections are stained with 1% osmium and the size of the lobes is measured. A positive inhibitor of skin 5Oc-reductrase will induce ,suppression of sebum production by inhibiting the rate of glandular cell 10 turnover, and showing reduced lobular size.
Representative compounds of Formulas I and Il were tested in the above described inhibition assay for Sor~-reductase type 1 and type 2 inhibition. For the inhibition of 5cc-reductase type 1, the compounds have IC50 values lower than 600 nM, with the majority of compounds in 1~ general having ICso values ranging from about 0.3 nM to about 200 nM.
For the inhibition of 50c-reductase type 2, the same compounds have IC50 values greater than about 155 nM, with the majority of compounds having ICso values greater than 1000 nM. The compounds in general have at least a 2-fold greater selectivity for inhibition of Soc-reducta.se 20 type 1 over type 2, with the majority of the compounds having a 10-fold or greater .selectivity for inhibition of 5(x-reductase type 1 over type 2.
The,se results demonstrate the utility of the compounds of the instant invention i~or the treatment of hyperandrogenic conditions.
A compound referrred to herein as a Soc-reductase 1 inhibitor 25 is a compound that shows inhibition of the 5(x-reductase 1 isozyme in the above-described assay.
A compound referrred to herein as a 5cc-reductase 2 inhibitor is a compound that shows inhibition of the 5(x-reductase 2 isozyme in the above-described assay.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the WO96/12487 ~ 9 9 ~ ~ PCT/US9S/13305 invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the m~mm~l being treated for any of the indications for the compounds of the invention indicated above.
S Likewi.se, the specific pharmacological response~s observed may vary according to and depending upon the particular active compound ,selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance 10 with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the .scope of the claims which follow and that such claims be interpreted a~s broadly as is reasonable.
Retinoid agents useful in the invention include; tretinoin (all trans retinoic acid, RETIN A), isotretinoin ( I 3-ci~s retinoic acid, 15 ACCUTANE), vitamin A derivatives, and the like. Retinoid agent.s are primarily involved in decreasing sebum production.
Antibacterials useful in the instant invention are active against variou,s bacteria which are a.~ociated with acne and include Gram-positive and Gram-negative clas.ses of bacteria. One particular 20 bacteria which i,s as.sociated with acne i~s Propi~ni~7acte~ ium acne.
The antibacterial can be selected from the cla.sses of aminoglycosides, amphenicol.s, ansamycins. beta-lactams including carbapenems, cephalosporins, cephamycin~. monobactams, oxacephem.s, penicillins; lincosamides, macrolides, polypeptide.s, tetracyclines, 2,4,-25 diaminopyrimidines" nitrofuran.s, quinolone.s, .sulfonamides" .sulfones, andother structural types.
- Specific antibacterialls which are non-limiting are listed in The Merck Index, Elevcnth Editi~n, 19~9, (published by Merck &
Co. Inc.) and include the following:
Amino~lycosides:
amikacin, apramycin, arbekacin, bamberrnycins, butirosin, dibekacin, dihydrostreptomycin, fortimicin(s), gentamicin, isepamicin, kanamycin, micronomicin, neomycin, neomycin undecylenate, ~ 9~ 97 9 netilmicin, paromomycin, ribostamycin, .sisomicin, spectinomycin, streptomycin, streptonicozid, tobramycin Amphenicols:
azidamfenicol, chloramphenicol, chloramphenicol palmitate, chloramphenicol pantothenate, florfenicol, thiamphenicol ~nsamyclns:
rifamide, rifampin, rifamycin SV, rifaximin Beta-Lactam,s:

Carbapenems:
imipenem Cephalosporins:
cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin, cefixime, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiarn, cefpimizole, cefpiramide, cefpodoxime proxetil~ cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin, cephaloridine, cephalosporin C, cephalothin, cephapirin sodium, cephradine, pivcefalexin Cephamycins:
cefbuperazone, cefmetazole, cefminox, cefotetan, cefoxitin Monbactams:
aztreonam, carumonam, tigemonam Oxacephems:
flomoxef, moxolactam 99 9~ 9 Penicillins:
amidinocillin, amidinocillin pivoxil, amoxicillin, ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin, bacampicillin, benzylpenicillinic acid, benzylpenicillin sodium, carbenicillin. carfecillin sodium, carindacillin, clometocillin, cloxacillin, cyclacillin, dicloxacillin, diphenicillin ,sodium, epicillin, fenbenicillin, floxacillin, hetacillin, lenampicillin, metampicillin, methicillin sodium, mezlocillin, nafcillin sodium, oxacillin, penamecillin, penethamate hydriodide, penicillin G
benetll~mine, penicillin G ben7.~tl~ine, penicillin G benzhydrylamine, penicillin G calcium, penicillin G hydrabamine, penicillin G potas,sium, penicillin G procaine, penicillin N, penicillin O, penicillin V, penicillin V
ben7.~thine, penicillin V hydrabamine, penimepicycline, phenethicillin potassium, piperacillin, pivampicillin, propicillin, (luinacillin, sulbenicillin, talampicillin, temocillin, ticarcillin Linco.samide~s:
clindamycin, lincomycin Macrolides:
azithromycin, carbomycin, clarithromycin, erythromycin, erythromycin acistrate, erythromycin e.stolate, erythromycin glucoheptonate, erythromycin lactobionate, erythromycin propionate, erythromycin .stearate, josamycin, leucomycins. rnidecamycins, miokamycin, oleandomycin, primycin, rokitarnycin, rosaramicin, roxithromycin, spiramycin, troleandonlycin Polypeptides:
amphomycin, bacitracin, capreomycin, colistin, enduracidin, enviomycin, fusafungine, gramicidin(,s), gramicidin S, mikamycin, polymyxin, polymyxin B-methanesulfonic acid, pristinamycin. ristocetin, teicoplanin, thio,strepton, tuberactinomycin, tyrocidine, tyrothricin, vancomycin, viomycin, viomycin pantothenate, virginiamycin, zinc bacitracin ~ 7 9 WO 96/12487 P~l/U~351l33os Tetracyclines:
apicycline, chlortetracycline, clomocycline, demeclocycline, doxycycline, guamecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, penimepicycline, pipacycline, 5 rolitetracycline, sancycline, senociclin, tetracycline 2.4-Diaminopyrimidines:
brodimoprim, tetroxoprim, trimethoprim 10 Nitrofurans:
furaltadone, furazolium chloride, nifuradene, nifuratel, nifurfoline, nifurpirinol, nifurprazine, nifurtoinol, nitrofurantoin Ouinolone.s:
amifloxacin, cinoxacin, ciprofloxacin, difloxacin, enoxacin, fleroxacin, flumequine, lomefloxacin, miloxacin, nalidixic acid, norfloxacin, ofloxacin, oxolinic acid, pefloxacin, pipemidic acid, piromidic acid, rosoxacin, temafloxacin, tosufloxacin, OPC 7251 (Otsuka) a fluoro4uinolone Sulfonamides:
acetyl sulfamethoxypyrazine, acetyl sulfi,soxazole, azosulfamide, benzylsulfamide, chloramine-B, chloramine-T, dichloramine-T, formosulfathiazole, N-formylsulfisomidine, N-beta-D-25 glucosylsulf~nil~mide, mafenide, 4'-(methylsulfamoyl)sulf~nil~nilide, p-nitrosulfathiazole, noprylsulfamide, phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine, succinylsulfathiazole.
sulfabenzamide, sulfacetamide, sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine, sulfadicramide, sulfadimethoxine, .sulfadoxine, 30 sulfaethidole, sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid, sulfamerazine, sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine, sulfamethoxazole, sulfamethoxypyridazine, sulfametrole, sulfamidochrysoidine, sulfamoxole, sulf~nil~mide, sulf~nil~midomethanesulfonic acid triethanolamine salt, 4-~ ~gg 97 ~ ~

sulfanilamidosalicylic acid, N-sulfanilylsulf~nil~mide, sulfanilylurea, N-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine, sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine, sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea, sulfatolamide, sulfisomidine, 5 sulfisoxazole Sulfones:
acedapsone, acediasulfone, acetosulfone sodium, dapsone, diathymosulfone, glucosulfone sodium, solasulfone, succisulfone, 10 sulfanilic acid, p-sulfanilylbenzylamine, p,p'-,sulfonyldianiline-N,N'-digalacto,side, sulfoxone sodium, thiazolsulfone Others:
cycloserine, mupirocin, tuberin, clofoctol, hexedine, 15 methenamine, methenamine anhydromethylene-citrate, methenamine hippurate, methenamine mandelate, methenamine ~sulfosalicylate, nitroxoline, xibornol and benzoyl peroxide.
Very useful antibacterial.s in the invention method are the following: clindamycin, erythromycin, teracycline, benzoyl peroxide 20 meclocycline, chloramphenicol, neomycin, metronidazole, and OPC 7251 (Ot.suka).

Keratolytic agents useful in the instant invention in some in,stance,s are active a,s bactericidal agents that can be uised for the 25 treatment of mild acne, e.g., salicylic acid. By the term "keratolytic agent" as used herein is meant a compound that displays properties of a keratolytic and can in some instances also display properties of an antibacterial, e.g., benzoyl peroxide. Keratolytics act by improving inflammatory and/or noninfl~mm~tory acne lesions by reducing the 30 population of P. acnes and facilitating a decrease in hyperkeratosis.
Specific keratolytics which are non-limiting are listed in The Merck Index, Eleventh Edition, 19~9, (published by Merck & Co. Inc.) and include the following: algestone acetophenide, azelaic acid, cyoctol, ~ 9 7 9 dichloroacetic acid, metronidazole, motretinide, resorcinol, salicylic acid, sulfur, tetroquinone, and alpha-hydroxy acids including glycolic acid.
Vely useful keratolytics in the invention method are the following: azelaic acid, salicylic acid, and glycolic acid.
Anti-infl~mm~tories useful in the instant invention are active against infl~mm~ion caused by various bacteria which are a~sociated with acne and include Gram-positive and Gram-negative clas.ses of bacteria. One particular bacteria which is as~ociated with acne is Propionibacterium acne.
The anti-infl~mm~tory can be steroidal or non-steroidal.
The non-steroidal anti-infl~mm~tory can be selected from the cla~e.s of aminoarylcarboxylic acid derivatives, arylacetic acid derivative.s, arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acid derivatives, pyrazoles, pyrazolone~, salicylic acid derivatives, thiazinecarboxamides, and other structural types.
Specific non-.steroidal anti-infl~mm~tories which are non-limiting are listed in The Merck Index, Eleventh Edition, 19~9, (published by Merck & Co. Inc.) and include the following:

Aminoarylcarboxylic acid derivatives:
enfenamic acid, etofenamate, flufenamic acid, i.~ionixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate, tolfenamic acid Arylacetic acid derivatives:
acemetacin, alclofenac, amfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenclofenac, fenclorac, fenclozic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac, isoxepac, lonazolac, metiazinic acid, oxametacine, proglumetacin, sulindac, tiaramide, tolmetin, zomepirac Arylbutyric acid derivatives:
bllm~li70n, butibufen, fenbufen, xenbucin WO 96/12487 ~ ~ ~ 9 g 9 ~1 9 PCTIUS9S/13305--~rylcarboxylic acid~s: r clidanac, ketorolac, tinoridine Arylpropionic acid derivatives:
alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, miroprofen, naproxen, oxaprozin, piketoprofen, pirprofen, pranoprofen, protizinic acid, suprofen, tiaprofenic acid Pyrazoles:
difenamizole, epirizole Pyrazolone.s:
apazone, benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, ramifenazone, .suxibuzone, thiazolinobutazone Salicylic acid derivatives:
acetaminosalol, aspirin, benorylate, bromosaligenin, calcium acetylsalicylate, diflunisal, eter,salate, fendosal, genti.sic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, me.salamine, morpholine salicylate, l-naphthyl .salicylate, olsalazine, parsalmide, phenyl acetylsalicylate, phenyl ,salicyla~ alacetamide, salicylamide O-acetic acid, salicylsulfuric acid, sal.salate, sulfasalazine Thiazinecarboxamide derivative.s:
droxicam, isoxicam, piroxicam, tenoxicam Other Structural Types:
epsilon-acetamidocaproic acid, S-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, difenpiramide, ditazol, emorfazone, guaiazulene, nabumetone, WO96/12487 ~ ~ 7 9 PCTIUS9S113305 nimesulide, orgotein, oxaceprol, paranyline, perisoxal, pifoxime, proquazone, proxazole, tenidap Specific steroidal anti-infl~mm~tories are listed in The 5 Merck Index, Eleventh Edition, 1989, (published by Merck & Co. Inc.) and include the following:

Glucocorticoids:
21-acetoxypregnenolone, alclometasone, algestone, 10 amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, de,soximetasone, dexamethaxsone, diflorasone, diflucortolone, defluprednate, enoxolone, fluazacort, flucloronide, flumethasone, l~S flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone ~lujorometholone, fluperolone acetate, fluprednidene acetat, fluprednisolone, flurandrenolide, formocortal, halcinonide, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, hydrocortisone acetate, hydrocortisone phosphate, hydrocorti.sone 21-sodium succinate, 20 hydrocortisone tebutate, maziprednone, medrysone, meprednisone, methylprednisonole, mometasone furoate, paramethasone prednicarbate, prednisolone, predni,solone 21-diethylaminoacetate, prednisolone sodium phosphate, predni,solone sodium succinate, prednisolone ,sodium 21-m-sulfobenzoate, prednisolone 21-stearoylglycolate, prednisolone tebutate, 25 prednisolone 21-trimethylacetate, prednisone, prednival, prednylidene, prednylidene 21-diethylaminoacetate, tixocotrol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide.
Very useful anti-infl~mm:~tories in the invention method are 30 the following:glucocorticoids, including prednisone, predni,solone and the like.
The 5 alpha reductase 1 or 2 inhibitor, or mixture thereof, retinoid agent, anti-fl~mm~tory, keratolytic and anti-infl~mm~tory can each be ~-1ministered orally, systemically or topically, as separate or WO96/1248~ Q9 ~ 7 9 PCT/US95113305~

concurrent dosage forms, or together as one formulation. A useful protocol is the use of the anti-infl~mm~tory, keratolytic and antibacterial topically and the use of the 5 alpha reductase 1 and/or 2 inhibitor orally.
For combination treatment where the combination agents are in separate S dosage formulations, they can be administered concomitantly, or they each can be a-lministered separately at staggered times.
For example, a compound of Formula I, e.g., 4,7-beta-dimethyl-4-aza-5-alpha-cholestan-3-one, and retinoid, i.e., tretinoin, can be administered together in a single topical dosage formulation, or each active agent can be separately administered in a particular dosage formulation, e.g., as a separate oral (50c-reductase inhibitor) and topical (retinoid) dosage formulations, or a topical dosage formulation of the retinoid in combination with an oral dosage formulation of a compound of Formula I. See, e.g., U.S. Patent No.'s 4,377,5~4 and 4,760,071 which describe dosages and formulations for 5c~-reductase inhibitors.
One useful combination is tretinion, erythromycin and a 5(x-reductase 1 inhibitor, e.g., 3-oxo-4-aza-4,7,B-dimethyl- 16~-(4-chlorophenoxy)-50c-androstane.
In the methods de.scribed above, the daily dosage of the 5 alpha reducta.se 1 inhibitor compounds of Formula I and II may be varied over a wide range from 0.1 mg to 1,000 mg per adult human/per day. An effective amount of one of the novel compounds of this invention is ordinarily from about 0.002 mgs/kg to 50 mg.s./kg of body weight per day, and more particularly the range is from about 0.01 mgs/kg to 7 mgs/kg of body weight per day.
The daily dosage of the tretinoin is topically administered in a 0.025% to 0.1% by weight cream or gel.
The daily dosage of the isotretinoin is systemically from about 0.01 mg/kg to 2 mg/kg per adult human/per day.
The daily dosage of the keratolytic is topically ~flministered in a 0.025% to 0.1% by weight cream or gel.
The daily dosage of the antibacterial systemically is from about one mg to 2000 mg per adult human/per day, and more particularly from about 200 mg to 1000 mg per adult human/per day. The daily ~ 7 ~

- ~3 -amount of antibacterial is from 1 mgs/l~g to 50 mg.s/kg of human body weight daily.
The daily dosage of the anti-inflarnmatory topically or systemically is from about 0.01 mg to 2000 mg per adult human/per day, 5 and more particularly from about one mg to 1000 mg per adult human/per day. The daily amount of anti-infl~mm~tory is from 0.02 mgs/kg to 40 mgs/kg of human body weight daily.
For mild to moderate acne, topical daily therapy is generally indicated to avoid the side effect,s of the more rigorous systemic therapy 10 with its attendant side effects. For moderate to ~evere acne, systemic therapy is generally used, which can also be combined with topical therapy, where warranted. Duration of therapy, depending on the .severity, can la.st for 3-6 months, and in some cases, for several years.
Advantageously, the combination of the present invention 15 may be a~lmini~tered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. The combination for the present invention can also be ~lmini~tered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal route.s, using those forms of transdermal skin patches well 20 known to those of ordinary skill in that art. To be ~lministered in the form of a transdermal delivery system, the dosage a(lministration will, of course, be continuous rather than intermittent throughout the dosage reglmen.
For the treatment of acne vulgaris, the compounds of the 25 instant invention can also be combined with a therapeutically effective amount of a 5O~-reductase 2 inhibitor, such as finasteride, in a single oral, systemic, or parenteral pharmaceutical dosage formulation. Also, for the skin and scalp related disorders of acne vulgaris, the compounds of the instant invention and a 5O~-reductase 2 inhibitor can be formulated for 30 topical ~lmini.~tration. Alternatively, a combined therapy can be employed wherein the compound of Formula I and the 5c~-reductase 2 inhibitor are ~lmini~tered in separate oral, systemic, parenteral or topical dosage formulations. For example, a compound of Formula I and finasteride can be a~lmini~tered in a single oral or topical dosage WO 96/12487 ~ 7 PCT/US9S/13305~

formulation, or each active agent can be administered in a separate dosage formulation, e.g., in separate oral dosage formulations, or an oral dosage formulation of finasteride in combination with a topical dosage formulation of a compound of Formula I. See, e.g., U.S. Patent No.'~
5 4,377,5~S4 and 4,760,071 which describe dosages and formulations for Soc-reductase inhibitors. Where the active agents are in separate dosage formulations, they can be ~clministered concomitantly, or they each can be administered at separately staggered times.
Other 5~x-reductase 2 inhibitors, both steroidal and non-10 steroidal, which can be employed in the instant invention include (listed by company of development and publications/patents containing the pertinent disclosure):

STEROIDAL:
SmithKline Beecham (SKB) -Epristeride (SK&F 105657) described in PCT applications: WO91/13550, WO 93/19758; 4-aza-un~sat'd-steroid-17-acyl derivatives which are described in WO 94/00121; 17-acyl-3-carboxyestranes which are described in WO 94/00125; 17-(ar)alkylacyl 20 analogs as dual inhibitor~ and described in WO94/11386; 170c-acyl-3-carboxysteroid,s which are described in WO 94/1138s5;

Sankyo - Japanese Patent J05/170789, which de.~;cribes l l-oxygenated 4-aza-17-(benzhydrylcarbamoyl) steroids; ~T05/213987, which describes B-25 noranalogs; EP 048s4094 which discloses 17-N-(benzhydryl; benzyl carbamoyl) analogs as SKB type inhibitors;

Glaxo - WO93/13124 and US 5,52~,5~9 which describe 4,6-cyclo-6-aza derivatives; WO 94/14833, which describe~ 6-aza-17-aryl X compounds.
30 including e.g., anilides;

Farmitalia -Turosteride, US 5,155,107 contains the azasteroid disclosure and WO 92/20700 discloses SKB analogs; WO 94/03475 discloses fluorinated amide side-chains; WO 94/03474 and WO 94/03476 disclose 35 17-carboxamides of o~-aminoketones and fluorinated acyl ureas; ~reat ~ 7 g Brit~in Patent 2,273,096 describes azasteroidal 16,17-piperidinone derivatives;

Ciba-Gei~y - EP 0538192, which discloses 4-azasteroidal 17-acyls with 5 cyano substitution;

Richter Gedeon - WO 94/07909, which discloses piperidino/pyrrolidino 4azasteroidal 17carboxamides;

10 Merrill-Dow - US 5,143,909, US 5,120,g40 and US 5,130,424, which disclo,se 4-amino-3-oxo-4-ene steroids; EP 435321, which di.scloses A-nor-3-carboxysteroid.s;

