Note: Descriptions are shown in the official language in which they were submitted.
o
This invention relates to cycloaliphatic thiones, in
particular steroid thiones.
Compared with the aryl thiones, very few aliphatic
thiones are known. Low molecular weight aliphatic thiones
are known only to exist as trimeric species, i.e. 1~3,5 -
trithianes. Higher molecular weight aliphatic thiones do
exist in monomeric form, but tautomerisation to the corres-
ponding enethiol occurs to a major extent unless the
structure renders it unli~ely or impossible.
Steroid 1,4-diene-3-thiones would on theoretical grounds
be considered to favour the enethiol form in view of the
conjugation present but it has now been found however that,
surprisingly,the cross-conjugated thione system found in a
steroid 1,4-diene-3-thione or related compounds such as the
thione analogue of santonin, exists in thione form as a stable
entity.
The new compounds may be considered as cyclohexa-2,5-
diene-l-thiones which may be substituted or form part of a poly-
cyclic ring structure. However, in order to avoid isomerisation
to tautomeric thiophenols, the 4-position of the
cyclohexadiene ring should be disubstituted, i.e. should not
carry a hydrogen atom . Such thiones can be represented, in
general, by the formula
- 2 -
1058~0
~/
wherein the substituents R, which may be the same or
different, represent hydrogen atoms or hydrocarbyl groups
and the groups Rl represent hydrocarbyl groups or
adjacent pairs of substituents R, or R and Rl together
with the carbon atoms to which they are attached may
constitute a non-aromatic ring structure, with the proviso
that one of the ad;acent pairs of R and Rl forms part of
a ring structure, said hydrocarbyl groups or ring structure
if desired carrying one or more substituents.
- Where any of the groups R and Rl are hydrocarbyl
groups, these may, for example~ be alkyl groups having 1-6
carbon atoms e.g. methyl groups as in santonin or in
pregnanes. One of the adjacent pairs R and R represents
a cyclic group, which may be monocyclic or, as in steroids
or in santonin, polycyclic. In both the latter cases,
one group Rl is alkyl while the other forms part of a ring
structure. Such ring structures may be carbocyclic as in
corticosteroids or may contain heterocyclic rings, e.g. the
~ '
.
105816
lactone ring in santonin. Santonin has the formula:-
CH3
_CH3
3 1 -
The compounds of the invention may carry substituents~
e.g. oxo or hydroxy groups, protected oxo or hydroxy groups
such as acetal, ketal, ester or ether groups ,carboxyl~
groups, esterified carboxyl groups, mercapto groups, halogen
atoms, e.g. chlor~ne or fluorine atoms, or alkyl groups e.g.
having 1-6 carbon atoms. Acetal or ketal groups may be
cyclic or acyclic groups derived from mono or dihydric
alcohols having 1-5 carbon atoms. Ester groups may be
derived from aliphatic, araliphatic or aromatic carboxylic
acids, preferably having 1-8 carbon atoms. Ether groups may
be alkoxy, aralkoxy or aryloxy groups, preferably having 1-8
carbon atoms, or silyloxy groups, e.g. having three hydro-
carbon substituents which may be alkyl, aralkyl or arylgroups, preferably having 1-8 carbon atoms.
These compounds may be prepared by any conventional
procedure which is suitable.
According to one feature of the present invention
_ 4 _
'~, ^ .
~i
~058~0
there is provided a process for the prepaFation of a cot~pound
of the formula:
R ~_R
R ~ R
wherein the s~bstituents ~ which may be the same or
different, represent hydrogen atoms or hydrocarbyl groups
and the groups R represent hydracarbyl groups or adjacent
pairs of substituents R, or R and Rl together with the
carbon atoms to which they are attached may constitute a non-
aromatic ring structure, with the proviso that one of the
adjacent pairs of R and R forms part of a ring structure~
said hydrocarbyl groups or ring structure if desired carrying
one or more substituents, which process comprises reacting a
corresponding cyclohexa-2,5-dien-1-one with a reagent serving
to replace a keto group by a thione group. One reagent
lS which serves to replace a keto-group by a thione group is
hydrogen sulphide and an acid, but this reagent is not
ideally suited to compounds in the corticosteroid field because
of acid catalysed dienone-phenol rearrangement tot-the corres-
ponding phenol or thiophenol, and because of sensitivity of.
the 17-side chain.
