Note: Descriptions are shown in the official language in which they were submitted.
Z33~
-- 1 --
mis application is a division of Canadian application
No. 307,894 filed July 21, 1978, which relates to l9-nor-pregna-
1,3,5(10),6,8,14-hexaene-20-ones, -to a process for -their prepara-
tion, and to pharmaceutical compositions containing them.
The inventions of both the parent and present divisional
applications are based upon the observation that certain l9-nor-
pregna-1,3,5(10),6,8,14-hexaene-20-ones, which can be defined by
the following general formula ~
CH2R3
C=o
Y~W
~ (I~,
~ .
possess anti-mitotic activity with minimal or no hormonal side
effects and are, thus, useful in the treatment of diseases
characterized by rapid and/or abnormal cell proliferation,
particularly in the treatment and control of psoriasis.
In the above general formula (I):
A is hydrogen, lower alkyl, fluoro or fluoro-substituted methyl;
Rl is hydrogen, lower alkyl, or an acyl radical of a carboxylic
acid having up to 12 carbon atoms;
W is (H,H): (H, lower alkyl), (H,~-OR2)~ with R2 being hydrogen
or an acyl radical of a carboxylic acid having up to 12 carbon
.Z3337
-- 2 --
atoms, or =CHT, with T being hydrogen, lower alkyl, fluorine,
; or chlorine;
Q is OR4 (with R4 being hydrogen or an acyl radical of a carboxy-
lic acid having up to 12 carbon atoms); hydrogen, provided W
is (H,H), or (H, lower alkyl), or together with W represents
a 16a,17-lower alkylidenedioxy grouping;
Y is (H,H), (H,OH), or oxygen;
Z is hydrogen, chlorine or bromine;
R3 is hydrogen or an acyl radical of a carboxylic acid having
up to 12 carbon atoms; or OR3 together with Q represents
an alkylidene dioxy or alkylorthoalkanoate grouping; and
when Q is hydroxy and R3 is hydrogen, the 17a,20;20,21-
bismethylenedioxy derivatives thereof.
In general, the compounds of formula (I) are novel
compounds, although at least one compound embraced by such
formula, viz. l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-
triol-20-one 3,21-diacetate [and possibly, by implication, its
3-(free hydroxy) analog], is described in the prior art ~Heller
et al., J. Am. Chem. Soc. 89, 1919 et sequ. (19G7)]. The thera-
peutic activity thereof, or of related compounds, is, however,
neither disclosed nor suggested by the prior art.
Thus, claimed as novel compounds of the invention in
the parent application are the compounds of the general formula
(I) with the exception of the 21-acetate and 3,21-diacetate of
19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one.
Accordingly, the invention of the present divisional
application is directed to an anti-mitotic pharmaceutical com-
position comprising, (a) as an active ingredient, an anti-
mitotic effective amount of the 21-acetate or 3,21-diacetate
Z~337
of l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one,
or a mixture thereof, together with (b) a non-toxic, pharmaceutic-
ally acceptable carrier.
The pharmaceutically acceptable carrier preferably
used is a carrier suitable for topical application. The propor-
tion of active steroid in the topical composition depends on the
precise type of formulations to be prepared, but is generally
within the range of from 0.0001% to 5% by weight. Generally,
however, for most types of topical preparations the proportions
- 10 of active steroid used will be within the range of from 0.1 to
3% and preferably 0.1 to 1%.
The l9-nor-pregnahexaene-20-ones are crystalline
solids, usually white to off-white in color, which are insoluble
in water and soluble in most organic solvents, particularly in
acetone, dioxane, dimethylformamide, and dimethylsulfoxide,
although of limited solubility in non-polar solvents such as
dialkylethers and alkylhydrocarbons.
The l9-nor-pregnahexaene-20-ones of formula (I) exhibit
anti-mitotic activity and, in particular, are useful in the treat-
ment and control of psoriasis.
Useful 19-nor-pregnahexaene-20-ones of formula (I)
include 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a-
21-triol-20-one 21-acetate and the 6-methyl, 6-fluoro, 6-difluoro-
methyl and 6-trifluoromethyl derivatives thereof 9 as well as the
16-desmethyl analogs and the 16~ -methyl epimers thereof,
16a-hydroxy-substituted compounds of formula (I) and ester and
16a,17a-alkylidenedioxy derivatives thereof such as l9-nor-
pregna-1,3,5(10),6,8,14-hexaene-3,16a,17a,21-tetrol-20-one
16-21-diacetate and 16a,17a-isopropylidenedioxy-19-nor-pregna-
1,3,5(10),6,8,14-hexaene-3,21-diol-20-one 21-acetate,
lLZ3~37
-- 4 --
16-alkylidene-substituted compounds of formula I such as
16-methylene-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17~21-
triol-20-one 21-acetate and the 3-acetate and 3-methyl ether
derivatives thereof, and the 15-chloro derivatives of the
foregoing.
Of the compounds of formula I, especially use-ful for
the treatment of psoriasis are the 16a-alkyl-substituted com-
pounds ~i.e. compounds of formula (I) wherein W is (H,a-alkyl)~,
preferred compounds being the 16a-methyl-19-nor-pregna-1,3,5(10)-
6,8,14-hexaene-20-ones of the general formula
- fH2R3
C=O
~ ~ CH3
~ (II),
R10
wherein Rl, R3 and R4 are as defined above for formula (I).
Among the compounds of formula (II), particularly use-
ful anti-psoriatic agents are those wherein R4 is hydrogen and,
of these, especially those wherein R3 is hydrogen or acetyl. Of
the foregoing, a particularly preferred species is 16a-methyl-
l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one
21-acetate, which exhibits superior anti-mitotic activity at
topical doses as low as 20 micrograms when administered topically
to mice in whlch epidermal mitosis has been stimulated by prior
37
application of croton oil. Further preferred compounds of formula
II include the 3-acetate and 3-benzoate ester and the 3-methyl
ether derivatives of the former; 16a-methyl-19-nor-pregna-
1,3,5~10),6,8,14-hexaene-3,17a,21-triol-20-one, and the 21-
propionate, 17-propionate and 17,21~di-n-butyrate ester deriva-
tives of the latter.
The l9-nor-pregnahexaene-20-ones of formula I are
conveniently prepared from the corresponding l9-nor-pregna-
1,3,5(10),6,8-pentaene-20-ones by dehydrogenation in position
14, most suitably by reaction with a molar equivalent of 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ) in an aprotic sol~ent
(usually dioxane) in an essentially neutral medium. - Alterna-
tively, an appropriate ll-unsubstituted pregna-1,4,6,8,14-
pentaene-3-one can be subjected to aromatization - e.g. by
means of a weak base, desirably in the presence of a soluble
halide salt such as lithium chloride -, or an appropriate
9a,11~-dihalogeno-pregna-1,4,6-triene-3-one can be subjected
to concomitant didehydrohalogenation and aromatization
(a) specific embodiment being concomitant 6-dehydrogenation,
didehydrochlorination and aromatiZation of an appropriate
9~ -dichloro-pregna~1,4-diene-3-one, suitably in situ, at
elevated temperatures, by means of DDQ as dehydrogenating agent
and in the presence of an acid in an aprotic solvent). - Isola-
tion of the respective l9-nor-pregnahexaene-20-ones is then
effected by methods well known in the steroid art.
When the above 14-dehydrogenation of a l9-nor-pregna-
1,3,5(10),6,8-pentaene-20-one precursor is carried out in the
presence of at least a molar equivalent of hydrogen chloride
and with about two molar equivalents of DDQ, there are formed
333~7
the respective 15-chloro-19-nor-pregnahexaene-20-ones of formula
(I) Thus, for example, reaction of 16~-methyl-19-nor-pregna-
1,3,5(10),6,8-pentaene-3,17a,21-triol-20-one 21-acetate in
dioxane with at least a molar equivalent of hydrogen chloride
and with about two molar equivalents of DDQ yields 15-chloro-
16~-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-
triol-20-one 21-acetate, having anti-mitotic activity. -
Similarly, by substituting hydrogen bromide for hydrogen
chloride, the respective 15-bromo compounds are obtained. -
Alternatively, a 15-chloro or -bromo substituent may be intro-
duced by reacting the respective 15-unsubstituted 1,3,5~10),6,8-
14-hexaene with halogenating agents such as molecular chlorine
or bromine, or N-halo-imides (e.g. N-halo-succinimide), or
hydrogen halide in the presence of DDQ.
The foregoing process utilizing hydrogen chloride and
DDQ for preparing the 15-chloro-substituted compounds of this
invention is preferably carried out at room temperature (al-
though temperatures in the range of from about 0 to 100C may
be employed) and in dioxane (although other aprotic solvents
may be used, particularly ethers such as tetrahydrofuran, di-
ethylether and diglyme). When carried out at room temperature,
the reaction is usually complete in 30 minutes as determined by
thin layer chromatography, although at lower temperatures it
may take up to 24 hours before complete conversion of a 19-nor-
pregna-1,3,5(10),6-8-pentaene-20-one to the corresponding
15-chloro-14-dehydro compound has been effected. Although 9 in
the process, only a molar equivalent of hydrogen chloride is
required per mole of the pregnapentaene-20-one starting compound,
it is preferred to use large excesses of hydrogen chloride (e.g.
3337
-- 7 --
a saturated solution of hydrogen chloride in dioxane) since
the rate of reaction is thereby increased and the process is
completed in thirty minutes or less.
Many of the 19-nor-pregna-1,3,5(10),6,8-pentaene-
20-one intermediates from which the 19-nor-pregnahexaene-20-
ones may be obtained are known in the art (e.g. described in
U.S. Patent Specifications Nos. 3,182,057 and 3,182,075) and
have been prepared by reaction o~ a 9a,11~-dichloro-1,4-
pregnadiene-17a,21-diol-3,20-dione 21-alkanoate (e~g. 16a-
methyl-9a,11~-dichloro-1,4-pregnadiene-17a,21-diol-3,20-dione
21-acetate) with a weak base, preferably in the presence of
lithium chloride. Weak bases useful in this process are
pyridine, collidine, lutidine and, preferably, dimethyl-
formamide. Other l9-nor-pregnapentaene-20-one interrnediates
may also be prepared from the corresponding 9a,11~-dichloro-
1,4-pregnadiene-3,20-diones in similar manner.
