INTERMEDIAIRES POUR LA PRODUCTION DE STEROIDES A ACTIVITE PHARMACEUTIQUE

INTERMEDIATES FOR PHARMACEUTICALLY ACTIVE STEROIDS

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
Compounds of the formula (IV) are provided:
<IMG> (IV)
wherein:
X is a protected carbonyl group: R1 is a C1-5 alkyl group, a C3-6 alkenyl
group, a C3-6 cycloalkyl group or an alkylphenyl group in which the alkyl
moiety is C1-3 alkyl and the phenyl moiety is optionally substituted; R2
is a hydroxyl group, or a group OR4 wherein R4 is a C2-7 acyl group, a
C1-4 alkyl group, or an optionally substituted benzyl group; R3 is hydrogen
or a C1-5 alkyl group; or R2 and R5 together represents an oxo group. These
compounds are useful as intermediates in the preparation of certain steroids
intended for the treatment of androgen dependent skin disorders.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula IV
<IMG> (IV)
wherein
X is a protected carbonyl group;
R1 is a C1-5 alkyl group, a C3-6 alkenyl group, a C3-6 cycloalkyl group or an
alkylphenyl group in which the alkyl moiety is C1-3 alkyl and the phenyl moiety
is unsubstituted or substituted by inert substituents;
R2 is a hydroxyl group, or a group OR4 wherein R4 is a C2-7 acyl group, a C1-4
alkyl group, or an unsubstituted or substituted by inert substituents benzyl
group;
R3 is hydrogen or a C1-5 alkyl group; or
R2 and R5 together represents an oxo group, which process comprises substituting
a compound of formula II
<IMG> (II)
wherein X is as defined in formula IV with the required groups R1, where R1
is as defined in formula IV; and thereafter if required, converting the
17-carbonyl group in the compound thus formed to a group CR2R3 where R2 and R3
are defined in formula IV and do not together represent an oxo group.
19

2. A process according to claim 1 which process comprises reacting
a compound of formula II as defined in claim 1, with a compound of formula
R1Y; wherein R1 is a methyl group; and Y is a halide, tosylate, mesylate or
azide group, in the presence of a strong base of low nucleophilicity, and
thereafter if desired converting the 17-carbonyl group in the compound thus
formed to a group CR3OH by reduction when R3 is hydrogen or by reaction with
C1-5 alkyl Crignard reagent or C1-5 alkyl metallic complex when R3 is C1-5
alkyl, and then optionally protecting the CR3OH moiety by acylation or
etherification.
3. A process according to claim 1, wherein R1 is a C1-5 alkyl
group, a C3-6 cycloalkyl group or an alkylphenyl group in which the alkyl
moiety is C1-3 alkyl and the phenyl group is unsubstituted or substituted by
inert substituents.
4. A process according to claim 2 wherein R1 is a C1-5 alkyl group,
a C3-6 cycloalkyl group or an alkylphenyl group in which the alkyl moiety is
C1-3 alkyl and the phenyl group is unsubstituted or substituted by inert
substituents.
5. A process according to claim 3, wherein R1 is a methyl, ethyl or
propyl group.
6. A process according to claim 4, wherein R1 is a methyl, ethyl or
propyl group.
7. A process according to claim 1 or 2, wherein R1 is an allyl or
butenyl group.
8. A process according to claim 5, wherein R1 is a methyl group.
9. A process according to claim 6, wherein R1 is a methyl group.
10. A process according to claim 3, 5 or 8 wherein R2 is a hydroxyl
group or a hydroxyl group acylated by a C2-7 acyl group, and R3 is hydrogen.

11. A process according to claim 4, 6 or 9 wherein R2 is a hydroxyl
group or a hydroxyl group acylated by a C2-7 acyl group, and R3 is hydrogen.
12. A process according to claim 3, 5 or 8, wherein R2 is a hydroxyl
group or a hydroxyl group acylated by a C2-7 acyl group, and R3 is a methyl or
ethyl group.
13. A process according to claim 4, 6 or 9, wherein R2 is a hydroxyl
group or a hydroxyl group acylated by a C2-7 acyl group, and R3 is a methyl or
ethyl group.
21

