EP0000609B1 - 19-Nor pregnahexaènes, procédé pour leur préparation et compositions pharmaceutiques les contenant - Google Patents

19-Nor pregnahexaènes, procédé pour leur préparation et compositions pharmaceutiques les contenant Download PDF

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Publication number
EP0000609B1
EP0000609B1 EP78200112A EP78200112A EP0000609B1 EP 0000609 B1 EP0000609 B1 EP 0000609B1 EP 78200112 A EP78200112 A EP 78200112A EP 78200112 A EP78200112 A EP 78200112A EP 0000609 B1 EP0000609 B1 EP 0000609B1
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Prior art keywords
pregna
methyl
hexaene
triol
acetate
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German (de)
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EP0000609A1 (fr
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Charles Jesse Casmer
Richard William Draper
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MSD International Holdings GmbH
Scherico Ltd
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Scherico Ltd
Technobiotic Ltd
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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
    • 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
    • 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
    • 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

Definitions

  • 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 diseases characterized by rapid and/or abnormal cell proliferation, particularly in the treatment and control of psoriasis.
  • the compounds of formula (I) are novel compounds, although at least one compound embraced by such formula, viz. 19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17 ⁇ ,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 therapeutic activity thereof, or of related compounds, is, however, neither disclosed nor suggested by the prior art.
  • Claimed as per-se 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-3,17 ⁇ ,21-triol-20-one.
  • Lower alkyl groups included within the definitions of A, R, 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.
  • acyl radicals of carboxylic acids having up to twelve carbon atoms included within the definitions of R 1 , R 2 , R 3 and R 4 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 containing from 1 to 5 carbon atoms or halogen.
  • Typical ester groups of the 19-nor-pregnahexaenes of the formulations of our invention are thus derived from carboxylic acids such as alkanoic acids exemplified by acetic, propionic, trimethylacetic, butyric, isobutyric, valeric, isovaleric, caproic, tert.-butylacetic, enanthic, caprylic, capric, cyclopentylpropionic, undecylic, lauric, and adamantanecarboxylic acids; substituted alkanoic acids such as phenoxyacetic, trifluoroacetic, and ⁇ -chloropropionic and ⁇ -benzoylaminoisobu.tyric acids; from aromatic acids including benzoic, toluic, p-chlorobenzoic, p-fluorobenzoic, p-methoxybenzoic, and 3',5'-dimethylbenzoic acids; aryl-alkano
  • Preferred acyl radicals as defined by R 1 , R 2' R 3 and R 4 in formula (1) are those derived from lower alkanoic acids, having preferably up to 8 carbon atoms, such as radicals obtained 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.
  • 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, isopropylidene, n-butylidene, and sec.-butylidene.
  • hydrocarbon radicals having preferably up to 4 carbon atoms including radicals such as methylene, ethylidene, n-propylidene, isopropylidene, n-butylidene, and sec.-butylidene.
  • the 19-nor-pregnahexaene-20-ones of this invention are crystalline solids, usually white to off- white in color, which are insoluble in water and soluble in most organic solvents, particularly in acetone, dioxane, dimethylformamide, and dimethylsulfoxide, although of limited solubility in non-polar solvents such as dialkylethers and alkylhydrocarbons.
  • the 19-nor-pregnahexaene-20-ones of formula (1) exhibit anti-mitotic activity and, in particular, are useful in the treatment and control of psoriasis.
  • Useful 19-nor-pregnahexaene-20-ones of formula (I) include 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate and the 6-methyl, 6-fluoro, 6-difluoromethyl and 6-trifluoro derivatives thereof, as well as the 16-desmethyl analogs and the 16 ⁇ -methyl epimers thereof; 16o;-hydroxy-substituted compounds of formula (l) and ester and 16 ⁇ ,17 ⁇ -alkylidenedioxy derivatives thereof such as 19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,16 ⁇ ,17 ⁇ ,21- tetrol-20-one 16,21-diacetate and 16 ⁇ ,17 ⁇ -isopropylidenedioxy-19-nor-pregna-1,3,5,(10),6,8,14-hexaene-3,21-diol-20-one 21-acetate; 16
  • 16 ⁇ -alkylsubstituted compounds i.e. compounds of formula (I) wherein W is (H, ⁇ -alkyl)
  • preferred compounds being the 16 ⁇ -methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-20-ones of the general formula wherein
  • particularly useful anti-psoriatic agents are those wherein R 4 is hydrogen and, of these, especially those wherein R 3 is hydrogen or acetyl.
  • R 4 is hydrogen
  • R 3 is hydrogen or acetyl.
