CA1118410A - 19-nor-pregnahexaenes, process for the preparation thereof, and pharmaceutical compositions containing them - Google Patents
19-nor-pregnahexaenes, process for the preparation thereof, and pharmaceutical compositions containing themInfo
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- CA1118410A CA1118410A CA000307894A CA307894A CA1118410A CA 1118410 A CA1118410 A CA 1118410A CA 000307894 A CA000307894 A CA 000307894A CA 307894 A CA307894 A CA 307894A CA 1118410 A CA1118410 A CA 1118410A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/005—Ketals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
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Abstract
A B S T R A C T
Disclosed are 16-Nor-pregnahexaenes of the general formula
Disclosed are 16-Nor-pregnahexaenes of the general formula
Description
~118410`
NOVEL l9-NOR-PREGNAHEX~ENES, PROCESS FOR
THE PREPARATION THEREOF, AND PHARMACEUTI-CAL COMPOSITIONS CONTAINING THEM
This invention relates to 19-nor-pregna-1,3,5(10),6,8,14-hexaene-20-ones, to a process for their preparation, and to pharmaceutical compositions containing them.
The invention is based upon the observation that certain 19-nor-pregna-1,3,5(10),6,8,14-hexaene-20-ones, which can be defined by the general formula (I) as set forth hereinbelow, possess anti-mitotic activity with minimal or no hormonal side effects and are~ thus, useful in the treatment of disea-ses characterized by rapid and/or abnormal cell proliferation, particularly in the treatment and control of psoriasis.
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. (1967)~. The thera-peutic activity thereof, or of related compounds r is ~ how-ever, neither disclosed nor suggested by the prior art.
Accordingly, the active compounds of the novel therapeu-tic compositions of the invention are defined by the follo-wing general formula . -- 2 --C--o ~W
~ (I), wherein A is hydrogen, lower alkyl, fluoro or fluoro-sub-stituted methyl;
Rlis hydrogen, lower alkyl, or an acyl radical of a carbo-xylic acid having up to 12 carbon atoms;
W is (H,H); (H, lower alkyl); (H,a-OR2), with R2 being hydrogen or an acyl radical of a carboxylic acid having up to 12 carbon 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 carboxylic acid having up to 12 carbon atoms); hydrogen, provided W is (H,H), or (H, lower alkyl); or together with W representsa 16a,17a-lower alkylidenedioxy grouping;
Y is (H,H), (H,OH), or oxyyen;
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 repre-sents an alkylidenedioxy or alkylorthoalkanoate grouping;
and when Q is hydroxy and R3 is hydrogen, the 17a,20;20,21-bismethylenedioxy derivatives thereof.
Claimed as per-se novel compounds of the invention are the compounds of 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.
Lower alkyl groups included within the definitions of A, Rl and W are preferably those having up to four carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, and tert.-butyl, although higher homologs such as pentyl and hexyl fall within the scope of this invention.
The acyl radicals of carboxylic acids having up to twelve carbon atoms included within the definitions of Rl, R~, R3 and R4 may be saturated or unsaturated, straight-chain or branched-chain aliphatic, cycloaliphatic or cycloaliphatic-aliphatic, aromatic, aryl-aliphatic, or alkyl-aromatic, and may be substituted, e.g., by hydroxy, aryloxy, alkoxy contai-ning from 1 to 5 carbon atoms or halogen. Typical ester groups of the l9-nor-pregnahexaenes of the formulations of our in-vention are thus derived from carboxylic acids such as alka-noic acids exemplified by ac~tic, propionic, trimethylacetic, butyric, isobutyric, valeric, isovaleric f caproic, tert.-butylacetic, enanthic, caprylic, capric, cyclopentylpropionic, undecylic, lauric, and adamantanecarboxylic acids; substitu-ted alkanoic acids such as phenoxyacetic, trifluoroacetic, and ~-chloropropionic and ~-benzoylaminoisobutyric acids;
from aromatic acids including benzoic, toluic, ~-chloroben-zoic, ~-fluorobenzoic, p-methoxybenzoic, and 3',5'-dimethyl-benzoic acids;aryl-alkanoic acids such as phenylacetic and phenylpropionic acids; unsaturated acids such as acrylic and sorbic acids; and dibasic acids such as succinic, tartaric and phthalic acids.
Preferred acyl radicals as defined by Rl, R2, R3 and R4 in for-mula (I) are those derived from lower alkanoic acids, having preferably up to 8 carbon atoms, such as radicals obtained v from acetic, propionic, butyric, valeric, caprylic, caproic, tert.-butylacetic acid and the like, as well as acyl radicals derived from aromatic carboxylic acids having up to 8 carbon atoms, preferably from benzoic acid.
The alkylidene groups contemplated in the compounds of our invention are preferably lower alkylidenes, i.e. hydrocarbon radicals having preferably up to 4 carbon atoms including radicals such as methylene, ethylidene, n-propylidene, iso-propylidene, n-butylidene, and sec.-butylidene.
The l9-nor-pregnahexaene-20-ones of this invention are cry-stalline solids, usually white to off-white in color, which are insoluble in ~ater and soluble in most organic solvents, particularly in acetone, dioxane, dimethylformamide, and di-methylsulfoxide, although of limited solubility in non-polar solvents such as dialkylethers and alkylhydrocarbons.
The l9-nor-pregnahexaene-20-ones of formula (~ exhibit anti-mitotic activity and, in particular, are useful in the treat-ment and control of psoriasis.
Useful l9-nor-pregnahexaene-2Q-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, 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;
16-alkylidene-substituted compounds of formula I such as 16-methylene-19-nor-pregna-1,3,5(10~,6,8,14-hexaene-3,17a,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 useful for the treatment of psoriasis are the 16a-alkyl-su~stituted 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 C=O
~OR4,_CH3 . (II), ~ ~ ' wherein Rl, R3 and R4 are as defined above for formula (I).
Among the compounds of formula (II), particularly useful 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 activi-ty at topical doses as low as 20 micrograms when administered topically to mice in which epidermal mitosis has been stimu-lated 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 derivatives of the latter.
The l9-nor-pregnahexaene-20-ones of formula I are conve-niently 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 solvent (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 9a,11~-dichloro-pregna-1,4-diene-3-one, suitabl-y in situ, at elevated temperatures, by means of DDQ as dehydrogena-ting agent and in the presence of an acid in an aprotic sol-vent). - Isolation 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 l~-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 the respective 15-chloro-19-nor-pregnahexaene-20-ones of formula (I). Thus, for example, reaction of 16a-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 equivalen*s of DDQ yields 15-chloro-16a-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-~romo compounds are ob-tained. - Alternatively, a 15-ch~oro or -bromo substituent may be introduced 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 inven-tion is preferably carried out at room temperature (although temperatures in the range of from about O 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 correspon-ding 15-chloro-14-dehydro compound has been effected. Although, in our process, only a molar equivalent of hydrogen chloride is required per mole of the pregnapentaene-20-one starting compound, we prefer to use large excesses of hydrogen chlori-de (e.g. a saturated solution of hydrogen chloride in dioxane) since the rate of reaction is thereby increased and the pro-cess is completed in thirty minutes or less.
Many of the l9-nor pregna-1,3,5(10),6,8-pentaene-20-one inter-mediates from which the 19-nor-pregnahexaene-20-ones of this invention 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 of 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 pre-sence of lithium chloride. Weak bases useful in this process are pyridine, collidine, lutidine and, preferably, dimethyl-formamide. Other l9-nor-pregnapentaene-20-one intermediates 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),6,8-pentaene-20-one intermediates are also knownin the art and may be pre-pared from the corresponding 9(11)-dehydro derivatives accor-ding 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 may 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 occur when halogenating a 16-methylene-17à-hydroxy-1,4,9(11)-pregnatriene-3,20-dione, one may pro-tect the 17a-hydroxyl function thereof, e.g. by esterifica-tion, after introduction of the 9(11)-double bond. After preparing the corresponding 9a,11~-dichloro derivative of the 17a-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-i~l8410 1,3,5(10),6,8,14-hexaene-~3-ol of formula (I) [e.g. 16-methylene-l9-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-3,17a,21-triol-20-one of this invention [e.g. 16-methylene-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one].
When converting a l9-nor-pregna-1,3,5(10),6,8-pentaene-20-one to the corresponding l9-nor-pregna-1,3,5(10),6,8,14-hexaene-20-one by reaction with DDQ as described hereinabove, 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-alkanoa-tes, usually 21-acetates; the corresponding 21-free-hydroxy compound is then easily obtained from the 21-alkanoate via known hydrolytic procedures, such as with aqueous sodium bi-carbonate in methanol or by utilizing diastase enzyme of malt in aqueous ethanol using known procedures.
In general, when a 21-mono-lower alkanoate or a 17,21-di-lower alkanoate derivative of a 3-~ree-hydroxy)-19-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-:.
~l~B41~
hydroxy)-l9-nor-pregnahexaene-20-one of formula tI) may be prepared by reaction of the respective 17-free-hydroxy com-pound [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 pre-sence of a strong acid (e.g. ~-toluenesulfonic acid) followed by hydrolytic cleavage of the resulting 17a,21-orthoester by means of aqueous acid (e.g. aqueous acetic acid), thence se-paration and isolation of the 17-mono-ester using known tech-niques, usually including chromatographic methods, whereby there is obtained a 17-mono-alkanoate (e.g. the 17-propio-nate). 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 chromatographic techniques.
A 3,17-die~ter derivative of formula (I) is conveniently prepared from a corresponding 3-~ree-hydroxy)-17a,21-ortho-ester (obtainable as described hereinabove) by reaction thereof with an acid anhydride or acid halide in pyridine (e.g. acetic anhydride in pyridine) to form the correspon-ding 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).
The 3,21-diester derivatives of formula (I) are conveniently prepared from the corresponding 21-monoesters; the 3,17a,21-trlesters may be prepared from the corresponding 17a,21- or 3,17a-diesters utilizing conventional esterification techni-ques.
To prepare a 3-monoester derivative of formula (I) it is often necessary to protect the 21-hydroxyl group (e.g. by an 11~8410 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-methoxyethox~-methyl-ammonium chloride in acetonitrile) prior to reaction thereof with a weak base in the presence of lithium chloride to produce the corresponding 3-~free-hydro-xy)-l9-nor-pregna-1,3,5(10),6,8-pentaene-20-one [e.g. lGa-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-20-one 21-methoxyethoxymethyl ether]. Reaction of such 21-protected l9-nor-pregna-1,3,5(10),6,8-pentaene-20-one with DDQ yields the corresponding 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 thereof according to standard esteri-fication procedures (e.g. by reaction with acetic anhydride in pyridine), yields the corresponding 3-monoester deriva-tive. Upon deprotection of the 21-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. 16a-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 conveniently prepared via known etherification 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 deriva-tive is prepared from the corresponding 3-hydroxy-21-mono-ester 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 func-tions at 17 and 21 may be conveniently obtained from a 3-alkoxy-21-monoester derivative via hydrolysis such as with aqueous sodium bicarbonate in methanol. - In order to pre-pare a 3-alkoxy-17-monoester derivative of a compound of formula (I) [e.g. 16a-methyl-19-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 deri-vative of a 3,17a,21-triol of formula (I) according to pro-cedures described hereinabove, followed by reaction thereof with a diazoalkane (e.g. diazomethane) to produce the corre-sponding 3-alkoxy-17a,21-orthoester derivative, followed by cleavage of the 17a,21-orthoester grouping 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 16a,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-hexaene-20-one or at an earlier stage of the synthesis; how-ever, a 17a,21-alkylidenedioxy grouping is preferably intro-duced after 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),6,8,14-hexaene-20-ones of formula (I) may be prepared from the corresponding 16a,17a-di-(free-hydro-xy)- or 17a,21-di-(free-hydroxy)-steroids upon reaction with a ketone or aldehyde (e.g. acetone, acetaldehyde, acetopheno-ne) 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-pre-gnapentaene or l9-nor-pregnahexaene system by known reactions such as that utilizing formaldehyde in the presence of acid.
The following ~xamples illustrate the invention:
16a-METHYL-l9-NOR-PREGNA-1l3,5(10),6,8,14-HEXAENE-3,17a,21-_ A. 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-20-one 21-Acetate To a refluxing solution of lithium chloride (120 g) and concentrated hydrochloric acid (1.8 ml) in dimethylforma-mide (750 ml), add 9a,11~-dichloro-16a-methyl-1,4-pregna-diene-17a,21-diol-3,20-dione 21-acetate (30 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 filtra-lS tion, washthe precipitate with ethyl acetate and air dry, to obtain 16a-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]26 = ~101 (dioxane); ~met [in nm] =
230 (~ =81,100), 258 ( =3600), 26g (=4900), 280 ( =5600), 292 ( =4100), 326 (~=2400), 346 ( ~=8001.