14. A process according to claim 3, 5 or 8, wherein R2 and R3
together represent an oxo group.
15. A process according to claim 4, 6 or 9, wherein R2 and R3
together represent an oxo group.
16. A process according to claim l, 3 or 5, wherein X is a ketal,
kemithioketal or thioketal group.
17. A process according to claim 2, 4 or 6, wherein X is a ketal,
hemithioketal or thioketal group.
18. A process according to claim 3, wherein R1 is a methyl or
ethyl group;
R2 us a hydroxyl group or a hydroxyl group acylated by a C2-9 acyl group;
R3 is hydrogen or a methyl or ethyl group; or
R2 and R3 together represent an oxo group.
19. A process according to claim 4, wherein
R1 is a methyl or ethyl group;
R2 is a hydroxyl group or a hydroxyl group acylated by a C2-7 acyl group;
R3 is a hydrogen or a methyl or ethyl group; or
R2 and R3 together represent an oxo group.
20. A process according to claim 18, wherein R2 is a hydroxyl,
acetoxy, propionyloxy, caproyloxy or heptanoyloxy group.
21. A process according to claim 19, wherein R2 is a hydroxyl,
acetoxy, propionyloxy, caproyloxy or heptanoyloxy group.
22. A process according to claim 20, wherein R2 is a .beta.-hydroxy
group.
23. A process according to claim 21, wherein R2 is a .beta.-hydroxy
group.
24. A process according to claim 18, 20 or 22, wherein X is a
ketal, hemithioketal or thioketal group.
25. A process according to claim 19, 21 or 23, wherein X is a
22

ketal, hemithioketal or thioketal group.
26. A process according to claim 1 or 2 for preparing androst-5-
en-3,3-ethylenedioxy-16,16-dimethyl-17 -ol.
27. A process according to claim 5, wherein R1 is a methyl group,
and X is a ketal, hemithioketal or thioketal group.
28. A process according to claim 6, wherein R1 is a methyl group,
and X is a ketal, hemithioketal or thioketal group.
29. A process according to claim 3, 5 or 8, wherein R2 is a
hydroxyl group or a hydroxyl group acylated by a C2-7 acyl group, and R3 is
hydrogen, and X is a ketal, hemithioketal or thioketal group.
30. A process according to claim 4, 6 or 9 wherein R2 is a
hydroxyl group or a hydroxyl group acylated by a C2-7 acyl group, and R3 is
hydrogen, and X is a ketal, hemithioketal or thioketal group.
31. A process according to claim 3, 5 or 8, wherein R2 is a
hydroxyl group or a hydroxyl group acylated by a C2-7 acyl group, and R3 is
a methyl or ethyl group, and X is a ketal, hemithioketal or thioketal group.
32. A process according to claim 4, 6 or 9, wherein R2 is a
hydroxyl group or a hydroxyl group acylated by a C2-7 acyl group, and R3 is
a methyl or ethyl group, and X is a ketal, hemithioketal or thioketal group.
33. A process according to claim 3, 5 or 8, wherein R2 and R3
together represent an oxo group, and X is a ketal, hemithioketal or thioketal
group.
34. A process according to claim 4, 6 or 9, wherein R2 and R3
together represent an oxo group, and X is a ketal, hemithioketal or thioketal
group.
23

Description

3~
This appllcation is a division of our application Serlal No.
248,260, filed March 19, 1976.
~ he inventlon relates to novel compounds useful as intermedia~es
in the preparation of certain steroids intended for the treatment of androgen
dependent skin disorders.
Many skin conditions, such as acne and seborrhoea, are throught to
arise because of excessive secre~ion of sebum from the sebaceour glands under
androgenic stimulatlon. It is now believed that testosterone, the principal
circulating androgen, i8 converted to 5~-dihydrotestosterone (DHT) at
androgen target cells, and therefore that lt i9 DHT that i9 the biologically
active androgen causing this stlmulation. The enzyme responsIble for this
conversion is ~4 - 3-ketosterold-~-reductase. Thus it will be realized
that a compound capable of lnhiblting the effect of this en~yme on cir-
culating testosterone, or having anti-androgenic activlty by virtue of its
ab~lity to compete with DHT for target sites, wlll be of use in the treatment
of the aforesaid skin conditions.
It has now been discovered that certain novel androstene related
to testosterone, but di-substltuted in the 16 position by certain hydrocarbon
groups, have 5 reductase inhlbitory activity, and that the corresponding
andro~tenes are weak anti-androgens by vlrtue of thèir ability to compete
with D~T for target sites. The androstenes also possess a very weak anti-
androgenicity of this competitive nature. These steroids are therefore
useful in the treatment of the a~oresaid skln condition~, such as acne and
seborrhoea. It i9 bel~eved that tre~tment of other androgen dependent
disorders associated wlth the skin and hair folllcles such as female hirsutism,
androgenic alopecia and male pattern baldness in women is al~o possible with
these steroids.
It ls kncwn (~. Voigt and S.~. Hsia, Endrocrinology, 1973j 92,
1216-122Z) that 4-androsten-3-one-17-carboxylic acid, of ~ormula (A) below~
and it~ methyl ester have ~-reductase inhibitory activlty:
~ COOH
~ '
o~\ J (A )