The 9a,11~-dichloro-1,4-pregnadiene-17a~21-diol-3,20-
dione precursors to the l9-nor-pregna-1,3,5(10)s6,8-pentaene-
20-one intermediates are also known in the art and may be
prepared from the corresponding 9(11)-dehydro derivatives
according to procedures such as described in U.S. Patents Nos.
2,894~963 and 3,009,933.
When preparing a 16-alkylidene compound of formula (I)
(i.e. a compound wherein W is =CHT), one rnay start with a 9a,11~-
dichloro-16-alkylidene-1,4-pregnadiene-17a,21-diol-3,20-dione
21-lower alkanoate precursor and convert it to a 16-alkylidene-
l9-nor-pregna-1,3,5~10),6,8-pentaene and thence to the 14-
dehydro analog of formula (I) according to the process described
hereinabove. - Alternatively, to minimize side reactions which
~` li233;~7
-- 8 --
occur when halogenating a 16-methylene-17a-hydroxy-1,4,9~
pregnatriene-3,20-dione, one may protect the 17~-hydroxyl
function thereof, e.g. by esterification, af-ter introduction
of the 9(11)-double bond. After preparing the corresponding
9,11~-dichloro derivative of the 17~-hydroxy-protected
derivative of a 16-methylene-1,4,9(11)-pregnatriene-3,20-
dione (e.g. 16-methylene-9a,11~-dichloro-1,4-pregnadiene-
17a,21-diol-3,20-dione 17,21-diacetate) and thence conversion
thereof to a 16-alkylidene-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-3-ol of formula (I) [e.g. 16-methylene-19-nor-pregna-
1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 17-21-diacetate],
the 17a-hydroxy protecting groups may be easily removed via
known techniques (e.g. by means of aqueous sodium bicarbonate
in methanol), to obtain a 16-alkylidene-19-nor-pregna-1,3,5(10)-
6,8,14-hexaene-3,17~,21-triol-20-one [e.g. 16-methylene-19-nor-
pregna-1,3,5(10),6,8,14-hexaene-3,17~,21-triol-20-one]~
When converting a l9-nor-pregna-1,3,5(10),6,8-
pentaene-20-one to the corresponding 19-nor-pregna-1,3,5(10)-
6,8,14-hexaene-20-one by reaction with DDQ as described herein-
above, it is often necessary that the 21-hydroxyl group and any
16-hydroxyl group which may be present be protected, such as by
an acyl function. It is preferred to utilize lower alkanoate
ester derivatives (usually acetates) of the l9-nor-pregna-
pentaene-20-one intermediates, thereby producing the l9-nor-
pregnahexaene-20-ones of formulae (I) and (II) as 21-alkanoates,
usually 21-acetates, the corresponding 21-free-hydroxy compound
is then easily obtained from the 21-alkanoate via known hydroly-
tic procedures, such as with aqueous sodium bicarbonate in meth-
anol or by utilizing diastase enzyme of malt in aqueous ethanol
1~1.;~333~
g
using known procedures.
In general, when a 21-mono-lower alkanoate or a
17,21-di-lower alkanoate derivative of a 3-(free-hydroxy)-
l9-nor-pregna-hexaene-20-one of formula (I) is desired, it
is preferable to use as starting compound a l9-nor-pregna-
1,3,5(10),6,8-pentaene-20-one intermediate containing the
desired 21-mono-alkanoate or 17,21-di-alkanoate ester function
prior to reaction with DDQ.
A 17-mono-lower alkanoate ester derivative of a
3-(free-hydroxy)-19-nor-pregnahexaene-20-one of formula (I)
may be prepared by reaction of the respective 17-fre-hydroxy
compound [e.g. 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol~20-one] in an aprotic solvent (e.g.
dimethyl-sulfoxide) with at least one molar equivalent of a
tri-lower alkyl orthoester (e.g. triethylorthopropionate) in
the presence of a strong acid (e.g. p-toluenesulfonic acid)
followed by hydrolytic cleavage of the resulting 17a,21-
orthoester by means of aqueous acid (e.g. aqueous acetic acid),
thence separation and isolation of the 17-mono-ester using
known techniques, usually including chromatographic methods,
whereby there is obtained a 17-mono-alkanoate (e.g. the 17-
propionate). By this procedure, there is usually also produced
some of the corresponding 21-mono-alkanoate derivatives (e.g.
the 21-propionate) which may also be isolated via chromato-
graphic techniques.
- A 3,17-diester derivative of formula (I) is convenient-
ly prepared from a corresponding 3-(free-hydroxy)-17a,21-ortho-
ester (obtainable as described hereinabove~ by reaction thereof
with an acid anhydride or acid halide in pyridine (e.g. acetic
~l~Z3~3~
- 10 -
anhydride in pyridine) to form the cor~responding 3-
(esterified-hydroxy)-17a,21-orthoester, which, after
hydrolytic cleavage of the 17a,21-orthoester group by
means of aqueous acetic acid, yields a 3,17-diester of
formula (I).
~he 3,21-diester derivatives of formula (I) are
conveniently prepared from the corresponding 21-monoesters;
the 3,17a,21-triesters may be prepared from the correspond-
ing 17a,21- or 3,17a-diesters utilizing conventional esteri-
fication techniques.
To prepare a 3-monoester derivative o~ formula (I)
it is often necessary to protect the 21-hydroxyl group (e.g.
by an ether derivative such as the 21-methoxyethoxymethyl
ether) in the 9a,11~-dichloro-1,4-pregnadiene-3,21-dione
precursor (e.g. by reaction of 16a-methyl-9a,11~-dichloro-
1,4-pregnadiene-17a,21-diol-3,20-dione with N,N,N-triethyl-N-
methoxyethoxymethyl-ammonium chloride in acetonitrile) prior
to reaction thereof with a weak base in the presence of lithium
chloride to produce the corresponding 3-(free-hydroxy)-19-nor-
pregna-1,3,5(10),6,8-pentaene-20-one re.g. 16~-methyl-19-nor-
pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-20-one 21-methoxy-
ethoxymethyl ether]. Reaction of such 21-protected l9-nor-
pregna-1,3,5(10),6,8-pentaene-20-one with DDQ yields the corres-
ponding l9-nor-pregna-1,3,5(10),6,8,14-hexaene-20-one [e.g. 16a-
methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-
one 21-methoxyethoxymethyl ether], which, upon treatment there-
of according to standard esterification procedures ~e.g~ by
reaction with acetic anhydride in pyridine), yields the corres-
ponding 3-monoester derivative. Upon deprotection of the 21-
l~Z~33~
position (e.g. cleavage of the 21-ether function by means of
zinc bromide in methylene-chloride), there is then produced
the desired 3-monoester of formula (I) [e.g. 16~-methyl-19-nor-
pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 3-acetate~.
The 3-alkoxy derivatives of formula (I) are convenient-
ly prepared via known etherirification techniques such as those
utilizing a diazoalkane (e.g. diazomethane in ether). Thus,
a 3-alkoxy-21-monoester or a 3-alkoxy-17,21-diester derivative
is prepared from the corresponding 3-hydroxy-21-monoester or
3-hydroxy-17,21-diester derivative, respectively, by reaction
with a diazoalkane in ether. - A derivative of formula (I)
having a 3-alkoxy group and free hydroxyl functions at 17 and
21 may be conveniently obtained from a 3-alkoxy-21-monoester
derivative via hydrolysis such as with aqueous sodium bicar-
bonate in methanol. - In order to prepare a 3-alkoxy-17-
monoester derivative of a compound of formula (I) ~e.g. 16a-
methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-
20-one 17-acetate 3-methyl ether] it is preferable to first
prepare a 17a,21-orthoester derivative of a 3,17a,21-triol of
formula (I) according to procedures described hereinabove,
~ollowed by reaction thereof with a diazoalkane (e.g. diazo-
methane) to produce the corresponding 3-alkoxy-17a,21-orthoester
derivative, followed by cleavage of the 17a,21-orthoester group-
ing by means of dilute acid to obtain the desired 3-alkoxy-17-
monoester derivative of formula (I).
When preparing a 16a,17a-alkylidenedioxy derivative of
formula (I), the 16~,17a-alkylidenedioxy function may be intro-
duced into the molecule after preparation of the corresponding
16a,17a-di-(free-hydroxy)-19-nor-pregna-1,3,5(10),6,8,14-
~. ~
~:~23337
hexaene-20-one or at an earlier stage of the synthesis, however,
a 17a,21-alkylidenedioxy grouping is preferably introduced
a~ter preparation of the corresponding 17a,21-di-(free-hydroxy)-
l9-nor-pregna-1,3,5(10), 6,8,14-hexaene-20-one. Both, the
16a,17a- and the 17a,21-alkylidenedioxy derivatives of the
l9-nor-pregna-1,3,5(10),5,8,14-hexaene-20-ones of formula (I)
may be prepared from the corresponding 16a,17a,di-(free-hydroxy)-
or 17a,~1-di-(free-hydroxy)-steroids upon reaction with a
ketone or aldehyde (e.g. acetone, acetaldehyde, acetophenone)
in the presence of a mineral acid (e.g. hydrochloric acid).
The 17a,20;20,21-bismethylenedioxy function can be introduced
prior to or after introduction of the l9-nor-pregnapentaene
- or l9-nor-pregnahexaene system by known reactions such as that
utilizing formaldehyde in the presence of acid.
The l9-nor-pregnahexaene-20-ones are used in elicit-
ing a mitotic inhibitory response in a warm-blooded animal
having a disease characterized by rapid cell proliferation.
This is achieved by administering to said animal a non-toxic,
mitotic-inhibitory effective amount of a l9-nor-pregnahexaene-
20-one of formula (I) defined hereinabove, usually together
with a non-toxic, pharmaceutically acceptable carrier, parti-
cularly in the treatment and control of proliferative skin
diseases, primarily for the treatment of psoriasis via the
topical route.