B. 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17~,21-triol-20-one 21-Acetate To a solution of 16a-methyl-19-nor-pregna-1,3,5(10),6,8-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 solution, and then again with 1~8410 water. Evaporate the ethyl acetate solution in vacuo to a small volume and separate the resultant precipitate by filtration, to obtain 16a-methyl-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 filtrate 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]D = ~95 (dioxane), m.p. = 218 - 221C; A methanol [in nm] = 248 (~ =36,000), 257 (~ =46,400), 266 (~ =49,200), 288 (shoulder) ( =13,900), 298 (~ =19,000), 310 (~ =17,900).
OTHER 19-NOR-PREGNA-1,3,5(10),6,8,14-HEXAEME-3,17a,21-TRIOL-A. l9-Nor-pregna-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;
NOVEL l9-NOR-PREGNAHEX~ENES, PROCESS FOR
THE PREPARATION THEREOF, AND PHARMACEUTI-CAL COMPOSITIONS CONTAINING THEM
This invention relates to 19-nor-pregna-1,3,5(10),6,8,14-hexaene-20-ones, to a process for their preparation, and to pharmaceutical compositions containing them.
The invention is based upon the observation that certain 19-nor-pregna-1,3,5(10),6,8,14-hexaene-20-ones, which can be defined by the general formula (I) as set forth hereinbelow, possess anti-mitotic activity with minimal or no hormonal side effects and are~ thus, useful in the treatment of disea-ses characterized by rapid and/or abnormal cell proliferation, particularly in the treatment and control of psoriasis.
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. (1967)~. The thera-peutic activity thereof, or of related compounds r is ~ how-ever, neither disclosed nor suggested by the prior art.
Accordingly, the active compounds of the novel therapeu-tic compositions of the invention are defined by the follo-wing general formula . -- 2 --C--o ~W
~ (I), wherein A is hydrogen, lower alkyl, fluoro or fluoro-sub-stituted methyl;
Rlis hydrogen, lower alkyl, or an acyl radical of a carbo-xylic acid having up to 12 carbon atoms;
W is (H,H); (H, lower alkyl); (H,a-OR2), with R2 being hydrogen or an acyl radical of a carboxylic acid having up to 12 carbon 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 carboxylic acid having up to 12 carbon atoms); hydrogen, provided W is (H,H), or (H, lower alkyl); or together with W representsa 16a,17a-lower alkylidenedioxy grouping;
Y is (H,H), (H,OH), or oxyyen;
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 repre-sents an alkylidenedioxy or alkylorthoalkanoate grouping;
and when Q is hydroxy and R3 is hydrogen, the 17a,20;20,21-bismethylenedioxy derivatives thereof.
Claimed as per-se novel compounds of the invention are the compounds of 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.
Lower alkyl groups included within the definitions of A, Rl and W are preferably those having up to four carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, and tert.-butyl, although higher homologs such as pentyl and hexyl fall within the scope of this invention.
The acyl radicals of carboxylic acids having up to twelve carbon atoms included within the definitions of Rl, R~, R3 and R4 may be saturated or unsaturated, straight-chain or branched-chain aliphatic, cycloaliphatic or cycloaliphatic-aliphatic, aromatic, aryl-aliphatic, or alkyl-aromatic, and may be substituted, e.g., by hydroxy, aryloxy, alkoxy contai-ning from 1 to 5 carbon atoms or halogen. Typical ester groups of the l9-nor-pregnahexaenes of the formulations of our in-vention are thus derived from carboxylic acids such as alka-noic acids exemplified by ac~tic, propionic, trimethylacetic, butyric, isobutyric, valeric, isovaleric f caproic, tert.-butylacetic, enanthic, caprylic, capric, cyclopentylpropionic, undecylic, lauric, and adamantanecarboxylic acids; substitu-ted alkanoic acids such as phenoxyacetic, trifluoroacetic, and ~-chloropropionic and ~-benzoylaminoisobutyric acids;
from aromatic acids including benzoic, toluic, ~-chloroben-zoic, ~-fluorobenzoic, p-methoxybenzoic, and 3',5'-dimethyl-benzoic acids;aryl-alkanoic acids such as phenylacetic and phenylpropionic acids; unsaturated acids such as acrylic and sorbic acids; and dibasic acids such as succinic, tartaric and phthalic acids.
Preferred acyl radicals as defined by Rl, R2, R3 and R4 in for-mula (I) are those derived from lower alkanoic acids, having preferably up to 8 carbon atoms, such as radicals obtained v from acetic, propionic, butyric, valeric, caprylic, caproic, tert.-butylacetic acid and the like, as well as acyl radicals derived from aromatic carboxylic acids having up to 8 carbon atoms, preferably from benzoic acid.
The alkylidene groups contemplated in the compounds of our invention are preferably lower alkylidenes, i.e. hydrocarbon radicals having preferably up to 4 carbon atoms including radicals such as methylene, ethylidene, n-propylidene, iso-propylidene, n-butylidene, and sec.-butylidene.
The l9-nor-pregnahexaene-20-ones of this invention are cry-stalline solids, usually white to off-white in color, which are insoluble in ~ater and soluble in most organic solvents, particularly in acetone, dioxane, dimethylformamide, and di-methylsulfoxide, although of limited solubility in non-polar solvents such as dialkylethers and alkylhydrocarbons.
The l9-nor-pregnahexaene-20-ones of formula (~ exhibit anti-mitotic activity and, in particular, are useful in the treat-ment and control of psoriasis.
Useful l9-nor-pregnahexaene-2Q-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, 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;
16-alkylidene-substituted compounds of formula I such as 16-methylene-19-nor-pregna-1,3,5(10~,6,8,14-hexaene-3,17a,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 useful for the treatment of psoriasis are the 16a-alkyl-su~stituted 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 C=O
~OR4,_CH3 . (II), ~ ~ ' wherein Rl, R3 and R4 are as defined above for formula (I).
Among the compounds of formula (II), particularly useful 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 activi-ty at topical doses as low as 20 micrograms when administered topically to mice in which epidermal mitosis has been stimu-lated 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 derivatives of the latter.
The l9-nor-pregnahexaene-20-ones of formula I are conve-niently 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 solvent (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 9a,11~-dichloro-pregna-1,4-diene-3-one, suitabl-y in situ, at elevated temperatures, by means of DDQ as dehydrogena-ting agent and in the presence of an acid in an aprotic sol-vent). - Isolation 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 l~-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 the respective 15-chloro-19-nor-pregnahexaene-20-ones of formula (I). Thus, for example, reaction of 16a-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 equivalen*s of DDQ yields 15-chloro-16a-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-~romo compounds are ob-tained. - Alternatively, a 15-ch~oro or -bromo substituent may be introduced 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 inven-tion is preferably carried out at room temperature (although temperatures in the range of from about O 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 correspon-ding 15-chloro-14-dehydro compound has been effected. Although, in our process, only a molar equivalent of hydrogen chloride is required per mole of the pregnapentaene-20-one starting compound, we prefer to use large excesses of hydrogen chlori-de (e.g. a saturated solution of hydrogen chloride in dioxane) since the rate of reaction is thereby increased and the pro-cess is completed in thirty minutes or less.
Many of the l9-nor pregna-1,3,5(10),6,8-pentaene-20-one inter-mediates from which the 19-nor-pregnahexaene-20-ones of this invention 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 of 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 pre-sence of lithium chloride. Weak bases useful in this process are pyridine, collidine, lutidine and, preferably, dimethyl-formamide. Other l9-nor-pregnapentaene-20-one intermediates 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),6,8-pentaene-20-one intermediates are also knownin the art and may be pre-pared from the corresponding 9(11)-dehydro derivatives accor-ding 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 may 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 occur when halogenating a 16-methylene-17à-hydroxy-1,4,9(11)-pregnatriene-3,20-dione, one may pro-tect the 17a-hydroxyl function thereof, e.g. by esterifica-tion, after introduction of the 9(11)-double bond. After preparing the corresponding 9a,11~-dichloro derivative of the 17a-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-i~l8410 1,3,5(10),6,8,14-hexaene-~3-ol of formula (I) [e.g. 16-methylene-l9-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-3,17a,21-triol-20-one of this invention [e.g. 16-methylene-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one].
When converting a l9-nor-pregna-1,3,5(10),6,8-pentaene-20-one to the corresponding l9-nor-pregna-1,3,5(10),6,8,14-hexaene-20-one by reaction with DDQ as described hereinabove, 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-alkanoa-tes, usually 21-acetates; the corresponding 21-free-hydroxy compound is then easily obtained from the 21-alkanoate via known hydrolytic procedures, such as with aqueous sodium bi-carbonate in methanol or by utilizing diastase enzyme of malt in aqueous ethanol using known procedures.
In general, when a 21-mono-lower alkanoate or a 17,21-di-lower alkanoate derivative of a 3-~ree-hydroxy)-19-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-:.
~l~B41~
hydroxy)-l9-nor-pregnahexaene-20-one of formula tI) may be prepared by reaction of the respective 17-free-hydroxy com-pound [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 pre-sence of a strong acid (e.g. ~-toluenesulfonic acid) followed by hydrolytic cleavage of the resulting 17a,21-orthoester by means of aqueous acid (e.g. aqueous acetic acid), thence se-paration and isolation of the 17-mono-ester using known tech-niques, usually including chromatographic methods, whereby there is obtained a 17-mono-alkanoate (e.g. the 17-propio-nate). 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 chromatographic techniques.
A 3,17-die~ter derivative of formula (I) is conveniently prepared from a corresponding 3-~ree-hydroxy)-17a,21-ortho-ester (obtainable as described hereinabove) by reaction thereof with an acid anhydride or acid halide in pyridine (e.g. acetic anhydride in pyridine) to form the correspon-ding 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).
The 3,21-diester derivatives of formula (I) are conveniently prepared from the corresponding 21-monoesters; the 3,17a,21-trlesters may be prepared from the corresponding 17a,21- or 3,17a-diesters utilizing conventional esterification techni-ques.
To prepare a 3-monoester derivative of formula (I) it is often necessary to protect the 21-hydroxyl group (e.g. by an 11~8410 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-methoxyethox~-methyl-ammonium chloride in acetonitrile) prior to reaction thereof with a weak base in the presence of lithium chloride to produce the corresponding 3-~free-hydro-xy)-l9-nor-pregna-1,3,5(10),6,8-pentaene-20-one [e.g. lGa-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-20-one 21-methoxyethoxymethyl ether]. Reaction of such 21-protected l9-nor-pregna-1,3,5(10),6,8-pentaene-20-one with DDQ yields the corresponding 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 thereof according to standard esteri-fication procedures (e.g. by reaction with acetic anhydride in pyridine), yields the corresponding 3-monoester deriva-tive. Upon deprotection of the 21-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. 16a-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 conveniently prepared via known etherification 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 deriva-tive is prepared from the corresponding 3-hydroxy-21-mono-ester 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 func-tions at 17 and 21 may be conveniently obtained from a 3-alkoxy-21-monoester derivative via hydrolysis such as with aqueous sodium bicarbonate in methanol. - In order to pre-pare a 3-alkoxy-17-monoester derivative of a compound of formula (I) [e.g. 16a-methyl-19-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 deri-vative of a 3,17a,21-triol of formula (I) according to pro-cedures described hereinabove, followed by reaction thereof with a diazoalkane (e.g. diazomethane) to produce the corre-sponding 3-alkoxy-17a,21-orthoester derivative, followed by cleavage of the 17a,21-orthoester grouping 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 16a,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-hexaene-20-one or at an earlier stage of the synthesis; how-ever, a 17a,21-alkylidenedioxy grouping is preferably intro-duced after 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),6,8,14-hexaene-20-ones of formula (I) may be prepared from the corresponding 16a,17a-di-(free-hydro-xy)- or 17a,21-di-(free-hydroxy)-steroids upon reaction with a ketone or aldehyde (e.g. acetone, acetaldehyde, acetopheno-ne) 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-pre-gnapentaene or l9-nor-pregnahexaene system by known reactions such as that utilizing formaldehyde in the presence of acid.
The following ~xamples illustrate the invention:
16a-METHYL-l9-NOR-PREGNA-1l3,5(10),6,8,14-HEXAENE-3,17a,21-_ A. 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-20-one 21-Acetate To a refluxing solution of lithium chloride (120 g) and concentrated hydrochloric acid (1.8 ml) in dimethylforma-mide (750 ml), add 9a,11~-dichloro-16a-methyl-1,4-pregna-diene-17a,21-diol-3,20-dione 21-acetate (30 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 filtra-lS tion, washthe precipitate with ethyl acetate and air dry, to obtain 16a-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]26 = ~101 (dioxane); ~met [in nm] =
230 (~ =81,100), 258 ( =3600), 26g (=4900), 280 ( =5600), 292 ( =4100), 326 (~=2400), 346 ( ~=8001.