3~i
However these two compounds are
structurally less closely relat~d to the androst~nes dlsclosed and cla1med
in the above-m~ntioned paren~ applica~ion than is testosterone, th~
standard reference androgen.
It is also known from US Patent No: 3853926 that 17~-hydroxy-
16,16-dimethyl estr-4-en-3-one, of formula (B) below, is an anti-androgen
and has the capacity to suppress the secretion of sebum ln rats:
0
C~
~ ~ C113 (B)
O
This steroid ls an estrene9 while our novel unsaturated steroids are
; androstenes. The fact that 19-nor test-osterone, an estrene, and most 9
derivatives thereof are gestgens and testosterone, an androstene, -ls an
.androgen, clearly shows that no prediction as to pharmaceutical activity
can safely be made from the one class of steroid to the other.
Accordingly, the lnvention of our parent application provides
compounds of the ~ormula (I):
R4 R
0~ ( ) ~:
wherein:
R3 ie a Cl 5 alkyl group, a C3 6 alkenyl group, a C3 6 cycloalkyl
group or an alkylphenyl group in which the alkyl moiety contains 1 to 3
carbon atoms and the phenyl moiety is optionally substituted; R~ is a hydroxyl : :
~roup, or a group OR6 whereln R6 is a C2 7 acyl group9 a Cl 4 acyl grou~ or an
- 2 _ : `
'~
. :' ',: ..... . ' . . . '
- - , , ~. :: : . .

optionally substituted benzyl group; R5 is hydrogen or a Cl 5 alkyl group,
or R4 and R5 together with the carbon atom to which they are joined represent
a carbonyl group.
In formula (I) R3 will often be a Cl 5 alkyl group, a C3 6 cycloa~kyl
group or an alkylphenyl group in which the alkyl moiety contains 1 to 3 carbon
atoms and the phenyl group is optionally substituted.
Suitable examples oE R3 includes the fol]owing group:
methyl, ethyl, propyl, cyclopropyl, cyclopentyl, cylcohexyl, ben~yl and phenyl-
ethyl. The phenyl moieties of the benzyl and phenylethyl groups may be sub-
stituted by, for example, a Cl_4 alkyl, halogen or nitro group. R3 may alsosuitably be an allyl or butenyl group. Preferably R3 is a methyl, ethyl or n-
or iso-propyl group, most preferably a methyl group.
R4 ls most suitably a hydroxyl group. However, when R4 is a group
OR6, suitable e~am~les of R6 include the following groups; acetyl, n- and iso-
......
propionyl, n-, sec- and tert-butyryl, caproyl, heptanoyl, methyl, ethyl, n- and
iso-propyl and n- sec- and tert- butyl, and benzyl. The phenyl moiety of the benz- -
yl group may be substituted by~ for example~ a Cl 4 allcyl, halogen or nitro group.
Suitable examples of R5 include hydrogen, and the methyl, ethyl, n-
and iso- propyl, and n- butyl groups, Preferably R5 is hydrogen or a methyl
group, most preferably hydrogen. Suitably R4 has the~ configurat-Lon
A preferred class of compounds of the formula (I) are those of the
formula (II):
\ ~ S ~ 9 (II)
0~\~ ' ' '
wherein: ~
R7 is a hydroxyl group, or a hydroxy group acylated by a C2 7 acyl
graup; ~ is hydrogen, or a Cl 4 alkyl group; or R7 and R8 taken together with
the carbon atom to which they are jolned form a carbonyl group; and Rg is a
Cl 3 alkyl group.
--3--

9~
When R7 is a hydroxyl group acylated by a C2 7 acyl group, it is
suitably an acetoxy, n- or i90- propionoxy, caproyloxy or heptanoyloxy
group.
R7 i9 preferably a hydroxyl group~
It i9 preferred that R7 has the gconfiguration.
R8 is suitably hydrogen or methyl, most suitably hydrogen.
R9 is suitably a methyl or ethyl group, preferably a methyl group.
Wlthin the compounds of the Eormula (II), a partieularly preferred
class of compounds are those of the formula (III):
10 R11
~ R (III)
wherein: O ~
Rlo i9 a hydroxyl group or a hydroxyl group acylated by a C2 7 acyl
group, Rl~ is hydrogen, or a methyI or ethyl group; or Rlo and Rll taken togeth~with the carbon atom to which they are joined repre~ent a carbonyl group; and
R12 is a methyl or ethyl group.
Examples of groups Rlo include hydroxyl, acetoxy, n- or iso- pro-
pionloxy, caproyloxy and heptanoyloxy groups.
~ Preferably, Rlo is a hydroxyl group, and normally the group Rlo will
be in the ~configuration.
Preferably Rll is hydrogen, or a methyl group, or Rlo and Rll taken
together with the carbon atom to whlch they are ~oined represent a carbonyl
group.
More suitably Rll is a hydrogen atom.
Preferably R12 i9 a methyl group.
One compound within the ~ormula (III) of particular utility due to
its 5-~-reductase inhlbitory ac~ivlty is androst-4~en-16,16-dimethyl-17~-ol-3-
one.
. .
The invention of the parent applica~ion ~lso pro~ides a process for
t~e preparation of the compounds of the formula (I), ~hich process comprises
reacting a compound of the formula (IV):
.
-- 4 --
.