NON-STEROIDAL:
Fujisawa - J05/178856, which discloses indolidine-butyric acid~; WO
93/05019, which discloses 3,4-disubstd indole derivatives; EP 0519353, which discloses indolizines; WO 93/16996, which disclo.se~s 1,3-di,sub,stituted indoles;
Ono - J05140062,which di,scloses nitro sub,stituents on oxybutric bearin~
ring;

Kyowa Hakko Ko vo KK - EP 511477, which discloses a 5-substituted 2~ indole on an Ono like structure, particularly KF- 1867~ (Al,~o described by T. Kumazawa, Pharmac. Soc. Japan, 114th Mtg, Abstract 30);

Pfizer- WO 93/02050, which di,sclo,ses 1,3-disubstituted indole Ono-Fujisawa type compounds;
Yamanouchi - WO 13828, which discloses Ono-like compounds with reversed amide linkages; WO 93/24442 and JP 05331059 which di,sclose p-sub.stituted benzoic acids;

WO96/12487 ~ 9 ~ 7 9 PCT/US95/13305 - g6 -Mitsubishi Kasei - EP 579223, which discloses benzamide derivative,s ofl-amino-6-carboxydecalines; JP 06025211, which disclose.s flavone-2-benzoic acids; JP 06025277, which discloses 16-ring dilactone tetraenes (Snow Brand Milk Prod Co Ltd.);

I,illy - EP 0532190, 0591582, 05915~s3) which disclose azaphenanthrenes;

Indena SpA - Extracts of Curcubita .seeds di.sclolsed in FR269~791.
The dosage regimen utilizing the compound~i of the pre~ent invention is selected in accordance with a variety of factors includin~
type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the 15 renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug re~luired to prevent, counter, arrest or reverse the progress of the condition.
Optimal preci.sion in achieving concentration of drug within the range 20 that yields efficacy without toxicity re~uires a regimen based on the kinetics of the drug's availability to target sites. This involves a con~ideration of the distribution, equilibrium. and elimination of a drug.
In the methods of the present invention the combination of 5 alpha reductase I and/or 2 inhibitor, ~ retinoid, e.g., tretionoin/
25 isotretinoin, antibacterial, keratolytic and anti-infl~mmatory, herein described in detail, are typically ~lmini$tered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably .selected with re~pect to the intended form of administration, that is, oral tablet.s, capsule.s, elixirs, 30 .syrups and the like, and consi.stent with conventional pharmaceutical practices.
Oral ~lministration can be conducted in the form of a tablet or capsule, the combination drug component.s can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, ~ ~2~9~ ~7~

- ~7 -glycerol, water and the like. Capsule,s cont~ining the combination agents of this invention can be prepared by mixing combination agents of the present invention with lactose and magnesium stearate, calcium stearate, starch, talc, or other carrier.s, and placing the mixture in gelatin capsule.
5 Tablets may be prepared by mixing the combination ingredients with conventional tableting ingredients such as calcium pho.sphate, lactose.
corn starch or magnesium stearate. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binder.s include 10 starch, gelatin, natural sugar~s such as glucose or beta-lacto~se, corn ,sweeteners, natural and synthetic gums such a,s acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, ,sodium benzoate, sodium acetate, 15 sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The oral composition,s can be provided in the form of scored or unscored tablets cont~ining 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, and 100.0 milligram,s of the active ingredients, the 5 alpha reductase 1 inhibitor, 20 tretinoin/isotretinoin, anti-infl~mm~tory, keratolytic, antibacterial. for the symptomatic adju,stment of the dosage to the patient to be treated.
Topical pharmaceutical composition,s may be, e.g., in the form of a solution, cream, ointment, gel, lotion, shampoo or aerosol formulation adapted for application to the ,skin. Topical pharmaceutical 25 compositions useful in the method of treatment of the pre,sent invention may include about 0.001% to 15% by weight each of 5 alpha reductase 1 inhibitor compound, anti-infl~mm~tory, keratolytic, antibacterial in admixture with a pharmaceutically acceptable carrier. Topical preparations containing the combination active drug components can be 30 admixed with a variety of carrier material,s well known in the art, such as, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, PPG2 myristyl propionate, and the like, to form, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin WO 96/12487 ~ PCIIUS95113305 lotion,s, and ~shampoos in cream or gel formulation~s. See, e.g., EP 0 2~5 382.
Liquid forms of the combination can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, 5 topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. The liquid form~s can contain suitably flavored suspending or dispersing agents such as the synthetic and natural gum,s, for example, tragacanth, acacia, methyl-cellulose and the like. Other dispersing agents which may 10 be employed include glycerin and the like. For parenteral administration, sterile suspensionls and solutions are desired. I~sotonic preparation,s which generally contain suitable pre~servatives are employed when intravenous administration is desired.
The combination agents of the pre,sent invention can also be 15 administered in the form of liposome delivery ,system.s, ~such as small unilamellar ve.sicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipid,s, ,such as chole,sterol, stearylamine or phosphatidylcholine,s.
Compounds of Structures I and II, of the pre~sent invention, 20 can also be delivered by the use of monoclonal antibodie,s a,s individual carriers to which the compound molecules are coupled. The compounds of the present invention may al,so be coupled with soluble polymer,s a,s targetable drug carriers. Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol.
25 polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a cla~i~ of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyortho-30 esters, polyacetals, polydihydropyrans, polycyanoacrylate,s and cro~s-linked or amphipathic block copolymers of hydrogels.
The following examples are provided to further illustrate details for the preparation of the compounds of the pre~sent invention.
The examples are not intended to be limitation,s on the scope of the ~ 99 97 9 instant invention in any way, and they should not be so construed.
Furthermore, the compounds described in the following examples are not to be construed as forrning the only genus that i~ considered as the invention, and any combination of the compounds or their moieties may itself fo~n a genus. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are in degrees Celsius unless noted otherwise.
The Rf values cited were carried out on ,standard thin layer chromatographic Si gel plate,s. The elution .solvent system used is given in the parentheses following the Rf value.
The fast atom bombardment (FAB) mass spectral values are reported as (M+l) molecular ion peaks, being the molecular weight plu.s one atomic mass unit. The electron impact (EI) mass spectrum values are reported as molecular ion peaks and are indicated in parenthese.s, either being (M) or (M+2), the molecular weight, MW, or the MW plus two atomic units.
The nuclear magnetic re.~onance data wa,s taken at 400 MHz in CDC13 and is tabulated for uni~ue proton value~i of each compound at the end of the Examples. The coupling con.stant J is given in Hertz, Hz.

EXAMPLE I

Synthe.sis of 7-Oxo-Chole~terol-3-acetate~ ( I ) Cholesteryl acetate (CA) i,s known in the art and can be oxidized to the known 7-oxo-derivative 1 by the analogou,s procedure described in the JCS Perkins article by Pearson, "supra".

~ E~AMPLE 2 Synthesis of 7-Ethyl-7-Hydroxy-cholesterol~ (2) To a solution of I from Example 1, being 5.0 g (11.32 mmol) in dry tetrahydrofuran at 0~C was added dropwise 56.6 ml ethyl magnesium bromide ( 1 M) over 5-10 minute.~. The reaction mixture was 79 ~
WO 96/12487 ~ 2 PCTIUS9S/13305 ~ - 90 -then allowed to stir at room temperature for 24 hours, then poured intosaturated aqueous ammonium chloride. The THF ,solvent was removed under vacuum and the aqueous phase extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated to yield a 5 yellowish-white foam. The Rf value was 0.2 (30% EtOAc/hexane).
Proton NMR confirmed the assigned structure of the title compound '~
which was used in the next step without further purification.

Synthesis of 7-Ethyl-Cholest-4,6-Dien-3-one, (3) The above Grignard product _, 5.13 g ( I 1.9 mmol) wa,s dissolved in 50 ml toluene and cyclohexanone and about 40 ml of ~solvent distilled off under vacuum. To thi~s was added 7.2 g aluminum 15 i,sopropoxide and the reaction mixture refluxed overnight for 15 hour.s.
The mixture was cooled, diluted with ethyl acetate, washed with sodium potassium tartarate, brine, and the organic layer was concentrated under vacuum and the residue steam distilled. The residue was extracted with ethyl acetate, the ethyl acetate layer, washed with brine, dried and 20 purified by column chromatography on silica gel, eluting with 5%
EtOAc/hexane to yield the title compound 3. Rf=0.~ (20%
EtOAc/hexane). Mass spec: 412(M=I) by FAB, Calc'd. 411.9.

Synthe,sis of 7~-ethyl-chole,st-5-en-3-one. (4) To a solution of 3.1 g of 3, from Example 3, in 46 ml ammonia, 10 ml THF, 10 milliliters toluene, was added 449 mg of metallic lithium in ,small pieces. After .stirring the blue solution for 2 30 hours at -7~~C, a solution of 1,2-dibromethane in 2 ml THF was added.
After .stirring the solution at -7~~C for 10 minute,s, 2.1 g of ammonium chloride was added and the mixture stirred for 10 minutes. The exce~ss ammonia was removed by evaporation under a nitrogen stream. The reaction mixture wa.s diluted with brine, extracted with ethyl acetate. The WO96/12487 ~ ~ 199 9 7 9 P~ S/13305 organic layer was washed with brine, dried and concentrated to yield crude brown viscous liquid 4 which was used as such in Example 5.
Rf=0.70 (20% EtOAc/hexane). Mass Spec. 412 (EI); calculated MW
412.70.

Synthe,si,s of 7~-ethyl-cholest-4-en-3-one, (5) To a solution of 4, from Example 4, being 3.1 g in 30 ml THF wa,s added 1.1 ml DBU (l,~S-diazabicyclo[5.4,0]undec-7-ene under nitrogen with stirring. The mixture was refluxed for 1.5 hours, then cooled and diluted with NH4CI. Then THF ,solvent wa,s removed under vacuum and the residue extracted with ethyl acetate. The organic layer was then washed with water, brine, dried and concentrated under reduced pressure to yield a crude viscous oil. The titled product 5 was purified by chromatography on silica gel using 10% EtOAc/hexane as eluant. Mass Spec 412 (EI), calc'd MW 412.70. Rf=0.6 (20% EtOAc/hexane).

Synthe,si,s of 7-ethyl- 17~-(6-methyl-2-heptyl)-5-oxo-A-nor-3,5-secoandrostan-3-oic acid. (6) To a solution of 1.0 g of 5 in I ~ ml t-butyl alcohol at ~0~C
was added 300 mg sodium carbonate in 1.~ ml water followed by a dropwise addition over 15-20 minutes of a mixture of 2.74 g .sodium periodate with 20.3 mg potassium permanganate in 15 ml water. The reaction mixture was heated at ~0~C for 2 hours, cooled, filtered, the residue washed with water, and then the filtrate concentrated under vacuum, acidified with aqueous HCI, extracted with ethyl acetate and the organic layer washed with a~lueous NaHSO3, brine, dried and concentrated to yield crude 6. The proton NMR confirmed the assigned ,structure. Fast atom bombardment yielded an m/z molecular ion of 434(m+2); calculated 432.69.

WO96/12487 ~ 2 ~ ~ ~ 9 7 ~ PCTIUS95113305 Synthesis of 7-Ethvl-4-methyl-4-aza-chole~t-5-en-3-one~ (7) To a solution of 6, 500 mg in 10 ml ethylene glycol wa~;
5 added 1.3 g sodium acetate and 1.0 g methylamine hydrochloride. After stirring the reaction mixture 4 hours at 1 ~0~C, the mixture was cooled, diluted with water, extracted with ethyl acetate, dried and concentrated to afford crude title compound 7. Proton NMR confirmed the a,ssigned structure. Rf=0.70 (20% EtOAc/hexane).
10 Mass Spectral m/z ion (FAB) ,showed 429 (M+2). calculated, 427.72.
Analysis: Calc. for C29H49 NO
Calcd: C, 81.44; H, 11.55; N, 3.27 Found: C, ~s2.19; H, 10.92; N, 3.11 EXAMPLE ~s Synthesis of 7-Ethyl-4-methyl-4-Aza-Cholestan-3-one, (~) To a solution of 7 from Example 7, being 1 ~0 mg in 5 ml 20 acetic acid was added 54 mg platinum dioxide and the resulting mixture was evacuated and flushed with hydrogen. The reaction was shaken overnight at room temperature under hydrogen. Filtered, washed solid with EtOAc, combined EtOAc layers were washed with aqueous NaHCO3, brine, dried, concentrated to yield the title compound ~s.
25 Mass spectral analysis by FAB yielded m/z ion of 431 (m+2), calculated 429.74.
Analysis for C29 H51 NO
Calcd: C, ~ 1.06; H, 11.96, N, 3.26 Found: C, ~1.42; H, 12.24; N, 3.16 , ~ 0 ~ ~ ~ 9 9 7 9 WO 96/12487 PCTIUS9S/1330~;

, ~XAMPLE 9 Svnthesi.s of 7-Ethyl-4-Aza-Cholest-5-en-3-one~ (9) The seco acid 6, 0.5 g. and amrnonium acetate, 0.5 g, in 3.5 ml acetic acid were refluxed for 3 hours. The reaction mixture was cooled, water added and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to yield a residue which was eluted on a silica gel colurnn with 10% EtOAc/hexane to give pure title compound 9, mp. 147-149~C.
Mass Spec. 414 (Mtl). Calc'd; 413.69.
Rf=0.45 (30% EtOAc/hexane).
Analysis for C2~H49 NO, MW 413.69 Calcd: C, 81.30; H, 11.45; N, 3.39 Found: C, gl.30; H, 11.87; N, 3.45 Synthe~is of 7,B-Ethyl-4-aza-Soc-cholestan-3-one. (10) Following the general analogous procedure described in Example 8, 9 wa,s catalytically hydrogenated to yield the titled compound, 10. Chromatography on ~ilic;~ gel with 50% EtOAc:hex~ne eluant yielded pure product, mp. 169- 170~C.
Analysis for C2~H4gNO, MW=415.17.
Calcd: C; 80.90; H, 11.88; N, 3.37 Found: C; 81.02; H, 12.57; N, 3.47 Mass Spec.: 416 (M+l) Rf=0.30 (30% EtOAc/hexane).

Svnthesi,s of 7-Allyl-3.7-dihydroxy-chole.st-5-ene. (11) Following the analogous general Grignard procedure of Example 2, allyl magnesium bromide was reacted with Compound 1 in 7 ~ ~

dry THF to yield the titled product 11. Proton NMR confirmed the assigned structure.
Ma~s Spec. 441 (M+ 1). Calc'd. 440.71.
Rf=0.25 (30% EtOAc/hexane).

Synthe~i~ of 7-allyl-cholest-4.6-dien-3-one. (12) Following the analogous general Oppenauer oxidation 10 procedure of Example 3, compound 11 wa.s oxidized to yield the titled compound 12. Proton NMR confirmed the a~.~iigned ~;tructure a~ well the (FAB) mas.s spec. 423 (M+l) Calc'd. 422.35.
Rf=0.7~ (30% EtOAc/hexane).

Synthesi~ of 7-Allyl-chole~t-5-en-3-one. (13) Compound 12, wa~ subjected to the analogou.s metal-ammonia reduction conditions of Example 4 to yield the title compound Rf=0.5 (5% EtOAc/hexane).

F,XAMPLE l$

Synthe~i~ of 7-Allyl-Chole~t-4-en-3-one, (14) Following the general DBU catalyzed i~omerization condition~ of Example 5, compound 13 wa~ analogou!ily treated to yield the title compound 14.
Ma~;~ Spec. 425 (M+l) by FAB. Calc'd.: 424.37 Rf=0.45 (5% EtOAc/hexane).

~ 2 ~ ~ 9 ~ 7 9 WO 96/12487 P~ J,,9S/13305 _ 95 _ Synthesis of 7-Propvl-cholest-4-en-3-one. (1~) 1.0 g of the 7-allyl-enone 14, 5 ml EtOAc and 50 mg 5 triphenylphosphine rhodium chloride (Wilkinson's catalyst) were allowed to stir two hours (under H2 atmosphere). The reaction products were filtered through 25 ml silica gel, and evaporated to dlyness to yield fairly pure title product, 1 g, as cor~llmed by proton NMR.
Mass Spec. 427 (M+l) Calc'd.: 426.39 10 Rf=0.15 (~% EtOAc/hexane).

Synthesis of 7-Propyl-5-oxo-A-nor-3.~S-seco-chole~tanoic acid. (19) Following the general procedure of Example 6 for the oxidative Ring A cleavage, compound 1~5 (7-propyl analogue) was analogously treated to yield the above-titled seco-acid 19. The assigned structure wa.~ confirmed by proton NMR.
Ma~s Spec.: 447 (M+1) (FAB) Calc'd.: 446.3 20 Rf=0.1 (20% EtOAc/hexane).

Synthesi~; of 7-Propyl-4-methyl-4-aza-cholest-5-en-3-one. (20) Following the general procedure of Example 7, compound 19, was analogously treated with methylamine hydrochloride and sodium acetate in ethylene glycol to yield the above-titled liquid product 20. The assigned structure was confirmed by proton NMR.
- Mass Spec. 442 (M+l) (FAB), Calc'd.: 441.74 C,H,N
30 analysis for C H N O as 0.2 H2O, MW=441.74;
Calcd: C, ~0.91; H, 11.63; N, 3.15 Found: C, 81.00; H, 12.06; N, 2.93 Rf=0.3 (20% EtOAc/hexane).

W096/12~87 ~ Q ~ ~ 7 ~ nJsgsll330s--Synthesi,s of 7-Propyl-4-methvl-4-aza-50~-cholestan-3-one, (21) Following the analogous general procedure of Example 8, 5 compound 20 was catalytically hydrogenated in HOAc to yield the title uid compound 21. Proton NMR confirrned the assigned structure.
Mass spec. 444 (M+l) (FAB), C,H,N analysis for C H N;
Calcd: C, ~sl.19; H, 12.05; N, 3.16 MW=443.41.
Found: C, ~0.7~; H, 12.06; N, 3.22 10 Rf=0.17 (20% EtOAc/hexane).

Synthesis of 7-Propyl-4-aza-cholest-;5-en-3-one, (22) Following the analogous procedure of Example 9, compound 19 was treated with ammonium acetate in acetic acid to yield the titled compound, 22. Recrystallized from EtOAc/Et2O to yield a white crystalline solid, mp. 91-94~C, C,H,N analysis a.s the 0.25 H2O
hydrate: Calc'd MW 427.39 20 Calcd: C, ~0.59; H, 11.54; N, 3.24 Found: C, ~0.59; H, 11.69; N, 3.36 M~i,s Spec. 42~ (M+l).

Synthe.sis of 7-Propyl-4-aza-5u-cholestan-3-one~ (23) Following the analogous procedure described in Example ~¢~
compound 22 was catalytically hydrogenated to yield the title compound 23, mp. 65-6~~C.
30 Analy.si.~ for C,H,N, calc'd as 0.25 H2O hydrate:
Calcd: C, ~0.21; H, 11.95; N, 3.23 Found: C, g0.20; H, 12.14; N, 3.07 Mass Spec. = 430 (M+l ) calc'd MW 429.40.
Rf=0.12 (20% EtOAc/hexane).

~ 99 979 Synthesi,s of 7-Methyl-7-Hydroxy-cholesterol. (24) Following the analogou,s Grignard procedure of Example 1, cholesteryl acetate-7-one 1 was reacted with methyl magnesium bromide under .standard Grignard conditions to yield title compound 24, a solid.
NMR confirmed the assigned structure and mass spectral analysis confirmed the molecular weight.

Synthe,sis of 7-Methyl-Cholest-4.6-Dien-3-one. (25) Following the analogous procedure of Example 2, the above Grignard product 24, was subjected to Oppenauer oxidation conditions to yield the title compound, 7,~-methyl-cholest-4,6-dien-3-one, 25.

Synthesi,s of 7,B-methyl-cholest-5-en-3-one. (26) Following the analogous procedure of Example 4 for the metal-ammonia reduction, 25 wa,s similarly treated with lithium in ammonia/THF/toluene to yield title compound 26.

Synthesi,s of 7~3-methyl-chole,st-4-en-3-one. (27) Following the general isomerization procedure of Example 5 u,~ing DBU in THF, 26 was analogously treated to yield the title 30 compound 27.

WO96/12487, ,~ Q PCI/US95/1330 _ 9~ _ Synthesis of 7-methyl- 17~-(2~6-Dimethylhexyl)-5-oxo-A-nor-3,5-.secoandrostan-3-oic acid~ (2~) Following the general procedure of Example 6 for the oxidative Ring A cleavage, compound 27 was analogous treated to yield the above titled seco-acid 2~S. The proton NMR confirmed the assigned .structure.