B. 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17~,21-triol-20-one 21-Acetate To a solution of 16a-methyl-19-nor-pregna-1,3,5(10),6,8-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 solution, and then again with 1~8410 water. Evaporate the ethyl acetate solution in vacuo to a small volume and separate the resultant precipitate by filtration, to obtain 16a-methyl-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 filtrate 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]D = ~95 (dioxane), m.p. = 218 - 221C; A methanol [in nm] = 248 (~ =36,000), 257 (~ =46,400), 266 (~ =49,200), 288 (shoulder) ( =13,900), 298 (~ =19,000), 310 (~ =17,900).
OTHER 19-NOR-PREGNA-1,3,5(10),6,8,14-HEXAEME-3,17a,21-TRIOL-A. l9-Nor-pregna-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-1,4-pregnadiene-17a,21-diol-3,20-dione 17,21-di-n-butyrate;
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 that 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]D6 = +122 (Chloroform)i ~ methanol [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-1,3,5(10),6,8-pentaene-3,17a,21-triol-20-one 17,21-di-n-butyrate; m.p. =
200 - 202C, [a]D6 = -15 (dioxane); ~ meax nol [in nm] = 228 ( =67,000), 257 ( =4,000),268 (~ =5,100), 279 (~ =5,700), 290 ( =4,000), 325 (~ =2,300), 340 (~ =2,700)i 3) 19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-20-one 21-acetate; m.p. = 185 - 190C, [a]D = +91 f ) ~ methanol lin nm~ = 229 (~ =66 400~
258 (~ =3,600), 268 ( =4,900), 281 (~ =5,700), 291 (~ =4,200), 327 (~ =2,600), 340 (~ =3,100).
B. l9-Nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one Derivatives In a manner similar to that described in ~xample lB, treat each of the l9-nor-pregna-1,3,5(10),6,8-pentaenes obtainable from Example 2A with DDQ in dioxane and iso-late and purify each of the resultant products in a manner similar to that described,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]26 = +95 (chloroform); A max [in nm] = 253 ( =51,300), 262 ( =51,800), 284 (~ =13,400), 295 ( =18,100), 306 ( =16,800), 327 (~ =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. =
188 - 190C, [a]D6 = -201 (chloroform); ~ mmathan tin nm] = 246 (~ =38,700), 255 ( =51,300), 264 ~1 (~ =51,300), 287 (~ =15,300), 297 (~ =20,000), 309 (~ =18,700), 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 - 216C, [a]D6 = -30 (dioxane), ~mmax ~in nm] = 245 (~ =38,000), 253 (~ =49,g00), 262 (~ =46,700), 286 (~ =13,300), 295 (~ =17,900), 307 (~ =16,500), 338 ( =2,000), 355 (~ =1,600).
3-ALKOXY DERIV~TIVES OF l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXA~NE-3,17a,21-TRIOL-20-ONES
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-pregna-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 of 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 (4:1). Remove the band containing the desired product (as visualized under ultraviolet light) by extraction with ethyl acetate.
Evaporate the ethyl acetate and crystallize the resultant 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 (chloroform)i ~methanol [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).
B. Other 3-Methoxy-l9-nor-pregna-l~3~5(lo)~6~8~l4-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-17a,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 solutions, 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.
19-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,21-TRIOL-20-ONES
A. 16c-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one To a solution of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate (1 gj 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/e-thyl acetate,to obtain 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one; yield = 697 mg; [a]D5 =
-188 (dioxane); m.p. = 220 - 225C; ~ methanol [in nm3 =
246 (~ =35,000), 255 (~ =45,100), 264 ( =45,900), 285 ( =13,800), 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-19-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),6,8,14-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-20-ONES
A. 21-Propionate and 17-Propionate of 16a-Methyl-l9-nor-~egna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one (1) To a solution of 16a-methyl-19-nor-pregna-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 ~1~84iQ
silica gel, eluting with methylene-chloride/ether (19:1). Combine the like early fractions as determi-ned by thin-layer chromatography, evaporate, crystal-lize the resultant residue from ether, and filter,to obtain 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-propionate; yield =
138 mg; m.p. = 218 - 222 C; [a]D = -109 (chloro-form); ~maxhanol [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 obtain 16a-methyl-19-nor-pregna-1,3,5(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-Monoest.e'rs of Other l9-Nor-pregna-1,3,5(10), 6,8,14-hexa-ene-3,17~,21-trio1-20-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 19-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-mllar 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.
.. ~ , .
: . ` . '; ~ ':' ' ' 15-CHLORO-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,21-A. 15-Chloro-16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-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 for 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-pregna-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 (chloroform);
~ max [in nm] = 258 ( =44,700), 266 (E =49,200), 290 (E =12,500), 303 ( =15,000), 315 (~ =14,600), 336 (~ =3,900), 354 ( =2,900).
B Other 15-Chloro-l9-nor-Pregna-1,3,5(10),6,8,14-hexaene-.
3,17a,21-triol-20-ones In similar manner, treat each of the l9-nor-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, 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-1,3,5(10),6,8,14-hexaene-3,17~,21-triol-20-one 21-acetate.
A. 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-19-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]26 = -93 (chloroform);Amethanl [in nm] = 388 ( =29,300), 246 (~ =32,600), 255 (~ =41,360), 264 (~ =41,60n), 283 ( =14,500), 293 (~ =18,000), 306 (~ =16,700), 330 (~ =600).
B. 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-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 3-benzoate 21-acetate;
m.p. = 197 - 202 C; [a]D = -68 (chloroform); ~ maxh nol [in nm] = 238 (~ =39,300), 256 (t =44,800), 265 (~ =45,500), 283 (~ =16,000), 295 (~ =17,900), 307 ( =17,000).
C. 3-Carboxylate Esters of Other 19-Nor-pregna-1,3,5(10), 6 8 14-hexaene Derivatives , (1) In similar manner treat each of the 3-(free-hydroxy)-or 3,21-di-(free-hydroxy)-19-nor-pregna-1,3,5(10), 6,8,14-hexaene compounds obtainable from Examples 2B, 5 and 6 (possibly containing a further 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 each of the 3,17a,21-tri-(free-hydroxy)-19-nor-pregna-1,3,5(10),6,8,14-hexaenes prepared in Example
Isolate and purify each of the resultant products in a manner similar to that 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]D6 = +122 (Chloroform)i ~ methanol [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-1,3,5(10),6,8-pentaene-3,17a,21-triol-20-one 17,21-di-n-butyrate; m.p. =
200 - 202C, [a]D6 = -15 (dioxane); ~ meax nol [in nm] = 228 ( =67,000), 257 ( =4,000),268 (~ =5,100), 279 (~ =5,700), 290 ( =4,000), 325 (~ =2,300), 340 (~ =2,700)i 3) 19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-20-one 21-acetate; m.p. = 185 - 190C, [a]D = +91 f ) ~ methanol lin nm~ = 229 (~ =66 400~
258 (~ =3,600), 268 ( =4,900), 281 (~ =5,700), 291 (~ =4,200), 327 (~ =2,600), 340 (~ =3,100).
B. l9-Nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one Derivatives In a manner similar to that described in ~xample lB, treat each of the l9-nor-pregna-1,3,5(10),6,8-pentaenes obtainable from Example 2A with DDQ in dioxane and iso-late and purify each of the resultant products in a manner similar to that described,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]26 = +95 (chloroform); A max [in nm] = 253 ( =51,300), 262 ( =51,800), 284 (~ =13,400), 295 ( =18,100), 306 ( =16,800), 327 (~ =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. =
188 - 190C, [a]D6 = -201 (chloroform); ~ mmathan tin nm] = 246 (~ =38,700), 255 ( =51,300), 264 ~1 (~ =51,300), 287 (~ =15,300), 297 (~ =20,000), 309 (~ =18,700), 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 - 216C, [a]D6 = -30 (dioxane), ~mmax ~in nm] = 245 (~ =38,000), 253 (~ =49,g00), 262 (~ =46,700), 286 (~ =13,300), 295 (~ =17,900), 307 (~ =16,500), 338 ( =2,000), 355 (~ =1,600).
3-ALKOXY DERIV~TIVES OF l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXA~NE-3,17a,21-TRIOL-20-ONES
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-pregna-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 of 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 (4:1). Remove the band containing the desired product (as visualized under ultraviolet light) by extraction with ethyl acetate.
Evaporate the ethyl acetate and crystallize the resultant 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 (chloroform)i ~methanol [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).
B. Other 3-Methoxy-l9-nor-pregna-l~3~5(lo)~6~8~l4-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-17a,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 solutions, 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.
19-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,21-TRIOL-20-ONES
A. 16c-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one To a solution of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate (1 gj 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/e-thyl acetate,to obtain 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one; yield = 697 mg; [a]D5 =
-188 (dioxane); m.p. = 220 - 225C; ~ methanol [in nm3 =
246 (~ =35,000), 255 (~ =45,100), 264 ( =45,900), 285 ( =13,800), 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-19-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),6,8,14-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-20-ONES
A. 21-Propionate and 17-Propionate of 16a-Methyl-l9-nor-~egna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one (1) To a solution of 16a-methyl-19-nor-pregna-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 ~1~84iQ
silica gel, eluting with methylene-chloride/ether (19:1). Combine the like early fractions as determi-ned by thin-layer chromatography, evaporate, crystal-lize the resultant residue from ether, and filter,to obtain 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-propionate; yield =
138 mg; m.p. = 218 - 222 C; [a]D = -109 (chloro-form); ~maxhanol [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 obtain 16a-methyl-19-nor-pregna-1,3,5(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-Monoest.e'rs of Other l9-Nor-pregna-1,3,5(10), 6,8,14-hexa-ene-3,17~,21-trio1-20-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 19-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-mllar 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.
.. ~ , .
: . ` . '; ~ ':' ' ' 15-CHLORO-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,21-A. 15-Chloro-16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-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 for 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-pregna-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 (chloroform);
~ max [in nm] = 258 ( =44,700), 266 (E =49,200), 290 (E =12,500), 303 ( =15,000), 315 (~ =14,600), 336 (~ =3,900), 354 ( =2,900).
B Other 15-Chloro-l9-nor-Pregna-1,3,5(10),6,8,14-hexaene-.
3,17a,21-triol-20-ones In similar manner, treat each of the l9-nor-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, 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-1,3,5(10),6,8,14-hexaene-3,17~,21-triol-20-one 21-acetate.
A. 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-19-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]26 = -93 (chloroform);Amethanl [in nm] = 388 ( =29,300), 246 (~ =32,600), 255 (~ =41,360), 264 (~ =41,60n), 283 ( =14,500), 293 (~ =18,000), 306 (~ =16,700), 330 (~ =600).
B. 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-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 3-benzoate 21-acetate;
m.p. = 197 - 202 C; [a]D = -68 (chloroform); ~ maxh nol [in nm] = 238 (~ =39,300), 256 (t =44,800), 265 (~ =45,500), 283 (~ =16,000), 295 (~ =17,900), 307 ( =17,000).
C. 3-Carboxylate Esters of Other 19-Nor-pregna-1,3,5(10), 6 8 14-hexaene Derivatives , (1) In similar manner treat each of the 3-(free-hydroxy)-or 3,21-di-(free-hydroxy)-19-nor-pregna-1,3,5(10), 6,8,14-hexaene compounds obtainable from Examples 2B, 5 and 6 (possibly containing a further 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 each 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 of 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;
2) 16a-methyl-19-nor-pregna-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-diacetate;
4) 16~-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 3,21-dibenzoate;
2) 16a-methyl-19-nor-pregna-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-diacetate;
4) 16~-methyl-19-nor-pregna-1,3,5(10),6,8,14-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),6,8,14-hexaene-3,17a,21-triol-20-one 3,21-dibenzoate.
16a-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,21-TRIOL-11,20-DIONE 3-sENzoATE 21-A OE TATE
A. 16a-Methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-11,20-dione 3-Benzoate 21-Acetate To a solution of 9a-bromo-16a-methyl-1,4-pregnadiene-17a,21-diol-3,11,20-trione 21-acetate (30 ~) in pyridine (240 ml~ add benzoyl chloride (60 ml) and heat the reac-~ion 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 graaient.
Combine the like fractions containing the desired pro-duct as determined by thin-layer chromatography, evapo-rate, then crystallize the resultant residue from ether, to obtain 16a-methyl-19-nor-pregna-1,3,5(10),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);
~methanOl ~in nm] = 215 ( =40~600)~ 2 max 314 ( =7,900).