We have found that the treatment of a cyclohexa-2,5-
_ 5_
. . .
lS~5B~tjO
diene-l-one with phosphorus pentasulphide or boron pentasulphide
gives the corresponding thione in high yields. Any non-reactive
solvent is appropriate for the reaction, for example
tertiary amines such as triethylamine or pyridine; hydrocarbons
such as alkanes, e.g. hexane, and light petroleum, or arenes
e.g. benzene and toluene; ethers such as tetrahydrofuran and
dioxan; nitriles such as acetonitrile and tertiary amides
such as dialkyl formamides and acetamides. Tertiary amide
solvents, however, react with the reagent, and are best
used as co-solvents. Advantageously the solvent is a
non-polar solvent, desirably an aryl hydrocarbon solvent,
especially toluene.
The phosphorus or boror. polysulphide must of course
be used in a molecular ratio of at ~ast 1:5 with the ketone
substrate and preferably in excess, e.g. a ratio of 2 : 1 of
more. The reaction is advantageously effected at a moderately
elevated temperature, e.g. 60-100C.
Reactive groups in the substrate molecule, other than
the keto group to be reacted must, of course, be protected.
In particular, reactive hydroxyl or mercapto groups should
be protected as esters, e.g. acetyl, benzoyl, or trifluor-
acetyl esters orethers~ ~ me~hyl,methyleDedioxy or silyl ethers.
In the steroids, 17,21-diol systems may be protected as
17,21-diacylates or 17,20:20,21-bismethylenedioxides. The
A y
~os~o
relatively hindered steroid ll~-hydroxy group needs no protection
~rom ~he polysulphide however, and keto groups other than
the 3-keto react slowly with the reagent and thus may not
need protection. Ester groups, amide groups and thioester
groups are all less reactive than the ketones and thus
similarly need no protection.
3-Thiones of steroid 1,4-dienes, possess interesting
pharmacological activity of generally the same type as that
of the parent 3-ones but characterised by particularly
favourable assimilation into the body. Such steroids may be
of the androstane, cholestane, oestrane or pregnane series. In
particular, corticosteroid 3 thiones, especially when possessing
an ll-oxygen function, e.g. a hydroxy or keto group, and a
17-oxygen function, e.g. a hydroxy or esterified hydroxy
group, espeeially with a 17-aliphatic group as in the
pregnane series, are noteworthy and the molecule should
advantageously carry the typical corticoid 17,20,21
substituents, i.e. should be 20-keto-17,21-diols, mono-
or diesters thereof, or ketalised derivatives such as
acetonides and 17,20:20,21-bismethylenedioxy compounds.
Other advantageous substituents include a 16a- or ~- methyl
group, a 7-mercapto group and a 9a-halo, especially fluoro,
substituent.
Particular corticoid compounds of note according to
~ ,~1
~.os~160
the present invention include the 3-thione analogues of
dexamethasone, betamethasone and prednisone and acetonides,
bismethylenedioxy derivatives and 17- and/or 21- acylates
thereof.
; 5 Other noteworthy steroid 1,4-diene-3-thiones according
to the invention include aldosterone inhibitors such as the
thione analogue of 1(2)-dehydro-spironolactone, i.e. 17-
hydroxy-7-mercapto-17a-pregna-1,4-diene-3-thione 21-
carboxylic acid r- lactone, 7-acetate.
Apart from their interesting pharmacological activity,
the cyclohexa-2,5-diene-1-thiones are useful active inter-
mediates in the preparation of other compounds. Oxidation
with peracids such as m-chloroperbenzoic acid yields the
corresponding l-thione oxides (S-oxides) which comprise a
further feature of this invention. The S-oxides are also
surprisingly stable, but decompose when illuminated to form
the corresponding l-one. This facility of returning to the
parent l-one via the S-oxide makes the l-thiones particularly
useful intermediates in reaction sequences for which the
l-ones themselves are not well suited.
'~ ~
, . _ ~ _
1~ 5~ 1 ~ 0
Thienol etherification may conveniently be achieved
by treating the l-thione with an enol-alkylating agent
such as trialkyloxonium hexafluorophophate or tetra-
fluoroborate in an inert solvent such as a halogenated
alkane, e.g. methylene chloride.