Synthe~sis of 7-Methyl-4-aza-cholest-5-en-3-one, (29) Following the general procedure of Example 9, compound 2~ was analogously treated with ammonium chloride in acetic acid to 15 yield the above-titled product 29.
Ma,s,s Spectral m/z ion (FB) ,showed 400.2 (M+l ) (M+2).calculated, 399.

Synthe.sis of 7-Methyl-4-Aza-Chole,stan-3-one, (30) Following the analogous general procedure of Example ~, compound 29 was catalytically hydrogenated in HOAc to yield the title compound 30.
25 Mass spectral analysis by EI yielded m/z ion of 401 calculated 401.

EXAMPLE 2~

Synthe,si,s of 7-Methyl-4-methyl-4-Aza-Chole,st-5-en-3-one, (31) The seco acid 2~, was treated analogou~ily a,s in Example 7 to give pure title compound 31.
Mass Spec. 414 (m+l ) by FAB, calc'd., 413.

WO96112487 ~ 9 9 7 9 PCTIUS9S/13305 _ 99 _ Synthesis of 7,B-Methyl-4-methyl-4-aza-~(x-cholestan-3-one~ (32) Following the general analogous procedure described in 5 Example g, 31 was catalytically hydrogenated to yield the titled compound, 32. Chromatography on silica gel with 30~ EtOAc/hexane, eluant yielded pure product.
Mass Spec. (EI) 415, calc'd., 415.

SYnthesi,s of 4-methyl-4-aza-chole.st-5-en-3,7-dione~ (34) An oxidation procedure is carried out on 4-methyl-4-aza-cholest-5-en-3-one 33 to yield the title compound, 34. (See USP
3,264,301 by Doorenboos and J. Org. Chem. 1961, Vol. 26, p. 454~.) The compound 33 was heated at 70~C with a mixture of pyridinium dichromate/t-butyl hydroperoxide in benzene over a 3-4 hour period to produce 34.

Synthe,sis of 7~-Acetoxy-4-methyl-4-aza-5Ol-cholestan-3-one. (37) Compound 34 is hydrogenated by the analogous procedure of Example 8 to produce the 7-H analog 35, and the 7~-ol, 36. Acylation 25 of 36 with acetic anhydride, in the presence of pyridine, 4-dimethylaminopyridine in methylene chloride at 23~C for 24 hrs.
produces the title compound 37.

Synthesi,s of 7-Beta Methyl-4-aza-5a-cholest- 1 -en-3-one. (49) To a solution of 280 mg (0.698 mmol) of 30 in 4 milliliters toluene, was added 178.8 mg DDQ, 0.7186 mg BSTFA and 8.163 mg triflic acid and the reaction contents allowed to stir at room temperature ~ ~ ~ Q 9 ~7 9 ~

for 24 hours: Methyl acetoacetate, ~s. l mg, was added and the reaction refluxed for 24 hours. The contents were cooled, diluted with ethyl acetate, washed with aqueous sodium carbonate, aqueous sodium bisulfite, brine, dried over magnesium sulfate and concentrated to yield 5 an oil. The crude compound was purified by preparative TLC on silica gel, eluting with 3:1 CHCl3/acetone to yield pure 49, whose proton NMR
confirmed the assigned structure.
The following Table list.s the unique proton NMR values (400 MHz in CDC13) for each compound. The data are reported as: s =
10 singlet, d = doublet, m = multiplet, J = coupling constant. The absorption values are given in delta (o) scale with a reference point signal from tetramethylsilane, and are illustrated for the C-l~, C-l9 and C-21 angular ring methyl protons and protons a,ssociated with uni~lue portions of the molecule.
The numbering of the 4-aza steroid is given by the following structure:

28~
-9~

0~ N~
R 4-azasteroid WO 96/12487 ~ PCT/US95/13305 - TABLE
Compound No. 1 ~¢-CH3 19-CH3 21 -CH3 Others 2 s 0.660 s 1.030 d 0.940 6H s 6.120 0.662 1.060 J=7 (values given for second isomer) 3 s0.755 .s 1.061 dO.91S 4Hand6Hs J=7 5.61, 5.97 4 s 0.720 s 1.110 d 0.930 4 CH2 m 2.~3 -J=7 3.28 s 0.730 s 1.12 d 0.930 4H s 5.74 J=7 6 s 0.66 s 0.963 d 0.~94 J=7 7 ,s 0.692 s 0.977 d 0.908 N-CH3 s 3.153 J=7 P~ s 0.690 s 0.830 d 0.900 N-CH3 s 2.93 9 s 0.653 s 0.991 d 0.903 6H d 4.91 J=4 J=7 s 0.675 s 0.~0~ d O.~S93 SH, m, 2.97 -J=7 3.13 11 s 0.66 s 0.90 d 0.915 allylic H m(5.~S-J=7 5.94) WO96/12487 ~ 9 ~1 Q PCI/US95113305 Compound No. 1 ~-CH3 19-CH3 21 -CH3 Other.s 12 s 0.7~ s 1.07 dO.96 allylic H m(5.73-J=7 5.85) 13 s 0.70 s 1.08d 0.90 6H, s (5.23) J=7 14 s 0.73 s 1.13d 0.93 4H ,s 5.72 J=7 1~ s 0.71 s 1.13d 0.93 4H s 5.71 J=7 19 s 0.65 s 0.963d 0.91 J=7 s 0.691 s 0.974d 0.902 (6H) - d,4.92 J=7 (J=4) (N-CH3) 3.16 21 s 0.665 s 0.795d 0.~3 J=7 (N-CH3) s 2.92 SH m (2.96-3.00) 22 s 0.6~0 s 1.01d0.~90 (6H) d 4.~6 J=7 J=4 23 s 0.680 s 0.808d 0.~4 SH m (3.0-3.1) J=7 24 s,0.6~, s,0.94,d 0.91 6H, s,5.19,5.21 0.69 1.04 J=7 ~ 7 9 WO 96/12487 ~ PCT/US9S/13305 Compound No. 1 ~-CH3 19-CH3 21 -CH3 Others s, 0.76 s, 1.07 dO.92 4H, 6H5.59, J=7 5.92 27 s, 0.70 s, 1.15 d 0.92 7-CH3, d, 1.04, J=7 J=6.5 4H, s, 5.71 2~ s, 0.69 s, 1.12 d 0.92 7-CH3, d, 0.96, J=7 J=6.5 29 s, 0.69 s, 1.04 d 0.91 7-CH3, d, 0.97, J=7 J=6.5 6H, d, 4.59, J=3.0 s, 0.67 s, 0.835 dO.91 7-CH3, d, 1.00, J=7 J=6.5 SH, dd, J=3.3, 12.63 31 s, 0.69 s, 1.00 dO.95 7-CH3, d, 1.05, J=7 J=6.5 6H, d, J=3.0 32 s, 0.6g .s, O.g25 dO.91, 7-CH3, d, 1.05, J=7H J=6.5 4-CH3, s, 3.92 33 s, 0.69 s, 1.23 dO.91 C6 - s, 5.42 J=7 N-CH3, s, 3.14 - Ma~s Spec (EI)=413 WO96/12487 ~ 91 PCT/US95/1330S--Compound No. I g-CH3 19-CH321 -CH3 Others 49 s, 0.69 s, 0.90d 0.915 C-7CH3, 1.02, J=7 d, J=6, C-2, 1 H, 5.79, dd J=2.5 J=9.1 s, 0.62 s, 1.01d 0.~6 C-5, lH, 3.02, J=7 dd J=3.~7 J=12.9 C-7Ph, SH, m, 7.1-7.3 51 s, 0.63 s, 1.02d 0.2 C-5, l-H, 3.2, dd J=7 J=5.2 J=10.5 C-7Ph, SH, m, 7.02-7.3 Examples for Formula ~I
The starting material 4-aza-4-methyl-5a-androstan-3,17-5 dione (Compound A in Scheme 1 above, for Formula II) can be made according to the methods described in Rasmusson, et al., J. Med. Chem., 27, p. 1690-1701 (1924). The starting material 4-aza-4,7,~-dimethyl-5a-androstan-3,17-dione can be synthesized according to the procedure described in Example 33, below.

~ a ~9 9 7 ~

4-Aza-4-methyl-50c-androstan-3 ~ 16-dione Step 1: 4-aza-4-methyl-5~-androstan-3.17-dione-16-oxime To 2-methyl-2-propanol (14 mL) in a round-bottom flask under a stream of nitrogen gas was added potassium tert-butoxide (740 mg, 6.59 mmol). After complete solution was achieved, 4-aza-4-methyl-5a-androstan-3,17-dione (1.0 g, 3.30 mmol) was added and stirring was continued for 1 hour affording a gold-colored ~olution. To the reaction mixture was added dropwise with stirring isoamyl nitrite (0.884 mL, 6.5 mmol), and stirring was continued overnight at room temperature affording a deep-orange solution. The mixture was then diluted with an equal volume of water and acidified to pH ~2 with 2 N hydrochloric acid.
Diethyl ether was added, and the solid that formed was filtered, washed with ether, and dried in vacuo, to yield the title compound.

Step 2: 4-aza-4-methyl-Soc-androstan-3-one- 16-oxime (B) To a mixture of 4-aza-4-methyl-5a-androstan-3,17-dione-16-oxime (596 mg, 1.79 mmol) in ethylene glycol (5 mL) were added 98% hydrazine (57 ~lL, 1.74 mmol) and powdered potassium hydroxide (568 mg, 10.12 mmol). The mixture was heated for 16 h at 140~, cooled, and neutralized with 2N hydrochloric acid. The resulting solid was filtered, washed with water, and dried in vacuo to yield the title compound; mass spectrum: m/z 318(M).

Step 3: 4-aza-4-methyl-Soc-androstan-3.16-dione (152) A mixture of 4-aza-4-methyl-50~-androstan-3-one- 16-oxime ~218 mg, 0.684 mmol) and sodium bisulfite (249 mg, 23.9 mmol) in 50%
aqueous ethanol (10 mL) was heated for 3 h at reflux temperature. Dilute - hydrochloric acid (0.5 N, 33 mL) and methylene chloride (50 mL) were added, and the mixture was vigorously agitated for several minlltes. The organic layer was separated and washed with sodium hydrogencarbonate solution, saturated brine solution, dried (Na2SO4), and evaporated. The WO96112487 ~ ? 9 PCT/US9S~13305 desired product was purified by flash silica gel chromatography using 15% acetone/methylene chloride as eluant to yield the title compound;
FAB mass spectrum: m/z 304 (M+l).
400 MHz 1H NMR (CDC13): ~ 0.~9 (s, 3H); 0.91 (s, 3H); 2.90 (s, 3H);
5 and 3.05 (dd, 1 H).

~XAMPLE 34 3-Oxo-4-aza-4-methyl- 16~-hydroxy-Soc-andro.stane (53) A solution of 4-aza-4-methyl-50c-androstan-3,16-dione (100 mg, 0.330 mmol) in methanol (2 mL) was cooled in an ice bath and treated with sodium borohydride (3~s mg, 0.9~9 mmol) for 1 h. The reaction mixture was diluted with water and extracted with methylene chloride (2 x 20 mL). The combined organic extracts were washed with lS saturated brine solution, dried (Na2SO4), and evaporated. The desired product was purified by flash silica gel chromatography using 10%
acetone/methylene chloride as eluant to yield the title compound; FAB
mas~s spectrum: m/z 306 (M+l).
400 MHz lH NMR (CDC13): ~ 0.~ (s, 3H); 0.95 (s, 3H); 2.90 (s, 3H);
3.00 (dd, lH); and 4.39 (m, lH).

3-Oxo-4-aza-4-methyl- 16,B-methoxy-So~-alldrostane (54) To a solution of 3-oxo-4-aza-4-methyl-16~-hydroxy-5Oc-androstane (35 mg, 0.115 mmol) in dimethyl ,sulfoxide (1.0 mL) was added powdered potassium hydroxide (32 mg, 0.575 mmol). After stirring for 15 min at room temperature under an nitrogen atmosphere, iodomethane (36 ~1, 0.575 mmol) was added and ~stirring was continued for a further 4 hours. The mixture wa,s diluted with diethyl ether (30 mL), which was washed with water, saturated brine solution, dried (Na2S04), and evaporated. The desired product was purified by flash silica gel chromatography using 10% acetone/methylene chloride a~s eluant to yield the title compound; mass spectrum: m/z 391 (M).

WO96/12487 ~ 7 ~ PCT/US9Stl3305 - 400 MHz lH NMR (CDC13): ~ 0.88 (s, 6H); 2.90 (s, 3H); 3.00 (dd, lH);
3.21 (s, 3H); and 3.~3 (m, lH).

s 3-Oxo-4-aza-4-methyl- 16~-allyloxy-5O~-androstane (55) This compound was prepared in a similar fashion as Example 35, but substituting allyl bromide in place of iodomethane to yield the title compound; mass spectrum: m/z 345 (M).
400 MHz IH NMR (CDC13): ~ 0.~S~S (s, 3H); 0.90 (~, 3H); 2.90 (s, 3H);
3.00 (dd, lH); 3.90 (m, 2H); 3.99, (m, lH); 5.11-5.27 (m, 2H); and 5.~s3-5.93 (m, lH).

3-Oxo-4-aza-4-methvl-16,B-(n-propyloxy)-50c-andro,stane (56) A solution of 3-oxo-4-aza-4-methyl- 16,B-allyloxy-Soc-androstane in ethyl acetate (0.~5 mL) wa.s hydrogenated at atmospheric pressure in the presence of platinum oxide (4 mg) for 30 min at room temperature. The catalyst was removed by filtration through a Millex-HV 0.45 ~m Filter Unit. Purification was achieved by flash silica gel chromatography using 10% acetone/methylene chloride as eluant to yield the title compound; mass spectrum: m/z 348 (M+l ).
400 MHz NMR (CDC13): o 0.88 (s, 3H); 0.~S9 (s, 3H); 2.90 (s, 3H); 3.00 (dd, lH); 3.2~S (t, 2H); and 3.92 (m, lH).

EXAMPLE 3Ps - 3-Oxo-4-aza-4-methvl- 16~-(acetamido)-Sa-androstane (57) - Step 1: 3-Oxo-4-aza-4-methyl-16~-(amino)-5O~-androstane (C) A solution of 4-aza-4-methyl-5Oc-androstan-3-one- 16-oxime (150 mg, 0.471 mmol) in ethanol (IS mL) - acetic acid (7 mL) was hydrogenated at atmospheric pressure in the presence of platinum oxide W096/1248~ a ~ PCI/US9S/13305 - lO~S-(50 mg) overnight at room temperature. The catalyst was removed by filtration through a Millex-HV 0.45 ,um Filter Unit, and the filtrate wa.s evaporated. The residue was dissolved in methylene chloride (50 mL), and the solution was washed with saturated sodium hydrogencarbonate 5 solution, saturated brine solution, dried (Na2SO4), and evaporated to afford the desired amine.

Step 2: 3-Oxo-4-aza-4-methyl-16~-(acetamido)-Soc-androstane (57) The amine from Step I (56 mg, 0.184 mmol) was dissolved 10 in methylene chloride (1.0 mL) and treated with pyridine (0.6 mL), 4-dimethylaminopyridine (5 mg), and acetic anhydride (0.3 mL) for 2 h at room temperature. The mixture was diluted with methylene chloride (50 mL), and the solution was washed with water, 1 N hydrochloric acid, saturated sodium hydrogencarbonate ,solution, saturated brine solution, 15 dried (Na2SO4), and evaporated. The product was purified by flash silica geI chromatography using 2% methanol/methylene chloride as eluant to yield the title compound; mass spectrum: m/z 346 (M).
400 MHz 1H NMR (CDC13): ~ 0.~2 (s, 3H); 0.87 (s, 3H); 1.93 (s, 3H);
2.90 (s, 3H); 3.00 (dd, lH); 4.2~ (m, lH); and 5.54 (d, lH).

3-Oxo-4-aza-4-methyl- 16~-(benzamido)-50~-androstane (58) This compound was prepared in a similar fashion as 25 Example 38, but substituting benzoyl chloride in place of acetic anhydride to yield the title compound; mass spectrum: m/z 408 (M).
400 MHz lH NMR (CDC13): ~ 0.~9 (s, 3H); 0.90 (s, 3H); 2.90 (s, 3H);
3.01 (dd, lH); 4.48 (m, lH); and 6.12 (d, lH).

oa~s997~

3-Oxo-4-aza-4-methyl- 16~-(benzylaminocarbonyloxy)-So~-androstane (~9) To a solution of 3-oxo-4-aza-4-methyl-16~-hydroxy-Soc-androstane (40 mg, O.131 mmol) in methylene chloride (2 mL) were added triethylamine (67 ~L, 0.481 mmol), 4-dimethylaminopyridine (2 mg), and benzyl isocyanate (SO IlL, 0.405 mmol). The reaction mixture wa~s stiITed for 48 h at room temperature, evaporated, and then subjected 10 to flash silica gel chromatography using 15% acetone/methylene chloride a,s eluant to yield the title compound; FAB mass spectrum: m/z 439 (M+l).
400 MHz lH NMR (CDC13): ~ O.g7 (s, 6H); 2.90 (s, 3H); 3.00 (dd, lH);
4.33 (m, 2H); 4.90 (m, lH) and S.11 (m, lH).

3-Oxo-4-aza-4-methyl- 16a-hydroxy-50c-androstane (60) 20 Step 1: 3-Oxo-4-aza-4-methyl-160c-(4-nitrobenzoyloxy)-5a-androstane (D) To a solution of 3-oxo-4-aza-4-methyl-16~-hydroxy-Sa-androstane (34 mg, 0Ø111 mmol) in dry benzene (1.5 mL) were added triphenylphosphine (35 mg, 0.134 mmol), 4-nitrobenzoic acid (22 mg, 25 0.134 mmol), and diethyl azodicarboxylate (21 ~L, 0.134 mmol). The reaction mixture was heated for one hour at ~0~ (oil bath temperature) under a nitrogen atmosphere. After removal of the benzene by evaporation under diminished pressure, the crude product mixture was subjected to flash silica gel chromatography using 2% methanoV
30 methylene chloride as eluant to give desired product cont~min~ted with some triphenylphosphine (97 mg) which was saponified as de,scribed in Step 2.

W096/12487 '0 2 '~ 9 ~ ~ PCI[/U595113305 Step 2: 3-Oxo-4-aza-4-methyl-160c-hydroxy-Soc-androstane (60) The crude product from Step 1 (97 mg) was suspended in ethanol (0.5 mL) and treated with 0.4 N sodium hydroxide (0.36 mL, 0.144 mmol). After stirring 90 min at room temperature, the reaction 5 mixture was neutralized with several drops of glacial acetic acid, extracted with ethyl acetate (2 x 20 mL), washed with water (20 mL), saturated brine solution, dried (sodium sulfate), and evaporated. The product was obtained pure by flash silica gel chromatography using 20%
acetone/methylene chloride as eluant; mass spectrum: m/z 305 M.
10 400 MHz lH NMR (CDC13): ~ 0.70 (s, 3H); 0.~s5 (s, 3H); 2.90 (s, 3H);
3.02 (dd, lH); and 4.47 (m, lH).

3-Oxo-4-aza-4-methyl- 160c-methoxy-So~-androstane (61) To a solution of 3-oxo-4-aza-4-methyl-16cc-hydroxy-Soc-androstane (20 mg, 0.065 mmol) in dimethyl sulfoxide (0.6 mL) was added powdered potassium hydroxide (1 ~s mg, 0.325 mmol). After stirring for l S min at room temperature under an nitrogen atmosphere, 20 iodomethane (20 ~1, 0.325 mmol) was added and stirring was continued overnight at room temperature. The mixture was diluted with diethyl ether (25 mL), which was washed with water (2 x 10 mL), dried (Na2SO4), and evaporated. The desired prod~ct was purified by flash silica gel chromatography using 10% acelone/methylene chloride as 25 eluant to yield the title compound; mas~ spectrum: m/z 319 (M).
400 MHz lH NMR (CDC13): o 0.70 (s, 3H); 0.~7 (s, 3H); 2.90 (s, 3H);
3.01 (dd, lH); 3.22 (s, 3H); and 3.92 (m, lH).