  • a particularly preferred species is 16 ⁇ -methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17 ⁇ ,21-triol-20-one 21-acetate, which exhibits superior anti-mitotic activity at topical doses as low as 20 micrograms when administered topically to mice in which epidermal mitosis has been stimulated by prior application of croton oil.
  • Further preferred compounds of formula II include the 3-acetate and 3-benzoate ester and the 3-methyl ether derivatives of the former; 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one; and the 21-propionate, 17-propionate and 17,21-di-n-butyrate ester derivatives of the latter.
  • the 19-nor-pregnahexaene-20-ones of formula I are conveniently prepared from the corresponding 19-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.
  • DDQ 2,3-dichloro-5,6-dicyanobenzoquinone
  • aprotic solvent usually dioxane
  • an appropriate 11-unsubstituted pregna-1,4,6,8,14-pentaene-3-one can be subjected to aromatization - e.g.
  • an appropriate 9 ⁇ ,11 ⁇ -dihalogeno-pregna-1,4,6-triene-3-one can be subjected to concomitant didehydrohalogenation and aromatization (a specific embodiment being concomitant 6-dehydrogenation, didehydrochlorination and aromatization of an appropriate 9 ⁇ ,11 ⁇ -dichloro-pregna-1,4-diene-3-one, suitably in situ, at elevated temperatures, by means of DDQ as dehydrogenating agent and in the presence of an acid in an aprotic solvent).
  • - Isolation of the respective 19-nor-pregnahexaene-20- ones is then effected by methods well known in the steroid art.
  • reaction of 16a-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17 ⁇ ,21-triol-20-one 21-acetate in dioxane with at least a molar equivalent of hydrogen chloride and with about two molar equivalents of DDQ yields 15-chloro-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.
  • hydrogen bromide for hydrogen chloride, the respective 15-bromo compounds are obtained.
  • a 15-chloro 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-halosuccinimide), or hydrogen halide in the presence of DDQ.
  • halogenating agents such as molecular chlorine or bromine, or N-halo-imides (e.g. N-halosuccinimide), or hydrogen halide in the presence of DDQ.
  • the foregoing process utilizing hydrogen chloride and DDQ for preparing the 15-chloro- substituted compounds of this invention is preferably carried out at room temperature (although temperatures in the range of from about 0° to 100°C may be employed) and in dioxane (although other aprotic solvents may be used, particularly ethers such as tetrahydrofuran, diethylether and diglyme).
  • room temperature temperatures in the range of from about 0° to 100°C may be employed
  • dioxane although other aprotic solvents may be used, particularly ethers such as tetrahydrofuran, diethylether and diglyme.
  • the reaction is usually complete in 30 minutes as determined by thin layer chromatography, although at lower temperatures it may take up to 24 hours before complete conversion of a 19-nor-pregna-1,3,5(10),6,8-pentaene-20-one to the corresponding 15-chloro-14-dehydro compound has been effected.
  • Weak bases useful in this process are pyridine, collidine, lutidine and, preferably, dimethylformamide.
  • Other 19-nor-pregnapentaene-20-one intermediates may also be prepared from the corresponding 9 ⁇ ,11 ⁇ -dichloro-1,4-pregnadiene-3,20-diones in similar manner.
  • the 9 ⁇ ,11 ⁇ -dichloro-1,4-pregnadiene-17 ⁇ ,21-diol-3,20-dione precursors to the 19-nor-pregna-1,3,5(10),6,8-pentaene-20-one intermediates are also known in the art and may be prepared from the corresponding 9(11)-dehydro derivatives according to procedures such as described in U.S. Patents Nos. 3,894,963 and 3,009,933.
  • the corresponding 9 ⁇ ,11 ⁇ -dichloro derivative of the 17 ⁇ -hydroxy-protected derivative of a 16-methylene-1,4,9(l 11)-pregnatriene-3,20-dione e.g.
  • a 17-mono-lower alkanoate ester derivative of a 3-(free hydroxy)-19-nor-pregnahexaene-20-one of formula (I) may be prepared by reaction of the respective 17-free-hydroxy compound [e.g. 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17 ⁇ ,21-triol-20-one] in an aprotic solvent (e.g. dimethylsulfoxide) with at least one molar equivalent of a tri-lower alkyl orthoester (e.g. triethylortho- propionate) in the presence of a strong acid (e.g.
  • an aprotic solvent e.g. dimethylsulfoxide
  • a tri-lower alkyl orthoester e.g. triethylortho- propionate
  • a 3,17-diester derivative of formula (I) is conveniently prepared from a corresponding 3-(free-hydroxy)-17a,21-orthoester (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 corresponding 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).