B. 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a, 21-triol-11,20-dione 3-Benzoate 21-Acetate To a solution of 16a-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-11,20-dione 3-ben~oate 21-acetate (10.4 g) in dioxane (S00 ml) add DDQ (13.33 g = 2.4 equi-valents) and heat the reaction mixture at reflux tempe-rature for 48 hours. Then evaporate in 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 1~8410 petroleum ether/ether gradient. Combine the like frac-tions containing the desired product as determined by thin-layer chromatography, 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-~riol-11,20-dione 3-benzoate 21-acetate; m.p. 144 -145C; [a~D6 = +1 (dioxane); ~ methanol [in nm] = 234 ( =37,700), 270 ( =42,900), 277 (shoulder)(~ =40,400), 312 (~ =9,000), 349 (~ =6,000) 365 ~ =5,300).
EXA~PLE 9 16a-METHYL-19-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,21-TRIOL-11,20-DIONE
By sub~ecting 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione 3-benzoate 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 - 165C; [a]D
-107 (dioxane); ~ meax a ol [in nm] = 236 (~ =24,100), 276 ( =34,000), 317 (~ =5,600), 378 (~ =5,700).
OTHER ESTER DERlVATIVES ~F 16a-METHYL-19-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-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione By sub~ecting 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-1~841(~
11,20-dione 17-propionate (25 mg; the residue from the most polar band).
B. 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione3,17,21-Tripropionate To a suspension of 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 ~-toluenesul~onic acid t200 mg) 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); ~ max [in nm] =
233 (~ =26,300), 260 (shoulder) (~ =30,700), 269 ( =36,100), 278 ( =34,800), 316 ( =7,700), 345 (shoul-der) (~ =5,400), 364 (~ =4,600).
C. 16a-Methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione 3,21-Diace'ate 5ubject 16~-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 of Example 7A, to obtain 16a-methyl-lg-nor-pre-gna-1,3,5(10),6,8,14-hexaene-3,17,21-triol-11,20-dione 3,21-diacetate; [a]D6 = -1 (dioxane); ~methanol [in nm~ =
234 (~ =25,900), 269 (~ =33,300), 278 ( =29,300), 315 (~ =7,800), 348 (~ =5,300), 365 (~ =4~700) D . 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione 3,21-Dipropionate Following the procedure of Example 10C, by utilizing an equivalent quantity o~ propionic anhydride instead of acetic anhydride, there is obtained 16a-methyl-19-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); ~mmexhanol [in nm] = 233 ( =24,000), 269 (~=32,700), 279 (shoulder) (~=28,500), 315 (~ =7,100), 349 (~ =5,000), 365 (~--4,300).
16a-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-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-tripropionate (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, 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:
41~) 502 mg). After purification by recrystallization from petroleum ether/ether: [a]26 = -136 (dioxane);
~methanol [in nm] = 237 (~ =30/200), 2~4 (~ =34~000)' 253 (~ =~5,100), 262 (~ =44,200), 281 ~ =16,200), 291 (~ =20,300), 304 (~ =18,500), 328 (~ =900), 344 (~ =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);
~ [in nm] = 236 (shoulder)(~ =28,100), 244 max (~ =33,800), 256 (~ =40,200), 265 (~ =40,200), 287 (shoulder) ( =12,600), 297 (~ =16,400), 308 ( =15,500), 337 (~ =2,700).
6-FLUORO-16a-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3 17a,21-TRIOL-20-ONE 21-ACETATE
A. 6-Fluoro-16a-meth_l-19-nor-pregna-1,3,5(10j,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 aqueous 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-17,21-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 mg; ~a]D = +88.0 (dioxane); m.p. = 238 - 241C;
Amax [in nm] = 238 (~ =50,500), 270 (~ =5,000), 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-3~7a,21-triol-20-one 21-Acetate _ Subject 6-fluoro-16a-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17~,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; ~ mmaexhan [in nm] = 248 (shoulder) ( =36,300), 255 (~ =48,100), 265 ( =49,200), 288 (~ =13,900), 299 (F~=19,500), 311 ( ~=18,500), 342 (~ = 2,100), 359 ( =1,500).
16~-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,11~,17a, 21-TETROL-2 a - ONE 21-ACETATE
. 16~-Methyl-pregna-1,4,6,8-tetraene-11~,17a,21-triol-_,20-dione 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 acetate (10.3 g) and reflux the reaction mixture with stirring for 48 hours. Filter the reaction mixture, evaporate the filtrate in vacuo to a low volume, pour into 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~ ,17a,21-triol-3,20-dione 21-acetate, yield:
1.96 g; m.p. = 175 - 180 C; [a]D = ~786 (pyridine);
~max [in nm] = 230 (shoulder) (~ =10,600), 264 ( =10,000), 388 (~=6,500).
B. 16~-Methyl-l9-nor-pregna-1,3,5(10),6,8-pen-taene-3,11~,17a, 21-tetrol-20-one 21-Acetate To a solution of 16~-methyl-pregna-1,4,6,8-tetraene-11~,17a,21-triol-3,20-dione 21-acetate (850 mg) in tetra-hydrofuran (200 ml) add 1 N hydrochloric acid (20 ml~.
Stir the reaction mixture 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 ~o 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);
~meaxhanol lin nm] = 233 (~ =69,100), 267 ~ =4,800), 278 (~ =5,400), 315 (~ =1,900), 327 (~ =2,300) 340 (~ =2,700).
C. 16~-Methyl-l9-nor-pregna-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-tetrol-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-acetate, yield: 91 mg; m.p. = 185 -195C; A methanol [in nm] = 244 (~ =35,10Q), 254 max ( =44,000), 263 ( =44,000), 285 (shoulder) (~ = 12,400), 295 ( =16,000), 306 (~ =14,90Q), 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-1,4,6,8-tetraene-17a,21-diol-3,11,20-trione 21-Acetate To a solution of 16~-methyl-pregna-1,4,6,8-tetraene-11~,17a,21-triol-3,20-dione 21-acetate (500 mg) in methy-lene chloride (50 ml) add finely powdered manganese dio-xide (5 g), and stir at room temperature for 20 hours.
Separate the manganese dioxide by filtration and wash with methylene chloride. Evaporate the combined ~iltrate and methylene chloride washings and crystallize the resultant 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).
10 B. 16~-Methyl-l9-nor-pre~na-1,3,5(10)',6,8-pentaene-3,17a,21-triol-ll,-2'0-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 DDQ in dioxane and isolate the resultant product in a manner similar to that des'cribed,to obtain 16~-methyl-19-nor-pregna-1,3,5(10),6,8~14-hexaene-3,17a,21-triol-11,20-dione 21-acetate.
16a-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,11~,17a, A. 16a-Methyl-17a,20;20,21-bismethylenedioxy-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, lV
14-hexaene-3,17a,21-triol-11,20-dione (4.3 g) in methy-lene chloride (200 ml) under an atmosphere of nitrogen, add formaldehyde (200 ml, 37 % aqueous 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 with methylene chlori-de, combine the organic layer and the methylene chloride extracts and wash with aqueous sodium bicarbonate, then with water. Evaporate the organic solution and chromato-graph the resultant residue over silica gel,eluting with a petroleum ether/ether 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-methyl-17a,20;20,21-bismethylenedioxy-19-nor-pregna-1,3,5(10), 6,8,14-hexaene-3-ol-11-one.
B. 16a-Methyl-17a,20;20,21-bismethylenedioxy-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,11~-diol Subject 16a-methyl-17a,20;20,21 - bismethylenedioxy-19-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,2a;20~21 - bismethylenedioxy-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,11a-diol (from the combined early fractions) and 16a-methyl-17a,20;20,21-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-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,11~,17a,21-tetrol 20-one Add a suspension of 16a-methyl-17a,20;20,21-bismethylene-dioxy-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,11~-diol (990 mg = 2.5 mmol) to aqueous 45 % hydrofluoric acid t2.5 ml) at 0C and stir the resulting suspension at 0C
for 1.5 hours. Bring the reaction mixture to neutrality by adding aqueous 5 ~ potassium bicarbonate, then extract with ethyl acetate, wash the combined extracts with water and evaporate to a small volume. Separate the re-sultant crystals by filtration and dry, to obtain 16a-methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,11~,17a, 21-tetrol 20-one.
ALTER~ATE PREPARATION OF 16a-METHYL-l9-NOR-PREGNA-1,3,5(10), 6,8,14-HEXAENE-3,11~,17a,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 mixture is at about pH 7, then remove the methanol 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; yield:
44 mg; m.p. = 160 - 163 C; -[a]D6 = -161 (diGxane), A methanol lin nm3 = 263 (shoulder) ~ =24,600), 245 max ~ =31,000), 255 (~ =38,000), 264 (~ =38,700), 286 (shoulder) ( =12,800)l 296 ( =16,200), 308 ( =15,100), 338 (~ =2,700).
OTHER l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,21-TRIOL-A. Other 19-Nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-20-ones In a manner similar to that described in Example lA, ~841~
treat each of the following 9,11~-dihalogeno-1,4-pregna-dienes with lithium chloride in dimethylformamide.
1) 6a~16a-dimethyl-9a~ -dichloro-l~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-lp4-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-16a,17a,21-triol-3,20-dione 16,21-diacetate;
16a-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,21-TRIOL-11,20-DIONE 3-sENzoATE 21-A OE TATE
A. 16a-Methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-11,20-dione 3-Benzoate 21-Acetate To a solution of 9a-bromo-16a-methyl-1,4-pregnadiene-17a,21-diol-3,11,20-trione 21-acetate (30 ~) in pyridine (240 ml~ add benzoyl chloride (60 ml) and heat the reac-~ion 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 graaient.
Combine the like fractions containing the desired pro-duct as determined by thin-layer chromatography, evapo-rate, then crystallize the resultant residue from ether, to obtain 16a-methyl-19-nor-pregna-1,3,5(10),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);
~methanOl ~in nm] = 215 ( =40~600)~ 2 max 314 ( =7,900).
B. 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a, 21-triol-11,20-dione 3-Benzoate 21-Acetate To a solution of 16a-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-11,20-dione 3-ben~oate 21-acetate (10.4 g) in dioxane (S00 ml) add DDQ (13.33 g = 2.4 equi-valents) and heat the reaction mixture at reflux tempe-rature for 48 hours. Then evaporate in 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 1~8410 petroleum ether/ether gradient. Combine the like frac-tions containing the desired product as determined by thin-layer chromatography, 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-~riol-11,20-dione 3-benzoate 21-acetate; m.p. 144 -145C; [a~D6 = +1 (dioxane); ~ methanol [in nm] = 234 ( =37,700), 270 ( =42,900), 277 (shoulder)(~ =40,400), 312 (~ =9,000), 349 (~ =6,000) 365 ~ =5,300).
EXA~PLE 9 16a-METHYL-19-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,21-TRIOL-11,20-DIONE
By sub~ecting 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione 3-benzoate 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 - 165C; [a]D
-107 (dioxane); ~ meax a ol [in nm] = 236 (~ =24,100), 276 ( =34,000), 317 (~ =5,600), 378 (~ =5,700).
OTHER ESTER DERlVATIVES ~F 16a-METHYL-19-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-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione By sub~ecting 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-1~841(~
11,20-dione 17-propionate (25 mg; the residue from the most polar band).
B. 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione3,17,21-Tripropionate To a suspension of 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 ~-toluenesul~onic acid t200 mg) 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); ~ max [in nm] =
233 (~ =26,300), 260 (shoulder) (~ =30,700), 269 ( =36,100), 278 ( =34,800), 316 ( =7,700), 345 (shoul-der) (~ =5,400), 364 (~ =4,600).
C. 16a-Methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione 3,21-Diace'ate 5ubject 16~-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 of Example 7A, to obtain 16a-methyl-lg-nor-pre-gna-1,3,5(10),6,8,14-hexaene-3,17,21-triol-11,20-dione 3,21-diacetate; [a]D6 = -1 (dioxane); ~methanol [in nm~ =
234 (~ =25,900), 269 (~ =33,300), 278 ( =29,300), 315 (~ =7,800), 348 (~ =5,300), 365 (~ =4~700) D . 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione 3,21-Dipropionate Following the procedure of Example 10C, by utilizing an equivalent quantity o~ propionic anhydride instead of acetic anhydride, there is obtained 16a-methyl-19-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); ~mmexhanol [in nm] = 233 ( =24,000), 269 (~=32,700), 279 (shoulder) (~=28,500), 315 (~ =7,100), 349 (~ =5,000), 365 (~--4,300).
16a-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-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-tripropionate (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, 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:
41~) 502 mg). After purification by recrystallization from petroleum ether/ether: [a]26 = -136 (dioxane);
~methanol [in nm] = 237 (~ =30/200), 2~4 (~ =34~000)' 253 (~ =~5,100), 262 (~ =44,200), 281 ~ =16,200), 291 (~ =20,300), 304 (~ =18,500), 328 (~ =900), 344 (~ =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);
~ [in nm] = 236 (shoulder)(~ =28,100), 244 max (~ =33,800), 256 (~ =40,200), 265 (~ =40,200), 287 (shoulder) ( =12,600), 297 (~ =16,400), 308 ( =15,500), 337 (~ =2,700).