WO96/12487 ~ 7 9 PCI'IUS9SI13305 4-Aza-4,7,B-dimethyl-50c-androstan-3.16-dione (62) Step 1: 4-aza-4.7,~-dimethvl-5Oc-androstan-3,17-dione- 16-oxime To 2-methyl-2-propanol (28 mL) in a round-bottom flask under a stream of nitrogen gas was added potassium te~t-butoxide (1.35 g, 12.1 mmol). After complete solution was achieved, 4-aza-4,7,B-dimethyl-Soc-androstan-3,17-dione (1.92 g, 6.0 mmol) was added and stirring was continued for 1 hour affording a gold-colored solution. To the reaction mixture was added dropwise with stirring isoamyl nitrite (1.63 mL, 12.1 mmol), and stirring was continued overnight at room temperature affording a deep-orange solution. The mixture was then diluted with an equal volume of water, acidified to pH ~2 with 2 N
hydrochloric acid, and extracted with diethyl ether (3 x 50 mL). The combined ether extract.s were washed with saturated brine solution, dried (sodium sulfate), and evaporated. The crude product was subjected to flash silica gel chromatography using 5% methanol/methylene chloride as eluant to yield the title compound.
Step 2: 4-aza-4 7,1~-dimethyl-5Oc-androstan-3-one-16-oxime To a mixture of 4-aza-4,7,13-dimethyl-5a-androstan-3,17-dione-16-oxime (2.7 g, 7.79 mmol) in ethylene glycol (30 mL) were added 9g% hydrazine (0.27 mL, 8.57 mmol) and powdered potassium hydroxide (2.62 g, 46.~s mmol). The mixture was heated for 3 h at 140~, cooled, diluted with water (100 mL), neutralized with concentrated hydrochloric acid to give a tan precipitate that was filtered and dried (1.7 g). Flash silica gel chromatography of this material using initially 2%
~ methanol/methylene chloride and subsequently 5% methanol/methylene 30 chloride as eluant gave pure product.

Step 3: 4-aza-4.7~-dimethyl-5Oc-androstan-3.16-dione (62) A mixture of 4-aza-4,7~-dimethyl-Soc-androstan-3-one-16-oxime (0.55 g, 1.65 mmol) in 60% acetic acid (20 mL) was heated at WO 96/12487~ PCT/US95113305 reflux temperature for 4P, hours. The cooled mixture was diluted with water (25 mL) and extracted with methylene chloride (3 x 50 mL). The combined extracts were washed with saturated sodium hydrogen-carbonate solution, dried (sodium sulfate), and evaporated. Flash silica 5 gel chromatography using 2% methanol/methylene chloride afforded pure product; mass spectrum: m/z 317 (M[).
400 MHz lH NMR (CDC13): ~ 0.~s~ (s, 3H); 0.g9 (s, 3H); 1.00 (d, 3H);
2.90 (s, 3H); and 3.07 (dd, lH).

~XAMPLE 44 3-Oxo-4-aza-4.7,~-dimethyl- 16,B-hydroxy-50c-androstane (63) A solution of 4-aza-4,7,13-dimethyl-So~-androstan-3,16-dione (390 mg, 1.23 mmol) in methanol (8 mL) was cooled in an ice bath and 15 treated with sodium borohydride (140 mg, 3.6~S mmol) for 30 min. The reaction mixture was diluted with water and extracted with methylene chloride (3 x 50 mL). The combined organic extract,s were washed with saturated brine solution, dried (Na2SO4), and evaporated. The desired product was purified by flash silica gel chromatography using initially 20 10% acetone/methylene chloride and subsequently 20% acetone/
methylene chloride as eluant to yield the title compound; mass ,spectrum:
m/z 391(M).
400 MHz lH NMR (CDC13): ~ 0.~3 (s, 3H); 0.96 (s, 3H); 1.03 (d, 3H);
2.90 (s, 3H); 3.00 (dd, lH); and 4.36 (m, lH).

3-Oxo-4-aza-4~7~3-dimethyl- 16~-methoxy-5c~-androstane (64) To a solution of 3-oxo-4-aza-4,7,B-dimethyl-16,B-hydroxy-30 5cc-androstane (20 mg, 0Ø063 mmol) in dimethyl sulfoxide (0.5 mL) was added powdered potassium hydroxide (1 ~ mg, 0.313 mmol). After stirring for 15 min at room temperature under an nitrogen atmosphere, iodomethane (20 !11, 0.313 mmol) was added and stirring was continued overnight at room temperature. The mixture was diluted with diethyl ~ 7 Q
WO 96112487 PC~IUS9S/13305 ether (25 mL), which was washed with water, saturated brine solution, dried (Na2SO4), and evaporated. The desired product was purified by flash .silica gel chromatography using 1.5% methanol/methylene chloride as eluant to yield the title compound; mass spectrum: m/z 334 (M+l).
400 MHz lH NMR (CDC13): ~ 0.83 (s, 3H); 0.89 (s, 3H); 1.03 (d, 3H);
2.90 (s, 3H); 3.00 (dd, lH); 3.24 (s, 3H); and 3.80 (m, lH).

3-Oxo-4-aza-4~7,13-dimethyl- 16,~-ethyloxy-~o~-androstane (65) This compound was prepared in a similar fashion as Example 45, but substituting iodoethane in place of iodomethane arld potassium hydride in N,N-dimethylformamide in place of pota,ssium hydroxide in dimethyl sulfoxide; mass spectrum: m/z 347 (M).
400 MHz lH NMR (CDC13): ~ 0.83 (s, 3H); 0.90 (s, 3H); 1.03 (d, 3H);
1.1~ (t, 3H); 2.90 (s, 3H); 3.00 (dd, lH); 3.39 (m, 2H); and 4.40 (m, lH).

3-Oxo-4-aza-4.7~-dimethyl- 16~-allyloxy-5a-andro,stane (66) This compound wa,s prepared in a ,similar fashion as Example 45, but substituting allyl bromide in place of iodomethane; mass spectrum: m/z 359 (M).
400 MHz lH NMR (CDC13): ~ 0.83 (s, 3H); 0.91 (s, 3H); 1.04 (d, 3H);
2.90 (s, 3H); 3.00 (dd, lH); 3.90 (m, 2H); 3.96 (m, lH); 5.11-5.29 (m, 2H); and 5.85-5.93 (m, lH).

3-Oxo-4-aza-4.7~-dimethyl- 16~-benzvloxy-5a-andro.stane (67) This compound was prepared in a similar fashion a.s Example 46, but substituting benzyl bromide in place of iodoethane;
mass spectrum: m/z 409 (M).

WO96/12487 2 ~ Q 7 ~ PCT/US9S/1330S~

400 MHz 1H NMR (CDC13): ~ 0.85 (s, 3H); 0.95 (s, 3H); 1.04 (d, 3H);
2.90 (s, 3H); 3.00 (dd, lH); 4.01 (m, lH); 4.43 (~, 2H); and 7.31 (m, 5H).

s 3-Oxo-4-aza-4,7~-dimethyl- 16,1~-(3,3-dimethylallyloxy)-5a-andro~tane (68) This compound was prepared in a .similar fashion as Example 45 but substituting 3,3-dimethylallyl bromide in place of 10 iodomethane;
400 MHz lH NMR (CDC13): ~ 0.~2 (~, 3H); 0.90 (s, 3H); 1.02 (d, 3H);
1.67 (s, 3H); 1.71 (s, 3H); 2.90 (s, 3H); 3.00 (dd, lH); 3.93 (m, lH); and 5.31 (m, 1 H).

3-Oxo-4-aza-4,7~-dimethyl- 16~-(n-propyloxy)-5c~-androstane (69) A solution of 3-oxo-4-aza-4,7,~-dimethyl-16~-allyloxy-So~-androstane (13.0 mg, 0.036 mrnol) in ethyl acetate (0.5 mL) was hydro-genated at atmospheric pressure in the presence of platinum oxide (4 mg) for 30 min at room temperature. The catalyst was removed by filtration through a Millex-HV 0.45 ~lm Filter Unit. Purification was achieved by flash silica gel chromatography using I % methanol/methylene chloride as eluant to yield the title compound; mass spectrum: m/z 361 (M).
400 MHz lH NMR (CDC13): ~ 0.~2 (s, 3H); 0.g9 (s, 3H); 0.~9 (t, 3H);
1.05 (d, 3H); 2.90 (s, 3H); 3.00 (dd, lH); 3.29 (t, 2H); and 3.~S9 (m, lH).

3-Oxo-4-aza-4,7,~-dimethyl- 16,(~-(3-methyl- 1 -butyloxy)-5Oc-androstane (70) A solution of 3-oxo-4-aza-4,7~-dimethyl- 16,B-(3,3-dimethyl-allyloxy)-5Oc-androstane (12 mg) in ethyl acetate (0.5 mL) was hydro-genated at atmospheric pressure in the presence of 10% palladium-on-WO96/12487 ~ 7 ~ PCIlUS9Stl3305 charcoal (3 mg) for 30 min at room temperature. The catalyst was removed by filtration through a Millex-HV 0.45 ~m Filter Unit.
Purification was achieved by flash silica gel chromatography using 2%
methanol/methylene chloride as eluant to yield the title compound; mass 5 spectrum: m/z 389 M.
400 MHz lH NMR (CDC13): ~ 0.82 (s, 3H); 0.88 (s, 3H); 1.03 (d, 3H);
2.90 (s, 3H); 3.00 (dd, lH); 3.33 (m, 2H); and 3.gg (m~ lH).

3-Oxo-4-aza-4.713-dimethyl- 16~-(t-butoxy)-Soc-androstane (71) To a solution of 3-oxo-4-aza-4,7,3-dimethyl- 16,(~-hydroxy-5a-androstane (20 mg, 0.063 mmol) in methylene chloride (0.5 mL) cooled in an ice-bath were added t-butyl trichloroacetimidate (23 ~L, 15 0.126 mmol) and trifluoromethanesulfonic acid (0.56 !lL, 0.0063 mmol).
The reaction mixture was allowed to reach room temperature, and after one hour additional amounts of t-butyl trichloroacetimidate (23 !lL) and trifluoromethanesulfonic acid (0.56 ,uL) were added. After one hour, a third addition of each reagent was made, and the reaction mixture was 20 ,stirred for 5 h at room temperature. The mixture was diluted with diethyl ether (50 mL), washed with 1 N aqueous sodium hydroxide (10 mL), 1 N
hydrochloric acid (10 mL), saturated sodium hydrogencarbonate solution, dried (sodium sulfate), and evaporated. The crude product was purified by flash silica gel chromatography using 10% acetone/methylene chloride 25 as eluant to yield the title compound; mass spectrum: m/z 375 (M).
400 MHz 1H NMR (CDC13): ~ 0.82 (s, 3H); 0.90 (s, 3H); 1.03 (d, 3H);
1.11 (s, 9H); 2.90 (s, 3H); 3.00 (dd, 1 H); and 4.00 (m, 1 H).

3-Oxo-4-aza-4~7~-dimethyl- 16~-(4-cyanophenoxy)-50~-androstane (72) To a solution of 3-oxo-4-aza-4,7~-dimethyl-16~-hydroxy-Soc-androstane (20 mg, 0.063 mmol) in N,N-dimethylformamide (0.5 mL) was added powdered potassium hydride (35 weight%) (15 mg, 0.126 WO 96/12487 ~ PCI~/US9S/13305 mmol). After stirring for l S min at room temperature under an nitrogen atmosphere, 4-fluorobenzonitrile (38 mg, 0.315 mmol) was added and stirring was continued for 2 hour.s at room temperature. The mixture was diluted with methylene chloride (25 mL) and quenched in ice-water. The 5 aqueous layer was extracted with methylene chloride (3 x 25 mL) and the combined organic layer.s were washed with saturated brine solution, dried (sodium sulfate) and evaporated. The desired product was purified by flash silica gel chromatography using initially 1.5% methanol/methylene chloride and subsequently 2% methanol/methylene chloride as eluant to 10 yield the title compound; mass spectrum: m/z 420 (M).
400 MHz lH NMR (CDC13): ~ 0.8s6 (s, 3H); 0.92 (s" 3H); 1.04 (d, 3H);
2.90 ~.s, 3H); 3.02 (dd, lH); 4.76 (m, lH); 6.~7 (m, 2H); and 7.53 (m, 2H).

3-Oxo-4-aza-4,7~-dimethyl- 16,B-(4-trifluoromethylphenoxy)-5a-androstane (73) This compound was prepared in a similar fashion as 20 Example 53, but substituting 4-fluorobenzotrifluoride in place of 4-fluorobenzonitrile; mass spectrum: m/z 463 (M).
400 MHz IH NMR (CDC13): ~ 0.85 (s, 3H); 0.93 (s, 3H); 1.04 (d, 3H);
2.90 (s, 3H); 3.02 (dd, lH); 4.76 (m, lH); 6.88 (d, 2H); and 7.50 (d, 2H).

3-Oxo-4-aza-4~7,B-dimethyl- 16,B-(4-chlorophenoxy)-50~-androstane (74) This compound was prepared in a similar fashion as Example 53, but substituting 1-chloro-4-fluorobenzene in place of 4-30 fluorobenzonitrile; mass spectrum: m/z 430 (M+l).
400 MHz 1H NMR (CDC13): ~ 0.85 (s, 3H); 0.93 (s, 3H); 1.03 (d, 3H);
2.90 (s, 3H); 3.02 (dd, lH); 5.28 (m, lH); 6.74 (d, 2H); and 7.19 (d, 2H).

~ ~ ~ 7 9 ~ 9 ~ ~
WO 96/12487 PCI'IUS9S/13305 3-Oxo-4-aza-4~7,13-dimethyl- 16,B-(4-fluorophenoxy)-5a-androstane (75) This compound was prepared in a similar fashion as S Example 53, but substituting 1,4-difluorobenzene in place of 4-fluorobenzonitrile; mass spectrum: m/z 414 (M+1).
400 MHz IH NMR (CDC13): o 0.85 (s, 3H); 0.94 (s, 3H); 1.04 (d, 3H);
2.91 (s, 3H); 3.02 (dd, lH); 4.65 (m, lH); 6.75 (m, 2H); and 6.92 (m, 2H).

3-Oxo-4-aza-4,7~-dimethyl- 16a-hydroxy-Sa-androstane Step 1: 3-Oxo-4-aza-4,7,B-dimethyl- 16~-(4-nitrobenzoyloxy)-5a-androstane (F) To a solution of 3-oxo-4-aza-4,7,B-dimethyl-16,13-hydroxy-50c-androstane (178 mg, 0.560 mmol) in d~ benzene (10 mL) were added triphenylphosphine (294 mg, 1.12 mmol), 4-nitrobenzoic acid (187 mg, 1.12 mmol), and diethyl azodicarboxylate (176 ~L, 1.12 mmol). The reaction mixture was heated for one hour at ~0~ (oil bath temperature) under a nitrogen atmosphere. After removal of the benzene by evaporation under dimini~hed pressure, the crude product mixture wa~
subjected to flash silica gel chromatography using 2% methanol/
methylene chloride as eluant to give desired product contaminated with some triphenylphosphine (404 mg) which was saponified as described in Step 2.
400 MHz 1 H NMR (CDC13): ~ 0.g0 (s, 3H); 0.88 (s, 3H); 1.03 (d, 3H);
2.90 (s, 3H); 3.05 (dd, lH); and 5.48 (m, lH).
Step 2: 3-Oxo-4-aza-4,7~-dimethyl- 16a-hydroxy-So~-androstane (76) The crude product from Step 1 (404 mg) was suspended in ethanol (S mL) and treated with 0.4 N sodium hydroxide (1.82 mL, 0.72 W096/12487 Q ,~ q ~7 9 P~ 35/1330S

mmol). After stirring 90 min at room temperature, the reaction mixture was neutralized with several drops of glacial acetic acid, extracted with ethyl acetate (100 mL), washed with water (2 x 25 mL), saturated brine solution, dried (sodium sulfate), and evaporated. The product was S obtained pure by flash silica gel chromatography using 20% acetone/
methylene chloride as eluant; mass spectrum: m/z 319 (M).
400 MHz lH NMR (CDC13): ~ 0.71 (s, 3H); 0.~s2 (s, 3H); 1.02 (d, 3H);
2.90 (s, 3H); 3.03 (dd, lH); and 4.42 (m, lH).

3-Oxo-4-aza-4~7,~-dimethyl-160c-(n-propyloxy)-50c-androstane (77) To a solution of 3-oxo-4-aza-4,7~-dimethyl-16a-hydroxy-Sa-androstane (20 mg, 0.063 mmol) in N,N-dimethylformamide (0.65mL) was added potassium hydride (35 weight%) (15 mg, 0.126 mmol). After stirring for 15 min at room temperature under a nitrogen atmosphere, allyl bromide (27 ,ul, 0.315 mmol) was added and stirring was continued for 2 h. Additional amounts of potassium hydride (15 mg) and allyl bromide (27 ~lL) were added, and stirring was continued 20 overnight. The mixture was diluted with diethyl ether (50 mL) and water (10 mL). The organic layer was washed with I N hydrochloric acid (10 mL), water (10 mL), saturated brine .solution, dried (Na2SO4), and evaporated. The desired product was purified by flash silica gel chromatography using 2% methanol/metllylene chloride as eluant. This 25 material was hydrogenated in ethyl ace~ate (0.5 mL) in the presence of 10% palladium-on-charcoal for 2 hours. The catalyst was removed by filtration through a Millex-HV 0.45 llm Filter Unit. Purification was achieved by flash silica gel chromatography using 10% isopropanol/
hexane as eluant to yield the title compound; mass spectrum: m/z 361 30 (M)-400 MHz lH NMR (CDC13): o 0.76 (s, 3H); 0.82 (s, 3H); 0.90 (t, 3H);
1.02 (d, 3H); 2.90 (s, 3H); 3.02 (dd, lH); 3.29 (t, 2H); and 3.98 (m, lH).

WO96112487 2 ~ 9 ~ 9 ~ ~ PCT/US95/13305 3-Oxo-4-aza-4.16a-dimethyl- 16~-hydroxy-5a-androstane (7g) To a solution of 4-aza-4-methyl-5Oc-androstan-3,16-dione (50 mg, 0.165 mmol) cooled to -40~ was added dropwi~e with stirring methylmagnesium bromide (3.0 M solution in diethyl ether) (275 IlL, 0.825 mmol). The reaction mixture was allowed to reach room temperature and stirred for 2 h under a nitrogen atmosphere. The reaction was quenched with saturated ammonium chloride solution (25 mL) and extracted with methylene chloride (2 x 50 mL). The combined organic extracts were washed with saturated brine solution, dried (sodium sulfate) and evaporated. The desired product was obtained pure by flash silica gel chromatography using 2% methanol/methylene chloride as eluant; mass spectrum: mlz 319 (M).
lS 400 MHz 1H NMR (CDC13): ~ 0.~8 (s, 3H); 0.9g (s, 3H); 1.31 (s, 3H);
2.90 (s, 3H); and 3.00 (dd, lH).

3-Oxo-4-aza-4.7~.16a-trimethyl-16~-hydroxy-5a-androstane (79) This compound was prepared in a ~imilar fa.shion a.~
Example 59, but substituting 4-aza-4,7,B-dimethyl-5a-andro,stan-3,16-dione in place of 4-aza-4-methyl-Sa-androstan-3,16-dione as starting material; mass spectrum: m/z 333 (M).
400 MHz lH NMR (CDC13): o 0.82 (s, 3H); 0.9~ (s, 3H); 1.01 (d, 3H);
1.30 (s, 3H); 2.90 (s, 3H); and 3.00 (dd, lH).

..
3-Oxo-4-aza-4.16a-dimethyl- 16~-methoxy-5a-androstane (~0) To a solution of 3-oxo-4-aza-4,16a-dimethyl- 16~-hydroxy-Sa-androstane (31 mg, 0.097 mmol) in N,N-dimethylformamide (0.5 mL) was added potassium hydride (35 weight%) (23 mg, 0.194 mmol).
After stirring for l S min at room temperature, iodomethane (32 ~lL, 0.4~5 WO 96/12487 Q ~ ~ PCT/US9S11-305--mmol) was added, and stirring was continued overnight at room temperature. The reaction mixture was diluted with diethyl ether, washed with 2N hydrochloric acid (10 mL), water (10 mL), saturated brine solution, dried (sodium sulfate), and evaporated. The desired product 5 was obtained pure by flash silica gel chromatography using 2% methanol/
methylene chloride as eluant; mass spectrum: m/z 333 (M).
400 MHz 1 H NMR (CDC13): ~ 0.88 (s, 3H); 0.90 (s, 3H~; 1.22 (,s, 3H);
2.90 (s, 3H); 3.00 (dd, lH); and 3.17 (s, 3H).