Thiones also react with 1,3-dipolar reagents to form
heterocyclic derivatives. Thus, for example, reaction of
a steroid-1,4-diene-3-thione with an aryl nitrile oxide,
; e.g. benzonitrile oxide yields a 3'-aryl-1',4',2'-oxathiazoline-
5'-spiro-3-steroid. Thus, with prednisone BMD there is
obtained 3'-phenyl-1',4',2'-oxathiazoline-5'-spiro-3-
(17,20:20,21-bismethylenedioxypregna-1,4-dien-11-one). The
aryl nitrile oxide may be prepared as described in Org.
Synth. 49 by treatment of the appropriate a-chloro aldoxime
with a tertiary amine such as triethylamine.
The androstane derivatives according to the invention
eg. 17-keto-, 17~-hydroxy- and 17~-hydroxy-17~-alkyl-androsta-
1,4-dien-3-thiones have been found useful as anabolic agents
and may advantageously be used to replace conventional agents.
They have been found of particular use in the treatment of
ostçoporosis, whether sterile,post menopausal or steroid
induced. A dosage of from 0.5 to 50 mg/day, preferably from
_ ,,~ ._
,, ,_ q
1~581~
1.0 to 15 mg/day, is desirable.
The corticoid derivatives according to the invention,
eg. the 3-thione analogues of betamethasone,dexamethasone,
prednisone, prednisolone,16a- and 16~-methyl prednisolone
and triamcinolone and their 17 and/or 21-esters and
acetonides, have been found to be anti-inflammatory agents
which are longer acting than the corresponding ketones and
have good topical activity with few side-effects. They
may be used in low concentration topically for the treatment
of e.g. rheumatoid arthritis and bursitis or may be
~ administered orally or parenterally in dosages similar to
; the parent oxygenated steroids. In this manner they are
especially suited to alternate day therapy.
The spironolactone compounds according to the invention
are aldosterone antagonists and may be used alone or in
combination with diuretics for the management of hypertensi3n,
congestive heart failure or chinosis. They may be
administered at a rate of 10-1000 mgfday, preferably from
40-400 mg/day and ar~ both orally active and good for
alternate day therapy.
The S-oxide deratives of the above compounds are
generally similar but are preferred for alternate day therapy.
They may be used for both intramuscular and topical applications.
,~
~ ~o
~j _ ,~ _
~0S8160
The compounds of the invention may be formulated in
compositions using any of the conventional pharmaceutical
carriers or excipients. The compounds may be administered
parenterally in combination with an injectable liquid
carrier such as sterile pyrogen-free water, sterile
peroxide-free ethyl oleate, dehydrated alcohol, propylene
glycol or a dehydrated alcohol/propylene glycol mixture.
Such compositions may be injected intravenously,
intramuscularly or intraperitoneally.
The compounds may be made up into orally administrable
compositions containing one or more physiologically compatible
car~iers and/or excipients, and may be solid or liquid.
The compositions may take any convenient form including,
for example, tablets, coated tablets, capsules, lozenges,
aqueous or oily suspensions, solutions, emulsions, syrups,
elixirs and dry products suitable for reconstitution with
water or another suitable liquid vehicle before use.
Tablets and capsules containing the new compounds may, if
desired, contain conventional ingredients such as binding
agents, for example syrup, acacia, gelatin, sorbitol,
tragacanth or polyvinyl-pyrollidone; fillers, for example
lactose, sugar, maize-starch, calcium phosphate, sorbitol or
r ~ _ J/ _
~058i~0
glycine; lubricants, for example magnesium stearate, talc,
polyethylene glycol or silica; disintegrants, for
example potato starch; or acceptable wetting agents such
as sodium lauryl sulphate. Tablets may be coated
according to methods well known in the art.
Liquid compositions may contain conventional
additives such as suspending agents, for example sorbitol
syrup, methyl cellulose, glucose/sugar syrup, gelatin,
hydroxymethylcellulose, carboxymethylcellulose, aluminium
stearate gel or hydrogenated edible fats, emulsifying agents,
for example lecithin, sorbitan monooleate or acacia; non-
aqueous vehicles, which may include edible oils, for example
; vegetable oils such as arachis oil~ almond oil, fractionated
coconut oil, fish-liver oils, oily esters such as polysorbate
80, propylene glycol, or ethyl alcohol; and preservatives,
for example methyl or propyl p-hydroxybenzoates or sorbic
acid. Liquid compositions may conveniently be encapsulated
in, for example, gelatin to give a product in dosage unit
form.