Psoriasis is characterized by increased epidermipo-
iesis associated with a high mitotic rate, rapid cell turnover
and altered keratinization. The psoriatic epidermis can be
normalized by slowing down cell growth through inhibiting
mitosis. All drugs currently used in psoriasis therapy are
.23337
- 13 -
known to directly or indirectly reduce epidermal mitotic
activity. Although there is no animal model for psoriasis,
many of these same drugs have been reported to have a similar
effect in models of epidermal hyperplasia which simulate
psoriasis in laboratory animals. Topically effective anti-
psoriatic drugs, including corticosteroids, anthralin, coal
tar and 5-fluorouracil, while relatively free of systemic side
effects, cause local adverse reactions. Thus, corticosteroid
therapy causes skin atrophy, telangiectasia and the formation
of striae, while anthralin and 5-fluorouracil are skin
irritants and require close clinical supervision for optimal
therapeutic benefit. Anthralin can also cause staining of the
skin.
As previously mentioned, it has now been discovered
that compounds according to general formula (I), including
the 21-acetate and 3,21-diacetate of 19-nor-pregna-1~3,5(10),6-
8,14-hexaene-3,17a,21-triol-20-one, reduce epidermal mitotic
activity without causing significant local or systemic hormonal
or toxic effects when applied topically to the skin of mice in
which epiderman mitosis has been stimulated.
Specifically, when treated by a procedure modified
from S. Belman and W. Troll, Cancer Research 32:450-454 (1972),
the 19-nor-preg~ahexaene-20-ones reduce croton-oil stimulated
epiderman mitosis in mice when applied topically. Moreover,
they are non-irritating without causing hormonal side effects,
which is surprising in view of the l9-nor-pregnahexaene-20-one
structure containing an aromatic A-ring such as in many estro-
gens, and a corticoid side chain such as in potent topical anti-
inflammatory agents.
3337
In the foregoing test, croton-oil is applied topically
to shaved mice, thus accelerating mitosis. A l9-nor-pregna-
1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one is applied
topically to the stimulated site, then 24 hours later portions
of the treated skin are excised for histologic processing,
mitotic figures per thousand basal interfollicular epidermal
cells being counted in a light microscope. Epidermal mitotic
counts from treated mice are compared to counts ~rom lesion
controls for statistically significant differences with an
analysis of variance. The mitotic count for each compound
tested is expressed as percent reduction o-f mitoses compared
with the number of mitoses on the skin of mice treated with
croton-oil aloneO In general, it was discovered that the 19-
nor-pregnahexaene-20-ones of formula I significantly reduce
croton-oil stimulated epidermal mitosis. For example, the 16~-
methyl-l9-nor-pregnahexaene-20-ones of formula (II) usually
exhibit over 60~/o inhibitions of mitoses at a 2 mg topical dose.
16-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-
triol-20-one 21-acetate exhibits about ~O reduction o~ mitosis
(even at a topical dose as low as 0.2 mg) which is approximately
10 times greater than the mitotic reduction exhibited by an
equal quantity (i.e. 0.2 mg) of betamethasone dipropionate
(a known anti-psoriatic agent) in the same animal modelO
The a~ti-mitotic activity is also demonstrated by
similar tests in mice whereby increased epidermal mitosis is
produced by ultraviolet irradiation according to procedures
modified from A. DuVivier and R.B. Stoughton, J. Investigative
Dermatology, 65:233-237 (1975)~ In these tests, it was demon-
strated that the l9-nor-pregnahexaene-20-ones~ particularly
` ~Z33~7
- 15 -
16a-methyl-l9-nor-pregna-l~3~5(lo)~6~8~l4-hexaene-3~l7a~2l-tri
20-one 21-acetate, significantly reduce epidermal mitotic rate
following 1, 5 or 9 topical applications (each wi-th 0.02 mg,
0~10 mg, and 0.5 mg doses) to ultraviolet stimulated hairless
mouse epidermis, advantageously causing an epidermal thinning
effect after multiple applications when the effect became
equivalent to that demonstrated by steroidal anti-psoriatic
agents such as betamethasone valerate. Since the compounds
defined by formulae (I) and (II) do not cause estrogenic or
other hormonal or toxic effects when applied topically as
demonstrated by tests in mice, continued applications of a
l9-n~r-pregnahexaene-20-one will not cause irritation or stain-
ing o~ the skin or skin atrophy as caused by known anti-psoriatic
agents. The foregoing mode of anti-psoriatic activity of the
19-nor-pregnahexaene-20-ones is different from that demonstrated
by known steroidal anti-psoriatic agents such as betamethasone
valerate which, when applied topically to ultraviolet stimulated
hairless mouse epidermis at doses equal to those of the l9-nor-
pregnahexaene-20-ones [e.g. 16a-methyl-19-nor-pregna-1,3,5(10),6-
8,14-hexaene-3,17a,21-triol-20-one-21-acetate] first cause an
epidermal thinning without reduction of mitoses.
rrhe l9-nor-pregnahexaene-20-ones, particularly 16a-
methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-
20-one 21-acetate, have also been found to exhibit anti-mitotic
activity when administered orally or parenterally to mice, with-
out causing significant local or systemic hormonal or toxic
effects.
L2~33~
- 16 -
In view of the anti-mitotic and anti-acanthotic (i.e.,
reduction of epidermal thickening) ac-tivity (as tested in
mice), of the l9-nor-pregnahexaene-20-ones, particularly when
applied topically, these compounds can thus be advantageously
used in treating and controlling psoriasis by applying topical-
ly to the affected area, in a concentration effective for the
treatment of psoriasis, a l9-nor-pregna-hexaene-20-one of
formula ~I), usefully together with a non-toxic pharmaceutically
acceptable carrier. Pr~ferred anti-psoriatic agents are the
16-methyl-19-nor-pregnahexaene-20-ones, especially the 16~-methyl
compounds of formula (II), particularly 16~-methyl-19-nor-pregna-
1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate and
the 3-acetate, 3-benzoate and 15-chloro derivatives thereof.
Included within the term "topically applying" are
applications onto the skin surface whereby the compounds are
effective in the treatment and control of skin diseases character-
ized by rapid and/or abnormal cell proliferation, e-g- psoriasis,
aerosol application; and subcutaneous injection application
whereby they are effective in the treatment of local epidermal
disorders.
Conveniently, a pharmaceutical formulation comprising a
l9-nor-pregnahexaene-20-one of formula (I), preferably a 16a-
methyl compound of formula (II), such as 16a-methyl-19-nor-
pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate,
in a non-toxic pharmaceutically acceptable carrier, usually in
concentrations from about 0.0001 percent to about 5 percent,
preferably from about 0.1 percent to about one percent, is
applied several times daily to skin affected by psoriasis until
~.~2~337
- 17 -
the psoriatic condition has improved. Topical applications may
then be continued at less frequent intervals (e~g. once a day)
to control mitoses in order to preven-t return of severe
psoriatic conditions. In general, application is in any
topical form including creams, lotions, aerosols and ointments,
prepared by combining the active ingredient wi-th conventional
pharmaceutical diluents and carriers as used in topical formula-
tions comprising steroids, conveniently in a liquid solvent,
preferably in a water-miscible liquid carrier made up of
hydrophylic liquids having a high solvating action, e.g. a
solution of 16a-methyl-19-nor-pregna-1,3,5tl0),6,8,14-hexaene-
3,17a,21-triol-20-one 21-acetate in polyethyleneglycol.
m e pharmaceutical formulations may be made according
to known procedures, some of which are described in detail here-
inbelow. Typical formulations include ointments, lotions, creams,sprays, powders, drops (e.g. ear drops), suppositories, and
aerosols, Ointments and creams may, for example, be formulated
with an aqueous or oily base with the addition of suitable thick-
ening and/or gelling agents. Such bases may, thus, for example,
include water and/ox an oil (such as liquid paraffin) or a
vegetable oil (such as peanut oil or castor oil). Thickening
agents which may be used according to the nature of the base
include soft paraffin, aluminium stearate, cetostearyl-alcohol,
polyethyleneglycols, woolfat, hydrogenated lanolin, beeswax, etc.
Lotions may be formulated with an aqueous or oily base and will,
in general, also include one or more of the following, namely,
stabilizing agents, emulsifying agents, dispersing agents, sus-
pending agents, thickening agents, coloring agents, perfumes and
~L~23337
- 18 -
the like. Powders may be formed with the aid of any suitable
powder base, e.g. talc, lactose, starch, etc. Drops may be
formul~ted with an aqueous base or non-aqueous base, also
comprising one or more dispersing agents, suspending agents,
solubilizing agents, etc.
The topical pharmaceutical compositions may also
include one or more preservatives or bacteriostatic agents,
e.g. methyl hydroxybenzoate, propyl hydroxybenzoate, chloro-
cresol, benzalkonium chloride, etc. They may also contain
other active ingredients such as antimicrobial agents,
particularly antibiotics.
As already mentioned, the proportion of active
steroid in the topical compositions depends on the precise
type of formulations to be prepared, but will generally be
within the range of from 0.0001% to 5% by weight. Generally,
however, for most types of topical preparations the propor-
tions of active steroid used will be within the range of
from 0.1 to 3% and preferably 0.1 to 1%. Based upon studies
in mice, when administered systemically, preferably parenter-
ally, the dosage necessary to produce an anti-mitotic response
is in the range of from about 1 to about 100 mg per kilogram
body weight.
The following non-limiting examples illustrate
the inventions of both the parent and divisional applica-
tions.
337
-- 19 --
EX~PLE 1
16a-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,?1-
TRIOL-20-ONE 21-ACETATE
A. 16-Methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17~,21~
triol-20-one 2~-Acetate
To a refluxing solution of lithium chloride (120 y) and
concentrated hydrochloric acid (1.~ ml) in dimethylforma-
mide (750 ml), add 9a,11~-dichloro-16a-methyl-1,4-pregna-
diene-17a,21-diol-3,20-dione 21-acetate (3~ g). Heat the
reaction mixture at reflux temperature for 15 minutes,
then pour into water/ice (6 liters). Extract the aqueous
mixture with ethyl acetate, wash the combined extracts
with water, then evaporate to a volume of about 350 ml.
Separate the resultant crystalline precipitate by :~iltra-
tion, washthe precipitate with ethyl acetate and air dry,
to obtain 16~-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-
3,17a,21-triol-20-one 21-acetate (yield 9.6 g); m.p. =
235 - 240C; [a]D6 = ~101 (dioxane); ~maxhan ~in nm~ =
230 ( =81,100), 258 (~ =3600), 269 ( =4900~, 280
(~ =5600), 292 ( =4100)~ 326 (~=2400), 346 ( ~=800).