  • pyridine e.g. acetic anhydride in pyridine
  • the 3,21-diester derivatives of formula (I) are conveniently prepared from the corresponding 21- monoesters; the 3,17 ⁇ ,21-triesters may be prepared from the corresponding 17 ⁇ ,21- or 3,17a-diesters utilizing conventional esterification techniques.
  • 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).
  • a 3-alkoxy-21- monoester or a 3-alkoxy-17,21 diester derivative is prepared from the corresponding 3-hydroxy-21- monoester or 3-hydroxy-17,21-diester derivative, respectively, by reaction with a diazoalkane in ether.
  • a derivative of formula (I) having a 3-alkoxy group and free hydroxyl functions at 17 and 21 may be conveniently obtained from a 3-alkoxy-21-monoester derivative via hydrolysis such as with aqueous sodium bicarbonate in methanol.
  • a 3-alkoxy-17-monoester derivative of a compound of formula (I) [e.g. 16 ⁇ -methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17 ⁇ ,21-triol-20-one 17-acetate 3-methyl ether] it is preferable to first prepare a 17 ⁇ ,21-orthoester derivative of a 3,17 ⁇ ,21-triol of formula (I) according to procedures described hereinabove, followed by reaction thereof with a diazoalkane (e.g.
  • the 16 ⁇ ,17 ⁇ -alkylidenedioxy function may be introduced into the molecule after preparation of the corresponding 16 ⁇ ,17 ⁇ -di-(free-hydroxy)-19-nor-pregna-1,3,5(10),6,8,14-hexaene-20-one or at an earlier stage of the synthesis; however, a 17a,21-alkylidenedioxy grouping is preferably introduced after preparation of the corresponding 17 ⁇ ,21-di-(free-hydroxy)-19-nor-pregna-1,3,5(10),6,8,14-hexaene-20-one.
  • Both, the 16 ⁇ ,17 ⁇ - and the 17 ⁇ ,21-alkylidenedioxy derivatives of the 19-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-hydroxy)- or l7 ⁇ ,21-di(free-hydroxy)-steroids upon reaction with a ketone or aldehyde (e.g. acetone, acetaldehyde, acetophenone) in the presence of a mineral acid (e.g. hydrochloric acid).
  • a ketone or aldehyde e.g. acetone, acetaldehyde, acetophenone
  • the 17 ⁇ ,20; 20,21- bismethylenedioxy function can be introduced prior to or after introduction of the 19-nor-pregna- pentaene or 19-nor-pregnahexaene system by known reactions such as that utilizing formaldehyde in the presence of acid.
  • Example 2A In a manner similar to that described in Example 1B, treat each of the 19-nor-pregna-1,3,5(10),6,8-pentaenes obtainable from Example 2A with DDQ in dioxane and isolate and purify each of the resultant products in a manner similar to that described, to obtain, respectively,
  • Example 5A By subjecting 16 ⁇ -methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17 ⁇ ,21-triol-11,20-dione (100 mg) to substantially the conditions of Example 5A, there are obtained respectively, 16 ⁇ -methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17 ⁇ ,21-triol-11,20-dione 21-propionate (25 mg; the residue from the least polar band), and 16 ⁇ -methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17 ⁇ ,21-triol-11,20-dione 17-propionate (25 mg; the residue from the most polar band).
  • Example 13C 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 described, to obtain 16 ⁇ -methyl-19-nor-pregna-1,3,5( 10),6,8,14-hexaene-3,17 ⁇ ,21 -trioi-11,20-dione 21-acetate.
  • Example 1A In a manner similar to that described in Example 1A, treat each of the following 9 ⁇ ,11 ⁇ -dihalogeno-1,4-pregnadienes with lithium chloride in dimethylformamide.
  • Example 8B In a manner similar to that described in Example 1B, treat each of the 19-nor-pregna-1,3,5(10),6,8-pentaenes obtainable from Example 8A with DDQ in dioxane and isolate and purify each of the resultant products, to obtain, respectively,
  • the method-of-use aspect of this invention resides in eliciting 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 19-nor-pregnahexaene-20-one of formula (I) defined hereinabove, usually together with a non-toxic, pharmaceutically acceptable carrier, particularly in the treatment and control of proliferative skin diseases, 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 normalized by slowing down cell growth through inhibiting mitosis.
  • 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-fluoroacil, while relatively free of systemic side effects, cause local adverse reactions.