X ~ ~ ~ 3 (1~)
where~n X ls a protected carbonyl group and R3 R4 and R5 are as defined
in formula tI), to generate an unprotected carbonyl group in place of the
protected carbonyl group X.
The double bond in Pormula (IV) rearranges during the de-protection
reaction to give the desired 4,5 bond in the product.
The process of that invention is a conventional de-protection of a
protected carbonyl group, Thus the group X may be a ketalised carbonyl group,
for examPle (CH ) ~ ~ wherein n i9 2 or 3 or RL wherein R X ls an alcohol
R X
or thiol re~idue ~X being oxygen or sulphur respectively), in which case the
de-protection i9 sultably carried out by acid hydrolysis; or it may be a
thioketalised carbonyl group, such as
(CH2 n~ / C or (CH2) / / C whereln n is 2 or 3, in which ca~e the de~
protection may sultably be carrled out using mercuric salts, or again by acid
hydrolysis.
. -
After this de-protec~ion reaction, if de~ired the following optlonal
steps may be carrled out:
(i) when R4 and R5 do not Porm a carbonyl group the group R4 may be
varied by conventional methods. For example, co~pounds of the formula (I)
wherein R4 is an acylated or etherified hydroxyl group may be prepared by
conventional acylation or etherification ofcompoun~ of the formula (~) where~n ;-
R4 is a hydroxyl group. Such reactlons include reaction of the hydroxyl moiety
with acyl chlorides or acyl anhydrid~s such as acetyl chlor~de or ace~ic
- anhydride under anhydrous conditions to give~acyl derivatives, and reaction of
5~
,

~O~L9~
a sodium salt of ~he hydroxyl moi~ty with an alkyl halide to give an etheri-
fied derivative.
(ii) compounds of the formula (I) wherein there i9 a 4,5 double
bond may be converted to their corresponding saturated analogues by any of the
usual reduction methods, such as hydrogenation with a palladium catalyst.
The compounds of the formula (IV3 are novel, are useful as in-
termédiates in the formation of the pharmaceutlcally active compounds of the
formula (I), and as such form the present invention.
The compounds of the formula (IV) may themselves be prepared by a
proce~s which comprises substituting a compound of the formula (V),
~_ O
(V)
at the 16 positlon with the required groups R3 and thereafter if desired
converting the 17 carbonyl group to other groups R4 and R5 by conventional
me~hods R4 and R5 are as defined ln formula (IV). Less preferably, the 16-
mono substituted intermediates in this reactlon may first be isolated, and
then further substltuted at the 16 positlon.
The substltution reaction may suitably be carried out by reac~ing
the chosen co~pound of the formula (V) with a compound R3Y in the presence of
a strong base of low nucleophillcity. Sultably Y i9 a halide, tosylate, mes-
.
ylate or azide, the baYe is a hydride such as sodium hydride, and the reactionis carried out in anhydrous conditions.
The optlonal conversion of the 17-carbonyl group into other groups
R4 and R5 may be carried out by the usual conventional methods. For example~
compounds wherein R4 i8 a hydroxyl group and R5 is ei~her hydrogen or a C~ 5
alkyl group may be formed from the corresponding 17-carbonyl compound by re-
duction or by reactlon with a Cl 5 alkyl Grlgnard reagent or a Cl 5 alkyl
- metalllc complex (suitably a Cl 5 alkyl lithium complex) respec~ivély. The
pedaet~ff may suitably be carried out using lithium alumlnum hydride. There-
after if desired, ~he thus formed R4 hydroxyl group may itself be acylated or
~ .
. I