B. 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-
triol-20-one 21-Acetate
To a solution of 16a-methyl-19-nor pregna-1,3,5(10),6 r 8-
pentaene-3,17a,21-triol-20-one 21-acetate (14.0 g~ in
dioxane (2 liters), add 2,3-dichloro-5,6-dicyanobenzogui-
none (9.98 g = 1.2 equivalents) and stir the reaction mix-
ture at room temperature for 4 y2 hours. Separate the pre-
cipitated solids by filtration and wash the precipitate
with dioxane. Combine the filtrate and washings and eva-
porate to a small volume. Dissolve the residue in ethyl
acetate, wash the ethyl acetate solution with water, then
with aqueous sodium bicarbonate solution, thereafter with
saturated sodium chloride solu~ion, and then again with
3~7
- 2~ _
wa-ter. Evaporate the ethyl acetate solution ln vacuo to
a small volume and separate the resultant precipitate by
filtra-tion, to obtain 16a-me-thyl-19-nor-pregna-
1,3,5(10),6,8~14-hexaene-3,17a,21-triol-20-one 21-ace-
tate (yield 6.48 g). Concentrate the fil-tra-te to dryness,
triturate the resultant residue with ether and filter, to
obtain an additional 4.47 g of 16a-methyl-19-nor-pregna-
1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate;
[a]D6 = -95 (dioxane), m.p. = 218 - 221C; A ma~'anl
~in nm] = 248 (~ =36,000), 257 (~ =46,400), 266 ( =49,2Q0),
288 (shoulder) (~ =13,900), 298 (~ =19,000), 310
(~ =17,900).
E~PLE 2
OTHER l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17~,21-TRIOL-
20-ONE DERIVATIVES
A. l9-Nor-pre~na-1,3,5(10),6,8-pentaene-3,17a,21-triol-
20-one Derivatives
In a manner similar to that described in Example lA,
treat each of the following 9a,11~-dihalogeno-1,4-pregna~
dienes with lithium chloride in dimethylformamide:
1) 9a,11~-dichloro-16~-methyl-1,4-pregnadiene-17a,21-
diol-3,20-dione 21-acetate;
2) 9a,11~-dichloro-16a-methyl~ -pre~nadiene-17a,21-
dicl-3,20-dione 17,21-di-n-butyratei
3) 9a,11~-dichloro-1,4-pregnadiene-17a,21-diol-3,20-
dione 21-acetate.
Isolate and purify each of the resultant products in a
manner similar to t~at described in Example lA, to obtain,
respectively,
1) 16~-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-
3,17a,21-triol-20-one 21-acetate; m.p. = 182 - 184C;
- 21 -
[a]D = +122 (chloroform)i ~ max [in nm] = 229
( =67,000), 258 (=3,700), 268 ( =4,800), 279
(~ =5,500), 291 ( =4,000), 327 (~ =2,400), 340
(~ =2,700);
2) 16a-methyl-19-nor-pregna-1,3,5tlO),6,8-pentaene-
3,17a,21-triol-20-one 17,21-di-n-butyrate; m.p. =
200 - 202C, [a]D6 = -15 (dioxane); ~ anol
[in mn] = 228 ~ =67,000), 257 ( =4,Q00),268
(~ =5,100), 279 ( =5,700), 290 (~ =4,000), 325
(~ =2,300), 340 (~ =2,700);
3) 19-nor-pregna-1,3,5(10~,6,8-pentaene-3,17a,21-triol-
20-one 21-acetatej m.p. = 185 - 190C~ [a]D = t91
(chloroform) ~ methanol [in m] 229 (~ 66 400)
258 ( =3,600), 268 ( =4,900), 281 (~ =5,700), 291
(~ -4,200), 327 ( =2,600), 340 (~ =3,100).
B. l9-Nor-pre~na-l~3~5(lo)~6~8~l4-hexaene-3~l7a~2l-tri
20-one Derivatives
In a manner similar to that described in Example lB,
trea-t each of the l9-nor-pregna-1,3,5(10),6,8-pentaenes
obtainable from Example 2A with DDQ in dioxane and i50-
late and purify each of the resultant products in a
manner similar to that descri~ed,to obtain, respectively,
1) 16~-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,17a,21-triol-20-one 21-acetate; m.p. = 177 - 179C,
[a]D = +95 (chloroform); ~ max rin nm] = 253
( =51,300), 262 ~ =51,800), 284 (~ =13,400), 295
18,100), 306 ( =16,800), 327 t~=2,800), 354
( = 1,700);
2) 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,17a,21-triol-20-one 17,21-di-n-butyrate; m.p. =
O [ ]26 = -201 (chloroform); ~ max
rin mn] = 246 (~ =38,700), 255 ( =51,300), 264
33~
- 22 -
(~ =51,300), 287 (~ =15,300), 297 (~ =20,000), 309
(~ =18,700) r 339 ( =2,000), 355 (~ =1,500);
3) 19-nor-pregna-1,3,5(10),6,8,14-hexAene-3,17a,21-triol-
20-one 21-acetate; m.p. = 212 - 216 C, [a~D = ~30
(dioxane)~ ~ max ~in nm] = 245 ( =38,000), 253
(~ =49,900), 262 (~ =46,700), 286 (~ =13,300), 295
(~ =17,900), 307 (~ =16,500), 338 (~ =2,000), 355
(~ =1,600).
EXAMPL~ 3
3-A~KOXY DERIVATI~TES OF l9-NOR-PREGNA-1,3,5(10),6,8,14-
HEXAENE-3,17a,21-TRIOL-20-O-l~ES
A. 3-Methoxy-16a-methyl-19-nor-pregna-1,3,5(10),6, 8!14-
hexaene-17a,21-diol-20-one 21-Acetate
To a solution of 16a-methyl-19-nor-pre~na-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 21-acetate (1 g) in ethyl
acetate (50 ml), add a solution o~ diazomethane in ether
(molar quantity of diazomethane being greater than that
of pregnahexaene). Allow the reaction mixture to stand
overnight at room temperature, then distill the excess
diazomethane and ether. Purify the resultant residue via
chromatography on silica gel preparative plates utilizing
as solvent system chloroform:ethyl acetate t4:1~. Remove
the band containing the desired product (as visualized
under ultraviolet light) b~ extraction with ethyl acetate.
Evaporate the ethyl acetate and crystallize the resultan-t
residue from petroleum ether/ether,to obtain 3-methoxy-
16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-17a,21-
diol-20-one 21-acetate; yield = 230 mg; m.p. = 186-188C;
[ a] D = -109 (chloro~orm); ~max [in nm] - 246
(~ =36,600), 254 ( =46,300), 264 (~ =47,000), 283
( =14,700), 293 (~ =20,200), 306 (~ =19,700), 335
(~ =1,700), 352 (~ =1,300).
Z333~
_ 23 -
B. Other 3-Methoxy-19-nor-pregna-1,3,5(10),6.8,1~-hexaene-
17a,21-diol-20-ones
_ _ _
In similar manner, treat each of the 3-(free-hydroxy)-
l9-nor-pregna-1,3,5(10),6,8,14-hexaenes of Example 2B
with diazomethane, to obtain, respectively,
1) 3-methoxy-16~-methyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-17a,21-diol-20-one 21-acetate;
2) 3-methoxy-16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-17~,21-diol-20-one 17,21-di-n-butyrate; and
3) 3-methoxy-19-nor-pregna-1,3,5(10)~6,8,14-hexaene-
17a,21-diol-20-one 21-acetate.
C. Other 3-Alkoxy Derivatives
Following the procedures of Examples 3A and 3B, but sub-
stituting for diazomethane other diazoalkane solu-tions,
e.g. diazoethane, there are obtained the corresponding
3-alkoxy derivatives, e.g. the 3-ethoxy derivatives,
corresponding to the 3-methoxy products of Examples 3A
and 3B.
EXA~IPLE 4
19-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,l7a,21-TRIOL-20-ONES
A. ~
-
3,17a,21-triol-20-one
To a solu-tion of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 21-acetate (1 g) in metha-
nol (70 ml) under an atmosphere of nitrogen, add aqueous
sodium bicarbonate (10 ~, 5 ml). Heat at reflux tempera-
ture for 30 minutes, cool, add dilute acetic acid until
the reaction mixture is at about pH 7, pour into water
and extract with ethyl acetate. Wash the combined extracts
with water, dry over magnesium sulfate, and evaporate.
Crystallize the resultant residue from chloroform/ethyl
l~.Z3337
- 24-
aceta-te,to obta.in 16~-methyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one; yield = 697 mg; [a]D6 =
-188 (dioxane); m.p. = 220 - 225C; ~ methanol [in nm] -
246 (~ =35,000), 255 ( =45,100), 264 ( =45,g00), 285
( -13,~00), 296 (~ =18,500), 308 (~ =17,900), 338
(~ =2,600), 355 ( =1,700)~
B. Other l9-Nor-pregna-1,3,5(10~,6,8,14-hexaene-3,17a,21-
triol-20-ones
In similar manner, treat each of 16~-methyl l9-nor-pregna-
1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate
and l9-nor-pregna-1,3,5(10),6,3,14-hexaene-3,17a,21-triol-
20-one 21-acetate with aqueous sodium bicarbonate and iso-
late and purify the resultant products in the described
manner, to obtain, respectively, 16~-methyl-19-nor-pregna-
1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one and l9-nor-
pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one.
EXAMPLE 5
17-MONO-LOWER ALKANOATES AND 21-MONO-LOWER ALKANOATES FROM
THE CORRESPONDING l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-
3,17a,21-TRIOL-,0-ONES
A. _-Pro ~onate and 17-Pro~ionate _f 16a-Meth~1-19-nor-
reqna-1,3,5(10),6,8,14-hexaene-3,17a,21--triol-20-one
(1) To a solution of 16a-me-thyl-19-nor-pre~na-1,3,5(10),
6,8,14-hexaene-3,17a,21-triol-20-one (697 mg) in di-
methylsulfoxide (9.7 ml), add triethyl orthopropio-
nate (0.97 ml) and p-toluenesulfonic acid (97 mg~.
Stir the reaction mixture at room temperature for
5 hours, then add acetic acid/water (14 ml, 9:1)
and stir the mixture at room temperature overnight.