; 20 The compounds may also be administered topically, Such
topical applications may, for example, be formulated in
hydrophobic or hydrophilic bases as ointments, creams, lotions,
paints and powders.
.. . ..
~.ossl~
The invention will now be more particularly described
in thefollowing Examples which should not be interpreted
as limiting the invention
Example 1
9~-Fluoro-16a-methyl-11,17~21-trihydroxypregna-1,4-diene-
20-one-3-thione 17,20;20~ 21-bismethvlene dioxide
Dexamethasone-BMD (l.Og), phosphoxus pentasulphide
(150 mg) and pyridine (15 ml) were stirred at 90C under
argon for 1 ho~r. The solution was cooled, filtered and
diluted with methylene chloride (100 ml). The purple
solution was washed in turn with dilute hydrochloric acid
(2 x 100 ml) and aqueous sodium bicarbonate, dried over
MgS04 and evaporated to dryness~ The residue was filtered
through activated magnesium silicate in methylene chloride
to give a purple product (290 mg) which was recrystallised
from methylene chloride/hexane to yield the ~itle product
(dexamethasone BMD-3-thione), m.p. 212C (dec.); ~1.0
(3H,d,J=6Hz,C-16 methyl protons); 1.2(3H,s,C-18 protons);
1.6(3H,s,C-l9 protons); 4.0(2H,s,C-21 protons); 4.3
(lH,broad d,J=lOHz,C-ll proton); 4.9-5.3(4H,m,BMD protons);
6.9(1H, broad s,C-4 proton); 7.0(2H,s,C-1,2 protons);
3500 cm ,(m),(OH), 1630 cm ,(s),(C=C). AmaX 331 nm
( 17900), 580 nm ( 25). Mass spectrum, M ,450. (Found
C,63.84%; H, 6.66%; S, 7.27%. C24H31F05S requires C,
63.97%; H,6.94%; S, 7.18%.).
Further elution of the column gave dexamethasone-
~A~
~3
_ ~ _
105~}~60
BMD (205 mg).
Example 2
9a-Fluoro-16~-methyl-llJ17,21-trihYdroxYpre~na-1,4-dien-
20-one-3-thione 17,21-dipropionate
Betamethasone 17,21-dipropionate (1.0 g),
phosphorus pentasulfide ~100 mg) and
pyridine (15 ml) were stirred at 80C for 45 minutes under
an atmosphere of argon. A further aliquot of phosphorus
pentasulphide (100 mg) was then added and the mixture was
stirred for another 90 minutes. The product (200 mg) was
isolated in the same manner as described in Example 1 and
recrystallised from methylene chloride/hexane to give blue
plates of the title product (betamethasone 17,21-dipropionate-
3-thione), m.p. 113C; 6 l.o (s,C-18 protons); 1.6 (s,C-l9
protons); 4.5 (lH,broad,C-ll proton); 4.6 (2H,AB-q,J=16Hz,
C-21 protons); 6.9 (lH,broad s, C-4 proton); 7.0 (2H,s,
C-1,2 protons). Y max 3570 cm , (m), (OH), 1735 cm , (vs),
(C=O), 1635 cm 1, (s),(C=C)- ~ 330 nm (E 19000), 575 nm
(e 24). Mass spectrum, M ,498. (Found: C, 64.74%;
H, 7.19%; S, 6.02%. C24H31F05S requires C, 64-59%;
H, 7.16%; S, 6.16%.).
Example 3
17,21-dihydroxypregna-1,4-dien-11,20-dione-3-thione 17,20;
_ ,~ _
~ss~o
20,21-bismethylenedioxide
Prednisone-BMD (4.0 g), phosphorus pentasulfide
(4.0 g) and toluene (40 ml) were stirred at 70C under
argon for 4 hours. The solution was cooled, filtered and
the residue was washed with toluene (15 ml). The filtrate
was evaporated to low vo~ume and chromatographed on
activated magnesium silicate with methylene chloride. The
fractions which were blue in colour were collected and
evaporated to dryness to give a blue solid (3.0 g, 72%),
which on recrystallisation from methylene chloride/hexane
yielded the title product (prednisone-BMD-3-thione) m.p.