3-Oxo-4-aza-4~7,B.160c-trimethyl- 16~-methoxy-5O~-androstane (81) This compound was prepared in a similar fashion as Example 61, but substituting 3-oxo-4-aza-4,7,B,16O~-trimethyl- 16~-15 hydroxy-So~-androstane in place of 3-oxo-4-aza-4,16cc-dimethyl- 16,B-hydroxy-5cc-androstane as starting material; mass spectrum: m/z 347 (M)-400 MHz lH NMR (CDC13): ~ 0.82 (s, 3H); 0.90 (s, 3H); 1.02 (d, 3H);
1.22 (s, 3H); 2.90 (s, 3H); 3.00 (dd, 1 H); and 3.18 (~, 3H).

3-Oxo-4-aza-4~7,B-dimethyl- 16~-methanethio-5Oc-andro~stane (82) Step 1: 3-Oxo-4-aza-4,7~-dimethyl-16,B-(acetylthio)-5Oc-androstane (G) A 25-mL round-bottom flask was charged with dry tetra-hydrofuran (4 mL) and triphenylphosphine (177 mg, 0.676 mmol) under a nitrogen atmosphere. The flask was cooled in an ice-bath and diisopropyl azodicarboxylate (133 ~L, 0.676 mmol) was added, and the mixture was stirred for 30 min at 0~. To the reaction mixture was added a solution of 3-oxo-4-aza-4,7,13-dimethyl-16O~-hydroxy-50c-androstane (108 mg, 0.338 mmol) and thiolacetic acid (49 ~L, 0.676 mmol) in tetrahydrofuran (2.0 mL). The reaction mixture was stirred for 1 h at 0~

W096112487 ~ 2 ~ 5Jl330s and then an additional hour at room temperature. The mi~ture was evaporated and subjected to flash chromatography on silica gel using 10% acetone/methylene chloride as eluant to give the desired product cont;~min~tcd with some triphenylphosphine. The mixture was used S without further purification in Step 2.
400 MHz IH NMR (CDC13): ~ 0.80 (s, 3H); 0.82 (s, 3H); 1.00 (d, 3H);
2.28 (s, 3H); 2.90 (s, 3H); 3.00 (dd, lH); and 3.~0 (m, lH).

Step 2: 3-Oxo-4-aza-4,7,B-dimethyl- 16,B-(mercapto)-5a-androstane (H) To a solution of product mixture from Step 1 (20g mg) in ethanol (4.0 mL) was added 0.4N .sodium hydroxide (1.8 mL, 0.716 mrnol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h, neutralized with several drops of acetic acid, diluted with ethyl acetate (100 mL), washed with water (2 x 10 mL), saturated brine solution, dried (sodium sulfate), and evaporated. Pure 16-mercaptan was obtained by flash silica gel chromatography using 20%
acetone~exane as eluant.
400 MHz lH NMR (CDC13): o 0.82 (s, 3H); 0.93 (s, 3H); 1.02 (d, 3H);
2.90 (s, 3H); 3.00 (dd, lH); and 3.28 (m, lH).

Step 3: 3-Oxo-4-aza-4,7,~-dimethyl- 16,B-(methanethio)-5a-androstane (~2) To a solution of 3-oxo-4-aza-4,7,3-dimethyl- 16~-(mercapto)-5a-androstane ( l ~S mg, 0.054 mmol) in dry tetrahydrofuran (0.5 mL) wa.s added sodium hydride (80% dispersion in mineral oil) (3.2 mg, 0.108 mmol) under a nitrogen atmosphere. After stirring 15 min at room temperature, iodomethane (17 ~lL, 0.270 mmol) was added, and stirring was continued for 3 h at room temperature. The reaction mixture was diluted with methylene chloride (50 mL), washed with water (10 mL), saturated brine solution, dried (sodium sulfate), and evaporated. Flash silica gel chromatography using 10% isopropanol/hexane as eluant afforded pure desired product; mass spectrum: m/z 349 (M).

WO96/12487 3~ ~ PCI/US95/13305 400 MHz lH NMR (CDC13): ~ 0.~2 (s, 3H); 0.91 (.s, 3H); 1.04 (d, 3H);
2.10 (s, 3H); 2.90 (s, 3H); 3.01 (dd, lH); and 3.0g (m, lH).
"

3-Oxo-4-aza-4,7,~ -dimethyl- 16~-ethanethio-So~-androstane (~s3) This compound was prepared in a similar fashion as Example 53, but substituting iodoethane in place of iodomethane in Step 3; mass spectrum: m/z 363 (M).
10 400 MHz lH NMR (CDC13): o 0.~2 (s, 3H); 0.91 (s, 3H); 1.03 (d, 3H);
1.24 (t, 3H); 2.57 (q, 2H); 2.90 (s, 3H); 3.00 (dd~ lH); and 3.1 ~ (m, lH).

3-Oxo-4-aza-4,7,13-dimethyl- 16~-(1 -propanethio)-50~-androstane (~4) This compound was prepared in a similar fashion as Example 53, but substituting l-iodopropane in place of iodomethane in Step 3; mass spectrum: m/z 377 (M).
400 MHz lH NMR (CDC13): o 0.~2 (s, 3H); 0.90 (~, 3H); 0.9~s (t, 3H);
1.03 (d, 3H); 2.51 (t, 2H); 2.90 (s, 3H); 3.01 (dd~ lH); and 3.13 (m, lH).

3-Oxo-4-aza-4.7,~-dimethyl- 16~-ethane~sLIlfonyl-5(x-androstane (~5) To a solution of 3-oxo-4-aza-4,7,B-dimethyl-16,B-ethanethio-Soc-androstane (17 mg, 0.047 mmol) in methanol (1.0 mL) was added a solution of OXONE, monopersulfate compound (19 mg) in water (1 mL).
After stirring 2 h at room temperature, an additional amount of OXONE
(19 mg) in water (0.5 mL) was added, and ~stirring was continued for 10 min. The reaction mixture was diluted with water (25 mL) and extracted with methylene chloride (3 x 50 mL). The combined organic extract~s were washed with saturated brine solution, dried (sodium sulfate), and evaporated. Flash silica gel chromatography using 2% methanol/

~ ~t9~ 9 7 9 WO 96/12487 ' PCI/US95/1330S

methylene chloride as eluant afforded pure desired product; mass spectrum; m/z 395 (M).
400 MHz 1H NMR (CDC13): ~ 0.85 (s, 3H); 0.92 (s, 3H); 1.03 (d, 3H);
1.39 (t, 3H); 2.91 (s, 3H); 2.99 (~1, 2H); 3.00 (dd, lH); and 3.41 (m, lH).

3-Oxo-4-aza-4.7,(3-dimethvl- 16~-fluoro-Sa-androstane To a solution of 3-oxo-4-aza-4,7~3-dimethyl- 160c-hydroxy-10 50~-androstane (1~ mg, 0.056 mmol) in methylene chloride (0.5 mL) at room temperature diethylaminosulfur trifluoride (19 ~L, 0.144 mmol).
After stirring one hour at room temperature, the reaction mixture was diluted with methylene chloride (25 mL), washed with water (25 rnL), saturated sodium hydrogen carbonate solution (10 mL), saturated brine 15 solution (10 mL), dried (sodium sulfate), and evaporated. The product was purified by flash silica gel chromatography using 10%
acetone/methylene chloride as eluant to yield the title compound; mass spectrum: m/z 321 (M).
400 MH~ lH NMR spectrum (CDC13): ~ 0.~S7 (s, 3H); 0.92 (s, 3H); 1.04 20 (d, 3H); 2.90 (s, 3H); 3.01 (dd, lH); and 5.12 (dm, lH).

EXAMPLE 6g Preparation of 4-aza-4,7,B-dimethyl-5a-androstan-3,17-dione (Compound 25 E in Scheme 5 above) Step 1: Synthe,sis of 3-Acetoxv-Androst-5-en- 17-ol To a solution of 100 mg (0.303 mmol) of 3-acetoxy-androst-5-en-17-one in 3 ml EtOH at -10~C, was added 22.9 mg (0.606 mmol) of 30 sodium borohydride with stirring. After the reaction mixture was stirred for one and 1/2 hours, the mixture was diluted with 10 ml water, the ethanol solvent removed under vacuum, and the residue extracted with ethyl acetate. The organic layer was washed with aqueous Na2CO3, brine, dried over sodium sulfate and concentrated to leave a residue of 35 crude title compound. Proton NMR confirmed the assigned structure.

Wo96/12~7~ Q7 ~ PCT/US95113305--Step 2: Synthesis of 3-Acetoxy-Androst-5-en-17-ol, 17-t-butyl-dimethylsilyl ether To a solution of the androstan- 1 7-ol, from the previou,s 5 synthesis being 4.5 g (13.55 mmol) in 50 ml. dimethylformamide at 23~C was added 2.76 g (40-65 mmol) imidazole followed by 3.063 g (20.32 mmol) of t-butyldimethylsilyl chloride. The reaction mixture wa,s stirred and a solid began to precipitate. Twenty additional ml of DMF were added and the mixture further stirred overnight. The 10 mixture was poured into 1 liter water, the solid filtered and washed with water. The solid wa~s dissolved in ethylacetate, the organic layer washed with brine and dried over sodium ,sulfate, concentrated to yield the silyl protected 17-ol title compound. The proton NMR confirmed the assigned .structure.
Step 3: 7-one- 1 7,B-ol. I 7-t-butyldimethylsilyl ether To a solution of the TBMS protected 17-ol from the previous synthesi.s, being 5.6 g (12.55 mmol) in 100 ml acetonitrile at 23~C was added 90% t-butyl hydrogen peroxide, 3.958 g (43.92 mol), 20 and 138 mg chromium hexacarbonyl. After refluxing the mixture under nitrogen for 24 hours, the reaction mixture was poured into one liter water, solid was filtered, the residue washed with 500 ml water and the -residue dissolved in 350 ml methylene chloride. The organic layer was wa.shed with brine, dried over sodium ,sulfate and concentrated to yield 25 crude material. Thin layer chromatography (3:1 hexane/ethyl acetate on silica gel) showed the presence of starting material. The solid was purified by column chromatography over silica gel by elution with 7%
ethyl acetate/hexane to yield the title compound. Proton NMR confirmed the assigned .structure.

~ 9~7~
WO 96/12487 P~ g~11330S

Step 4: Synthesis of 3,7-dihydroxy-7-methyl-androst-5-en-17~-ol, 17-t-butyldimethylsilvl ether To a solution of the product from the previous synthesis, being 440 mg (0.956 mmol) in dry tetrahydrofuran at 0~C was added 5 dropwise methyl magnesium chloride over 5-10 minutes. The reaction mixture was then allowed to stir at room temperature for 24 hours, then poured into saturated aqueous ammonium chloride. The THF solvent was removed under vacuum and the aqueous phase extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated to 10 yield crude product. Proton NMR confirmed the assigned structure of the title compound which was used in the next step without further purification.

Step 5: Synthesis of 7-methyl-androst-4,6-dien-3-one-I7,13-ol, 17-t-butyldimethyl.silyl ether The above Grignard product, 3.5 g (7.142 mmol) wa.sdi.ssolved in 50 ml toluene/50 ml. cyclohexanone and 20 ml of solvent distilled off under vacuum. To this was added 4.54 g alllminllm isopropoxide and the reaction mixture refluxed overnight for 15 hours.
20 The mixture was cooled, diluted with ethyl acetate, washed with sodium potassium tartarate, brine, and the organic layer was concentrated under vacuum and the residue steam distilled. The re.sidue wa.s extracted with ethyl acetate, washed with brine, dried and purified by column chromatography on silica gel, eluting with 5% EtOAc/hexane to yield the 25 title compound.

Step 6: Synthesis of 7,13-methyl-androst-5-en-3-one-17~-ol, t-butyldimethylsilyl ether To a solution of 370 mg of the product of the previous 30 synthesis, in 5.5 ml ammonia, 1 ml THF, 1 ml toluene, was added 50 mg.of metallic lithium in small pieces. After stirring the blue solution for 2 hours, a solution of 1,2-dibromethane in 2 ml THF was added. After stirring the solution at -7g~C~ for 10 minutes, 250 mg of ammonium chloride was added and the mixture stirred for 10 minutes. The excess wo 96/12487 9 ~ PCI/US95113305 ammonia was removed by evaporation under a nitrogen steam. The reaction mixture was diluted with brine, extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to yield crude material which was used as such in the next synthesis.

Stçp 7: Synthesis of 7~-methyl-androst-4-en-3-on-17,~-ol, t-butyldimethylsilyl ether To a solution of the product of the previous synthesis, being 432 mg in 4 ml THF was added 150 microliters DBU ( 1 ,~-diaza-bicyclo[5.4,0] undec-7-ene under nitrogen with stirring. The mixture wa~
refluxed for 1.5 hours, then cooled, diluted with NH4CI solution. The solvent THF was removed under vacuum and the residue extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to yield crude material. The titled product was purified by chromatography on silica gel using 10% EtOAc/
hexane as eluant.

Step ~: Synthesis of 17,~-(t-butyldimethylsilyloxy)-7,B-methyl-5-oxo-A-nor-~.5-secoandrostan-3-oic acid To a solution of ~4 mg of the product of the previous synthesis in 15 ml. t-butyl alcohol at ~0~C wa~ added 24~ mg ~odium carbonate in 1.5 ml water followed by a dropwi~e addition over 15-20 minutes of a mixture of 2.273 g sodium periodate with 16.~s mg potassium permanganate in 8 ml. water. rl~he reaction mixture wa~ heated at ~sO~C for 2 hours, cooled, filtered, the residue wa~hed with water, and then the extract L- concentrated under vaccum. The extract was acidified with aqueous HCl, extracted with elhyl acetate and the organic layer washed with aqueous NaHS03, brine, dried and concentrated to yield crude 9. The proton NMR confirmed the assigned structure.
Stçp 9: Synthesis of 4,713-dimethyl-4-aza-androst-5-en-3-one-17~-ol. t-butyldimethylsilyl ether To a solution of the product of the previou.s synthesis, ~40 mg in 5 ml ethylene glycol, was added 1.5 g sodium acetate and 737 mg.

~ 9 ~ ~
WO 96/12487 P~~ 9S/13305 methylamine hydrochloride. After stirring the reaction mixture 4 hours at 1 ~sO~C, the mixture was cooled, diluted with water, extracted with ethyl acetate, dried and concentrated to afford crude title compound. Proton NMR confirmed the assigned structure.
s Step 10: Synthesis of 4,7~3-dimethyl-4-aza-androst-5 -en-3-one-17,13-ol To a solution of 700 mg of the product of the previous example, in 20 ml of acetonitrile at 0~C, was added 500 microliters.
10 aqueous HF. After stirring the reaction mixture for one hour, the HF was neutralized with aqueous sodium carbonate, diluted with water, acetonitrile removed under vacuum, and the residue extracted with ethyl acetate. The organic layer was dried, concentrated to give crude title compound which was further purified by preparative chromatography on 15 silica gel using 3:1 chloroform/acetone.

Step 1 l: Synthesis of 4.7~-dimethyl-4-aza-androstan-3-one- 17,B-ol To a solution of the product of the previous .synthesi.s, being 350 mg in 10 ml acetic acid was added 100 mg pl~tinl-m dioxide and the 20 resulting mixture was evacuated and flushed with hydrogen. The reaction was shaken overnight at room temperature under 40 Psig hydrogen pressure. The solution was filtered concentrated. The residue was worked up with ethyl acetate, the organic layer was then concentrated under vacuum, diluted with ethyl acetate, washed with 25 aqueous NaHCO3, brine, dried, concentrated to yield the title compound.
Mass Spec: 320 (M+l).

Step 12: Synthe,sis of 4-aza-4.7,~-dimethyl-5cc-androstan-3.17-dione ~ The product of the previous synthesis, 1.013 g (3.176 mmol) 30 was placed with 6 ml methylene chloride into a dry flask. Powdered molecular 4A sieves, 1.6 g, and 0.558 g (4.76 mmol) of N-methyl-morpholine-N-oxide (NMO) and then tetrapropyl-ammonium perrllth~n~te (TPAP), 55 mg (0.159 mmol) were added. The reaction was stirred for 2 hours, diluted with 150 ml ethyl acetate and filtered. The WO96/12487 ~ ? ~ PCT/US95113305 - 12g-filtrate was evaporated to dryness to yield crude product which was recrystallized from EtOAc to yield pure product, mp 135-138~C.
Elemental Analysis Calc'd for C20H3 l NO2, mw=317.4 Calc'd: C, 75.67; H, 9.84; N, 4.41 Found: C, 75.16; H, 10.22; N, 4.13 Mas.s Spec. 31 ~ (M+ 1).
The following Examples (69 to 117) are prepared in a similar fashion as Example 53, but substituting the appropiate 4-fluoro derivativels in place of 4-fluorobenzonitrile.

3-Oxo-4-aza-4,7,13-dimethyl- 16~- (4-methylsulfonylphenoxy)-5a-androstane 15 Ma.ss specrum: m/z 474 (M+l).
400 MHz lH NMR (CDC13): o 0. 85 (s, 3H); 0.93 (s, 3H); 1.04 (d, 3H);
2.90 (s, 3H); 3.00 (s, 3H); 4.~0 (m,lH); 6.92 (d. 2H); 7.gl (d, 2H).

3-Oxo- 4-aza- 4.7~3-dimethyl-16~-(3-pyridyloxy)-~Sa-andro~tane Mass spectrum: m/z 397 (M+l).
400 MHz lH NMR (CDC13): ~ 0.~s5 (s, 3H); 0.94 (s, 3H~; 1.04 (d, 3H);
2.91 (s, 3H); 3.02 (dd, lH); 4.75 (m, lH); 7.21 (m, 2H); ~.22 (m, 2H).

3-Oxo-4-aza-4.7,B-dimethyl- 16,B-(4-phenylphenoxy)-Soc-andro.stane Mass spectrum: m/z 472 (M+l).
30 400 MHz lH NMR (CDC13): ~ 0.~S5 (s, 3H); 0.96 ( s, 3H); 1.05 (d, 3H);
2.91 (~s, 3H); 3.02 (dd, lH); 4.76 (m, lH); 6.9 (d, 2H); 7.26 (m, lH); 7.43 (m, 2H); 7.52 (m, 4H).

~ a ~ ~ 9 9 9 7 ~
WO 96/12487 P~-l/u~S113305 3-Oxo- 4-aza- 4,7,13- dimethvl-16~-(3-chlorophenoxy)-So~-andro.~tane Mass spectrum: mlz 431 (M+ 1).
400 MHz lH NMR(CDC13):~O.g5(s,3H); 0.93 (s, 3H), 1.05 (d, 3H);
2.90 (s, 3H); 4.6~s (m, lH); 6.71 (m, lH); 6.gO (m, lH); 6.88 (m, lH);
7.13 (m, lH).

3-Oxo-4-aza-4,7,13-dimethyl- 16~-(4-trifluoromethoxyphenoxy)-50c-androstane Mass spectrum: mlz 4~0(M+l).
400 MHz lH NMR (CDC13): ~ 0.85 (s, 3H); 0.94 (s, 3H); 1.04 (d, 3H);
2.91 (s, 3H); 3.02 (dd, lH); 4.69 (m, lH); 6.7~ (m, 2H); 7.09 (m, 2H).

3-Oxo-4-aza-4.7~-dimethyl- 16~-(2-chlorophenoxv)-Soc-androstane Mass spectrum: m/z 431 (M+ 1).
400 MHzlHNMR (CDC13): ~ 0.85 (s, 3H); 0.99 (s, 3H); 1.04 (d, 3H);
2.91 (s, 3H); 3.03 (dd, lH); 4.~0 (m, lH); 6.81 (m, 2H); 7.24 (m, lH);
7.32 (m, 2H).

3-Oxo- 4-aza-4.7~-dimethyl- 16~-(2-pyrazinyloxy)-Scx-androstane Mass spectrum: rn/z 398 (M+l).
400 MHzlHNMR (CDC13): ~ 0.~5 (s, 3H); 0.95 (s, 3H); 1.04 (d, 3H);
2.90 (s, 3H); 3.02 (dd, lH); 5.34 (m, lH); ~.04 (d, 2H); 8.15 (lH).