Pour the reaction mixture into water, separate
the resultant precipitate by filtration and wash it
with water, then chromatograph the precipitate over
-
Z33~3 ~
- 25 -
silica gel, eluting with methylene-chloride/ether
(19:1). Combine the like early frac-tions as de-termi-
ned by thin-layer chromatography, evaporate, crys-tal-
lize the resultant residue from ether, and filter, to
obtain 16a-methyl-19-nor-pre~na-1,3,5(10),6,8,14-
' hexaene-3,17a,21-triol-20-one 21-propionate; yield =
138 mg; m p = 218 - 222C; [a]D6 = -109 (chloro-
) ~ methanol [in nm] = 246 ( =36,500), 255
( =47,400), 264 (--48,200), 286 (~ =13,900), 296
(~ =19,300), 309 (~ =18,200), 338 (~ =2,000), 355
( =1,500).
(2) Continue eluting with the same solvent and combine the
like later fractions as determined by thin-layer
chromatography, evaporate, crystallize the resultant
precipitate from ether/petroleum ether and filter,
to o~tain 16a-methyl-19-nor-pregna-1,3 t 5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 17 propionate; yield =
41 mg; m.p. = 115 - 120 C; [a]D = -212 (chloroform).
B. 21- and 17-Monoesters of Other-l9-Nor-pregna-1,3,5(10),
6,8,14-hexaene-3,17a,21-triol-20-ones
In similar manner, treat each of 16~-methyl-19-nor-pregna-
1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one and l9-nor-
pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one with
triethyl orthopropionate and p-toluene~sulfonic acid, fol-
lowed by treatment with aqueous acetic acid, and isolate
and purify each of the resultant products in a manner si-
milar to that described hereinabove, to obtain, respecti-
vely, 16~-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,17a,21-triol-20-one 21-propionate and 16~-methyl-19-nor-
pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 17-
propionate, l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,
21-triol-20-one 21-propionate and 19-nor-pregna-1,3,5(10~,
6,8,14-hexaene-3,17a,21-triol-20-one 17-propionate.
~.2~;337'
- 26 -
EXAMPLE 6
15-CHLORO-19-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,21-
TRIOL-20-ON~S
A. 15-Chloro-16a-methyl-19-nor-pregna-1,3,5(10),6,8,1~-
hexaene-3,17a,21-triol-20-one 21-Acetate
To a saturated solution of hydrogen chloride gas in
dioxane (50 ml), add 16a-methyl-19-nor-pregna-1,3,5~10),
6,8-pentaene-3,17a,21-triol-20-one 21-acetate (382 mg),
warm slightly to dissolve. To the resulting solution add
2,3-dichloro-5,6-dicyanobenzoquinone (454 mg) and stir
the reaction mixture at room temperature ~or 30 minutes.
Evaporate the dioxane, dissolve the resultant residue in
ether and percolate the ether solution through an alu-
mina column. Evaporate the combined eluates and chromato-
graph the resultant residue over silica gel eluting with
petroleum ether/ether gradient elution. Combine the like
fractions containing the desired product as determined by
thin-layer chromatography and evaporate the combined elu-
ates. Recrystallize the resultant residue from ether/
petroleum ether and filter the resultant precipitate,
to give 15-chloro-16a-methyl-19-nor-pre~na-1,3,5(10),
6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate; yield =
131 mg; m.p. = 225 - 228 C; [a]D = -185 tchloro~orm);
~ max [in nm] = 258 (~ =44,700), 266 (E =49,200),
290 (~ =12,500), 303 (~ =15,000), 315 ('- =14,600), 336
( =3,900), 354 ( =2,900).
B. Other 15-Chloro-19-nor-pregna-1,3,5~10),6,8,14-hexaene-
3,17a,21-triol-20-ones
In similar manner, treat each of the l9-~or-pregnapentae-
nes obtainable from Example 2A with DDQ and hydrogen
chloride, and isolate and purify each of the resultant
products in a manner similar to that described herein-
above, to obtain, respectively,
.
3;:337
- 27 -
1) 15-chloro-16~-methyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21--triol-20-one 21-acetate;
2) 15-chloro-16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 17,21-di-n-butyrate;
3) 15-chloro-19-nor-pregna-1,3,5tlO)r6,8,14-hexaene-
3,17a,21-triol-20-one 21-acetate.
EXA~IPLE 7
PREPARATION OF 3-CARBOXYLATE ESTERS
A 16a-Methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,17a,21-triol-20-one 3,21-Diacetate
To a solution of 16a-methyl-1~-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 21-acetate (450 mg) in pyri-
dine (2 ml), add acetic anhydride (1 ml) and allow the
reaction mixture to stand at room temperature overnight.
Pour the reaction mixture into dilute hydrochloric acid,
separate the resultant precipitate by filtration, wash it
with water, dry and crystallize from ether, to obtain
16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-
triol-20-one 3,21-diacetate; yield = 232 mg; m.p. = 153 -
157C~ [a]D6 = _93 (chloroform);~methanol [in nm] = 388
( =29,300), 246 (~ =32,600~, 255 ( =41,360), 264
~ 1,600), 283 (~ =14,500), 2~3 (~ =18,000), 306
(~ =16,700), 330 (~ =600).
B. 16a-Methyl-l9-nor-pre~na-l~3~5(lo)~6~8~l4-hexaene-3~l7a~2
triol-20-one 3-Benzoate 21-Acetate
.,
In the procedure of Example 7A, by substituting for acetic
anhydride an equivalent quantity of benzoyl chloride,
there is obtained 16a-methyl-19-nor-pregna-1,3,5(10),6,8,
14-hexaene-3,17a,21-triol-20-one ~-benzoate 21-acetate;
m.p. = 197 - 202C; [a]D6 = -68 (chloroform); ~max nol
~in nm] = 238 (~ =39,300), 256 (~ =44,800), 265 (~ =45,500),
283 ( =16,000), 295 (~ =17,900), 307 ~ =17,000).
~ ~3337
- 28
C. 3-Carbo~ylate Esters of Other 19-Nor-pregna-1,3,5(10),
6,8,14-hexaene Derivatives
(1) In similar manner -treat each o~ the 3-(free-hydroxy)-
or 3,21-di-(free-hydroxy)-19-nor-pregna-1,3,5(10),
6,8,14-hexaene compounds obtainable ~rom Examples 2~,
5 and 6 tpossibly containing a ~urther free hydroxy
group in position 17) with acetic anhydride in pyri-
dine or benzoyl chloride in pydridine/ to obtain the
corresponding 3-acetate or 3--benzoate ester -thereof,
or the corresponding 3,21-diacetate or 3,21-dibenzoate,
respectively.
(2) Treat eaGh of the 3,17a,21-tri-(free-hydroxy)-19-nor-
pregna-1,3,5(10),6,8,14-hexaenes prepared in Example
4 with acetic anhydride in pyridine or benzoyl chlo-
ride in pyridine according to procedures o~ above
Examples 7A and 7B, to obtain, respectively,
1) 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,17a,21-triol-20-one 3,21-diacetate;
23 16a-methyl-19-nor-pre~na-1,3,5(10),6,8,14-hexaene-
-3,17a,21-triol-20-one 3,21-dibenzoate;
3) 16~-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,17a,21-triol-20-one 3,21-diace-tate;
4) 16~-methyl-19-nor-pregna-1,3,5(10),6,$,14-hexaene-
3,17a,21-triol-20-one 3,21-dibenzoate;
5) 19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-
triol-20-one 3,21-diacetate;
6) 19-nor-pregna-1,3,5(10),6,8,1~-hexaene-3,17a,21-
triol-20-one 3,21-dibenzoate.
z333~
~ 29 -
E~AMPLE 8
16a-METHYL-19-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,21-
TRIOL-11,20-DIONE 3-BENZOA~E 21-ACETATE
A. 16a-Methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-
triol-11,~0-dione 3-Benzoate 21-Acetate
To a solution of 9~-bromo-16a-methyl-1,4-pregnadiene-
17a,21-diol-3,11,20-trione 21-acetate (30 g) in pyridine
(240 ml) add ben~oyl chloride (60 ml) and heat the reac-
tion mixture at 60C for 20 hours, cool and pour into di-
lute hydrochloric acid. Extract the aqueous solution with
ethyl acetate, wash the combined extracts with water, and
evaporate. Chromatograph the resultant residue over sili-
ca gel eluting with petroleum ether/ether gradient~
Combine the like fractions containing the desired pro~
duct as determined by thin-layer chromato~raphy, evapo-
rate, then crystallize the resultant residue from ether,
to obtain 16a-methyl-1~-nor-pregna-1,3,5(10) r 6,8-pentaene-
3,17a,21-triol-11,20-dione 3-benzoate 21-acetate (yield
13.1 g); m.p. = 183 - 184 C; [a]D = ~63 (dioxane);
~mmaexhanol ~in nm] = 215 (~ =40,600), 237 (~ =38,400),
314 ( =7,900)
B. 16a-~eth~l-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,
21-triol-11,20-dione 3-Bengoa-te 21-~cetate
To a solution of 16a-methyl-19-nor-pregna 1,3,5(10),6,8-
pentaene-3,17a,21-triol-11,20-dione 3-benzoate 21-acetate
(10.4 g) in dioxane (500 ml) add DDQ (13.33 g = 2.4 equi-
valents) and heat the reaction mixture at reflux tempe-
rature for 48 hours. Then evaporate 1n vacuo, dissolve
the resultant residue in methylene chloride and perco-
late through alumina ("activity V", i.e. anhydrous alu-
mina the activity of which has been modified by addition
of 15 % water). Evaporate the combined eluates to a small
volume and chromatograph over silica gel, eluting with
~ ~ ~333~
30 -
pe-troleum ether/ether gradient. Combine the like frac-
tions containing the desired product as de-termined by
-thin-layer chroma-tography, and evaporate, then recrystal-
lize -the resultant residue from ether, to obtain 16a-
methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-
triol-11,20-dione 3-benzoate 21-acetate; m.p. 144 -
145C; [a~D = +1 (dioxane); ~ methanol [in nm~ = 234
~ =37,700), 270 ( =42,900), 277 (shoulder)(~ =40,400),
312 (~ =9,000), 349 (~ =6,000) 365 (~ =5,300).