184-187C. ~0.9(3H,s,C-18 protons); 1.5(3H,s,C-l9 protons);
4.0(2H,s,C-21 protons); 5.0-5.4(4H,m,BMD protons);
6.8-7.0(2H,m,C-2,4 protons); 7.5(1H,d,J=lOHz,C-l proton).
V 1710 cm ,(s),(C=O), 1630 cm ,(s),(C=C). AmaX 330 nm
(E 19500), 565 nm (s 20). Mass spectrum, M ,416. (Found:
C, 66.42%; H, 6.69%; S, 7.44%. C23H2805S requires C,
66.32%; H, 6.78%; S, 7.70%.). m-Chloroperbenzoic acid
oxidation of this diene-thione gave the yellow syn-anti
thione-S-oxide derivatives, m.p. 203-204, [a~DH2C12 + 130,
a 358 nm (s 16000). Although the syn-anti isomers were
sep~rable by p.l.c. they rapidly interconverted on standing.
On irradiation (tungsten lamp) the S-oxidesin dichloromethane
gave the l,4-dien 3-one starting material.
7 . . .~
'-A~ ,5
~-o~ o
Using the above procedure (but with benzene as solvent
and reaction temperature 20C) androsta-1,4-dien-3,17
dione was converted into androsta-1,4-dien-17-one-3-thione
Yield 70%; m.p. 163-5C; AmaX 330 nm (E ~ 19 ,000)
This thione was then reacted with diphenyl diazomethane
at room temperature to yield 3(diphenylmethylene)-
androst-1,4-dien-17-one.
Example 4
9~-Fluoro-16~-methyl-11,17,21-trihydroxypregna-1,4-dien-
20-one-3-thione 17,21-dipropionate
Betamethasone 17,21-dipropionate (2.3 g) in toluene
(60 ml) with P2S5 (2.0 g) was stirred at 75-80C for
4 hours.
., .2, )~
~. - ~ _
, ..
~05~ ;0
The mixture was then cooled and filtered through an activated
magnesium silicate CH2C12 column. Elution with further
CH2C12gave the 3-thione (1.45 g, 60%).
By the foregoing prccedure, the following compounds were
also prepared:
17-keto androsta-1,4-diene-3-thione, m.pt 163-5C,
Found C 75.9,H 8.0, S 10.4, Calcd. C 76.0, H 8.1, S 10.7,
17~-hydroxyandrosta-1,4-diene-3-thione
17~-hydroxy-17a-alkyl androsta-1,4-diene-3-thione
and the 17,21-diesters-3-thiones of prednisone, prednisolone,
;~ 16a-methylprednisolone, 16~-methylprednisolone, dexamethasone,
triamcinolone acetonide and other 17,21-diesters of
betamethasone.
Example 5
9a-Fluoro-16~-methyl-11,17-21-trihydroxypregna-lt4-dien-
20-one-3-thione
The product of Example 4 (500 mg~ in methanol
(100 ml) was deoxygenated and stirred at 0C under argon.
N/10 Na0H (20 ml, 2 equiv.) was added and the solution was
stirred at 0C for 2 hours. Acetic acid (1 drop) was added
and the mixture partitioned between CH2C13 and water. The
organic layer was dried, evaporated to dryness and
recrystallised from acetone/hexane to give blue microneedles
m.pt. 170-4C.
i
1 1
,~ _
~os8~6~
Analysis: Calc. E'ound
C 64.68 64.72%
H 7.16 7.03%
S 7.85 7.38%
PMR: ~ HAssi~nment H
1.1-1.3 6H (m)C-16 and C-18
methyls
lo 6 3H (S) C-l9
4.2-4.5 3H(m) C-21 and C-ll
6.7-7.2 3H(m) vinyl
K~ .
lR: ~' cm : 3500 (vs). 1710 (m), 1640 (vs).
max.
By the foregoing procedure were also prepared the
3-thiones of prednisone, prednisolone, 16~-methylprednis~one,
16~-methylprednisolone, and dexamethasone.
Example 6
9~-Fluoro-16r~-meth~1-11,17,21-trihy~oxypregna-1,4-dien-20-
one-3-thione 17,21-dipropionate S-oxide
The product of Example 4 (100 mg) in CH Cl was stirred
in the dark and m-chloroperbenzoic acid (50 mg) was added.