6-FLUORO-16a-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3 17a,21-TRIOL-20-ONE 21-ACETATE
A. 6-Fluoro-16a-meth_l-19-nor-pregna-1,3,5(10j,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 aqueous 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-17,21-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 mg; ~a]D = +88.0 (dioxane); m.p. = 238 - 241C;
Amax [in nm] = 238 (~ =50,500), 270 (~ =5,000), 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-3~7a,21-triol-20-one 21-Acetate _ Subject 6-fluoro-16a-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17~,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; ~ mmaexhan [in nm] = 248 (shoulder) ( =36,300), 255 (~ =48,100), 265 ( =49,200), 288 (~ =13,900), 299 (F~=19,500), 311 ( ~=18,500), 342 (~ = 2,100), 359 ( =1,500).
16~-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,11~,17a, 21-TETROL-2 a - ONE 21-ACETATE
. 16~-Methyl-pregna-1,4,6,8-tetraene-11~,17a,21-triol-_,20-dione 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 acetate (10.3 g) and reflux the reaction mixture with stirring for 48 hours. Filter the reaction mixture, evaporate the filtrate in vacuo to a low volume, pour into 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~ ,17a,21-triol-3,20-dione 21-acetate, yield:
1.96 g; m.p. = 175 - 180 C; [a]D = ~786 (pyridine);
~max [in nm] = 230 (shoulder) (~ =10,600), 264 ( =10,000), 388 (~=6,500).
B. 16~-Methyl-l9-nor-pregna-1,3,5(10),6,8-pen-taene-3,11~,17a, 21-tetrol-20-one 21-Acetate To a solution of 16~-methyl-pregna-1,4,6,8-tetraene-11~,17a,21-triol-3,20-dione 21-acetate (850 mg) in tetra-hydrofuran (200 ml) add 1 N hydrochloric acid (20 ml~.
Stir the reaction mixture 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 ~o 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);
~meaxhanol lin nm] = 233 (~ =69,100), 267 ~ =4,800), 278 (~ =5,400), 315 (~ =1,900), 327 (~ =2,300) 340 (~ =2,700).
C. 16~-Methyl-l9-nor-pregna-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-tetrol-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-acetate, yield: 91 mg; m.p. = 185 -195C; A methanol [in nm] = 244 (~ =35,10Q), 254 max ( =44,000), 263 ( =44,000), 285 (shoulder) (~ = 12,400), 295 ( =16,000), 306 (~ =14,90Q), 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-1,4,6,8-tetraene-17a,21-diol-3,11,20-trione 21-Acetate To a solution of 16~-methyl-pregna-1,4,6,8-tetraene-11~,17a,21-triol-3,20-dione 21-acetate (500 mg) in methy-lene chloride (50 ml) add finely powdered manganese dio-xide (5 g), and stir at room temperature for 20 hours.
Separate the manganese dioxide by filtration and wash with methylene chloride. Evaporate the combined ~iltrate and methylene chloride washings and crystallize the resultant 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).
10 B. 16~-Methyl-l9-nor-pre~na-1,3,5(10)',6,8-pentaene-3,17a,21-triol-ll,-2'0-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 DDQ in dioxane and isolate the resultant product in a manner similar to that des'cribed,to obtain 16~-methyl-19-nor-pregna-1,3,5(10),6,8~14-hexaene-3,17a,21-triol-11,20-dione 21-acetate.
16a-METHYL-l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,11~,17a, A. 16a-Methyl-17a,20;20,21-bismethylenedioxy-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, lV
14-hexaene-3,17a,21-triol-11,20-dione (4.3 g) in methy-lene chloride (200 ml) under an atmosphere of nitrogen, add formaldehyde (200 ml, 37 % aqueous 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 with methylene chlori-de, combine the organic layer and the methylene chloride extracts and wash with aqueous sodium bicarbonate, then with water. Evaporate the organic solution and chromato-graph the resultant residue over silica gel,eluting with a petroleum ether/ether 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-methyl-17a,20;20,21-bismethylenedioxy-19-nor-pregna-1,3,5(10), 6,8,14-hexaene-3-ol-11-one.
B. 16a-Methyl-17a,20;20,21-bismethylenedioxy-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,11~-diol Subject 16a-methyl-17a,20;20,21 - bismethylenedioxy-19-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,2a;20~21 - bismethylenedioxy-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,11a-diol (from the combined early fractions) and 16a-methyl-17a,20;20,21-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-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,11~,17a,21-tetrol 20-one Add a suspension of 16a-methyl-17a,20;20,21-bismethylene-dioxy-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,11~-diol (990 mg = 2.5 mmol) to aqueous 45 % hydrofluoric acid t2.5 ml) at 0C and stir the resulting suspension at 0C
for 1.5 hours. Bring the reaction mixture to neutrality by adding aqueous 5 ~ potassium bicarbonate, then extract with ethyl acetate, wash the combined extracts with water and evaporate to a small volume. Separate the re-sultant crystals by filtration and dry, to obtain 16a-methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,11~,17a, 21-tetrol 20-one.
ALTER~ATE PREPARATION OF 16a-METHYL-l9-NOR-PREGNA-1,3,5(10), 6,8,14-HEXAENE-3,11~,17a,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 mixture is at about pH 7, then remove the methanol 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; yield:
44 mg; m.p. = 160 - 163 C; -[a]D6 = -161 (diGxane), A methanol lin nm3 = 263 (shoulder) ~ =24,600), 245 max ~ =31,000), 255 (~ =38,000), 264 (~ =38,700), 286 (shoulder) ( =12,800)l 296 ( =16,200), 308 ( =15,100), 338 (~ =2,700).
OTHER l9-NOR-PREGNA-1,3,5(10),6,8,14-HEXAENE-3,17a,21-TRIOL-A. Other 19-Nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-20-ones In a manner similar to that described in Example lA, ~841~
treat each of the following 9,11~-dihalogeno-1,4-pregna-dienes with lithium chloride in dimethylformamide.
1) 6a~16a-dimethyl-9a~ -dichloro-l~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-lp4-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-16a,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-3,20-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-2Q-one 21-acetate;
3) 6-fluoromethyl-19-nor-pregna-1,3 r 5(10),6,8-pentaene-3,17a,21-triol-20-one 21-acetate;
io:
4) 6-difluoromethyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-20-one 21-acetate;
5) 6-trifluoromethyl-19-nor-pregna-1,3,5(10),6,8-pentae-ne-3,17a,21-triol-20-one 21-acetate;
6) 19-nor-pregna-1,3,5(10),6,8-pentaene-3,16a,17a,21-tetrol-20-one 16,21-diacetate;
7) 6-fluoro-16a,17a-isopropylidenedioxy-19-nor-pregna-1,3,5(10),6,8-pentaene-3,21-diol-20-one 21-acetate;
8) 6-fluoro-16a-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3j17a,21-triol-20-one 21-acetate;
9) 6-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a, 21-triol-20-one 21-acetate;
10) 6,16~-dimethyl-19-nor-pregna~1,3,5(10),6,8-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) 6,16a-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-acetate;
3) 6-fluoromethyl-19-nor-pregna-1,3,5tlO),6,8,14-hexae-ne-3,17a,21-triol-20-one 21-acetate;
4) 6-difluoromethyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate;
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;
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7) 6-fluoro-16a,17a-isopropylidenedioxy-19-nor-preyna-1,3,5(10),6,8,14-hexaene-3,21-diol-20-one 21-acetate;
8) 6-fluoro-16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3l17a,21-triol-20-one 21-acetate;
9) 6-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17al21-triol-20-one 21-acetate;
10) 6,16~-dimethyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate.
. EXAMPLE 18 10 ALTERNATE PREPARATION OF 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 9a,11~-dichloro-16a-methyl-1,~-pregna-diene-17a,21-diol-3j20-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 reaction mixture on a steam bath for 48 hours, then at room tempera-ture for 40 hours. Concentrate the reaction mixture in vacuo to a low volume, then chromatograph the resultant residue over alumina (activity V), eluting with ether. Evaporate the combined eluates and recrystallize the resultant resi-due from acetone:hexane, to obtain 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate.
EXAMpLE 1 9 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 16~-methyl-pregna-1,4,6,8,14-pentae-ne-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 chromatograph~, elution of the least polar band with acetone and removal of the solvent. Treat for 16 hours with pyridine (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 method-of-use aspect of this invention resides in elici-ting a mitotic inhibitory response in a warm-blooded animal having a disease characterized by rapid cell proliferation, which comprises 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 skindiseases, primarily for the treatment of psoriasis via the topical route.
Psoriasis is characterized by increased epidermipoiesis associated with a high mitotic rate, rapid cell turnover and altered keratinization. The psoriatic epidermis can be nor-malized by slowing down cell growth through inhibiting mito-sis. All drugs currently used in psoriasis therapy are 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 therapeu-tic benefit. Anthralin can also cause staining of the skin.
It has now been discovered that compounds according to gene-ral formula (I) ~particularly 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate]
reduce epidermal mitotic acitivty without causing signifi-cant local or systemic hormonal or toxic effects when applied topically to the skin of mice in which epidermal mitosis has been stimulated.
Specifically, when treated b-y a procedure modified from S. Belman and W. Troll, Cancer Research 32:450-454 (1972), the l9-nor-pregnahexaene-20-ones of this invention, particu-larly the 16a-methyl derivatives of formula (II), reduce cro-ton-oil stimulated epidermal 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 estrogens, 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(lQ),6,8,14-hexaene-3,17a,21-triol-20-one of this in-vention is applied topically to the stimulated site, then 24 hours later portions of the treated skin are excised for hlstologic processing, mitotic figures per thousand ~asal interfollicular epidermal cells being counted in a light microscope. Epidermal mitotic counts from treated mice are compared to counts from lesion controls for statistically significant diferences with an analysis of variance. The mitotic count for each compound tested is expressed as per-cent reduction of mitoses compared with the number of mitoses o on the skin of mice treated with croton-oil alone. In gene-ral, it was discovered that the l9-nor-pregnahexaene-20-ones of this invention (formula I) significantly reduce cro-ton-oil stimulated epidermal mitosis. For example, the 15a-methyl-19-nor-pregnahexaene-20-ones of formula (II) usually exhibit over 60 % inhibitions of mitoses at a 2 mg topical dose. 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate (a preferred compound of the invention) exhibits about 80 % reduction of mitosis ~even at a topical dose as low as 0.2 mg) which is approxi-mately 10 times greater than the mitotic reduction exhibited by an equal quantity (i.e. 0.2 mg) of betamethasone dipro-pionate (a known anti-psoriatic agent) in the same animal model.
The anti~mitotic activity is also demonstrated by similar tests in mice whereby increased epidermal mitosis is pro-duced by ultraviolet irradiation according to procedures mo-dified from A. DuVivier and R.B. Stoughton, J. Investigative Dermatology, 65:233-237 (1975). In these tests, it was de monstrated that the 19-nor-pregnahexaene-20-ones of this in-vention, particularly 16a-methyl-19-nor-pregna-1,3,5(10),6,8, 14-hexaene-3,17a,21-triol-20-one 21-acetate, significantly re-duce epidermal mitotic rate following 1, 5 or 9 topical appli-cations (each with 0.02 mg, 0.10 mg, and 0.5 mg doses) to ultraviolet stimulated hairless mouse epidermis, advantageous-ly causing an epidermal thinning effect after multiple appli-cations when the effect became equivalent to that demonstra-ted by steroidal anti-psoriatic agents such as betamethasone valerate. Since the compounds of this invention such as de-fined by formulae (I) and (II) do not cause estrogenic orother hormonal or toxic effects when applied topically as demonstrated by tests in mice, continued applications of a 4iO
l9-nor-pregnahexaene-20-one of this invention will not cause irritation or staining of the skin or skin atrophy as caused by known anti~psoriatic agents. The foregoing mode of anti-psoriatic activity of the l9-nor-pregnahexaene-20-ones of this invention is different from that demonstrated by known steroidal anti-psoriatic agents such as betamethasone vale-rate which, when applied topically to ultraviolet stimulated hairless mouse epidermis at doses equal to those of our 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 mito-ses.
The l9-nor-pregnahexaene-20-ones of this invention, particu-larly 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate, have also been found to ex-hibit anti mitotic activity when a & inistered orally or parenterally to mice, ~-ithout causing significant local or systemic hormonal or toxic effects.