EXAMPLE 9
16a-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,21-
TRIOL-11,20-DIONE
By subjecting 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-11,20-dione 3-benzoa-te 21-acetate
to substantially the conditions of Example 4A, there is ob-
tained 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,17a,21-triol-11,20-dione; m.p. = 163 - 165 C; [a]D
-107 (dioxane); ~ max ~in nm] = 236 (~ =24,100)l 276
(~ =34,000), 317 (~ =5,600), 378 (~ =5,700).
EX~MPLE 10
OTHER ESTER DERIVATIVES OF 16a-METHYL-l9-NOR-PREGNA-
1,3,5(10),6,8,14-HEXAENE-3,17a,21-TRIOL-11,20-DIONE
A. The 21-Propionate and the 17-Propionate of 16a-Methyl-
19-nor-pre~na-1,3,5(10 ?, 6,8,14-hexaene-3,17a,21-tr ol-
_l,20-dione
By subjecting 16a-methyl-19-nor-pregna-1,3,5(10~,6,8,14-
hexaene-3,17a,21-triol-11,20-dione (100 mg) to substan-
tially the conditions of Example 5A~ there are obtained
respectively, 16a-methyl-19-nor-pregna-1,3,5(10~,6,8,14-
hexaene-3,17a,21-triol-11,20-dione 21-propionate (25 mg;
the residue from the least polar band), and 16a-methyl-
l9-nor-pregna-1,3,5(10),6,8/14-hexaene-3,17a,21-triol-
33~
- 31 -
11,20-dione 17-propionate (25 mg; the residue from the
most polar band~.
B. 16a-Methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,17a,21-triol-11,20-dione3,17,21-Tripropionate
To a suspension o~ 16a-methyl-19-nor-pregna-1,3,5(10),
6,8,14-hexaene-3,17a,21-triol-11,20-dione (2 g) in pro-
pionic acid (20 ml) containing ~-toluenesulfonic acid
(200 mgj at -5C, add dropwise over a 40-minute period
trifluoroacetic anhydride (8 ml). Allow the reaction
mixture to warm to room temperature, then stir for 24
hours. Pour the reaction mixture onto ice/water and ex-
tract with ethyl acetate. Wash the combined extracts
with aqueous sodium bicarbonate, then with water and
evaporate in vacuo. Chromatograph the resultant residue
over silica gel eluting with petroleum ether/ether gra-
dient. Combine the like fractions containing -the desired
product as determined by thin-layer chromatography, to
obtain 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexae-
ne-3,17a,21-triol-11,20-dione 3,17,21-tripropionate;
yield 2-04 g; [a]D6 = -82 (dioxane); ~ methanol [in nm] =
233 (~ =26,300), 260 (shoulder) (~ =30,700), 269
(~ =36,100), 278 ( =34,800), 316 ( =7,700), 345 (shoul-
der) ( =5,400), 364 ( f =4,600).
C. 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,17a,21-triol-11,20-dione 3,21-Diacetate
Subject 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexae-
ne-3,17a,21-triol-11,20-dione to substantially the con-
ditions o~ Example 7A, to obtain 16a-methyl-19-nor-pre-
gna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione
3,21-diacetate; [a]D = -1 (dioxane); ~ ethanol [in nm] =
234 (~ =25,900), 269 ( =33,30Q), 278 ( =29,300), 315
( =7,800), 348 (~ =5,300), 365 (~ =4~700).
~lZ~333~7
- 32 -
D. 16a-Methyl-19-nor-~__gna-1,3,5(10),6,8,14-he~aene-
3,17a,21-triol-11,20-dione 3,21-Dipropionate
Following the procedure of E~amp:Le 10C, by utilizing an
eq~livalent quantity of propionic anhydride instead of
acetic anhydride, there is obtained 16a-methyl-lg-nor-
pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-
dione 3,21-dipropionate; m.p. = 135 - 137C; ~a]D6 =
+2 (dioxare); ~methanol [in nm] = 233 ( =24,000), 269
(=32,700), 279 (shoulder) (~ =28,500), 315 (~ =7,100),
349 (~ =5,000), 365 (~ =4,300).
EXA~IPLE 11
16a-METHYL-l9-NOR-PREGNA-1,3,5(10),6!8,14-HEXAE~E-3,11~,`17a,21-
TETROL-20-ONE 3,17,21-TRIPROPIONATE AND 17,21-DIPROPIONATE
To a solution of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-11,20-dione 3,17~21-txipropionate
(1 g) in tetrahydrofuran~methanol ~50 ml, 1:1), dried over an
alumina column at 0C, add sodium borohydride (220 mg = 3
equivalents) portionwise over a 5-minute period. Stir the
reaction mixture for an additional 10 minutes, then bring
to neutrality by adding glacial acetic acid dropwise. Pour
the reaction mixture into water, extract with ethyl acetate t
wash the combined extracts with water and evaporate. Chromato-
graph the resultant residue over silica gel GF column,eluting
with chloroform/ethyl acetate (9:1). Combine the like frac-
tions as determined by thin-layer chromatography, and evapo-
rate each of the three different combined fractions to resi-
dues comprising, respectively,
1) 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,11a,17a,21-tetrol-20-one 3,17a,21-tripropionate (yield:
53 mg);
2) 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,11~,17a,21-tetrol-20-one 3,17a,21-tripropionate (yield:
lZ3;~3~
- 33 -
502 mg). ~Eter purification by recrystalliza-tion from
pe-troleum ether/ether: [a]26 = -136 (dioxane~;
~ma~ [in nm] = 237 (~ =30,200), 244 (~ =34,000),
253 (~ =45,100), 262 (~ =4~,200), 281 (~ =16,200), 291
( =20,300), 304 (~ =18,500), 328 (~ =900), 3~ ( =500);
3) 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,11~,17a,21-tetrol-20-one 17,21-dipropionate (yield:
93 mg). After purification by recrystallization from
petroleum ether/ether: [a]D = -145 (dioxane);
~ max [in nm] = 236 (shoulder)(~ =28,100), 244
(~ =33,800), 256 ( =40,200), 265 (~ =40,200), 287
(shoulder) (~ =12,600), 297 (~ =16,400), 308 ( =15,500),
337 ( =2,700).
EXAMPLE 12
6-FLUORO-16a-M~T}~L-19-NOR-PREGNA-1,3,5(10),6,8,1~-HE~AENE-
3,17a,21-TRIOL-20-ONE 21-ACETATE
A. 6-Fluoro-16a-methyl-19-nor-pregna-1.3,5(10),6,8-pentaene-
3,17a,21-triol-20-one 21-Acetate
Add 6a-fluoro-9a,11~-dichloro-16a-methyl-1,4-pregnadiene-
17a,21-diol-3,20-dione 21-acetate (4.2 g) to refluxing
dimethylformamide (200 ml) and continue heating at reflux
temperature for 30 minutes. Pour the reaction mixture
into saturated ~queous sodium chloride solution, separate
the resultant precipitate by filtration. Dissolve the pre-
cipitate in ethyl acetate, and fractionally crystallize
to obtain both, 6a-fluoro-16a-methyl-pregna-1,4,8(14 ?, 9 (11) -
tetraene-17a,21-diol-3,20-dione 21-acetate and 6-fluoro-
16a-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-
triol-20-one 21-acetate. Further purify the latter com-
pound by crystallization from methylene chloride, yield:
316 m~; [a]D = +88.0 (dioxane); m.p. = 238 - 241C;
~max [in nm] = 238 (~ =50,500), 270 ( =5,000),
33~
- 3~ -
. .
281 ( =5,000), 293 ( =3,400), 315 (shoulder) (~ =1,700),
330 (~ =2,400), 344 (~ -2,600).
B. 6-Fluoro-16a-methyl-19-nor-pregna-1`,3,5~10),6,8,14-
hexaene-3,17a,21-triol-20-one 21-Acetate
Subject 6-fluoro-16a-methyl-19-nor-pregna-1,3,5(10),6,8-
pentaene-3,17a,21--triol-20-one 21-acetate (200 mg) to
substantially the conditions of Example lB, to obtain
6-fluoro-16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 21-acetate, yield: 35 mg;
m.p. = 200 - 202C; ~ mmaex 1 [in nm] = 248 ~shoulder)
( =36,300), 255 (~ =48,100), 265 (~ =49,200), 288
- ( =13,900), 299 ( =19,500), 311 ( ~=18,500), 342
(~ = 2,100), 359 (~ -1,500).
.
EXAMPLE 13
16~-METHyL-l9-NoR-pREGNA-l~3~5(lo)~6~8~l4-HEx~ENE-3~ l7a~
. .
21-TETROL-2Q-ONE 21-ACETATE
A. 16~-Methyl-pregna-1,4,6,8-tetraene-11~,17a,21-triol-
3,20-di-one 21-Acetate
-
To a mixture of 9a-chloro-16~-methyl-pregna-1,4,6-triene-
11~,17a,21-triol-3,20-dione 21-acetate (3.44 g) in ace-
tone (700 ml) add potassium aceta-te (10.3 g) and reflux
the reaction mixture with stirring for ~8 hours. Filter
the reaction mixture, evaporate -the filtrate ln vacuo
to a low volume, pour in-to water and extract the aqueous
mixture with ethyl acetate. Wash the combined organic
extracts with water and evaporate to a volume of about
100 ml. Separate the resultant crystalline solid by
filtration, and dry, to obtain 16~-methyl-pregna-1,4,6,8-
tetraene-11~,17a,21-triol-3,20-dione 21-acetate, yield:
1.96 g; m.p. = 175 - 180 C; [a]D = +786 (pyridinel;
ethanol ~in nm] = 230 (shoulder) (~ =10,600), 264
max
( =10,000), 388 (~=6,500).
~lZ3337
- 35 -
B. 16~-Methyl-l9-nor-~E~e~na-l~3~5(lo)r6r8-pentaelle-3rll~rl7a/
21-tetrol-20-one 21-Acetate
To a solution of 16~-methyl-pregna-1,4,6,8-te-traene-
11~,17a,21-triol-3,20~dione 21-acetate t850 mg) in tetra-
hydrofuran (200 ml) add 1 N hydrochloric acid (20 ml).