etherified to give another group R4 by methods described in sub-paragraph
(i) above.
The compounds of the formula tv) may be prepared by the oxidation
of the corresponding 17-hydroxyl compound of the formula (VI) under neutral
or basic conditions:
01~
(VI)
X ~/.,~,
wherein X is as defined in formula (V).
This reaction is conveniently carried out using either silver
carbonate on an inert support such as Kieselguhr, or Collins~ reagent, which
is a mixture of chromium trio~ide and pyridine in methylene dichloride.
The compounds of the formula (Vl) may themselves be prepared by the
carbonyl protection of the corresponding compound of the formula (VII):
OM
~ r ` i ~ (VII)
This reaction will be carried out under conventional conditions to give the
desired protected carbonyl group X. For example, when a ketalised carbonyl
group is required, the compound of the formula (VII) is reacted with a suitable
alcohol or thiol in the presence o~ acid. In this way, ethyleneglycol, for
example, yields the 3,3-ethylenedioxy carbonyl protecting group.
During the reaction, the double bond shifts as shown below.
From the aforesaid description, it can be seen that a particularly
suitable preparative route for compounds of the formula (I) is as shown in
the dia8ram below:
'~' ' '
-7-
-- . . - - . .. . ..

~6~
.
OH
(VII )
p~otectlon
OH
rI )
~ r oxidation
.:
16 ,16 di~
subs-ti tution
. ' . '. .
R4 R5 O ./
( IV) ~\~R3 ~ R3 ( IV~ )
~/ \~~ 3 ,~ 3
X. ;~ ~, '
. < optional
: ~cc~bonyl conversion : ~:
:: ,
de-pro tecti.on
~R~
3 ;
~ 0~
., : : .,
--8-- .
:
. .
. ~ . ~ : . . . .. .

The thu~ formed compound of the formula (I) may thereafter by con-
verted into another compound of the formula (I) if desired by either or both
of the optional steps descrlbed in precedlng sub-paragraphs (i) and (li)-
The compounds of the formula (I) will normally be ~ade up into acream or ointment for topical adminlstration to the skin. A preferred com-
position is therefore a pharmaceutical composition for topical administra~10n
to the skin comprising a compolmd of the Eormula (I) which has been formulated
as a cream or ointmen~.
Cream or ointment formulations that may be used for compounds of
the formula (I) are conventional formulations well known in the art, for
example3 as described in standard ~e~t books of pharmaceutics and cosmetics,
such as Harry'c Cosmeticology published by Leonard Hill Books, and the
British Pharmacopoeia. A standard emulsifying ointment base or an anhydrous
polyethylene glycol are s~imple examples of such sui~able formulations.
It is believed that certain of the compounds of the formula (I)
are actlve via the oral route. Accordingly su~h compounds can be formulated
with inert carriers into compositions conventional for such administraticn,
such as tablets, capsules, syrups and the like.
The compounds of the formula (I) are particularly useful in the
treatment of acne and seborrhoea. Specifically then the invention provides
a mèthod of treatment of acne or seborrhoea comprising the admlnlstration of
an effective amount of a compound of the formula (I) to the sufferer.
Preferably the compounds of the formula tI~ will be administered
topically to the affected skin.
The compounds of the formula (I) have the advantage that they
combine effective relief in the treatment of androgen dependent skin disorders
with no apparent deleterious hormal side effects.
It will be appreciated that one or more of the antibactsrial
agents conventionally used in the treatment of acne and seborrhoea infections
may be incorporated lnto ~he compositions described above when these
_ 9 ~

compositions are to be used for s~ch treatment.
The following examples illustrate the preparation of the compounds
of the formula (I), and the preparation of their intermediates. A Pharma-
cological Section is also included:
EXAMPLE 1 --
OT-~
~J~ ;
<~ ~
O ' ~:~
Androstan-S-en-3,3-ethylenedioxy-17 -ol was obtained from andro~t-4-en-17~
ol-3-one as fine wh~te needles, m.p. 185-186 (from methanol/water), by using
thé procedure of J.A. Campbell, J.C. Babcock and J.A. Hogg, J. Am. Chem. Soc.,
1958, 80, 4717-4721.
EXAMPLE 2
o
o. ~\
~ ,
o
Silver carbonate on Kieselguhr (20 g) was dried by aæoetroplcally distillin~
off any moisture with benzene. The oxidising agent was suspended in dry
benzene (200 mlj and to thi~ was added androst-5-en-3,3-ethylenedioxy~17~-
ol tlg) in benzene (50 ml) and the mixture was refluxed for 4 hours. Complete
oxidatlon was achieved. The reactlon mixture was filtered and the filtrate
was evaporated to give androst-5~en-3,3-ethlenedioxy-17-one (0.95g) as fine
white needle~, m.p. 189-190, from methanol.
Complete oxldation was also achieved using chromium trloxide
;~ and pyridine in methylene chloride.
.
-- 10 --
.