3-Oxo-4-aza-4.7,B-dimethyl- 16,B-(2-pyrimidinyloxy)-5a-androstane Mass spectrum: m/z 39~ (M+l).

wo 96rl2487 ~ ?~ ~ ~ 9 ~ ~ ~ PCI/US9S/13305--400 MHz lH NMR (C~DC13): o 0.~5 (s, 3H); 0.95 (s, 3H); 1.04 (d, 3H);
2.90 (s, 3H); 3.02 (dd, lH); 5.35 (m, lH); 6.~9 (m, lH); ~S.15 (d, 2H);

3-Oxo-4-aza-4,7~-dimethyl- 1 6~-l 4-(1 -pyrryl)-phenoxyl -5Oc-androstane Mass spectrum: m/z 461 (M+l).
400 MHz lH NMR (CDC13): ~ 0.~5 (s, 3H); 0.95 (s, 3H); 1.05 (d, 3H);
2.91 (.s, 3H); 4.73 (m, lH); 6.30 (m, 2H); 6.84 (m, 2H); 6.96 (m, 2H);
10 7.25 (m, 2H).

3-Oxo- 4-aza-4.7,~-dimethyl- 1 6~-(3-cyanophenoxy)-5a-androstane 15 Mass spectrum: m/z 420 (M).
400 MHz lH NMR (CDC13): ~ 0.~5 (s,3H); 0.93 (s, 3H); 1.04 (d, 3H);
2.91 (.'i, 3H); 3.02 (dd, lH); 4.71 (m, lH); 7.05 (m, 2H); 7.22 (m, lH);
7.32 (m, lH).

3-Oxo-4-aza-4.7~-dimethyl- 16~-(1 -naphthyloxy)-5a-androstane Mass spectrum: m/z 445 (M).
400 MHz lH NMR (CDC13): ~ 0.~s6 (s. 3H); 1.03 (s, 3H); 1.07 (d, 3H);
2~ 2.92 (~, 3H); 3.02 (dd, lH); 6.70 (d, lH); 7.32 (m, 2H); 7.44 (m, 2H);
7.7~s (m, 1 H); ~s.24 ( 1 H).

3-Oxo-4-aza-4,7~-dimethyl- 1 6~-(3-chloro-4-methylphenoxy)-5Oc-androstane Mass spectrum: m/z 445(M+ l ).

WO96/12487 ~ 9 ~ ~ PCT/US9Stl3305 400 MHz lH NMR (CDC13): o 0.~4 (s, 3H); 0.92 (s, 3H); 1.04 (d, 2H);
2.26 (s, 3H); 2.92 (s, 3H); 4.76 (m, lH); 6.62 (m, lH); 6.81 (m, lH); 7.12 (d, lH).

EXAMPLE g I

3-Oxo-4-aza-4~7,3-dimethyl- 16~-~4-(5-oxazolyl)phenoxyl-5(x-andro.stane Mass spectrum: m/z 463(M+ 1).
400 MHz lH NMR (CDC13): ~ 0.85 (s, 3H); 0.95 (s, 3H); 1.05 (d, 3H);
10 2.91 (s, 3H); 4.76 (m, lH); 6.86 (d, 2H); 7.21 (s, lH); 7.53 (d, 2H); 7.~4 (s, lH).

15 3 -oxo-4-aza-4,7 ~-dimethyl- 16 ~-(4-nitrophenoxy)-Soc-andro,stane (101) This compound was prepared in a similar fashion a~
Example 53, but substituting 1-fluoro-4-nitrobenzene in place of 4-fluorobenzonitrile; 400 MHz lH NMR (CDC13): ~ 0.~5 (s, 3H); 0.94 (s, 3H); 1.05 (d, 3H); 2.92 (s, 3H); 3.03 (dd, lH); 4.~1 (q, lH); 6.87 (d, 2H);
~.17 (d, 2H).

EXAMPLE ~3 3-oxo-4-aza-4,7~-dimethyl- 16,B-(4-aminophenoxy)-5O~-androstane (102) To a solution of 3-oxo-4-aza-4,7,B-dimethyl-16~-(4-amino-phenoxy)-Soc-androstane (163 mg, 0.36 mmol) in ethylacetate (8s mL) and methanol (8 mL) was added 10% Pd on carbon (25 mg, 0.23 mmol). It was then stirred for four hours under a hydrogen atmosphere at room temperature. It was then filtered through celite and evaporated to afford 30 148 mg of the title compound. No purification was needed. Mass spectrum: m/z 411 (M+l). 400 MHz lH NMR (CDC13): ~ 0.g4 (s, 3H);
0.94 (s, 3H); 1.37 (d, 3H); 2.90 (s, 3H); 3.03 (dd, lH); 4.64 (q, lH); 6.70 (d, 2H); 6.7g (d, 2H).

Q 2 ~ 7 ~ ~

EXAMPLE ~s4 3-oxo-4-aza-4,7,(~-dimethyl- 16,13-(4-acetylaminophenoxy)-50c-androstane (103) S To a solution of 3-oxo-4-aza-4,7,~-dimethyl-16,B-(4-amino-phenoxy)-5(x-androstane (4g mq, 0.116 mmol) in methylene chloride (1 rnL) and pyridine (0.037 mL, 0.46 rnmol) was added acetic anhydride (0.022 mL, 0.23 mmol) and DMAP (5 mg, 0.04 mmol). The reaction was stirred overnight at room temperature under a nitrogen atmosphere. It 10 was then diluted with methylene chloride (50 mL), washed with water (50 mL) and brine (50 mL). The organic phase wa.s then dried over sodium sulfate and evaporated. The crude product was purified by preparative TLC (silica gel, 1000 microns) using 5% methanol/methylene chloride to give 51 mg of the title compound. Mass spectrum: m/z 453 (M+l). 400 MHz 1H NMR (CDC13): o 0.~4 (~, 3H); 0.93 (s, 3H); 1.04 (d, 3H); 2.13 (s, 3H); 2.92 (s, 3H); 3.03 (dd, lH); 4.6~ ((1. lH); 6.76 (d, 2H); 7.11 (s, 1 H); 7.33 (d, 2H).
.

EXAMPLE ~S5 3-oxo-4-aza-4,7~-dimethyl- 16,(~-(4-benzoylaminophenoxy)-50~-androstane (104) This compound was prepared in a similar fashion as Example ~4, but substituting benzoyl chloride in place of acetic 25 anhydride, triethylamine in place of pyridine and DMAP was not used;
mass spectrum: m/z 515 (M+1). 400 MHz IH NMR (CDC13): ~ 0.~4 (s, 3H); 0.94 (s, 3H); 1.05 (d, 3H); 2.92 (s, 3H); 3.04 (dd, lH); 4.73 (~1 lH); 6.g2 (d, 2H); 7.49 (m, 5H); 7.72 (,s, lH); 7.~4 (d, 2H).

~ 9 ~ 7 9 EXAMPLE ~S6 3-oxo-4-aza-4,7,B-dimethyl- 1 6~-(4-methylsulfonamidophenoxy)-5a-andro.stane (105) S This compound was prepared in a similar fashion as Example ~S4, but substituting tosyl chloride in place of acetic anhydride;
mass spectrum: m/z 565 (M~l). 400 MHz lH NMR (CDC13): a 0.~4 (s, 3H); 0.93 (s, 3H), 1.03 (d, 3H); 2.37 (s, 3H); 2.92 (s, 3H); 3.02 (dd, lH); 4.63 (q, lH); 6.34 (s, lH); 6.67 (d, 2H); 6.91 (d, 2H); 7.19 (d, 2H);
10 7.56 (d, 2H).

EXAMPLE ~7 3-oxo-4-aza-4-(2,4-dimethoxybenzyl)-7,13-methyl- 1 6,13-hydroxy-So~-15 androstane (106) This compound was prepared in a sirnilar fashion a,~
compound 63 described in the Scheme 5, except that the corresponding benzyl analog of (Compound E in Scheme 5) was made via similar ,synthesis of Example 6g, except 2,4-dimethoxy-benzylamine was u~ed in 20 place of methylamine in Step 9.

EXAMPLE ~P~

3-oxo-4-aza-4-(2,4-dimethoxybenzyl)-7,13-methyl- 1 6~B-(4-chloro-25 phenoxy)-Sa-androstane (107) ~ his compound was prepared in a similar fashion as Example 55, but substituting 3-oxo-4-aza-4-(2,4-dimethoxy benzyl)-7~-methyl-16~3-hydroxy-Sa-androstane in place of 3-oxo-4-aza-4,7,B-dimethyl- 1 6,B-hydroxy-50c-androstane. No purification was done prior to 30 the next reaction.

WO 96112487 ~ PCT/US95/13305 EXAMPLE ~9 3-oxo-4-aza-7,~-methyl- 16,B-(4-chlorophenoxy)-5(x-androstane ( l O~
To a solution of 3-oxo-4-aza-4-(2,4-dimethoxy benzyl)-7~-methyl-16,B-(4-chlorophenoxy)-50c-androstane (130 mg, 0.23 mmol) in methylene chloride (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred overnight at room temperature. Then the solvent was evaporated and the residue taken up in methylene chloride. The organic phase was washed with saturated ,sodium bicarbonate and brine. It was then dried over sodium sulfate and evaporated. The crude compound was purified by preparative TLC (silica gel, 1000 microns) using 20%
acetone/methylene chloride to yield the title compound. 400 MHz 1 H
NMR (CDC13): o 0.86 (s, 3H); 0.93 (s, 3H); 1.01 (d, 3H); 3.07 (dd, lH);
4.67 (4, lH); 5.49 (s, lH); 6.73 (d, 2H); 7.1~i (d, 2H).

3-oxo-4-a~a-7,(~-methyl- 16~-phenoxy-50c-androstane (109) To a solution of 3-oxo-4-aza-7~-methyl-16,~-(4-chlorophenoxy)-Soc-androstane in methanol was added 20% Pd on carbon. This solution was shaken under a hydrogen atmosphere at 4~s psig for one day. It was then filtered through celite and evaporated. The crude compound was then purified by flash ~ilica gel chromatography using 20% acetone/methylene chloride to elute the title compound. 400 MHz lH NMR (CDC13): ~ 0.~6 (s, 3H); 0.95 (s, 3H); 1.01 (d, 2H); 3.0~S
- (dd, 1 H); 4.71 (q, 1 H); 5.4~ (s, 1 H); 6.g 1 (d, 2H); 6.~9 (t, 1 H); 7.24 (t, 2H).

3-oxQ-4-aza-7~-methyl- 16~-phenoxy-50c-androst- 1 -ene (110) To a ~olution of 3-oxo-4-aza-7,~-methyl-16,~-phenoxy-Sa-androstane (145 mg, 0.35 mmol) in toluene (3 mL) was added DDQ (95 mg, 0.42 mmol), BSTFA (360 mg, 1.4 mmol) and triflic acid (4.04 mg, W096/12487 ~ 7 2 ~l/U~3~11330S

0.027 mmol). This solution was stirred overnight at room temperature under a nitrogen atmosphere. Then methylacetoacetate (4.06 mg, 0.035 mmol) was added and the solution was stirred. After one hour, the reaction was refluxed overnight. It was then poured into water (75 mL) cont~inin~ sodium carbonate (160 mg) and sodium bisufite (120 mg).
The aqueous phase was then extracted with methylene chloride (40 mL) (3x) and the organic phases were combined. The organic phase was washed with water (50 mL) and brine (50 mL). It wa.s dried over sodium sulfate and evaporated. The crude compound was purified by flash silica 10 gel chromatography using 15% acetone/methylene chloride to elute the title compound. 400 MHz 1H NMR (CDC13): ~ 0.92 (s, 3H); 0.96 (s, 3H); 1.02 (d, 3H); 3.34 (dd, lH); 4.72 (q, lH); 5.31 (,s, lH); 5.80 (d, lH);
6.gO (d, lH); 6.82 (d, 2H); 6.29 (t, lH); 7.24 (t, 2H).

3-oxo-4-aza-7,3-methyl- 16~-(4-chlorophenoxy)-50c-andro.st- 1 -ene (111) This compound was prepared in a similar fashion as Example 91, but substituting 3-oxo-4-aza-7~-methyl-16~-(4-chloro-20 phenoxy)-5Oc-androstane in place of 3-oxo-4-aza-7,13-methyl-16,B-phenoxy-50~-andro.stane. 400 MHz lH NMR (CDC13): ~ 0.92 (s, 3H);
0.95 (s, 3H); 1.02 (d, 2H); 3.34 (dd, lH); 4.67 (q, lH); 5.27 (s, lH); 5.~0 (d, lH); 6.73 (d, 2H); 6.78 (d, lH); 7.1~S (d, 2H).

3-oxo-4-aza-4~7~-dimethyl- 16~-phenoxy-5a-androstane (112) To a solution of 3-oxo-4-aza-7~-methyl-16~-phenoxy-Soc-androstane (60 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) wa,s 30 added sodium hydride (~ mg, 0.21 mmol), a 60% dispersion in mineral oil. After stirring for 30 min at room temperature under a nitrogen atmosphere, methyl iodide (40 mg, 0.28 mmol) was added. The reaction was stirred overnight. It was diluted with ethylacetate (50 mL) and washed with lN hydrochloric acid (50 mL), water (50 mL) and brine (50 WO96/12487 ~ 9 7 ~ PCT/US95/13305 mL). The organic phase wa.s dried over sodium sulfate and evaporated.
The crude product was purified by flash silica gel chromatography using 10% acetone/methylene chloride to elute the title compound. 400 MHz 1H NMR (CDC13): ~ 0.85 (s, 3H); 0.95 (s, 3H); 1.05 (d, 3H); 2.91 (s, 3H); 3.02 (dd, lH); 4.72 (q, lH); 6.~s1 (d, 2H); 6.~9 (t, lH); 7.24 (t, 2H).

3-oxo-4-aza-4,7,B-dimethyl- 16,13-(4-chlorophenoxy)-5a-andro,st- 1 -10 ene (113) This compound was prepared in a similar fashion asExample 93, but substituting 3-oxo-4-aza-7,B-methyl-16,~-(4-chloro-phenoxy)-5Oc-androstan-l-ene in place of 3-oxo-4-aza-7~-methyl-16,B-phenoxy-50c-androstane. 400 MHz lH NMR (CDC13): ~ 0.~s7 (s, 3H);
0.95 (s, 3H); 1.07 (d, 2H); 2.93 (s, lH); 3.34 (dd, lH); 4.68 (q, lH); 5.~s4 (d, lH); 6.69 (d, lH); 6.73 (d, 2H); 7.18 (d, 2H).

20 3-oxo-4-aza-4-(2,4-dimethoxybenzyl)-7~-methyl- 16~-(3-chloro-4-methylphenoxy)-5Oc-androstane (114) This compound was prepared in a similar fashion as Example 88, but substituting 2-chloro-4-fluorotoluene in place of 1-chloro-4-fluorobenzene. No purification was done prior to the next 25 reaction.

3-oxo-4-aza-7~-methyl- 16,B-(3-chloro-4-methylphenoxy)-5a-30 andro~stane (11 S) This compound was prepared in a similar fashion asExample ~9, but substituting 3-oxo-4-aza-4-(2,4-dimethoxy benzyl)-7~-methyl-16~-(3-chloro-4-methylphenoxy)-S x-androstane in place of 3-oxo-4-aza-4-(2,4-dimethoxy benzyl)-7,~-methyl- 16,13-(4-chlorophenoxy)-0 ~ 9 7 ~
, WO 96/12487 ' - ' PCT/US9S/13305 50c-androstane. 400 MHz lH NMR (CDC13): ~ 0.86 (s, 3H); 0.93 (s, 3H); 1.01 (d, 3H); 2.26 (s, 3H); 3.08 (dd, lH); 4.66 (q, lH); 5.59 (s, lH);
6.62 (m, lH); 6.~1 (d, lH); 7.06 (d, lH).

3-oxo-4-aza-7~-methyl- 1 6~-(4-methylphenoxy)-50c-androstane ( 1 16) This compound was prepared in a similar fashion a.s Example 90, but substituting 3-oxo-4-aza-7,~-methyl-16~-(3-chloro-4-10 methyl-phenoxy)-Soc-androstane in place of 3-oxo-4-aza-7~-methyl-16~B-(4-chloro-phenoxy)-5Oc-androstane. 400 MHz 1 H NMR (CDC13): ~ 0.~6 (s, 3H); 0.94 (s, 3H); 1.03 (d, 3H); 2.25 (s, 3H); 4.69 (q, lH); 6.71 (d, 2H); 7.03 (d, 2H).

EXAMPLE 9~

3-oxo-4-aza-7~-methyl- 1 6~-(4-methylphenoxy)-50~-androst- 1 -ene ( 1 17) This compound was prepared in a similar fashion as Example 91, but substituting 3-oxo-4-aza-7,(~-methyl-16,~-(4-methylphenoxy)-So~-20 androstane in place of 3-oxo-4-aza-7~-methyl- 1 6~-phenoxy-So~-androstane. 400 MHz lH NMR (CDC13): o 0.92 (s, 3H); 0.96 (s, 3H);
1.03 (d, 3H); 2.25 (s, 3H); 3.34 (dd, lH); 4.6~ (q, lH); 5.35 (s, lH); 5.~1 (d, lH); 6.71 (d, 2H); 6.79 (d, lH); 7.03 (d, 2H).

3-oxo-4-aza-7,B-methyl- 1 6,B-(4-methylphenoxy)-Soc-androstane ( 1 1 g) This compound was prepared in a similar fashion as Example 93, but substituting 3-oxo-4-aza-7~-methyl-16,~-(4-methyl-30 phenoxy)-So~-androstane in place of 3-oxo-4-aza-713-methyl-16~
phenoxy-Soc-androstane. 400 MHz lH NMR (CDC13): ~ 0.~5 (s, 3H);
0.94 (s, 3H); 1.04 (d, 3H); 2.25 (s, 3H); 2.91 (s, 3H); 3.05 (dd, lH); 4.69 (q, lH); 6.71 (d, 2H); 7.04 (d, 2H).

WO96/12487 ~ 7 9 PCT/US9S113305 3-Oxo-4-aza-4.7~B-dimethyl- 16,B-fluoro-50~-androstane This compound was prepared by treatment of intermediate 5 (12) (Scheme 5) with diethylaminosulfur trifluoride in methylene chloride at room temperature followed by chromatography on silica gel;
64% yield; m/z 321 (M); 400 MHz lH NMR spectrum (CDC13): 0.g7 (s, 3H); 0.92 (s, 3H); 1.04 (d, 3H); 2.90 (s, 3H), 5.12 (m, H).

3-Oxo-4-aza-4~7,(~-dimethyl- 16~-cyano-5(x-androstane This compound is obtained by conversion of intermediate (25) (Scheme 7) to its methansulfonate derivative by treatment with 15 methanesulfonyl chloride or methanesulfonic anhydride in methylene chloride in the presence of an organic base, such as pyridine and triethylamine, and 4-dimethylaminopyridine (DMAP). Displacement of the methanesulfonate group is effected by heating in an appropriate .solvent, such as N,N-dimethylformamide or dimethylsulfoxide, in the 20 presence of sodium or potassium cyanide.

3-Oxo-4-aza-4-methyl- 16~-(1 -hexyl)-5~ -androstane Step 1: 3-Oxo-4-aza-4-methyl- 16~-(1 -hexenyl)-50c-androstane To a 50-mL round-bottom fla~ik under nitrogen was added 1-hexyl-triphenylphosphonium bromide (141 mg, 0.33 mmol) followed by freshly distilled tetrahydrofuran (1 mL). The mixture was cooled to 0~C, 30 and butyllithium (2.5M solution in hexanes, 132 mL, 0.33 mmol) affording a bright orange solution. The solution was stirred at 0~C for 10 min., and was charged with a solution of 4-aza-4-methyl-50c-androstan-3,16-dione (50 mg, 0.165 mmol) in tetrahydrofuran (0.5 mL). The reaction mixture was allowed to reach room temperature and stirred 35 overnight. The mixture was then partitioned between water (10 mL) and WO96/12487 ~ 9 9 ~ ~ PCIJUS9S/13305 ethyl acetate (20 mL), the organic layer separated, washed with 0.5N
hydrochloric acid (2 x 10 mL), saturated brine solution, dried (Na2SO4), and evaporated. The title compound was purified by flash silica gel chromatography using 1 % methanol/methylene chloride as eluant. This S material (29.6 mg) was used without further purification in Step 2.

Step 2: 3-Oxo-4-aza-4-methyl- 16,~-(1 -hexvl)-5a-androstane A solution of the product obtained in Step 1 (22 mg) in ethyl acetate (0.5 mL) was hydrogenated in the presence of platinum oxide (5 mg) under a balloon atmosphere of hydrogen gas for 1 hour at room temperature. The catalyst was removed by filtration through a Millex-HV disposable filter, and the filtrate was evaporated. The title compound was purified by flash silica gel chromatography using 205'o acetone/hexane as eluant; yield 5.2 mg. Mass spectrum: m/z 374 (M+l ).
400 MHz lH NMR (CDC13): o 2.42 (dd, 2H), 2.90 (s, 3H), and 3.00 (dd, lH).