Stir the reaction mix-ture at room temperature for 1 hour,
then pour the reaction mixture into 1 liter of saturated
aqueous sodium chloride solution and extract with ethyl
acetate. Wash the combined ethyl acetate extracts with
water and evaporate to a volume of about 25 ml. Separate
the resultant crystalline precipitate by filtration and
dry~ to obtain 16~-methyl-19-nor-pregna-1,3,5(10),6,8-
pentaene-3,11~,17a,21-tetrol-20-one 21-acetate, yield:
368 mg; m.p. = 203 - 207 C; [a]D = -~172 (pyridine);
~ [in n~] = 233 (~ =69,100), 267 (~ =4,800), 278
max
(~ =5,400), 315 ( =1,900), 327 (~ =2,300) 340 (~ =2,700).
C. 16~-Methyl-l9-nor-pre~na-1,3,5(10),6,8,14-hexaene-
3,11~,17a,21-tetrol-20-one 21-Acetate
Subject 16~-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-
3,11~,17a,21-t~trol-20-one 21-acetate (199 mg) to sub-
stantially the conditions of Example lB, to obtain 16~-
methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,11~,17a,
21-tetrol-20-one 21-aceta-te, ~ield: 91 mg, m.p. = 18S -
A methanol ~in nm] = 244 ~ =35,100), 2
( =44,000), 263 ( =44,000), 285 (shoulder) ( = 12,400),
295 ( =16,000), 306 (~ =14,900), 337 ( =2,600), 354 `
(~ =2,200).
EXAMPLE 14
16~-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,21-
.
TRIOL-11,20-DIONE 21-ACETATE
A. 16~-Methyl-pregna-1,4,5,8-tetraene-17a,21-diol-3,11,20-
trione 21-Acetate
To a solution of 16~-methyl-pregna-1,4,6,8-tetraene-
3337
- 36 -
11~,17~,21-triol-3,20-dione 21-ace-tate (500 mg) in methy-
lene chloride (50 ml) add ~.inely powdered manganese dio-
xide (5 g), and stir at room temperature for 20 hours.
Separate the manganese dioxide b~ ~iltration and w~sh ~7i-th
me-thylene chloride. Evaporate the combined filtr~te and
methylene chloride washings and crystalli2e -the resul-tant
residue from ether~ to yield 16~-methyl-pregna-1,4,6,8-
tetraene-17a,21-diol-3,11,20-trione 21-acetate; m.p. =
185 -188C; [a]D = +1164 (chloroform).
B. 16~-Methyl-l9-nor-pregna-l~3~5(lo)~6~8-pentaene-3~l7a~2
triol--11,20-dione 21-Acetate
.
Subject 16~-methyl-pregna-1,4,6,8-tetraene-17a,21-diol-
3,11,20-trione 21-acetate to substantially the conditions
of Example 13B, to obtain 16~-methyl-19-nor-pregna-
1,3,5(10),6,8-pentaene-3,17a,21-triol-11,20-dione 21-ace-
tate.
C. 16~-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,17a,21-triol-11,20-dione 21-Acetate
In a manner similar to that described in Example 13C,
treat 16~-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-
3,17a,21-triol-11,20-dione 21-acetate with DD~ in dioxane
and isolate the resultant product in a manner s.imilar to
that described,to ob-tain 16~-methyl-19-nor-p~egna-
1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione
21-acetate.
EXAMPLE 15
16a-~ETHYL-19-NOR-PREGNA-1,3,5(10),6,8,14-~E~AENE-3,11~,17a,
21-TETROL-20-ONE
A. 16a-Methyl-17a,20;20,21-bismethylene~ioxy-19-nor-pregna-
1,3,5(10),6,8,14-hexaene-3-ol-11-one
To a solution of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,
~ ~ ~ z~333~
19-hexaene-3,17,21-triol-11,20-diolle (4.3 g) in methy-
lene chloride (200 ml) under an atmosphere of nitrogen,
add formaldehyde (200 ml, 37 % aq~eous solution) and
concentrated hydrochloric acid (200 ml). Stir the mix-
ture at room temperature for 4 hours, separate the two
layers, extract the aqueous layer wi-th methylene chlori-
de, combine the organic layer and the me-thylene chloride
extracts and wash with aqueous sodium bicarbonate, then
with wa-ter. Evaporate the organic solution and chromato-
graph the resultant residue over silica gel,eluting with
a petroleum ether/e-ther gradient. Combine the like frac-
tions containing the desired product as determined by
thin-layer chromatography and evaporate and crystallize
the resultant residue from ether, to obtain 16a-me-thyl-
17a,20;20,21-bismethylenedioxy-19-nor-pre~na-1,3,5(10),
6,8,14-hexaene-3-ol-11-one.
B. 16a-Methyl-17a,20j20,21-bismethylenedioxy-19-nor-pregna-
1,3,5(10),6,8,14-hexaene-3,11~-diol
Subject 16a-methyl-17a,20;23~21 - bismethylenedioxy-l~-
nor-pregna-1,3,5(10),6,8,14-hexaene-3-ol-11-one -to sub-
stantially the conditions of Example 11, to obtain 16a-
methyl-17a,20;20,21 - bismethylenedioxy-19-nor-pregna-
1,3,5(10),6,8,14-hexaene-3,11a-diol (from -the com~ined
early Eractions) and 16a-me-thyl-17a,20i20,21-bismethy-
lenedioxy-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,11~-
diol (from the combined like later fractions). Purify
by crystallization from ether.
C. 16a-Methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,11~,17a,21-tetrol 20-one
Add a s~lspension of 16a-methyl-17a,20i20,21-bismethylene-
dioxy-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,11~-diol
(990 mg = 2.5 mmol) to aqueous 45 % hydrofluoric acid
~;3337
- - 38 -
(2.5 ml) at 0C and stir the resulting suspension at 0C
for 1.5 hours. Bring the reac-tion mixture to neutrality
by ~dding aqueous 5 % potassium bicarbonate, -then ex-tract
with ethyl acetate, wash the combined ex-tracts with
water and evaporate to a small volume. Separate the re-
sultant crystals by fil-tration and dry, to obtain 16a-
methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,11~,17a,
21-tetrol 20-one.
EX~LE 16
ALTERNATE PREPARATION OF 16a-~THYL-l9-NOR-PREGNA-1,3,5(10),
. . _
6,8,14-HEXAENE-3,11~,17,21-TETROL-20-ONE
To a solution of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,11~,17a,21-tetrol-20-one 3,17a,21-tripropionate
(271 mg) in methanol (25 ml), add sodium bicarbonate (3.0 ml,
5 % aqueous solution) and stir overnight at room temperature.
Add dilute hydrochloric acid until the reaction mixt~lre is
at about pH 7~ then remove the me-thanol in vacuo. Add water
to the resultant residue and extract with ether. Wash the
combined ether extracts with water, dry over magnesium sul-
fate and evaporate. Crystallize the resultant residue from
methylene chloride~ether to obtain 16a-methyl-19-nor-pregna-
1,3,5(10),6,8,14-hexaene-3,11~,17a,21-tetrol~20-one; ~ield:
44 mg; m.p. = 160 - 163 C; [a}26 = -161 ~dioxane),
~ m~ anol ~in nm] = 263 (shoulder) (~ =24,600), 245
(~ =31,000), 255 ( =38,000), 264 ( =38,700), 286 (shoulder)
(~ =12,800), 296 (~ =16,200), 308 (~ =15,100~, 338 (~ =2,700).
EX~PLE 1i
OTHER 19-NOR-PREGNA-1,3,5(10),6,8,14-HE~ENE-3,17a,21-TRIOL-
20-ONES
A. Other l9-Nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-iriol-
20-ones
In a manner similar to that described in Example lA,
.
337
- 39 -
-
treat each o~ the following 9a,11~-dihalogeno-1,~-pregna-
dienes with lithium chloride in dimethylformamide.
1) 6a,16a-dimethyl-9a,11~-dichloro-1,4-pregnadiene-
17a,21-diol-3,20-dione 21-acetate;
2) 6a-fluoro-9a,11~-dichloro-1,4-pregnadiene-17a,21-
diol-3,20-dione 21-acetate;
3) 6a-fluoromethyl-9a,11~-dichloro-1,4-pregnadiene-
- 17a,21-diol-3,20-dione 21-acetate;
4) 6a-difluoromethyl-9a,11~-dichloro-1,4-pregnadiene-
17a,21-diol-3,20-dione 21-acetate;
5) 6a-trifluoromethyl-9a,11~-difluoro-1,4-pregnadiene-
17a,21-diol-3,20-dione 21-acetate;
6) 9a,11~-dichloro-1,4-pregnadiene-16~,17a,21-triol-
3,20-dione 16,21-diacetate;
7) 6a-fluoro-9a,11~-dichloro-16a,17a-isopropylidene-
dioxy-1,4-pregnadiene-21-ol-3,20-dione 21-acetate;
8) 6a-fluoro-9a,11~-dichloro-16a-methyl-1,4-pregna-
diene-17a,21-diol-3,20-dione 21-acetate;
9) 6a-methyl-9a,11~-dichloro-1,4-pregnadiene-17a,21-
diol-3,2Q-dione 21-acetate;
10) 6a,16~-dimethyl-9a,11~-dichloro-1,4-pregnadiene-
17a,21-diol-3,20-dione 21-acetate.
Isolate and purify each of the resultant products in a
manner similar to that described,to obtain, respecti-
vely,
1) 6,16a-dimethyl-19-nor-pregna-1,3,5(10),6,8-pentaene-
3,17a,21-triol-20-one 21-acetate;
2) 6-fluoro-19-nor-pregna-1,3,5(10),6,8-pentaene-
3,17a,21-triol-20-one 21-acetate;
3) 6-fluoromethyl-19-nor-pregna-1,3,5(10),6,8-pentaene-
3,17a,21-triol-20-one 21-acetate;
- 40 -
4) 6-difluorolnethyl-l9-nor-pregna-l~3~5(lo)~6~8-pentaene
3,17a,21-triol-20-one Zl-acetate;
5) 6-trifluoromethyl-19-nor-pregna-1,3,5(10),6,8-pentae-
ne-3,17a,21-triol-20-one 21-ace-tate;
6) 19-nor-pregna-1,3,5(10),6,8-pentaene-3,16a,17a,21-
tetrol-20-one 16,21-diacetate;
. 7) 6-rluoro-16a,17a-isopropylidenedioxy-19-nor-pregna-
1,3,5~10),6,8-pentaene-3,21-diol-20-one 21-acetate;
8) 6-fluoro-16-methyl-19-nor-pregna-1,3,5(10),6,8-
- pentaene-3,17a,21-triol-20-one 21-acetate;
9) 6-methyl-19-nor-pregna-i,3,5(10),6,8-pentaene-3,17a,
21-triol-20-one 21-acetate;
10) 6,16~-dimethyl-19-nor-pregna-1,3,5(10),~,8-pentaene-
3,17a,21-triol-20-one 21-acetate.