~694~
EXAMPLE 3
O
'' ~ ~H3
O~
O
. '
Androst-5-en-3,3-ethylenedioxy-17-one (2.92g) was dissolved in dry tetra-
hydrofuran ~60 ml). Sodium hydride (2.92g) was added, following by methyl
iodide (5 ml), and the reaction mixture was refluxed for 4 hours. The tetra-
hydrofuran was evaporated under reduced pressure and the residue was parti-
tioned between ethyl ace~ate and water. The ethyl acetate layer was washed
again with water, dried (anhydrous MgS04) and evaporated to dryness to give
a solid (3.21g~. This solid was recrystallised from methanollwater to gi~e
androst-5-en-3,3-ethylenedloxy-16,16-dimethyl-17-one (2.4g) as colourless
crystals, m.p. 138-142 .
The followlng compouDds were similarly prepared:
xample 3a
.
Androst-5-en-323-ethylenedioxy-16,16-diallyl-17-one, m.p. 100-101 (from
methanol);
: .''
Example 3b .
Androst-5-en-3,3-ethylenedioxy-l6,16-dibenzyl-17-one, as a white foram (infra-
red carbonyl absorption at 1725cm 1);
xample 3c
Androst-5-en-3,3-ethylenedioxy-16,16-di-n-butyl-17-one, m.p. 165 167D (from
methanol);
Example 3d
Androst-5-en-3,3-eth~enedioxy-16,16-diethyl-17-one, m.p. 146-148 (from
methanol~

3~
EXAMPLE 4: 12
CH3
0~
O
Androst-5-en,3-ethylenedioxy-16,16-dimeth~ 17~one (l.S~ as lissolved in
dry ether (100 ml) and lithium aluminum hydride ~O.lg) was added. The ~action
mixture was stirred at room temperature for 30 minutes and then excess of hy-
dride was destroyed by adding an excess of ethyl acetate. The mixture was
then shaken with a solution of potassium sodium tartrate, the organic phase
was separated and washed with water before being dried over anhydrous MgS0~.
Filtration and evaporation of the filtrate to dryness gave androst-5-en-3,3-
ethyl-enedioxy-16l16-dimethyl-17~-ol ~1.47g) as a white powder, m.p. 178-179,
from ethyl acetate.
The followlng compound was similarly prepared:
Example 4a
Androst-S-en-3,3-ethylenedioxy-16,16-diallyl-17~ol, m.p. 149-151.
EXAMPLE 5
4 6
Androst-5-en-3,3-ethylenedioxy-16~16-dimethyl-17~-ol (lg) was dissolved in
methanol (30 ml) and 2.5N hydrochloric acid (5 ml) was added. The mixture was c
refluxed for 1 hour to achieve complete hydrolysis of the ketal. The reaction
mixture was taken up in an excess of ethyl acetate and washed with water until
neutral. The organic phase was dried over MgS0~, filtered and the filtrate
:
~ d to dryness to give a white solid (0.88g). Recrystallisation from
petroleum ether ~60 - 80)/ethyl acetate gave androst-4-en-16,16-dimethyl-
(0 76e) as whlte needles, m.p. 170-172.
12

The following compounds was similarly prepared:
Example 5a
Androst-4-en-16,16-diallyl-17~-ol-3-one, as a thick oil with an infra red
carbonyl absorption at 1680cm
EXAMPLE 6 I ~ CH3
~ ~ ~ 3
0~
Androst-5-en-3,3-ethylenedioxy-16,16-dimethyl-17-one tO.25g) was dissolved
in methanol (7.5 ml) and 2.5N hydrochloric acid (1.5 ml) was added. The
solution was refluxed for 30 minutes and~ after cooling, an excess of ethyl
acetate was added. The organic phase was washed with water until neutral,
then dried (anhydrous MgSO~) and evaporated to dryness yielding a white solid
(0.2g) which was recrystallised from petroleum ether (60 -80) to give
androst-4-en-16,16-dime~hyl-3,17-dione (0.16 g) as white needles1 m.p. 164-165.
The folloYlng compounds were similarly prepared:
Example 6a -
Androst-4-en-16,16-diallyl-3,17-dione, m.p. 118-120 (from petroleum ether
60-80);
E~ample 6b
Androst-4-en-16,16-dibenzyl-3,17-dione, m.p. 150-152 (from petroleum ether
60-80);
Example 6c
Androst-4-en-16,16-di-n-butyl-3,17-dione9 as a thic~ oil with infra-red carbony]
absorptions at 1680cm 1 and 1720cm 1.
Example 6d
Androst-4-en-16,16 diethyl-3,17-dione, as a semi-crystallised oil with infra~
--1 --1
red carbonyl absorptions at 1680cm and 1720cm
OCOCH,
3 ;
CH3
,~
.