4-aza-4,7~3-dimethyl- 16b-(4-chlorobenzylidene)-Soc-androstan-3-one (128) Following Reaction ~cheme 14, solution of 4-aza-4,7~-dimethyl-S(x-androstan-3,17-dione (32 mg, 0.1 mmol), sodium hydride (S
mg, 1.02 eq), diethyl 4-chlorobenzylphosphonate (27 mg, 1.02 e~l) and DMF (0.SmL) were heated to 80~C for 1 hour. The reaction was cooled, diluted with dichloromethane and washed with water (x2), brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The desired product was purified by silica gel chromatography ~ (hexanes:isopropanol 4:1) tl.S:l mixture of E/Z isomers: m/z=389 lH NMR(500 MHz, CDC13):0.75 (s, 3H); 0.82 (s, 3H); 0.90 (d, 3H); 2.96 (s, 3H); 3.08 (dd, lH); 6.34 (s, 0.4H); 6.41 (s, 0.6H); 7.18-7.38 (m, 5H).

WO96/124~ g ~ 9 PCT/US95/13305~

4-aza-4.7,(~-dimethyl- 16-benzylidene-So~-androstan-3-one (127) This example was prepared in a similar fashion as 4-aza-4,7~-dimethyl- 16-(4-chlorobenzylidene)-50~-androstan-3-one but substituting diethyl benzylphosphonate for diethyl 4-chlorobenzyl-phosphonate: m/z= 390 1H NMR(500 MHz, CDC13): 0.75 (s, 3H); 0.88 (s, 3H); 1.05 (d, 3H);
2.94 (s, 3H); 3.08 (dd, lH); 6.28 (s, 0.4H); 6.35 (s, 0.6H); 7.15-7.35(m, 5H) .

4-aza-4,7~-dirnethyl- 16-(4-methylbenzylidene)-50~-androstan-3-one (129) This example was prepared in a similar fashion as 4-aza-4,7,B-dimethyl- 16-(4-chlorobenzylidene)-50c-androstan-3-one but substituting diethyl 4-methylphosphonate for diethyl 4-chlorobenzyl-phosphonate: m/z= 404 lH NMR (500 MHz, CDC13): 0.78 (s, 3H); 0.~s5 (s, 3H); 1.1 (d, 3H);
2.32 (s, 3H); 2.94 (s, 3H);3.0~ (dd, lH); 6.30 (s, 0.4H); 6.3~ (s, 0.6H);
7.10-7.24 (m, 5H).

4-aza-4.7~-dimethyl- 16-(4-chlorobenzyl)-50~-androstan-3-one (130) To a solution of 4-aza-4,7,B-dimethyl- 16-(4-chloro-benzylidene)-50c-androstan-3-one (33 mg) in ethanol (4 mL) was added 5% Rh/C and the black suspension stirred under ahydrogen balloon.
After 2 hours the mixture was filtered to remove catalyst, concentrated and purified on silica gel (hexanes:acetone 3: 1) to give the desired product as a 3: 1 mixture of isomers: m/z 427 ~WO96/12487 n ~ 7 9 PCT/US95/1330S

lH NMR (500 MHz, CDC13): 0.84 (s,3H); 0.86 (s,3H); 1.02 (d, 3H); 2.92 (bs, 2.7H); 2.93 (bs, 1.3H); 2.98 (s, 3H); 3.02 (dd, lH); 7.10 (d, 2H), 7.25 (d, 2H).

4-aza-4,7~-dimethyl- 16-(4-methylbenzyl)-5(x-androstan-3-one (131) This example was prepared similarly to the procedure used for 4-aza-4,7~-dimethyl- 16-(4-chlorobenzyl)-Soc-androstan-3-one: m/z=
10 40~
lH NMR (500 MHz, CDC13): 0.~s6( s, 6H); 1.04 (d, 3H); 2.33 (s, 3H);
2.95 (s, 2H); 2.96 (s, lH); 3.05 (dd, lH); 7.06-7.11 (m, 4H).

4-aza-4~7~-dimethvl- 16-(3-pyridylmethyl)-5a-androstan-3-one (132) This example was prepared similarly to the procedure used for 4-aza-4,7,B-dimethyl- 16-(4-chlorobenzyl)-So~-androstan-3-one except 3-pyridylmethyl-dimethylphosphonate was used:
20 m/z= 395 lH NMR (500 MHz, CDC13):0.89 (s, 3H); 0.88 (s, 3H); 1.03( d, 3H);
2.93 (bs, 2H); 2.94 (bs, lH); 2.9~ (.s, 3H); 3.04 (dd, lH); 7.10 (d, 2H), 7.25 (d, 2H); 7.58 (s, lH); 8.55 (s, 2H).

4-aza-4~7,B-dimethyl- 16a-methanesulfonyl-50c-androstan-3-one (119) Following Reaction Scheme 13, to a solution of 4-aza-4,7~-~ dimethyl- 160c-hydroxy-50~-androstan-3-one (65 mg, 0.2 mmol) in anhydrous dichloromethane was added a catalytic amount of DMAP
followed with methanesulfonic anhydride (45 mg, 1.1 eq). After 15 min, the reaction was diluted with dichloromethane, washed with lM HCl (x3), 1 M sodium bicarbonate, water and brine, dried over anhydrous WO96/12487 ~ 2 ~ Q PCT/US9S113305 magnesium sulfate filtered and concentrated to yield the desired compound of sufficent purity: m/z=398 lH NMR (S00 MHz, CDC13): 0.78 (s, 3H); 0.~5 (s, 3H); 1.02 (d, 3H);
2.95 (s, 3H); 3.1 (dd, 2H); 5.18 (m, lH);

4-aza-4~7~-dimethyl- 16~3-thiophenoxy-So~-androstan-3-one (120) To a solution of thiophenol (50 ~L, 2.5 eq) in anhydrous THF was added sodium hydride (20 mg, 2.6 e~l). After stirring 20 min, a THF solution of 4-aza-4,7,B-dimethyl- I 60c-methanec,ulfonyl-50~-androstan-3-one (65 mg. 0.2 mmol) was added and the mixture stirred 20 hours at ambient temperature. The reaction was ~luenched with 1 M
amrnonium chloride and diluted with ethyl acetate, washed with water l S and brine, dried over anhydrous magnesium sulfate filtered and concentrated. The desired compound was purified by silica gel chromatography (hexanes:isopropanol 9:1): m/z=412 lH NMR (S00 MHz, CDC13): 0.86 (s, 3H); 0.96 (s, 3H); 1.06 (d, 3H);
2.94 (s, 3H); 3.06 (dd, 2H); 3.65 (m, lH); 7.26-7.70 (m, SH).
EX~MPLE 111 4-aza-4,7~-dimethyl- 16~-(4-chlorothiophenoxy)-S(x-androstan-3-one (121) This compound was prepared in a similar fashion as 4-aza-4,7,B-dimethyl-16,B-thiophenoxy-5Oc-androstan-3-one but substituting 4-chlorothiophenol in place of thiophenol: m/z=446 lH NMR (S00 MHz, CDC13): 0.85 (s,3H); 0.96 (s, 3H); 1.04 (d, 3H);
2.94 (c" 3H); 3.02 (dd, 2H); 3.61 (m, lH); 7.22 (d, 2H); 7.32 (d, 2H).

WO96/12487 ~ 9 ~ 7 9 PCT/US95/13305 4-aza-4,7~-dimethyl- 16,B-(4-fluorothiophenoxy)-Soc-androstan-3-one (122) S This compound was prepared in a similar fashion as 4-aza-4,7,B-dimethyl-16,B-thiophenoxy-Soc-androstan-3-one but substituting 4-fluorothiophenol in place of thiophenol: m/z=431 1H NMR (S00 MHz, CDC13): 0.85 (s, 3H); 0.96 (s, 3H); 1.05 (d, 3H);
2.92 (s, 3H); 3.03 (dd, 2H); 3.51 (m, lH); 6.99 (d, 2H); 7.35 (d, 2H).

4-aza-4,7~B-dirnethyl- 16~B-(4-methylthiophenoxy)-Sa-androstan-3-one (123) This compound was prepared in a similar fashion as 4-aza-4,7,B-dimethyl-16~-thiophenoxy-So~-androstan-3-one but substituting 4-methylthiophenol in place of thiophenol:m/z=426 lH NMR(500 MHz, CDC13): 0.75 (s, 3H); 0.95 (s, 3H); 1.1 (d, 3H); 2.31 (s, 3H): 2.94 (s, 3H); 3.02 (dd, 2H); 3.59 (m, lH); 7.09 (d, 2H); 7.22 (d, 20 2H).

4-aza-4,7~-dimethyl- 16~3-(4-methoxythiophenoxy)-5a-androstan-3-one (124) This compound was prepared in a similar fashion as 4-aza-4,7~-dimethyl-16,13-thiophenoxy-50~-androstan-3-one but substituting 4-methoxythiophenol in place of thiophenol: m/z= 443 ~ lH NMR (500 MHz, CDC13): O.gl (s,3H); 0.93 (s,3H); l.lP~ (d,3H); 2.93 (s,3H); 3.02 (dd,2H); 3.50 (m,lH); 3.81 (s,3H); 7.45 (d,2H); 7.67 (d,2H).

WO96/12487 Q ~ ~ PCT/US9S113305 4-aza-4,7,13-dimethyl- 16,~-phenylsulfinyl-5O~-androstan-3-one (125) To a solution of 4-aza-4,7~-dimethyl-16~-thiophenoxy-Sol-androstan-3-one (20 mg, 0.05 mmol) in dicloromethane at 0~C was added mCPBA (11 mg, 1 eq) and the solution stirred 1 hour. The reaction was diluted with dichloromethane and washed with 1 M sodium bicarbonate, water, brine and dried over anhydrous sodium sulfate. The desired compound was purified by silica gel chromatography to yield a 4.6: 1 mixture of diastereomers: m/z=42~S
lH NMR(500 MHz, CDC13): 0.g3 (s, 3H); 0.92 (~, 3H); 1.01 (d, 3H);
2.92 (.s, 3H); 3.01 (dd, 2H); 3.19 (m, 0.85H); 3.55 (m, 0.15H); 7.5-7.70 (m, SH).

4-aza-4.7,B-dimethyl- 16~-phenylsulfonyl-5a-androstan-3-one (126) A solution of 4-aza-4,7,B-dimethyl- 16~-phenylsulfinyl-Soc-androstan-3-one 912 mg, 0.03 mmol) in dichloromethane was treated with mCPBA (9 mg, l.S eq) for 3 hours. The reaction was diluted with dichloromethane and washed with 1 M sodium bicarbonate, water, brine and dried over anhydrous sodium sulfate. The desired compound was purified by silica gel chromatography (hexanes:isopropanol 7:3): m/z=

lH NMR (500 MHz, CDC13): 0.~5 (s, 3H); 0.91 (!;, 3H); 1.0 (d, 3H); 2.95 (s, 3H); 3.05 (dd, 2H); 3.55 (m, 0.15H); 7.41 (t, lH); 7.55 (t, 2H); 7.90 (d, lH), 7.90 (d, lH) 3-Oxo-4-aza-4.16~-dimethyl-Soc-androstane This compound is made by converting the readily av~ilable 4-aza-4,16~-dimethyl-androstan-3,17-dione to the 17-triflate. Reduction of the 17-triflate through conventional methods yields the titled 16-,3methyl analog.

WO 96112487 ~ ~ ~ 9 9 9 7 ~ PCTIUS95113305 Mass spectrum: mlz 304 (M+ l ) 400 MHz NMR (CDCl3): ~ 0.76 (s, 3H); 0.85 (s, 3H); 1.04 (d, 3H); 2.90 (s, 3H); 3.01 (dd, lH).

Claims (33)

WHAT IS CLAIMED IS:

1. A method of treating acne comprising the step of administering to a person in need thereof a therapeutically effective amount of a 5.alpha.-reductase inhibitor and a retinoid agent and at least one member selected from the group consisting of an antibacterial agent, a keratolytic agent and an anti-inflammatory agent.

2. The method of Claim 1 wherein said 5.alpha.-reductase inhibitor is a 5.alpha.-reductase 1 inhibitor.

3. The method of Claim 2 further comprising a 5.alpha.-reductase 2 inhibitor.

4. The method of Claim 3 wherein said 5.alpha.-reductase 2 inhibitor is finasteride, epristeride or turosteride.

5. The method of Claim 2 wherein said 5.alpha.-reductase 1 inhibitor is selected from the group consisting of (I.):

I

or a pharmaceutically acceptable salt or ester thereof, wherein for Structure I:
R is selected from hydrogen, methyl, ethyl, -OH, -NH2, and -SCH3;
the dashed lines "~" a and b independently represent a single bond or a double bond providing that when b is a double bond, the 5.alpha.
hydrogen, Ha, is absent;
=Z is selected from:

1) oxo, 2) .alpha.-hydrogen and a .beta.-substituent selected from:
a) C1-C4 alkyl, b) C2-C4 alkenyl, c) CH2COOH, d) -OH, e) -COOH, f) -COO(C1-C4 alkyl), g) -OC(O)NR1R2 wherein R1 and R2 independently are selected from:
i) H, ii) C1-C4 alkyl, iii) phenyl, and iv) benzyl, or R1 and R2 together with the nitrogen atom to which they are attached represent a 5-6 membered saturated heterocycle, optionally containing one other heteratom selected from -O-, -S- and -N(R')- wherein R' is -H or methyl;
h) C1-C4 alkoxy, i) C3-C6 cycloalkoxy, j) -OC(O)-C1-4alkyl, k) halo, l) hydroxy -C1-C2 alkyl, m) halo-C1-C2 alkyl, n) -CF3, and o) C3-C6 cycloalkyl;
3) =CHR3; wherein R3 is selected from -H and C1-C4 alkyl;
and 4) spirocyclopropane-R3 of structure:

; and (II.) or a pharmaceutically acceptable salt or ester thereof wherein:
the C1-C2 carbon-carbon bond may be a single bond, or a double bond as indicated by the dashed line;
R4 is selected from the group consisting of hydrogen and C1-C10 alkyl;
R5 is selected from the group consisting of hydrogen and C1-C10 alkyl;
one of R6 and R7 is selected from the group consisting of hydrogen and methyl, and the other is selected from the group consisting of:
(a) amino;
(b) cyano;
(c) fluoro;
(d) methyl;
(e) OH;
(f) -C(O)NRbRC, where Rb and Rc are independently H, C1-6 alkyl, aryl, or arylC1-6alkyl; wherein the alkyl moiety can be substituted with 1-3 of: halo; C1-4alkoxy;
or trifluoromethyl; and the aryl moiety can be substituted with 1-3 of: halo; C1-4alkyl; C1-4 alkoxy; or trifluoromethyl;
(g) C1-10 alkyl-X-;
(h) C2-10 alkenyl-X-;
wherein the C1-10 alkyl in (g) and C2-10 alkenyl in (h) can be unsubstituted or substituted with one to three of:

i) halo; hydroxy; cyano; nitro; mono-, di- or trihalomethyl; oxo; hydroxysulfonyl; carboxy;
ii) hydroxyC1-6alkyl; C1-6alkyloxy; C1-6 alkylthio; C1-6alkylsulfonyl; C1-6 alkyloxycarbonyl; in which the C1-6 alkyl moiety can be further substituted with 1-3 of:
halo; C1-4 alkoxy; or trifluoromethyl;
iii) arylthio; aryl; aryloxy; arylsulfonyl;
aryloxycarbonyl; in which the aryl moiety can be further substituted with 1-3 of: halo; C1-4 alkyl; C1-4 alkoxy; or trifluoromethyl;
iv) -C(O)NRbRc; -N(Rb)-C(O)-Rc; -NRbRc;
where Rb and Rc are defined above;
(i) aryl-X-;
(j) heteroaryl-X-, wherein heteroaryl is a 5, 6 or 7 membered heteroaromatic ring containing at least one member selected from the group consisting of: one ring oxygen atom, one ring sulfur atom, 1-4 ring nitrogen atoms, or combinations thereof; in which the heteroaromatic ring can also be fused with one benzo or heteroaromatic ring;
wherein the aryl in (i) and heteroaryl in (j) can be unsubstituted or substituted with one to three of:
v) halo; hydroxy; cyano; nitro; mono-, di- or trihalomethyl; mono-, di- or trihalomethoxy;
C2-6 alkenyl; C3-6 cycloalkyl; formyl;
hydrosulfonyl; carboxy; ureido;
vi) C1-6 alkyl; hydroxy C1-6 alkyl; C1-6 alkyloxy;
C1-6 alkyloxy C1-6alkyl; C1-6 alkylcarbonyl;
C1-6 alkylsulfonyl; C1-6 alkylthio; C1-6 alkylsulfinyl; C1-6 alkylsulfonamido; C1-6 alkylarylsulfonamido; C1-6 alkyloxy-carbonyl;
C1-6 alkyloxycarbonyl C1-6alkyl; RbRcN-C(O)-C1-6alkyl; C1-6 alkanoylamino C1-6 alkyl; aroylamino C16 alkyl; wherein the C1-6 alkyl moiety can be substituted with 1-3 of:
halo; C1-4alkoxy; or trifluoromethyl;
vii) aryl; aryloxy; arylcarbonyl; arylthio;
arylsulfonyl; arylsulfinyl; arylsulfonamido;
aryloxycarbonyl; wherein the aryl moiety can be substituted with 1-3 of: halo; C1-4alkyl; C1-4alkoxy; or trifluoromethyl;
viii) -C(O)NRbRc; -O-C(O)-NRbRc; -N(Rb)-C(O)-Rc; -NRbRc; Rb-C(O)-N(Rc)-; where Rb and Rc are defined in (f) above; and -N(Rb)-C(O)-ORg, wherein Rg is C1-6alkyl or aryl, in which the alkyl moiety can be substituted with 1-3 of:
halo; C1-4alkoxy; or trifluoromethyl, and the aryl moiety can be substituted with 1-3 of: halo;
C1-4alkyl;C1-4alkoxy, or trifluoromethyl;
-N(Rb)-C(O) NRcRd, wherein Rd is selected from H, C1-6 alkyl, and aryl; in which said C1-6alkyl and aryl can be substituted as described above in (f) for Rb and Rc;
ix) a heterocyclic group, which is a 5, 6 or 7 membered ring, containing at least one member selected from the group consisting of: one ring oxygen atom, one ring sulfur atom, 1-4 ring nitrogen atoms, or combinations thereof; in which the heterocyclic ring can be aromatic, unsaturated, or saturated, wherein the heterocyclic ring can be fused with a benzo ring, and wherein said heterocyclic ring can be substituted with one to three substituents, as defined above for v ), vi), vii) and viii), excluding ix) a heterocyclic group; and (k) R6 and R7 taken together can be carbonyl oxygen;

(1) R6 and R7 taken together can be =CH-Rg, wherein Rg is defined in viii); and wherein:

X is selected from the group consisting of:
-0-; -S(O)n-; -C(O)-; -CH(Re)-; -C(O)-O-*; -C(O)-N(Re)-*;
-N(Re)-C(O)-O-*; -O-C(O)-N(Re)-*; -N(Re)C(O)-N(Re)-;
-O-CH(Re)-*; -N(Re)-; wherein Re is H, C1-3 alkyl, aryl, aryl-C1-3 alkyl, or unsubstituted or substituted heteroaryl, as defined above in (j);
wherein the asterisk (*) denotes the bond which is attached to the 16-position in Structure II; and n is zero, 1 or 2.

6. The method of Claim 5 wherein said 5.alpha.-reductase inhibitor is of the structural formula:

where R is H or CH3.

7. The method of Claim 5 wherein said 5.alpha.-reductase is of the structural formula:

8. The method of Claim 5 wherein said 5.alpha.-reductase inhibitor is of the structural formula:

9. The method of Claim 5 wherein Z is .alpha.-hydrogen and the .beta.-substituent is C1-C4alkyl, or C2-C4alkenyl.

10. The method of Claim 5 wherein said 5.alpha. reductase inhibitor compound of Formula II, R4 is hydrogen or methyl and R5is hydrogen or methyl.

11. The method of Claim 5 wherein said 5.alpha. reductase inhibitor compound of Formula II, R6 and R7 are selected from unsubstituted or substituted aryloxy, C1-10 alkyloxy or C1-10 alkylthio.

12. The method of Claim 5 wherein Formula II, the C1-C2 carbon-carbon bond is a single bond, R4 is methyl, R5 is methyl, R7 is selected from unsubstituted or substituted aryloxy, and R6 is hydrogen.

