CA1123337A - Anti-mitotic pharmaceutical compositions - Google Patents
Anti-mitotic pharmaceutical compositionsInfo
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- CA1123337A CA1123337A CA374,650A CA374650A CA1123337A CA 1123337 A CA1123337 A CA 1123337A CA 374650 A CA374650 A CA 374650A CA 1123337 A CA1123337 A CA 1123337A
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- pregna
- hexaene
- methyl
- triol
- acetate
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Abstract
ABSTRACT OF THE DISCLOSURE
An anti-mitotic pharmaceutical composition comprises.
(a) as an active ingredient, an anti-mitotic effective amount of the 21-acetate or 3,21-diacetate of 19-nor-pregna-1,3,5(10)-6,8,14-hexaene-3,17.alpha.,21-triol-20-one, or a mixture thereof, together with (b) a non-toxic, pharmaceutically acceptable carrier. The pharmaceutical composition of the invention is particularly useful in treating psoriasis.
An anti-mitotic pharmaceutical composition comprises.
(a) as an active ingredient, an anti-mitotic effective amount of the 21-acetate or 3,21-diacetate of 19-nor-pregna-1,3,5(10)-6,8,14-hexaene-3,17.alpha.,21-triol-20-one, or a mixture thereof, together with (b) a non-toxic, pharmaceutically acceptable carrier. The pharmaceutical composition of the invention is particularly useful in treating psoriasis.
Description
Z33~
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 ~
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 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 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), 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 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.
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.
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 ~
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 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 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), 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 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.
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 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
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 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~
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 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.
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 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~
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 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 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.
EX~PLE 1 16a-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,?1-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-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;
[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~
(~ =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 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.
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 ~
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' 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 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 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 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
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~
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 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.
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 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~
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 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 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.
EX~PLE 1 16a-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,?1-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-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;
[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~
(~ =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).
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_ 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 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.
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 ~
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' 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 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 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 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,$,14-hexaene-3,17a,21-triol-20-one 3,21-dibenzoate;
23 16a-methyl-19-nor-pre~na-1,3,5(10),6,8,14-hexaene--3,17a,21-triol-20-one 3,21-dibenzoate;
3) 16~-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 3,21-diace-tate;
4) 16~-methyl-19-nor-pregna-1,3,5(10),6,$,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.
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~ 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~
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).
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~
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 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~
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).
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).
.
16~-METHyL-l9-NoR-pREGNA-l~3~5(lo)~6~8~l4-HEx~ENE-3~ l7a~
. .
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 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).
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-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.
16a-~ETHYL-19-NOR-PREGNA-1,3,5(10),6,8,14-~E~AENE-3,11~,17a, 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 (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-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, .
-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;
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~
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).
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~
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 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~
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).
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).
.
16~-METHyL-l9-NoR-pREGNA-l~3~5(lo)~6~8~l4-HEx~ENE-3~ l7a~
. .
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 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).
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-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.
16a-~ETHYL-19-NOR-PREGNA-1,3,5(10),6,8,14-~E~AENE-3,11~,17a, 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 (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-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, .
-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;
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 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.
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.
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;~
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~
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
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;
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 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.
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.
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;~
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~
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
Claims (5)
1. An anti-mitotic pharmaceutical composition comprising, (a) as an active ingredient, an anti-mitotic effective amount of the 21-acetate or 3,21-diacetate of 19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17.alpha.,21-trriol-20-one, or a mixture thereof, together with (b) a non-toxic, pharmaceutically acceptable carrier.
2. A pharmaceutical composition according to claim 1 wherein the pharmaceutically acceptable carrier is a carrier for topical application.
3. A pharmaceutical composition according to claim 2, wherein the active ingredient is present in an amount of from 0.0001 to 5% by weight.
4. A pharmaceutical composition according to claim 3, wherein the active ingredient is present in an amount of from 0.1 to 3% by weight.
5. A pharmaceutical composition according to claim 4, wherein the active ingredient is present in an amount of from 0.1 to 1% by weight.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA374,650A CA1123337A (en) | 1977-07-26 | 1981-04-03 | Anti-mitotic pharmaceutical compositions |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81918277A | 1977-07-26 | 1977-07-26 | |
| US819,182 | 1977-07-26 | ||
| CA000307894A CA1118410A (en) | 1977-07-26 | 1978-07-21 | 19-nor-pregnahexaenes, process for the preparation thereof, and pharmaceutical compositions containing them |
| CA374,650A CA1123337A (en) | 1977-07-26 | 1981-04-03 | Anti-mitotic pharmaceutical compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1123337A true CA1123337A (en) | 1982-05-11 |
Family
ID=27165763
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA374,650A Expired CA1123337A (en) | 1977-07-26 | 1981-04-03 | Anti-mitotic pharmaceutical compositions |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1123337A (en) |
-
1981
- 1981-04-03 CA CA374,650A patent/CA1123337A/en not_active Expired
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