In view of the anti-mitotic and anti-acanthotic (i.e., re-duction of epidermal thickening) activity (as tested in mice), of the l9-nor-pregnahexaene-20-ones of this invention, parti-cularly when applied topically, the invention includes the concept of treating and controlling psoriasis which comprises applying topically to the affected area, in a concentration effective for the treatment of psoriasis, a 19-nor-pregna-hexaene-20-one of formula (I), usefully together with a non-toxic pharmaceutically acceptable carrier. Preferred anti-psoriatic agents of this invention are the 16-methyl-19-nor-pregnahexaene-20-ones, especially the 16a-methyl compounds of formula (II), particularly 16a-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.
i3 i8410 Included within the term "topically applying" are applica-tionsonto the skin surface whereby the compounds of the in-vention are effective in the treatment and control of skin diseases characterized by rapid and/or abnormal cell prolifera-tion, e.g. psoriasis; aerosol application; and subcutaneousinjection application whereby they are effective in the treat-ment of local epidermal disorders.
Conveniently, a pharmaceutical formulation comprising a 19-nor-pregnahexaene-20-one of formula (I), preferably a 16a-methyl compound of formula (II), such as16G-methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-ace-tate, 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 the psoriatic condition has improved. Topical - applications may then be continued at less frequent inter-vals (e.g. once a day) to control mitoses in order to pre-vent return of severe psoriatic conditions. In general, appli-cation is in any topical form including creams, lotions, aerosols and ointments, prepared by combining the active in-gredient with conventional pharmaceutical diluents and car-riers as used in topical formulations comprising steroids;
conveniently in a liquid solvent, preferably in a water-miscible liquid carrier made up of hydrophylic li~uids havinga high solvating action, e.g. a solution of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-ace-tate in polyethyleneglycol.
Thus, the pharmaceutical formulation aspect of this inven-tion resides in the concept of a pharmaceutical composition, preferably for topical application, comprising an anti-psoria-tically effective amount of a l9-nor-pregnahexaene-20-one of ~1184:~0 formula (I) together with a non-toxic pharmaceutically accep-table carrier. Preferred are topical formulations comprising 16a-methyl-19-nor-pregnahexaene-20-ones of formula (II), par-ticularly 16~-methyl derivatives thereof having a free hydro-xyl funetion at C-17, pharmaceutical formulations comprising 16~-methyl-19-nor-pregna-1~3,5(10),6,8,14-hexaene-3,17a-21, triol-20-one 21-acetate being particularly valuable.
The pharmaceutieal formulations may be made according to known procedures, some of which are described in detail here-inbelow. Typical formulations inelude ointments, lotions,ereams, sprays, powders, drops (e.g. ear drops), supposito-ries, and aerosols. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thiekening and/or gelling agents. Such bases may, thus, for example, include water and/or an oil (sueh as liquid paraffin) or a vegetable oil (sueh as peanut oil or castor oil). Thickening agents which may be used according to the nature of the base inelude soft paraffin, aluminium stearate, eetostearyl-aleohol, polyethyleneglycols, woolfat, hydroge-nated lanolin, beeswax, ete. Lotions may be formulated withan aqueous or oily base and will, in general, also include one or more of the following, namely, stabilizing agents, emulsi-fying agents, dispersing agents, suspending agents, thicke-ning agents, coloring agents, perfumes and the like. Powders may be formed with the aid of any suitable powder base, e.g.
tale, lactose, starch, ete. Drops may be formulated with an aqueous base or non-aqueous base, also comprising one or more dispersing agents, suspending agents, solubilizing agents, ete.
The topical pharmaceutical compositions according to the in-vention may also include one or more preservatives or bacte-riostatic agents, e.g. methyl hydroxybenzoate, propyl hydro-xybenzoate, chlorocresol, benzalkonium chloride, etc. They
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-2Q-one 21-acetate;
3) 6-fluoromethyl-19-nor-pregna-1,3 r 5(10),6,8-pentaene-3,17a,21-triol-20-one 21-acetate;
io:
4) 6-difluoromethyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-20-one 21-acetate;
5) 6-trifluoromethyl-19-nor-pregna-1,3,5(10),6,8-pentae-ne-3,17a,21-triol-20-one 21-acetate;
6) 19-nor-pregna-1,3,5(10),6,8-pentaene-3,16a,17a,21-tetrol-20-one 16,21-diacetate;
7) 6-fluoro-16a,17a-isopropylidenedioxy-19-nor-pregna-1,3,5(10),6,8-pentaene-3,21-diol-20-one 21-acetate;
8) 6-fluoro-16a-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3j17a,21-triol-20-one 21-acetate;
9) 6-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a, 21-triol-20-one 21-acetate;
10) 6,16~-dimethyl-19-nor-pregna~1,3,5(10),6,8-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) 6,16a-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-acetate;
3) 6-fluoromethyl-19-nor-pregna-1,3,5tlO),6,8,14-hexae-ne-3,17a,21-triol-20-one 21-acetate;
4) 6-difluoromethyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate;
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;
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7) 6-fluoro-16a,17a-isopropylidenedioxy-19-nor-preyna-1,3,5(10),6,8,14-hexaene-3,21-diol-20-one 21-acetate;
8) 6-fluoro-16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3l17a,21-triol-20-one 21-acetate;
9) 6-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17al21-triol-20-one 21-acetate;
10) 6,16~-dimethyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate.
. EXAMPLE 18 10 ALTERNATE PREPARATION OF 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 9a,11~-dichloro-16a-methyl-1,~-pregna-diene-17a,21-diol-3j20-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 reaction mixture on a steam bath for 48 hours, then at room tempera-ture for 40 hours. Concentrate the reaction mixture in vacuo to a low volume, then chromatograph the resultant residue over alumina (activity V), eluting with ether. Evaporate the combined eluates and recrystallize the resultant resi-due from acetone:hexane, to obtain 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate.
EXAMpLE 1 9 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 16~-methyl-pregna-1,4,6,8,14-pentae-ne-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 chromatograph~, elution of the least polar band with acetone and removal of the solvent. Treat for 16 hours with pyridine (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 method-of-use aspect of this invention resides in elici-ting a mitotic inhibitory response in a warm-blooded animal having a disease characterized by rapid cell proliferation, which comprises 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 skindiseases, primarily for the treatment of psoriasis via the topical route.
Psoriasis is characterized by increased epidermipoiesis associated with a high mitotic rate, rapid cell turnover and altered keratinization. The psoriatic epidermis can be nor-malized by slowing down cell growth through inhibiting mito-sis. All drugs currently used in psoriasis therapy are 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 therapeu-tic benefit. Anthralin can also cause staining of the skin.
It has now been discovered that compounds according to gene-ral formula (I) ~particularly 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate]
reduce epidermal mitotic acitivty without causing signifi-cant local or systemic hormonal or toxic effects when applied topically to the skin of mice in which epidermal mitosis has been stimulated.
Specifically, when treated b-y a procedure modified from S. Belman and W. Troll, Cancer Research 32:450-454 (1972), the l9-nor-pregnahexaene-20-ones of this invention, particu-larly the 16a-methyl derivatives of formula (II), reduce cro-ton-oil stimulated epidermal 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 estrogens, 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(lQ),6,8,14-hexaene-3,17a,21-triol-20-one of this in-vention is applied topically to the stimulated site, then 24 hours later portions of the treated skin are excised for hlstologic processing, mitotic figures per thousand ~asal interfollicular epidermal cells being counted in a light microscope. Epidermal mitotic counts from treated mice are compared to counts from lesion controls for statistically significant diferences with an analysis of variance. The mitotic count for each compound tested is expressed as per-cent reduction of mitoses compared with the number of mitoses o on the skin of mice treated with croton-oil alone. In gene-ral, it was discovered that the l9-nor-pregnahexaene-20-ones of this invention (formula I) significantly reduce cro-ton-oil stimulated epidermal mitosis. For example, the 15a-methyl-19-nor-pregnahexaene-20-ones of formula (II) usually exhibit over 60 % inhibitions of mitoses at a 2 mg topical dose. 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate (a preferred compound of the invention) exhibits about 80 % reduction of mitosis ~even at a topical dose as low as 0.2 mg) which is approxi-mately 10 times greater than the mitotic reduction exhibited by an equal quantity (i.e. 0.2 mg) of betamethasone dipro-pionate (a known anti-psoriatic agent) in the same animal model.
The anti~mitotic activity is also demonstrated by similar tests in mice whereby increased epidermal mitosis is pro-duced by ultraviolet irradiation according to procedures mo-dified from A. DuVivier and R.B. Stoughton, J. Investigative Dermatology, 65:233-237 (1975). In these tests, it was de monstrated that the 19-nor-pregnahexaene-20-ones of this in-vention, particularly 16a-methyl-19-nor-pregna-1,3,5(10),6,8, 14-hexaene-3,17a,21-triol-20-one 21-acetate, significantly re-duce epidermal mitotic rate following 1, 5 or 9 topical appli-cations (each with 0.02 mg, 0.10 mg, and 0.5 mg doses) to ultraviolet stimulated hairless mouse epidermis, advantageous-ly causing an epidermal thinning effect after multiple appli-cations when the effect became equivalent to that demonstra-ted by steroidal anti-psoriatic agents such as betamethasone valerate. Since the compounds of this invention such as de-fined by formulae (I) and (II) do not cause estrogenic orother hormonal or toxic effects when applied topically as demonstrated by tests in mice, continued applications of a 4iO
l9-nor-pregnahexaene-20-one of this invention will not cause irritation or staining of the skin or skin atrophy as caused by known anti~psoriatic agents. The foregoing mode of anti-psoriatic activity of the l9-nor-pregnahexaene-20-ones of this invention is different from that demonstrated by known steroidal anti-psoriatic agents such as betamethasone vale-rate which, when applied topically to ultraviolet stimulated hairless mouse epidermis at doses equal to those of our 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 mito-ses.
The l9-nor-pregnahexaene-20-ones of this invention, particu-larly 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate, have also been found to ex-hibit anti mitotic activity when a & inistered orally or parenterally to mice, ~-ithout causing significant local or systemic hormonal or toxic effects.
In view of the anti-mitotic and anti-acanthotic (i.e., re-duction of epidermal thickening) activity (as tested in mice), of the l9-nor-pregnahexaene-20-ones of this invention, parti-cularly when applied topically, the invention includes the concept of treating and controlling psoriasis which comprises applying topically to the affected area, in a concentration effective for the treatment of psoriasis, a 19-nor-pregna-hexaene-20-one of formula (I), usefully together with a non-toxic pharmaceutically acceptable carrier. Preferred anti-psoriatic agents of this invention are the 16-methyl-19-nor-pregnahexaene-20-ones, especially the 16a-methyl compounds of formula (II), particularly 16a-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.
i3 i8410 Included within the term "topically applying" are applica-tionsonto the skin surface whereby the compounds of the in-vention are effective in the treatment and control of skin diseases characterized by rapid and/or abnormal cell prolifera-tion, e.g. psoriasis; aerosol application; and subcutaneousinjection application whereby they are effective in the treat-ment of local epidermal disorders.
Conveniently, a pharmaceutical formulation comprising a 19-nor-pregnahexaene-20-one of formula (I), preferably a 16a-methyl compound of formula (II), such as16G-methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-ace-tate, 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 the psoriatic condition has improved. Topical - applications may then be continued at less frequent inter-vals (e.g. once a day) to control mitoses in order to pre-vent return of severe psoriatic conditions. In general, appli-cation is in any topical form including creams, lotions, aerosols and ointments, prepared by combining the active in-gredient with conventional pharmaceutical diluents and car-riers as used in topical formulations comprising steroids;
conveniently in a liquid solvent, preferably in a water-miscible liquid carrier made up of hydrophylic li~uids havinga high solvating action, e.g. a solution of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-ace-tate in polyethyleneglycol.
Thus, the pharmaceutical formulation aspect of this inven-tion resides in the concept of a pharmaceutical composition, preferably for topical application, comprising an anti-psoria-tically effective amount of a l9-nor-pregnahexaene-20-one of ~1184:~0 formula (I) together with a non-toxic pharmaceutically accep-table carrier. Preferred are topical formulations comprising 16a-methyl-19-nor-pregnahexaene-20-ones of formula (II), par-ticularly 16~-methyl derivatives thereof having a free hydro-xyl funetion at C-17, pharmaceutical formulations comprising 16~-methyl-19-nor-pregna-1~3,5(10),6,8,14-hexaene-3,17a-21, triol-20-one 21-acetate being particularly valuable.
The pharmaceutieal formulations may be made according to known procedures, some of which are described in detail here-inbelow. Typical formulations inelude ointments, lotions,ereams, sprays, powders, drops (e.g. ear drops), supposito-ries, and aerosols. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thiekening and/or gelling agents. Such bases may, thus, for example, include water and/or an oil (sueh as liquid paraffin) or a vegetable oil (sueh as peanut oil or castor oil). Thickening agents which may be used according to the nature of the base inelude soft paraffin, aluminium stearate, eetostearyl-aleohol, polyethyleneglycols, woolfat, hydroge-nated lanolin, beeswax, ete. Lotions may be formulated withan aqueous or oily base and will, in general, also include one or more of the following, namely, stabilizing agents, emulsi-fying agents, dispersing agents, suspending agents, thicke-ning agents, coloring agents, perfumes and the like. Powders may be formed with the aid of any suitable powder base, e.g.
tale, lactose, starch, ete. Drops may be formulated with an aqueous base or non-aqueous base, also comprising one or more dispersing agents, suspending agents, solubilizing agents, ete.