The solution was washed with aqueous sodium bicarbonate,
dried and evapo$~ted to dryness. Recrystallization of the
residue from CH2C12/hexane gave yellow crystals, m.pt. 110-115
C.
~0 5~ ~ ~ 0
NMR: ~ H Assignment
1.0-1.4 multiple methyl C-18, C-16 and ester
resonances
1.6 3H (s) C-19
4.55 2H (AB quart.) C-21 protons
6.2-7.3 3~ (m) vinyl protons
lR:~ 3500 (m). 1730 (vs). 1190 (vs) cm
max.
Analysis Found C,62,42; H, 7.21; S, 5.81 %
Reg C,62,66; H, 6.95; S, 5.98 %
By the foregoing procedure, the S-oxides of the
3-thiones of 17,21-diesters of prednisone, prednisolone,
16a-methylprednisolone, 16~-methylprednisolone and
dexamethasone and of triamcinolone acetonide were also prepared.
Example 7
9~-Fluoro-16g-methyl-11,12-21-trihydroxypregna-1,4-dien-
20-one-3-thione S-oxide
The procedure and scale of Example 6 was used to prepare
the title product from the product of Example 5.
Recrystallization from ethyl acetate/hexane gave yellow
crystals m.pt. 170-4 C.
19
- ,l~B'-
~5~S~l~O
PMR: ~ H Assignment H
1.1 3H (d)J=7Hz) C-16 methyl
1.1 3H (s) C-18
1.6 3H (s) C-l9
4.0 3H (bm) OH
4.4 2H (AB quartet) C-21
4.4 lH (bm) C-ll
6.5-7.1 3H (m) vinyl
lR:~aX ~m 3500 (vs), 1110 (m). Analysis Found C 61,85;
Reg C,62,24;H,6,
89;S,7,55 %
By the foregoing procedure, the S-oxides of the
3-thiones of prednisone, prednisolone, 16a-methylprednisolone,
16~-methylprednisolone, and dexamethasone were also prepared.
Example 8
_-phenyl-1',4'~2'-oxathiazoline-5'-spiro-3-(17,20:20~21-
bismethylenedioxypregna-1,4-dien-11-one
The product of Example 3 (416 mg) and PhCCl=NOH
(400mg) in dry benzene (10 ml) were treated with anhydrous
triethylamine (1 ml). The residue after evaporation was
passed through ac~ivated magnesium silicate and the product
was eluted with 70% CH2C12 in hexane.
_... -...
0
~OS81~0
: Recrystallization from CH2C12/hexane gave colorlessplates m.pt. 134 C UV:~ 246nm ( 20000), 300 nm ( 1700).
lR: ~ cm : 1700 (vs), 1660 (w).
PMR: ~ H Assignment H
0.9 3H (s) C-18
1.4 3H (two peaks) C-l9
4.0 2H (s) C-21
4.S-S.1 4H (m) BMD
0.0_7,0 3H (m) vinyl
7.3-7.7 5H (m) aryl
_ ~ _
A~
lOS8160
Example 9
3-Ethoxy-17.21-dihydroxypregna-1 3.5-triene-11 20-dione 17,~0-
20 21-bismethylene dioxide
Prednisone BMD 3 thione (from Example 3) (1 0 g) in dry
CH2C12 (25 ml) over 4A molecular sieve and under an
atmosphere of argon, was treated with 1 equiv (2.5 ml) of
triethyloxonium tetrafluoroborate in CH2C12 solution The
mixture was stirred for 2 5 hrs and then quenched with
1.4 equiv. (643 mg) of 1,8-bis-(dimethylamino)naphthalene.