Androst-4-en-16,16-dimethyl-17~-ol-3-one (0.158g) was dissolved in dry benzene
(4 ml) and dry pyrldine (0.14g) and acetyl chloride (0.12g) were added. The
mixture was refluxed for 30 minutes, cooled and poured into an excess of ethyl
acetate. The ethyl acetate solution was washed with dilute hydrochloric acid
and then water before being dried over anhydrous MgS04. Filtration and eva-
poration of the filtrate to dryness gave a solid (0.156g) which was recrystall-
ised from petroleum ether (60-80) to give androst-4-en-16,16-d:Lmethyl-17~- ol-
3-one acetat (O.lOOg) as white needles, ~.p. 153-155 .
The following compound was similarly prepared:
Example 7a
Androst-4-en-16,16-dimethyl-17~-ol-3-one hexanoate, m.p. 105-107 (from methanol)
EXA~LE 8
..
OH
O . ::
` ~
Androst-5-en-3,3-ethylenedioxy-16,16-dimethyl-17-one (0.5g) was dissolved in
dry ether and maintained in a nitrogen atmosphere. A large excess of methyl
lithium ~20 ml of a 1.75M solution in hexane) was added over a 10 minute period.
A precipitate formed immediately. The mixture was stirred for 2 hours at room
temperature before the excess of methyl lithium was destroyed by careful
addition of water. The product was extracted with ethyl acetate and the organic
phase was washed with water, dried~ (anhydrous MgS04) and evaporated to dryness
to yield a white solid (0.51g). This solid was recrystallised from petroleum
ether (60-80) to ~ive androst-5-en-3,3-e~hylenedioxy-16,16,17~-trimethyl-
17 ~ol (0.40g) as white crystals, m.p. 170-171.
EXAMPLE 9 OH CH
1 3
CE~3
` CH3
o ~` J
1~1
.
., .

Androst-5-en-3,3-ethylenedioxy-16,16-17~-trimethyl-17~-ol (l.lg) was dissolved
in methanol (50 ml) and 2.5N hydrochloric acid (10 ml) was added. The mixture
was refluxed Eor 15 m:Tnutes. The product was extracted with ethyl acetate and
the organic layer was washed with water until neutral. After drying over an-
hydrous MgS04 and filtration, the filtrate was evaporated to dryness to give
a crude solid (0.94g). This solid was recrystallised from petroleum ether
(60-80 ) to give androst=4-erl-16,16,1~trimethyl-17,~-ol-3-one (0.54g) as
white flakes~ m.p. 165-166.
Pharmacological Section
1. Androgenic/anabolic test and Anti-androgenic test
The method used was basically that of Hershberger et al., Proc.
Soc. Exp. Biol. Med., 83, 175, (1953) with minor modi~ications.
I~mature male rats weighing 50-60gwere castrated under nembutal
anaesthesia. The animals were dosed for Eour days starting on the Eifth day
after castration, The body weights of the animals were recorded during the
dosing period. On the tenth day after castration ~he animals were sacrificed `
and the weights of the seminal vesicles, ventral prostate, levator ani muscle
and thymus were measured, together with the total body weight. These data were
then compared with data Erom control animals. Compounds were made up as sol-
20 ~ utions or suspensions in arachis oil and they were dosed subcutaneously.
- Androgenic/anabolic tests
For this test the compounds were given at 50 mg/kg, subcutaneously,
and the results compared with control animals given testosterone at 1 mg/kg,
9ubcutaneously. Both sets of data were compared with that from castrated,
undosed control animals.
Anti-androgenic test
-For this test the compounds were given at 50 mg/kg, subcutaneously,
:-
concomitantly with testosterone at 1 mg/kg~ subcutaneously, to determine the
degree of inhib:Ltion compared with control animals given testosterone at 1 mg/kg
st~bcut~eously. Both sets of data were compared with that from castrated,
- undosed control animals.
-
--15-- -
~ . '
..

69~S
TA~E 1
. I -I
~ndrogenic ~esponse Anti-androgeni`c data
Compound ~ Rel. potency to % Inhibition
testosterone
of Example .
Seminal Prostate Semi~nal Prostate
. vesi~cle ves~cle
~ `~
2. Androgen displacement experiments
The ability of compounds to dlsplace L3H~ -dihydrotestosterone
from high affinity cytosol androgen binding proteins isolated from rat prostate
and epididymis was examined in vitro using the method of W.I.P. Mainwaring, F.R.
Mangan, P.A. Feherty and M. Freifeld, Molecular and Cellular Endocrinology,
1974, l, 113-128.
Samples of cytosol (0.1 ml) were incubated overnight in the presence
of 5 x 10 lOM L3H~ -5~.-dihydrotestosterone (47 Ci/mmoIe, The Radiochemical Centre,
Amersham) eit~er alone or together with the compound to be tested at 5 x lO 6,
5 x 10 and 2.5 x lO 7M. The ability ofcompounds to displace [ H~ -5~ -DHT from
the binding proteins was seen as a lowering of the counts bound in the supernatant.
TABLE 2
Displacement of H -S~-dih~drotestosterone from
androgen binding proteins
H -5~-DHT concentration 5 lO_loM
'`. ` ~:
~ - 16 -
/\
: .. , . . ... ~ , .
- :~ , : -, : ,
,, . .:
: :....
- -. :~.: . : . :