The topical pharmaceutical compositions according to the in-vention may also include one or more preservatives or bacte-riostatic agents, e.g. methyl hydroxybenzoate, propyl hydro-xybenzoate, chlorocresol, benzalkonium chloride, etc. They
11~8410 may also contain other active ingredients such as antimicro-bial agents, particularly antibiotics.
The inventive concept also includes pharmaceutical formu-lations for oral or parenteral administration, obtainable by standard procedures and comprising an anti-mitotic amount of a l9-nor-pregna-1,3,5(10),6,8,14-hexaene-20-one of formula (I) together with a non-toxic, pharmaceutically acceptable carrier.
The proportion of active steroid in the topical compositions according to the invention 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 proportions 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 parenterally, 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 Formulations exemplify some of the dosage forms in which the anti-mitotic agents of our invention may be employed. In each Formulation, the active ingredient is 16a-methyl-l9-nor-pregna-1,3,5(10),6,8,14-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 compounds of this invention, e.g. by its 3-acetate, 3-benzoate or 15-chloro derivative.
:
FO~ULATIONS
Formulation I: Ointment Formula 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17~,21-triol-20-one 21-acetate, micronized 1.0 - 20.0 mg Benzyl alcohol, NF* 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 50-55C 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-acetate1.0 - 20.0 mg Stearic acid, USP 60.0 mg Glyceryl monostearate, cosmetic grade 100.0 mg Propyleneglycol, USP 50.0 mg Polyethylene-sorbitan monopalmitate50.0 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 70C. 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 - 4~ -aqueous phase to the oily phase with high-speed stirring, allow resulting emulsion to gradually cool. Dissolve active ingredient in remaining quantity of propyleneglycol and add resulting solution to the above emulsion when the tempera-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 ("butylated hydroxytoluene") 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*), USP669.3 - 588.3 mg Procedure Prepare a 1 % solution o~ the sodium hydroxide in propylene-glycol and set aside. Separately, mix approximately one-hal~
the remaining propyleneglycol and the polyethyleneglycol 400, then dissolve the butylated hydroxytoluene 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 o Formulation IV: Lotion 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 Carbomer 940 tG.W. Goodrich) 3.0 mg Sodium hydroxide (charged as 4 ~ w/w aqueous solution) 0.05 mg Isopropanol 40~00 mg Purified water, 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 uni~orm. 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.
16a-Methyl-l9-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 mg171.25 mg126.00 mg Corn starch 25.00 mg 25.00 mg35.00 mg Polyvinylpyrrolidone 7.50 mg 7.50 mg 7.50 mg Magnesium stearate2.50 mg 2.50 mg3.50 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.
Formulation VI: Parenteral Compositions A. Intramuscular 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-acetate 1 - 20 mg Aluminium monostearate, USP 20.0 mg Propyl-PARAsEN (trademark), USP1.O mg Sesame oil, USP (heat treated), to make 1.0 ml Procedure 10 The other ingredients are dissolved in sesame oil and brought to a total volume of 1 ml.
"
B. Intramuscular or Subcutaneous Aqueous Suspension Formula 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate 1 - 20 mg Mono~asic 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 Ethylenediamine-tetracetate, disodium salt, USP 0.1 mg 25 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 Bi ~ ,
The inventive concept also includes pharmaceutical formu-lations for oral or parenteral administration, obtainable by standard procedures and comprising an anti-mitotic amount of a l9-nor-pregna-1,3,5(10),6,8,14-hexaene-20-one of formula (I) together with a non-toxic, pharmaceutically acceptable carrier.
The proportion of active steroid in the topical compositions according to the invention 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 proportions 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 parenterally, 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 Formulations exemplify some of the dosage forms in which the anti-mitotic agents of our invention may be employed. In each Formulation, the active ingredient is 16a-methyl-l9-nor-pregna-1,3,5(10),6,8,14-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 compounds of this invention, e.g. by its 3-acetate, 3-benzoate or 15-chloro derivative.
:
FO~ULATIONS
Formulation I: Ointment Formula 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17~,21-triol-20-one 21-acetate, micronized 1.0 - 20.0 mg Benzyl alcohol, NF* 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 50-55C 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-acetate1.0 - 20.0 mg Stearic acid, USP 60.0 mg Glyceryl monostearate, cosmetic grade 100.0 mg Propyleneglycol, USP 50.0 mg Polyethylene-sorbitan monopalmitate50.0 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 70C. 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 - 4~ -aqueous phase to the oily phase with high-speed stirring, allow resulting emulsion to gradually cool. Dissolve active ingredient in remaining quantity of propyleneglycol and add resulting solution to the above emulsion when the tempera-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 ("butylated hydroxytoluene") 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*), USP669.3 - 588.3 mg Procedure Prepare a 1 % solution o~ the sodium hydroxide in propylene-glycol and set aside. Separately, mix approximately one-hal~
the remaining propyleneglycol and the polyethyleneglycol 400, then dissolve the butylated hydroxytoluene 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 o Formulation IV: Lotion 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 Carbomer 940 tG.W. Goodrich) 3.0 mg Sodium hydroxide (charged as 4 ~ w/w aqueous solution) 0.05 mg Isopropanol 40~00 mg Purified water, 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 uni~orm. 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.
16a-Methyl-l9-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 mg171.25 mg126.00 mg Corn starch 25.00 mg 25.00 mg35.00 mg Polyvinylpyrrolidone 7.50 mg 7.50 mg 7.50 mg Magnesium stearate2.50 mg 2.50 mg3.50 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.
Formulation VI: Parenteral Compositions A. Intramuscular 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-acetate 1 - 20 mg Aluminium monostearate, USP 20.0 mg Propyl-PARAsEN (trademark), USP1.O mg Sesame oil, USP (heat treated), to make 1.0 ml Procedure 10 The other ingredients are dissolved in sesame oil and brought to a total volume of 1 ml.
"
B. Intramuscular or Subcutaneous Aqueous Suspension Formula 16a-Methyl-l9-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate 1 - 20 mg Mono~asic 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 Ethylenediamine-tetracetate, disodium salt, USP 0.1 mg 25 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 Bi ~ ,
Claims (35)
R1 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,.alpha.-OR2), with R2 being hydrogen or an acyl radical of a carboxylic acid having up to 12 carbon 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 carboxylic acid having up to 12 carbon atoms; hydrogen, provided W is (H,H) or (H, lower alkyl); or together with W represents a 16.alpha.,17.alpha.-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 alkylidenedioxy or alkylorthoalkanoate grouping;
and when Q is hydroxy and R3 is hydrogen, the 17.alpha.,20;
20,21-bismethylenedioxy derivatives thereof;
with the exception of the 21-acetate and the 3,21-di-acetate of 19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17.alpha.,21-triol-20-one;
which process comprises a process selected from the fol-lowing processes A to C:
(A) subjecting an appropriate 19-nor-pregna-1,3,5(10),6,8-pentaene derivative to dehydrogenation in position 14(15);
(B) subjecting an appropriate 11-unsubstituted pregna-1,4,6,8,14-pentaene-3-one to aromatization; and (C) subjecting an appropriate 9.alpha., 11.beta.- dihalogeno-pregna-
1,4,6-triene-3-one to concomitant didehydrohalogena-tion and aromatization;
it being understood that aromatization as per (B) and (C) inherently involves removal of the angular methyl at C-10;
the process being followed, if required, by subjecting the resulting 19-nor-pregna-,1,3,5(10),6,8,14-hexaene deri-vative to one or more of the following finishing steps:
(i) de-esterification and/or esterification at hydroxyl functions in one or more of positions 3, 11.beta., 16.alpha., 17.alpha. and 21;
(ii) alkylation and/or dealkylation at the hydroxyl function in position 3;
(iii) introduction or removal of a 16.alpha. , 17.alpha.-or 17.alpha.,21-alkylidenedioxy or of a 17.alpha.,20;20,21-bismethylenedioxy function;
(iv) reduction or oxidation of an 11-oxygen function;
(v) chlorination or bromination in position 15.
it being understood that aromatization as per (B) and (C) inherently involves removal of the angular methyl at C-10;
the process being followed, if required, by subjecting the resulting 19-nor-pregna-,1,3,5(10),6,8,14-hexaene deri-vative to one or more of the following finishing steps:
(i) de-esterification and/or esterification at hydroxyl functions in one or more of positions 3, 11.beta., 16.alpha., 17.alpha. and 21;
(ii) alkylation and/or dealkylation at the hydroxyl function in position 3;
(iii) introduction or removal of a 16.alpha. , 17.alpha.-or 17.alpha.,21-alkylidenedioxy or of a 17.alpha.,20;20,21-bismethylenedioxy function;
(iv) reduction or oxidation of an 11-oxygen function;
(v) chlorination or bromination in position 15.
2 Process according to claim 1(A), wherein the dehydrogena-tion is performed utilizing at least one molar equivalent of 2,3-dichloro-5,6-dicyanobenzoquinone as dehydrogenating agent, in an aprotic solvent.
3. Process according to claim 2, for the preparation of such compounds of formula (I) in which Z is a chlorine or bro-mine atom, wherein the dehydrogenation of the 19-nor-pregna-1,3,5(10),6,8-pentaene starting compound unsub-stituted in position 14 is performed, utilizing at least two molar equivalents of 2,3-dichloro-5,6-dicyanobenzo-quinone, in the presence of at least one molar equivalent of hydrogen chloride or hydrogen bromide, so as to achieve concomitant 15-halogenation.
4. Process according to claim 1(B), wherein the aromatization is performed by means of a weak base, in the presence of a soluble halide salt.
5. Process according to claim 4, wherein the halide salt is lithium chloride and the weak base is dimethylformamide.
6. Process according to claim 1(C), wherein an appropriate 9.alpha.,11.beta.-dichloro-pregna-1,4-diene-3-one is subjected to concomitant 6-dehydrogenation, didehydrochlorination and aromatization.
7. Process according to claim 6, wherein the reactions are performed in situ at elevated temperatures, by means of 2,3-dichloro-5,6-dicyanobenzoquinone as dehydrogenating agent and in the presence of an acid in an aprotic solvent.
8. Process according to claim 1, wherein there is used as starting material an appropriate compound wherein any acyl radicals represented by R1, R3 and/or R4 which may otherwise have all the meanings given in claim 1) have up to 8 carbon atoms and W is (H, .alpha. -methyl).
9. Process according to claim 8, wherein said starting material is subjected to the dehydrogenation of step (A) which is performed utilizing at least one molar equivalent of 2,3-dichloro-5,6-dicyanobenzoquinone as dehydrogenating agent, in an aprotic solvent.
10. Process according to claim 9, for the preparation of such compounds of formula (1) in which 2 is a chlorine or bromine atom, wherein the dehydrogenation of said starting compound unsubstituted in position 14 is performed utilizing at least two molar equivalents of 2,3-dichloro-5,6-dicyanobenzoquinone, in the presence of at least one molar equivalent of hydrogen chloride or hydrogen bromide, so as to achieve concomitant 15-halogenation.
11. Process according to claim 8, wherein said starting material is subjected to the aromatization of step (B) which is performed by means of a weak base, in the presence of a soluble halide salt.
12. Process according to claim 11, wherein the halide salt is lithium chloride and the weak base is dimethylformamide.
13. Process according to claim 8, wherein said starting material is subjected in step (C) to concomitant 6-dehydrogenation, didehydrochlorination and aromatization.
14. Process according to claim 13, wherein the reactions are performed in situ at elevated temperatures by means of 2,3-dichloro-5,6-dicyanobenzoquinone as dehydrogenating agent and in the presence of an acid in an aprotic solvent.
15. Process according to claim 8, wherein there is used as starting material an appropriate compound wherein Q is OR4 (R4 being as defined in claim 8);
each of A and Z is hydrogen;
Y represents (H,H);
any R1 substituent present is as defined in claim 8; and R3 is hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms.
each of A and Z is hydrogen;
Y represents (H,H);
any R1 substituent present is as defined in claim 8; and R3 is hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms.
16. Process according to claim 15, wherein said starting material is subjected to the dehydrogenation of step (A) which is performed utilizing at least one molar equivalent of 2,3-dichloro-5,6-dicyanobenzoquinone as dehydrogenating agent, in an aprotic solvent.
17. Process according to claim 15, wherein said starting material is subjected to the aromatization of step (B) which is performed by means of a weak base, in the presence of a soluble halide salt.