The solution was filtered to remove sieves and amine tetrafluoro-
borate and the fitra~e applied to 9, 20cm x 20cm preparative
chromatography plates. The band corresponding to the desired
product was removed from each plate and extracted with
CH2C12 The extracts on evaporation gave 0 38 g of product;
recrystallization ex hexane/CH2C12 gave off white crystals,
m.p.178-180 C
PMR: ~ H Assi~nment
0.8 3(s) C-18
1.25 3(t, J=7Hz) CH3-CH2-S
1.30 3(s) C-l9
2.75 2(q, J=7Hz) CH3-CH2-S
4.0 2(s) C-21
5~0-5.2 4(m) BMD-methylenes
5.3-5.8 3(m) C-2,4,6
6.45 l(d,J=lOHz) C-l
_ ~ _
lOS816i0
IR: (KBr~ 2950 (m), 1700 (s), 1100 (s), 1080 (s), 945 (s),
745 (m) cm [a]D = -216 C (c=1,20, CH2C12),
UV A 3 = 326 nm ( E = 6400)
max
Example 10
Preparation of 17-hydrox~-7-mercapto-17~-pregna-1l4-diene-
3-thione-21-carboxylic acid ~ -lactone~ 7-ac t _
To 17-hydroxy-7-mercapto-3-oxo-17a -pregn-1,4-diene-21-
carboxylic acid ~-lactone, 7-acetate (207 mg, 0,5 m,moles)
in toluene (6 ml), was added phosphorus pentasulfide (200 mg,
0.9 m.moles) in a flask fitted with a reflux condenser and
a gas inlet tube. The mixture under an argon atmosphere,
o + O
was heated to 70 - 5 with constant stirring until t,l,c,
revealed the onset of formation of undesired by-products
(4 hrs.)
The mixture was filtered, the insoluble material being
washed with methylene chloride and directly applied to an
activated magnesium silicatecolumn, Elution with methylene
chloride gave the product as a dark blue glass after solvent
removal under vacuum, The crude product was recrystallized
from acetone/hexane to yield 90 mg of pure thione as deep
blue micro needles (m,p, ~240 , loss of color and dec,).
UV: ~maX:330 m~ (E = 24,700) in MeOH
IR: vmax cm :3000 (m), 1775 (vs), 1690 (s), 1630 (s), 1180 (s),
1135 (s), 1025 (m), 805 (m),
~` A i 3
~ _
~05E~O
PMR: o H Assi~nment H
1.0 3 (s) C-18
1.3 ~ (s) C-19
2.35 3 (s) -S-~-Me
4.0 1 (m) C-1
7.5 2 (m~ C-2, C-4
Example 11
Reaction of Santonin with P2S5/tuluene
Santonin (2.0 g) and P2S5 (3 g) in toluene (40 ml)
were stirred at 70 C for 4 hrs. The reaction was then
found to be about 50% complete and the t.l.c~ showed that
the less polar product was blue in color. Further reaction
resultedin som~ decomposition products forming. Isolation
of the blue fraction on activated magnesium silicate gave
a blue crystalline s~lid. mp 143-144
Analysis: Found C,680~7; H,6095; S,12.22%
Reg C,68.67; H,6.91; S,12~22 %
lOS~l~O
Example 12
Pharmaceutical Compositions
Compositions containing the various classes of
compounds of the invention may be formulated as follows:-
a) 12,5g or 0.5g androstane steroid
8g methyl stearate
up to 200g lactose
The mixture is pressed after mixing and 1000 tablets
are prepared, A suitable dose could be from 1-4 per day
b) lOg or lOOg or 250g spironolactone steroid
5g methyl stearate
up to 500g lactose
The mixture may be pressed to provide 1000 tablets,
with a suitable dose rate of 1-4 per day.
c) 0.3 or 0.8g betamethasone derivative
or 3 or 7g prednisolone derivative
8g methyl stearate
up to 250g lactose
The mixture may be pressed to yield 1000 tablets,
with a suitable dose rate of 1-4 per day or 1-4 on alternate
days.
,~ 2~
~ ~S -
~0581f~0
Example 13
Compositions for topical application
a) For the preparation of an ointment are throughly
mixed
30g propylene glycol monostearate
30g sorbitol monostearate
O.Sg 4-chloro m-cresol or methyl paraben.
Add polyethylene glycol/propylene glycol to 1 kg.
Into this ointment are stirred
betamethasone derivative lg or 2g
or betamethasone dipropionate derivative O.Sg or lg
or prednisolone derivative 2g or 5g
The ointment is applied to the affected area 1-4
times daily. The area under treatment may, in the case of
arthritis or bursitis, be covered with a plastic film and
sealed at the edges with adhesive.
b) For the preparation of a cream,
The cream may be prepared in the same manner as
the ointment, except that the polyethylene glycol/poly-
propylene glycol are replaced by a mixture of liquid and
white petrol~t~m containing hydrogenated lanolin.