. . 2~5 x lQ M _ 5~Q x 10 M
Compound _ _ _ ___ _. _ __ ___ _ _ _ _ _
Prostate Epididymis P~ostate Epididymis Prostate Epididymis
__.___ ____~ __ _ ______ _~_._
36 0 50 4 81 64
6 16 0 27 0 80 48
9 32 0 46 4 88 8
_ :
: ' , - : ' ' '
'~.
,
'
,
; - 16a -
. ,.. ,, . , : .. : -,, j ,., ~ . ,.. . . .. , -
......

3. Inhibition of Testosterone S~-reductase
Determination of the activi~y of this enzyme ( ~'-3-ketosteroid
5~-reductase) was performed essentially as described by W.I.P. Mainwaring and
F.R Mangan, J. Endocrinology, 1973, 59, 121-139.
The percentage conversion of testosterone (T) to 5~-dihydrotesto-
sterone (DHT) in this system ranged from 15 to 30% with varlous preparations.
Inhibition of conversion was seen by a reduction in the cpm associated with
DHT.
cpm DHT
% conversion = - ~ 100%
cpm T ~ cpm DHT
% inhibition = % conversion without compound - % conversion
with compound
%conversion without compound
':r~P~ , 3
_____~ . . ____~__ ,
% lnhibi l;ion o:f 5c~-r~cluctase
CompoundCompound ~ t 1 x 10 5M
30.0 (3~
_____, ~
6 23.1 (2) `
,. ~ _
9 27.3 (2)
~__________~
.
( ) The figures in bracke-~s represent the number oE
experiments.
4, The effect of compounds on th_ testosterone-induced
growth of the hamster flank organ
In castrated male hamsters of unoperated female hamsters the flank
organ (a sebaceous gland) can be stimulated to grow by topical application of
testosterone. Testosterone is converted in this gland to ~dlhydrotesto-
sterone, (S, Takayashu and K. Adachi, Endocrinology9 1972, 905 73-80) which is
now thought to be the active androgen in most androgen-dependent target organs.
~--20 Ihe ability of compounds to inhibi~ this stimulation was assayed essentially
using the method descrlbed by W. Voight and S.L. ~sia, Endocrinology, 1973,
- 929 1216-1222~.
,.
~ --17- -~
...... .. , ~ . . . . . :

Adult male hamsters were castrated via the scrotal route. One week
later they were di~ded into groups of 4 animals and treated as follows. One
group was left untreated. A second received acetone alone to the flank organ
of the left slde of the animal and acetone containing 4~ g of testosterone per
day to the right side flank organ. Other groups received acetona alone to the
left side flank organ and acetone containing ~ g of testosteronc plus 400~ g
of compound per day to the right side flank organ.
At the end of three weeks treatment, the animals were k~lled, the
organs measured and placed in fixative for histological examination.
An active compound would inhibit the testosterone-induced growth
of the flank organ. Some of the compounds notably compounds such as 5, 6 and
9, were very effective in inhibiting the stimulation of the gland by testo-
sterone. ~istological examination confirmed that there had been a considerable
reduction in the si~e of the sebaceous glands of the flank organ.
5. The effect of compounds on sebum secretion in the rat
The ability of the compounds to inhibit sebum secretion in rats was
determined essentially by the method described by F.J. Ebling, J. of Investi-
gative Dermatology, 1974, 62, 161-171 and references therein.
Some of the compounds such as 5, 6 and 9, and in particular Compound
5, were very effective in inhibiting testosterone stimulated sebum secretion in
castrated male rats at 25 mg/kg, subcutaneously, but were ineEfective in inhib-
iting 5a-dihydrotestosterone stimulated sebum secretion at the same dose level.
This would indicate that such compounds were acting via 5d-reductase inhibition
and not via a classical anti-androgenic mechanism.
60 Toxicity
No toxic symptoms were detected whe~ compound 5 was dosed up to
900 mg/kg, orally, in mice.
~ ~ .
- .,
.
":
., .
~ " ~ ' ~ ''. '.
-18-