18. Process according to claim 17, wherein the halide salt is lithium chloride and the weak base is dimethylformamide.
19. Process according to claim 15, wherein said starting material is subjected in step (C) to concomitant 6-dehydrogenation, didehydrochlorination and aromatization.
20. Process according to claim 19, wherein the reactions are performed in situ at elevated temperatures, by means of 2,3-dichloro-5,6-dicyanobenzoquinone as dehydrogenating agent and in the presence of an acid in an aprotic solvent.
21. Process according to claim 15, wherein there is used as starting material, 16.alpha.-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17.alpha.,21-triol-20-one 21-acetate.
22. Process according to claim 21, wherein said starting material is subjected to the dehydrogenation of step (A), which is performed utilizing at least one molar equivalent of 2,3-dichloro-5,6-dicyanobenzoquinone as dehydrogenating agent, in an aprotic solvent.
23. 19-Nor-pregnahexaene derivatives of the general formula 1 (I), wherein A is hydrogen, lower alkyl, fluoro or fluoro-substituted methyl;
R1 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,.alpha.-OR2), with R2 being hydrogen or an acyl radical of a carboxylic acid having up to 12 carbon 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 carboxylic acid having up to 12 carbon atoms; hydrogen, provided W is (H,H) or (H, lower alkyl), or together with W represents a 16.alpha.,17.alpha.-iower 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 alkylidenedioxy or alkylorthoalkanoate grouping;
and when Q is hydroxy and R3 is hydrogen, the 17.alpha.,20;
20,21-bismethylenedioxy derivatives thereof;
with the exception of the 21-acetate and the 3,21-di-acetate of 19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17.alpha.,21-triol-20-one, whenever prepared by a process according to claim 1, or by an obvious chemical equivalent thereof.
R1 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,.alpha.-OR2), with R2 being hydrogen or an acyl radical of a carboxylic acid having up to 12 carbon 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 carboxylic acid having up to 12 carbon atoms; hydrogen, provided W is (H,H) or (H, lower alkyl), or together with W represents a 16.alpha.,17.alpha.-iower 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 alkylidenedioxy or alkylorthoalkanoate grouping;
and when Q is hydroxy and R3 is hydrogen, the 17.alpha.,20;
20,21-bismethylenedioxy derivatives thereof;
with the exception of the 21-acetate and the 3,21-di-acetate of 19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17.alpha.,21-triol-20-one, whenever prepared by a process according to claim 1, or by an obvious chemical equivalent thereof.
24. The compounds of the general formula (I) as defined in claim 23, whenever prepared by a process according to claim 2, or by an obvious chemical equivalent thereof.
25. The compounds of the general formula (I) as defined in claim 23, wherein Z is a chlorine or bromine atom, whenever prepared by a process according to claim 3, or by an obvious chemical equivalent thereof.
26 The compounds of the general formula (I) as defined in claim 23, whenever prepared by a process according to claims 4 or 5, or by an obvious chemical equivalent thereof.
27. The compounds of the general formula (I) as defined in claim 23, wherein Z is a chlorine or bromine atom, whenever prepared by a process according to claims 6 or 7, or by an obvious chemical equivalent thereof.
28. The compounds of the general formula (I) as defined in claim 23, wherein A is hydrogen, lower alkyl, fluoro or fluor-substituted methyl; R1 is hydrogen, lower alkyl, or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
W is (H,.alpha.-methyl);
Q is OR4, with R4 being hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms, or hydrogen;
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 8 carbon atoms; or OR3 together with Q represents an alkylidenedioxy or alkylorthoalkanoate grouping;
and when Q is hydroxy and R3 is hydrogen, the 17.alpha.,20;
20,21-bismethylenedioxy derivatives thereof;
whenever prepared by a process according to claims 8 or 9, or by an obvious chemical equivalent thereof.
W is (H,.alpha.-methyl);
Q is OR4, with R4 being hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms, or hydrogen;
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 8 carbon atoms; or OR3 together with Q represents an alkylidenedioxy or alkylorthoalkanoate grouping;
and when Q is hydroxy and R3 is hydrogen, the 17.alpha.,20;
20,21-bismethylenedioxy derivatives thereof;
whenever prepared by a process according to claims 8 or 9, or by an obvious chemical equivalent thereof.
29. The compounds of the general formula (I) as defined in claim 23, wherein A is hydrogen, lower alkyl, fluoro or fluoro-substituted methyl, R1 is hydrogen, lower alkyl, or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
W is (H,.alpha.-methyl);
Q is OR4, with R4 being hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms, or hydrogen;
Y is (H,H), (H, OH), or oxygen;
Z is chlorine or bromine;
R3 is hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms; or R3 together with Q represents an alkylidenedioxy or alkylorthoalkanoate grouping;
and when Q is hydroxy and R3 is hydrogen, the 17.alpha., 20;
20,21-bismethylenedioxy. derivatives thereof;
whenever prepared by a process according to claim 10, or by an obvious chemical equivalent thereof.
W is (H,.alpha.-methyl);
Q is OR4, with R4 being hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms, or hydrogen;
Y is (H,H), (H, OH), or oxygen;
Z is chlorine or bromine;
R3 is hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms; or R3 together with Q represents an alkylidenedioxy or alkylorthoalkanoate grouping;
and when Q is hydroxy and R3 is hydrogen, the 17.alpha., 20;
20,21-bismethylenedioxy. derivatives thereof;
whenever prepared by a process according to claim 10, or by an obvious chemical equivalent thereof.
30. The compounds of the general formula (I) as defined in claim 23, wherein A is hydrogen, lower alkyl, fluoro or fluoro-substituted methyl; R1 is hydrogen, lower alkyl, or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
W is (H, .alpha.-methyl);
Q is OR4, with R4 being hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms, or hydrogen;
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 8 carbon atoms; or OR3 together with Q represents an alkylidenedioxy or alkylorthoalkanoate grouping;
and when Q is hydroxy and R3 is hydrogen, the 17.alpha.,20;
20,21-bismethylenedioxy derivatives thereof;
whenever prepared by a process according to claims 11 or 12, or by an obvious chemical equivalent thereof.
W is (H, .alpha.-methyl);
Q is OR4, with R4 being hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms, or hydrogen;
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 8 carbon atoms; or OR3 together with Q represents an alkylidenedioxy or alkylorthoalkanoate grouping;
and when Q is hydroxy and R3 is hydrogen, the 17.alpha.,20;
20,21-bismethylenedioxy derivatives thereof;
whenever prepared by a process according to claims 11 or 12, or by an obvious chemical equivalent thereof.
31. The compounds of the general formula (I) as defined in claim 23, wherein A is hydrogen, lower alkyl, fluoro or fluoro-substituted methyl;
R1 is hydrogen, lower alkyl, or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
W is (H,.alpha.-methyl);
Q is OR4, with R4 being hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms, or hydrogen;
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 8 carbon atoms; or OR3 together with Q represents an alkylidenedioxy or alkylorthoalkanoate grouping;
and when Q is hydroxy and R3 is hydrogen, the 17 ,20;
20,21-bismethylenedioxy derivatives thereof;
whenever prepared by a process according to claims 13 or 14, or by an obvious chemical equivalent thereof.
R1 is hydrogen, lower alkyl, or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
W is (H,.alpha.-methyl);
Q is OR4, with R4 being hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms, or hydrogen;
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 8 carbon atoms; or OR3 together with Q represents an alkylidenedioxy or alkylorthoalkanoate grouping;
and when Q is hydroxy and R3 is hydrogen, the 17 ,20;
20,21-bismethylenedioxy derivatives thereof;
whenever prepared by a process according to claims 13 or 14, or by an obvious chemical equivalent thereof.
32. The compounds of the general formula (I) as defined in claim 23, wherein each of A and Z is hydrogen;
R1 is hydrogen, lower alkyl or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
W is (H,.alpha.-methyl);
Q is OR4;
Y is (H,H); and each of R3 and R4 is hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
whenever prepared by a process according to claims 15 or 16, or by an obvious chemical equivalent thereof.
R1 is hydrogen, lower alkyl or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
W is (H,.alpha.-methyl);
Q is OR4;
Y is (H,H); and each of R3 and R4 is hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
whenever prepared by a process according to claims 15 or 16, or by an obvious chemical equivalent thereof.
33. The compounds of the general formula (I) as defined in claim 23, wherein each of A and Z is hydrogen;
R1 is hydrogen, lower alkyl or an acyl radical of a carboxylic acid having up to 8 carbon atoms, W is (H,.alpha. -methyl);
Q is OR4;
Y is 1(H, H); and each of R3 and R4 is hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
whenever prepared by a process according to claims 17 or 18, or by an obvious chemical equivalent thereof.
R1 is hydrogen, lower alkyl or an acyl radical of a carboxylic acid having up to 8 carbon atoms, W is (H,.alpha. -methyl);
Q is OR4;
Y is 1(H, H); and each of R3 and R4 is hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
whenever prepared by a process according to claims 17 or 18, or by an obvious chemical equivalent thereof.
34. The compounds of the general formula (I) as defined in claim 23, wherein each of A and Z is hydrogen;
R1 is hydrogen, lower alkyl or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
W is (H,.alpha.-methyl);
Q is OR4;
Y is (H,H); and each of R3 and R4 is hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
whenever prepared by a process according to claims 19 or 20, or by an obvious chemical equivalent thereof.
R1 is hydrogen, lower alkyl or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
W is (H,.alpha.-methyl);
Q is OR4;
Y is (H,H); and each of R3 and R4 is hydrogen or an acyl radical of a carboxylic acid having up to 8 carbon atoms;
whenever prepared by a process according to claims 19 or 20, or by an obvious chemical equivalent thereof.
35. 16.alpha.-Methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17.alpha.,21-triol-20-one 21-acetate, whenever obtained by a process according to claims 21 or 22, or by an obvious chemical equivalent thereof.
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 (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81918277A | 1977-07-26 | 1977-07-26 | |
| US819,182 | 1977-07-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1118410A true CA1118410A (en) | 1982-02-16 |
Family
ID=25227423
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000307894A Expired CA1118410A (en) | 1977-07-26 | 1978-07-21 | 19-nor-pregnahexaenes, process for the preparation thereof, and pharmaceutical compositions containing them |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0000609B1 (en) |
| JP (1) | JPS5424864A (en) |
| AT (1) | ATA532778A (en) |
| AU (1) | AU518819B2 (en) |
| CA (1) | CA1118410A (en) |
| DE (1) | DE2861112D1 (en) |
| DK (1) | DK326478A (en) |
| FI (1) | FI782305A7 (en) |
| GR (1) | GR73119B (en) |
| NO (1) | NO782538L (en) |
| NZ (1) | NZ187926A (en) |
| PT (1) | PT68338A (en) |
| ZA (1) | ZA784081B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4897290A (en) * | 1986-09-26 | 1990-01-30 | Konishiroku Photo Industry Co., Ltd. | Method for manufacturing the substrate for liquid crystal display |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3410879A (en) * | 1967-04-12 | 1968-11-12 | American Home Prod | Process for preparing gonahexaenes |
-
1978
- 1978-07-18 ZA ZA00784081A patent/ZA784081B/en unknown
- 1978-07-20 DE DE7878200112T patent/DE2861112D1/en not_active Expired
- 1978-07-20 EP EP78200112A patent/EP0000609B1/en not_active Expired
- 1978-07-21 CA CA000307894A patent/CA1118410A/en not_active Expired
- 1978-07-21 AU AU38248/78A patent/AU518819B2/en not_active Expired
- 1978-07-21 PT PT68338A patent/PT68338A/en unknown
- 1978-07-21 FI FI782305A patent/FI782305A7/en unknown
- 1978-07-21 DK DK326478A patent/DK326478A/en not_active Application Discontinuation
- 1978-07-21 GR GR56836A patent/GR73119B/el unknown
- 1978-07-21 AT AT0532778A patent/ATA532778A/en not_active Application Discontinuation
- 1978-07-21 NZ NZ187926A patent/NZ187926A/en unknown
- 1978-07-24 JP JP9031978A patent/JPS5424864A/en active Pending
- 1978-07-24 NO NO782538A patent/NO782538L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK326478A (en) | 1979-01-27 |
| GR73119B (en) | 1984-02-03 |
| ATA532778A (en) | 1982-12-15 |
| JPS5424864A (en) | 1979-02-24 |
| PT68338A (en) | 1978-08-01 |
| DE2861112D1 (en) | 1981-12-10 |
| AU518819B2 (en) | 1981-10-22 |
| FI782305A7 (en) | 1979-01-27 |
| NO782538L (en) | 1979-01-29 |
| ZA784081B (en) | 1979-07-25 |
| EP0000609B1 (en) | 1981-09-23 |
| AU3824878A (en) | 1980-01-24 |
| EP0000609A1 (en) | 1979-02-07 |
| NZ187926A (en) | 1980-10-08 |
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| MKEX | Expiry |