13. The method of Claim 5 wherein said Formula II:
one of R6 and R7 is selected from the group consisting of hydrogen and methyl, and the other is selected from the group consisting of:
(b) cyano;
(c) fluoro;
(e) OH;
(g) C1-10 alkyl-X-; or C1-10 alkyl-X-, where alkyl can be substituted with aryl, and wherein aryl in turn can be substituted with 1-2 of halo or C1-6alkyl;
(h) C2-10alkenyl-X-;
(i) aryl-X-;
(j) heteroaryl-X-, wherein heteroaryl is a 5 or 6 membered heteroaromatic ring containing 1-2 ring nitrogen atoms;
wherein the aryl in (i) and heteroaryl in (j) can be unsubstituted or substituted with one to two of:
x) halo; cyano; nitro; trihalomethyl; trihalomethoxy; C1-6 alkyl; aryl; C1-6 alkylsulfonyl; C1-6 alkyl-arylsulfonamino;
xi) -NRbRC; Rb-C(O)-N(RC)-; wherein Rb and Rc are independently H, C1-6 alkyl, aryl, or arylC1-6alkyl;
wherein the alkyl moiety can be substituted with 1-3 of: halo; C1-4alkoxy; or trifluoromethyl; and the aryl moiety can be substituted with 1-3 of: halo; C1-4alkyl; C1-4 alkoxy; or trifluoromethyl;
xii) a heterocyclic group, which is a 5 membered aromatic ring, containing one ring nitrogen atom, or one ring oxygen and one ring nitrogen atom; and (k) wherein R6 and R7 taken together can be carbonyl oxygen;
and wherein:

X is selected from the group consisting of:
-O-; -S(O)n-; -CH(Re)-; -C(O)-N(Re)-*;
-O-C(O)-N(Re)-*;
wherein Re is H, C1-3 alkyl, aryl, aryl C1-3 alkyl;

wherein the asterisk (*) denotes the bond which is attached to the 16-position in Structure II; and n is zero or 2.

14. The method of Claim 5 wherein .said compound is selected from the group consisting of:
7.beta.-ethyl-4-methyl-4-aza-cholest-5-en-3-one;
7.beta.-ethyl-4-methyl-4-aza-cholestane-3-one;
7.beta.-ethyl-4-aza-5.alpha.-cholestan-3-one;
7.beta.-carboxymethyl-4-aza-cholest-5-en-3-one;
7.beta.-carboxymethyl-4-aza-cholestan-3-one;
7.beta.-propyl-4-methyl-4-aza-cholest-5-en-3-one;
7.beta.-propyl-4-methyl-4-aza-5.beta.-cholestan-3-one;
7.beta.-propyl-4-aza-5.alpha.-cholestan-3-one;
7.beta.-methyl-4-aza-cholest-5-en-3-one;
7.beta.-methyl-4-aza-cholestan-3-one;
4,7.beta.-dimethyl-4-aza-cholest-5-en-3-one;
4,7.beta.-dimethyl-4-aza-5a-cholestan-3-one;
4-methyl-4-aza-5.alpha.-cholestan-3,7-dione;
7.beta.-acetoxy-4-methyl-4-aza-5.alpha.-cholestane-3-one;
7.beta.-hydroxy-4-methyl-4-aza-5.alpha.-cholestane-3-one;
7.beta.-methoxy-4-methyl-4-aza-5.alpha.-cholestane-3-one;
7.beta.-hydroxymethyl-4-aza-5.alpha.-cholestane-3-one;
7.beta.-bromomethyl-4-aza-5.alpha.-cholestane-3-one;
7.beta.-chloromethyl-4-aza-5.alpha.-cholestane-3-one;
7.beta.-fluoromethyl-4-aza-5.alpha.-cholestane-3-one;
7.beta.-carboxy-4-aza-5.alpha.-cholestane-3-one;
7.beta.-trifluoromethyl-4-aza-cholest-5-en-3-one;
7.beta.-methoxy-4-methyl-4-aza-cholesta-5-en-3-one;
7.beta.-cyclopropyloxy-4-methyl-4-aza-5.alpha.-cholestane-3-one;
7.beta.-propylidene-4-methyl-4-aza-5.alpha.-cholestane-3-one;
7.beta.-(2-ethyl)spiroethylene-4-methyl-4-aza-5.alpha.-cholestane-3-one;
7.beta.-methyl-4-aza-50.alpha.-cholest-1-en-3-one;
4-aza-4,7.beta.-dimethyl-50.alpha.-androstane-3, 16-dione;
4-aza-4-methyl-5.alpha.-androstan-3, 16-dione;

3-oxo-4-aza-4-methyl-16.beta.-hydroxy-5.alpha.-androstane;
3-oxo-4-aza-4-methyl-16.beta.-(benzylaminocarbonyloxy)-5.alpha.-androstane;
3-oxo-4-aza-4-methyl-16.beta.-benzoylamino-5.alpha.-androstane;
3-oxo-4-aza-4-methyl-16.beta.-methoxy-5.alpha.-androstane;
3-oxo-4-aza-4-methyl-16.beta.-allyloxy-5.alpha.-androstane;
3-oxo-4-aza-4-methyl-16.beta.-(n-propyloxy)-5.alpha.-androstane;
3-oxo-4-aza-4-methyl-16.alpha.-hydroxy-5.alpha.-androstane;
3-oxo-4-aza-4-methyl-16.beta.-(phenoxy)-5.alpha.-androstane;
3-oxo-4-aza-7.beta.-methyl-16.beta.-(phenoxy)-5.alpha.-androst-1-ene;
3-oxo-4-aza-4-methyl-16.alpha.-methoxy-5.alpha.-androstane;
3-oxo-4-aza-4-methyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-7.beta.-methyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androst-1-ene;
3-oxo-4-aza-7.beta.-methyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-7.beta.-methyl-16.beta.-(3-chloro-4-methylphenoxy)-5.alpha.-androstane;
3-oxo-4-aza-7.beta.-methyl-16.beta.-(4-methylphenoxy)-5.alpha.-androstane;
3-oxo-4-aza-7.beta.-methyl-16.beta.-(4-methylphenoxy)-5.alpha.-androst-1-ene;
3-oxo-4-aza-7.beta.-methyl-16.beta.-[4-(1-pyrrolyl)phenoxy]-5.alpha.-androst-1-ene;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-hydroxy-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-methoxy-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-allyloxy-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3,3-dimethylallyloxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(n-propyloxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16,.beta.-(iso-pentoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,16.alpha.-dimethyl-16.beta.-hydroxy-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-ethyloxy-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-benzyloxy-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-hydroxy-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-methylthio-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(n-propylthio)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-fluoro-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-cyano-5.alpha.-androstane;
3-oxo-4-aza-4-methyl-16.beta.-(1-hexyl)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(n-propyl)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-benzyl-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorobenzyl)-5.alpha.-androstane;
3-oxo-4-aza-4,16.alpha.-dimethyl-16.beta.-methoxy-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-cyanophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-cyanophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-nitrophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(1-naphthyloxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-chloro-4-methylphenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylphenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(tert-butyloxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-methyl-1-butyloxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.alpha.-(n-propyloxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-trifluoromethylphenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-trifluoromethoxyphenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-ethylthio-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-ethylsulfonyl-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylsulfonylphenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(4-tolylsulfonylamino)phenoxy]-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-pyridyloxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[(4-phenyl)phenoxy)-5.alpha.-androstane;3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-fluorophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(2-pyrazinyloxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(5-oxazolyl)phenoxy]-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(2-pyrimidinyloxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(1-pyrryl)phenoxy]-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-aminophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-acetylaminophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-benzoylaminophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(phenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(2-chlorophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-chlorophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androst-1-ene;
3-oxo-4-aza-4,7.beta.-dimethyl-16-(4-chlorobenzylidene)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16-benzylidene-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16-(4-methylbenzylidene)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16-(4-chlorobenzyl)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16-(4-methylbenzyl)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16-(3-pyridylmethyl)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.alpha.-methanesulfonyl-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-thiophenoxy-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorothiophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-fluorothiophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylthiophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methoxythiophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-phenylsulfinyl-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-phenylsulfonyl-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.,16.beta.-trimethyl-16.beta.-(4-trifluoromethylphenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.,16.alpha.-trimethyl-16.beta.-hydroxy-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.,16.alpha.-trimethyl-16.beta.-methoxy-5.alpha.-androstane;
pharmaceutically acceptable salts thereof.

15. The method of Claim 14 wherein said 5.alpha. reductase inhibitor compound is selected from the group consisting of:
7.beta.-ethyl-4-methyl-4-azacholestan-3-one;
7.beta.-propyl-4-methyl-4-aza-5.alpha.-cholestan-3-one;
4,7.beta.-dimethyl-4-aza-5.alpha.-cholestan-3-one;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-cyanophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-cyanophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-nitrophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(1-naphthyloxy)-5.alpha.-androstane;

3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-chloro-4-methylphenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylphenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-trifluoromethylphenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-trifluoromethoxyphenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-methylsulfonylphenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(4-tolylsulfonylamino)phenoxy]-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[(4-phenyl)phenoxy)-5.alpha.-androstane;3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-fluorophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(5-oxazolyl)phenoxy]-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(1-pyrryl)phenoxy]-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-aminophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-acetylaminophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-benzoylaminophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(phenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(2-chlorophenoxy)-5.alpha.-androstane;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(3-chlorophenoxy)-5.alpha.-androstane;
and the pharmaceutically acceptable salts thereof.

16. The method of Claim 15 wherein said 5.alpha. reductase inhibitor compound is selected from:
4,7.beta.-dimethyl-4-aza-5.alpha.-cholestan-3-one;
3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy)-5.alpha.-androstane,3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-[4-(1-pyrryl)phenoxy]-5.alpha.-androstane,or a pharmaceutically acceptable salt thereof.

17. The method of Claim 1 wherein said retinoid agent is tr~tinoin or isotretinoin.

18. The method of Claim 1 wherein said antibacterial is selected from the group consisting of: aminoglycosides, amphenicols, ansamycins, beta-lactams, lincosamides, macrolides, polypeptides, tetracyclines, 2,4,diaminopyrimidines, nitrofurans, quinolones, sulfonamides, and sulfones, or mixture thereof.

19. The method of Claim 1 wherein said antibacterial is selected from the group consisting of:
(a) aminoglycosides, including amikacin, apramycin, arbekacin, bambermycins, butirosin, dibekacin, dihydrostreptomycin, fortimicin(s), gentamicin, isepamicin, kanamycin, micronomicin, neomycin, neomycin undecylenate, netilmicin, paromomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, streptonicozid, tobramycin;
(b) amphenicols, including azidamfenicol, chloramphenicol, chloramphenicol palmitate, chloramphenicol pantothenate, florfenicol, thiamphenicol;
(c) ansamycins including rifamide, rifampin, rifamycin SV, rifaximin;
(d) beta-lactams, including imipenem, cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin, cefixime, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam, cefpimizole, cefpiramide, cefpodoxime proxetil, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin, cephaloridine, cephalosporin C, cephalothin, cephapirin sodium, cephradine, pivcefalexin,cefbuperazone, cefmetazole, cefminox, cefotetan, cefoxitin, aztreonam, carumonam, tigemonam,flomoxef, moxolactam,amidinocillin, amidinocillin pivoxil, amoxicillin, ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin, bacampicillin, benzylpenicillinic acid, benzylpenicillin sodium, carbenicillin, carfecillin sodium, carindacillin, clometocillin, cloxacillin, cyclacillin, dicloxacillin, diphenicillin sodium, epicillin, fenbenicillin, floxacillin, hetacillin, lenampicillin, metampicillin, methicillin sodium, mezlocillin, nafcillin sodium, oxacillin, penamecillin, penethamate hydriodide, penicillin G
benethamine, penicillin G benzathine, penicillin G benzhydrylamine, penicillin G calcium, penicillin G hydrabamine, penicillin G potassium, penicillin G procaine, penicillin N, penicillin O, penicillin V,,penicillin V benzathine, penicillin V hydrabamine, penimepicycline, phenethicillin potassium, piperacillin, pivampicillin, propicillin, quinacillin, sulbenicillin, talampicillin, temocillin, ticarcillin;
(e) lincosamides, including clindamycin, lincomycin;
(f) macrolides, including azithromycin, carbomycin, clarithromycin, erythromycin, erythromycin acistrate, erythromycin estolate, erythromycin glucoheptonate, erythromycin lactobionate, erythromycin propionate, erythromycin stearate, josamycin, leucomycins, midecamycins, miokamycin, oleandomycin, primycin, rokitamycin, rosaramicin, roxithromycin, spiramycin, troleandomycin;
(g) polypeptides, including amphomycin, bacitracin, capreomycin, colistin, enduracidin, enviomycin, fusafungine, gramicidin(s), gramicidin S, mikamycin, polymyxin, polymyxin B-methanesulfonic acid, pristinamycin, ristocetin, teicoplanin, thiostrepton, tuberactinomycin, tyrocidine, tyrothricin, vancomycin, viomycin, viomycin pantothenate, virginiamycin, zinc bacitracin;
(h) tetracyclines, including apicycline, chlortetracycline, clomocycline, demeclocycline, doxycycline, guamecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, penimepicycline, pipacycline, rolitetracycline, sancycline, senociclin, tetracycline;
(i) 2,4-diaminopyrimidines, including brodimoprim, tetroxoprim, trimethoprim;
(j) nitrofurans, including furaltadone, furazolium chloride, nifuradene, nifuratel, nifurfoline, nifurpirinol, nifurprazine, nifurtoinol, nitrofurantoin;
(k) quinolones, including amifloxacin, cinoxacin, ciprofloxacin, difloxacin, enoxacin, fleroxacin, flumequine, lomefloxacin, miloxacin, nalidixic acid, norfloxacin, ofloxacin, oxolinic acid, pefloxacin, pipemidic acid, piromidic acid, rosoxacin, temafloxacin, tosufloxacin, OPC 7251 fluoroquinolone (Otsuka);
(l) sulfonamides, including acetyl sulfamethoxypyrazine, acetyl sulfisoxazole, azosulfamide, benzylsulfamide, chloramine-B, chloramine-T, dichloramine-T, formosulfathiazole, N-formylsulfisomidine, N-beta-D-glucosylsulfanilamide, mafenide, 4'-(methylsulfamoyl)sulfanilanilide, p-nitrosulfathiazole, noprylsulfamide, phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine, succinylsulfathiazole, sulfabenzamide, sulfacetamide, sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid, sulfamerazine, sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine, sulfamethoxazole, sulfamethoxypyridazine, sulfametrole, sulfamidochrysoidine, sulfamoxole, sulfanilamide, sulfanilamidomethanesulfonic acid triethanolamine salt, 4-sulfanilamidosalicylic acid, N-sulfanilylsulfanilamide, sulfanilylurea, N-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine, sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine, sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea, sulfatolamide, sulfisomidine, sulfisoxazole;
(m) sulfones, including acedapsone, acediasulfone, acetosulfone sodium, dapsone, diathymosulfone, glucosulfone sodium, solasulfone, succisulfone, sulfanilic acid, p-sulfanilylbenzylamine, p,p'-sulfonyldianiline-N,N'-digalactoside, sulfoxone sodium, thiazolsulfone;
and (n) the group consisting of:cycloserine, mupirocin, tuberin, clofoctol, hexedine, methenamine, methenamine anhydromethylene-citrate, methenamine hippurate, methenamine mandelate, methenamine sulfosalicylate, nitroxoline, xibornol, benzoyl peroxide, or mixtures thereof.

20. The method of Claim 19 wherein said antibacterial is clindamycin, OPC 7251 (Otsuka) fluoroquinolone or erythromycin.

21. The method of Claim 1 wherein said keratolytic agent is selected from the group consisting of algestone acetophenide, azelaic acid, benzoyl peroxide, benzoyl peroxide/erythromycin, cyoctol, dichloroacetic acid, metronidazole, motretinide, resorcinol, salicylic acid, sulfur, tetroquinone, alpha-hydroxy acids, glycolic acid, and mixtures thereof.

22. The method of Claim 21 wherein said keratolytic agent is benzoyl peroxide, benzoyl peroxide/erythromycin, or salicylic acid.

23. The method of Claim 1 wherein said anti-inflammatory is selected from the group consisting of:
aminoarylcarboxylic acid derivatives, arylacetic acid derivatives, arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acid derivatives, pyrazoles, pyrazolones, salicylic acid derivatives, thiazinecarboxamides, glucocorticoids or mixture thereof.

24. The method of Claim 1 wherein said anti-inflammatory is selected from the group consisting of: (a) aminoarylcarboxylic acid derivatives, including enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate, tolfenamic acid;
(b) arylacetic acid derivatives, including acemetacin, alclofenac, amfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenclofenac, fenclorac, fenclozic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac, isoxepac, lonazolac, metiazinic acid, oxametacine, proglumetacin, sulindac, tiaramide, tolmetin, zomepirac;
(c) arylbutyric acid derivatives, including bumadizon, butibufen, fenbufen, xenbucin;
(d) arylcarboxylic acids, including clidanac, ketorolac, tinoridine;
(e) arylpropionic acid derivatives, including alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, miroprofen, naproxen, oxaprozin, piketoprofen, pirprofen, pranoprofen, protizinic acid, suprofen, tiaprofenic acid;
(f) pyrazoles, including difenamizole, epirizole;

(g) pyrazolones, including apazone, benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, ramifenazone, suxibuzone, thiazolinobutazone;
(h) salicylic acid derivatives, including acetaminosalol, aspirin, benorylate, bromosaligenin, calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate.
lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-naphthyl salicylate, olsalazine, parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide, salicylamide O-acetic acid, salicylsulfuric acid, salsalate, sulfasalazine;
(i) one member selected from the group consisting of: epsilon-acetamidocaproic acid, S-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, difenpiramide, ditazol, emorfazone, guaiazulen~, nabumetone, nimesulide, orgotein, oxaceprol, paranyline, perisoxal, pifoxime, proquazone, proxazole, tenidap;
(j) glucocorticoids, including 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethaxsone, diflorasone, diflucortolone, defluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone flujorometholone, fluperolone acetate, fluprednidene acetat, fluprednisolone, flurandrenolide, formocortal, halcinonide, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, hydrocortisone acetate, hydrocortisone phosphate, hydrocortisone 21-sodium succinate, hydrocortisone tebutate, maziprednone, medrysone, meprednisone, methylprednisonole, mometasone furoate, paramethasone prednicarbate, prednisolone, prednisolone 21-diethylaminoacetate, prednisolone sodium phosphate, prednisolone sodium succinate, prednisolone sodium 21-m-sulfobenzoate, prednisolone 21-stearoylglycolate, prednisolone tebutate, prednisolone 21-trimethylacetate, prednisone, prednival, prednylidene, prednylidene 21-diethylaminoacetate, tixocotrol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, or mixture thereof.

25. The method of Claim 22 wherein said anti-inflammatory is prednisone.

26. A method of inhibiting acne-related 5.alpha.-reductase or the isozymes thereof, comprising the step of administering to a person in need of such inhibition a therapeutically effective amount each of the 5.alpha.-reductase inhibitor, retinoid agent and one member selected from an antibacterial, keratolytic and anti-inflammatory agent.

27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 5.alpha.-reductase inhibitor, retinoid agent and one member selected from an antibacterial, keratolytic and anti-inflammatory agent.

28. The pharmaceutical composition of Claim 27 wherein said 5-reductase inhibitor is a 5.alpha.-reductase 1 inhibitor.

29. The pharmaceutical composition of Claim 27 wherein said 5.alpha.-reductase inhibitor is a 5.alpha.-reductase 2 inhibitor.

30. The pharmaceutical composition of Claim 27 wherein said 5.alpha.-reductase inhibitor is a mixture of 5.alpha.-reductase 1 and 2 inhibitors.

31. The pharmaceutical composition of Claim 28 wherein the 5.alpha.-reductase 1 inhibitor is selected from the group consisting of: 4,7-.beta.-dimethyl-4-aza-5a-cholestan-3-one; 3-oxo-4-aza-4,7.beta.-dimethyl-16.beta.-(4-chlorophenoxy]-5.alpha.-androstane, 3-oxo-4-aza-4,7,.beta.-dimethyl- 16.beta.-[4-[1-pyrryl)phenoxy)-5.alpha.-androstane, or a pharmaceutically acceptable salt thereof.

32. The pharmaceutical composition of Claim 27 wherein said retinoid agent is tretinoin or isotretinoin.

33. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 5.alpha.-reductase 1 inhibitor, as defined in Claim 3, a retinoid agent and at least one member selected from an antibacterial, keratolytic and anti-inflammatory agent.