15 B. In a manner similar to that described in Example lB,
treat each of the l9-nor-pregna-1,3,5(10),6,8-pentaenes
obtainable from Example 8A with DDQ in dioxane and iso-
late and purify each of the resultant products,to obtain,
respectively,
1) 6,16-dimethyl-19-nor-pregna-1,3,5(10),6,8,14-hexae-
ne-3,17a,21-triol-20-one 21-acetate;
2) 6-fluoro-19-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,17a,21-triol-20-one 21-acet~te;
3) 6-fluoromethyl-19-nor-pregna-1,3,5(10),6,8,14-hexae-
ne-3,17a,21-triol-20-one 21-acetate;
4) 6-difluoromethyl-19-nor-pregna-1,3,5(10),6,~,14-
hexaene-3,17a,21-triol-20-one 21-a~etate;
5) 6-trifluoromethyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 21-acetate;
6) 19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,16a,17a,21-
tetrol-20-one 16,21-diacetate;
rz333~7
- 41 -
7) 6-fluoro-16a,17a-isopropylidenedioxy-19-nor-pregna-
1,3,5(10),6,8,14-hexaene-3,21-diol-20-one 21-ace-ta-te;
8) 6-fluoro-16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 21-acetate;
9) 6-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-
3,17a~21-triol-20-one 21-acetate,
10~ 6,16B-dimethyl-19-nor pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 21-acetate.
EXAMPLE 18
10 ALTERNATE PREPARAT_ON OF 16a-METHYL-l9-NOR-PREGNA~
1,3,5(10),_.8~14-HEXAENE-3,17a,21-TRIOL-20-ONE 21-ACETATE
To a solution of 9a,11~-dichloro-16a-methyl-1,4-pregna-
diene-17a,21-diol-3,20-dione 21-acetate (31 g) in dioxane
(1.8 liters), add a solution of hydrogen chloride gas
(66 g) in dioxane (420 ml) and DDQ (18.75 g). Stir the re-
action mixture on a steam bath for 48 hours, then at room
temperature for 40 hours. Concentrate the reaction mixture
in vacuo to a low volume, then chromatograph the resultant
residue over alumina (activity V), eluting with etheru
Evaporate the combined eluates and recrystallize the result-
ant residue from acetone:hexane, to obtain 16a-methyl-19-nor-
pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-2Q-one 21-
acetate.
EXAMPLE 19
ALTERNATE_PREPARATION OF 16a-METHYL-l9-NOR-PREGNA-
1~3~5(10)~6~8,14-HEXAENE-3.17a~21-TRIOL-20-ONE 3,21-DIACETATE
To a solution of 16a-methyl-pregna-1,4,6,8,14-pentaene-
3;~
- 42 -
17a,21-diol-3,20-dione 21-acetate (0.075 g) and lithium
chloride (0.075 g) in dimethylformamide (2 ml), add one
drop of concentrated hydrochloric acid and reflux for
half hour, then remove the solvent in vacuo, dissolve the
residue in a small amount of acetone, and add a large
quantity of water. Purify the resulting product by thin~
layer chromatography, elution of the least polar band with
acetone and removal of the solvent. Treat for 16 hours
with puridine (1 ml) and acetic anhydride (0.5 ml), add
water, and recrystallize the resulting precipitate from
acetone/hexane, to obtain 16a-methyl-19-nor-pregna-
1,3,5~10),6,8,14-hexaene-3,17a,21-triol-20-one 3,21-
diacetate.
The following Formulations examplify some of the
- dosage forms in which the ànti-mitotic agents may be
employed. In each Formulation, the active ingredient is
16-methyl-l9-nor-pregna-1,3,5(10)96,8,14-hexaene-3,17a,21-
triol-20-one 21-acetate. It will be appreciated, however,
that this compound is but a representative example and may
be replaced by equivalent quantities of other active com-
pounds, e.g. by its 3-acetate, 3-benzoate or 15-chloro
derivative.
2~33~7
- a3 _
FOR~IULAT~OMS
Formulation I: Ointmen-t
Formula
16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 21-acetate,
micronized 1.0 - 20.0 mg
Benzyl alcohol, ~F* 10.0 mg
Mineral oil, USP 50.0 mg
White petrolatum, USP, to make 1.0 g
Procedure
Mix and heat to 65C a weighed quantity of white petrolatum,
mineral oil, benzyl alcohol, and cool to 50-55 C with stir-
ring. Disperse active ingredient in a portion of the mineral
oil and then add to the above mixture with stirring. Cool to
room temperature.
Formulation II: Cream
Formula
16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 21-acetate 1.0 - 20.0 mg
Stearic acid, USP 60.0 mg
Glyceryl monostearate, cosmetic grade 100.0 mg
Propyleneglycol, USP 50.0 mg
Polyethylene-sorbitan monopalmitate 50.0 mg
Sorbitol solution, USP 30.0 mg
Benzyl alcohol, NF 10.0 mg
Purified water, USP, to make 1.0 g
Procedure
Heat the stearic acid, glyceryl monostearate and polyethyle-
ne-sorbitan monopalmitate to 70 C. In a separate vessel, dis-
-solve sorbitol solution, benzyl alcohol, water, and half
quantity of propylene-glycol and heat to 70 C. Add the
*) this refers to the requirements of the (U.S.) National
Formulary
;}3~
- ~4 ~
aqueous phase to the oily phase with high-speed stirring,
allow resulting emulsion to gradually cool. Dissolve ac-tive
ingredient in remaining quantity of propyleneglycol and add
resulting solution to -the above emulsion when the kempera-
ture of the latter is 37 - 40C. Mix uniformly with stirring
and cool to room temperature.
Formulation III: Gel
Formula
16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 21-acetate1.0 - 20.0 mg
Propyleneglycol, USP 300.0 mg
3,5-di-(tert.-butyl)-4-hydroxy-toluene
(I~butylated hydroxytoluenel')5.0 mg
Carbomer 940* 5.0 mg
Sodium hydroxide (added as a 1 ~ w~w
solution in propyleneglycol 0.7 mg
Polyethyleneglycol 400 (PEG~8*), USP 669.3 - 688.3 mg
Procedure
Prepare a 1 % solution of the sodium hydroxide in propylene-
glycol and set aside. Separately, mix approximat`ely one-half
the remaining propyleneglycol and the polyethyleneglycol 400 r
then dissolve the butylated hydroxy-toluene in this mixture.
Disperse the Carbomer 940 in the foregoing mixture with vi-
gorous agitation, then add the sodium hydroxide solution with
high-speed agitation to bring the pH of the solution up to 7.
Continue stirring until a thick gel forms. Dissolve the acti-
ve ingredient in the remaining propyleneglycol and add the
resulting solution to the gel slowly, with continuous stir-
ring.
*) see CTFA Dictionary
~333~
-45 ~
Formulation IV: Lotion
Formula
16a-Methyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 2l-ace-tate 1.0 - 20.0 mg
Carbomer 940 (G.W. Goodrich) 3.0 mg
Sodium hydroxide (charged as 4 % w/w
aqueous solution) 0.05 mg
Isopropanol 40.00 mg
Purified wa-ter, USP, to make 1.0 g
Procedure
Prepare 4 % aqueous sodium hydroxide solution and hold. Heat
the purified water to 60C, add Carbomer 940, and mix at
high speed until dispersed. Cool dispersion to room tempe-
rature and slowly charge sodium hydroxide solution until
uniform. Add 80 % of the isopropanol to the above with mix-
ing. Dissolve active ingredient in remaining isopropanol
and add to mixture with stirring. Adjust pH to 5.0 to 5.5
with further sodium hydroxide, if necessary.
Formulation V: Tablets
Formula 10 mg Tab. 25 mg Tab. 100 mg Tab.
16~-Methyl-l~-nor-
pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-
20-one 21-acetate 10.5* mg 26.25* mg 105.0* mg
Lactose, impalpable
powder 197.50 mg 171.25 mg126.00 mg
Corn starch25.00 mg 25.00 mg35.00 mg
Polyvinylpyrrolidone7.50 mg 7.50 mg 7.50 mg
Magnesium stearate 2.50 mg 2.50 mg 3.50 mg
* 5 % excess
Procedure
Prepare a slurry consisting of active ingredient, lactose
and polyvinylpyrrolidone. Spray dry the slurry. Add the
corn starch and magnesium stearate. Mix and compress into
tablets.
~33~
- 96 -
Formulation VI: _arenteral Compo~sitions
A. _n ramuscular or Subcutaneous Oil Injection
Formula
16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 21-aceta-te 1 - 20 mg
Aluminium monostearate, USP 20.0 mg
Propyl-PARABEN (trademark), USP 1.O mg
Sesame oil, USP (heat treated), to make 1.0 ml
- Procedure
The other ingredients are dissolved in sesame oil and
brought to a total volume of 1 ml.
B. Intramuscular or Subcutaneous Aqueous Suspensi-on
Formula
16a-Methyl-19-nor-pregna-1,3,5(10),6,8,14-
hexaene-3,17a,21-triol-20-one 21-acetate 1 - 20 mg
Monobasic sodium phosphate 6.0 mg
Dibasic sodium phosphate, anhydrous 0.5 mg
Polysorbate 80*, USP 0.05 mg
Benzyl alcohol, reagent grade 9.0 mg
Methyl-PARABEN, USP 1.3 mg
Propyl-pARABEN~ USP 0.2 mg
Sodium chloride, USP 2.5 mg
Sodium carboxymethylcellulose, USP 3.0 mg
Eth~lenediamine-te-tracetate, disodium salt, USP 0.1 mg
Water for injection, USP, to make 1.0 ml
Procedure
The other ingredients are dissolved in water and brought
to a total volume of 1 ml.
*) see CTFA Dictionary