  • corticosteroid therapy causes skin atrophy, telangiectasia and the formation of striae, while anthralin and 5-fluorouracil are skin irritants and require close clinical supervision for optimal therapeutic benefit.
  • Anthralin can also cause staining of the skin.
  • the 19-nor-pregnahexaene-20-ones of this invention when treated by a procedure modified from S. Belman and W. Troll, Cancer Research 32:450-454 (1972), the 19-nor-pregnahexaene-20-ones of this invention, particularly the 16a-methyl derivatives of formula (II), reduce croton-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 19-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.
  • an aromatic A-ring such as in many estrogens
  • a corticoid side chain such as in potent topical anti-inflammatory agents.
  • croton-oil is applied topically to shaved mice, thus accelerating mitosis.
  • a 19-nor-pregna-1,3,5( 10),6,8,14-hexaene.-3,17 ⁇ -,21 -trioi-20-one of this invention is applied topically to the stimulated site, then 24 hours later portions of the treated skin are excised for histologic processing, mitotic figures per thousand basal interfollicular epidermal cells being counted in a light microscope. Epidermal mitotic counts from treated mice are compared to counts from lesion controls for statistically significant differences with an analysis of variance.
  • the mitotic count for each compound tested is expressed as percent reduction of mitoses compared with the number of mitoses on the skin of mice treated with croton-oil alone.
  • the 19-nor-pregnahexaene-20-ones of this invention significantly reduce croton-oil stimulated epidermal mitosis.
  • the 16a-methyl-19-nor-pregnahexaene-20-one of formula (II) usually exhibit over 60% inhibitions of mitoses at a 2 mg topical dose.
  • 16 ⁇ -Methyl-19-nor-pregna-1,3,5(10),6,8;14-hexaene-3,17 ⁇ ,21-triol-20-one 21-acetate exhibits about 80% reduction of mitosis (even at a topical dose as low as 0.2 mg) which is approximately 10 times greater than the mitotic reduction exhibited by an equal quantity (i.e. 0.2 mg) of betamethasone dipropionate (a known anti-psoriatic agent) in the same animal model.
  • mice whereby increased epidermal mitosis is produced by ultraviolet irradiation according to procedures modified from A. DuVivier and R. B. Stoughton, J. investigative Dermatology, 65:233-237 (1975).
  • the 19-nor-pregnahexaene-20-ones of this invention significantly reduce epidermal mitotic rate following 1, 5 or 9 topical applications (each with 0.02 mg, 0.10 mg, and 0.5 mg doses) to ultraviolet stimulated hairless mouse epidermis, advantageously causing an epidermal thinning effect after multiple applications when the effect became equivalent to that demonstrated by steroidal anti-psoriatic agents such as betamethasone valerate.
  • the foregoing mode of anti-psoriatic activity of the 19-nor-pregnahexaene-20-ones of this invention is different from that demonstrated by known steroidal anti-psoriatic agents such as betamethasone valerate which, when applied topically to ultraviolet stimulated hairless mouse epidermis at doses equal to those of our 19-nor-pregnahexaene-20-ones [e.g. 16 ⁇ -methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17 ⁇ ,21-triol-20-one-21-acetate] first cause an epidermal thinning without reduction of mitoses.
  • known steroidal anti-psoriatic agents such as betamethasone valerate which, when applied topically to ultraviolet stimulated hairless mouse epidermis at doses equal to those of our 19-nor-pregnahexaene-20-ones [e.g. 16 ⁇ -methyl-19-nor-pregna-1,3,5(10),6,8,
  • the 19-nor-pregnahexaene-20-ones of this invention have also been found to exhibit anti-mitotic activity when administered orally or parenterally to mice, without causing significant local or systemic hormonal or toxic effects.
  • 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-pregnahexaene-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 16 ⁇ -methyl compounds of formula (II), particularly 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17 ⁇ ,21-triol-20-one 21-acetate and the 3-acetate, 3-benzoate and 15 chloro derivatives thereof.
  • topically applying applications onto the skin surface whereby the compounds of the invention are effective in the treatment and control of skin diseases characterized by rapid and/or abnormal cell proliferation, e.g. psoriasis; aerosol application; and subcutaneous injection application whereby they are effective in the treatment of local epidermal disorders.
  • skin diseases characterized by rapid and/or abnormal cell proliferation, e.g. psoriasis; aerosol application; and subcutaneous injection application whereby they are effective in the treatment of local epidermal disorders.
  • a pharmaceutical formulation comprising a 19-nor-pregnahexaene-20-one of formula (I), preferably a 16a-methyl compound of formula (II), such as 16 ⁇ -methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17 ⁇ ,21-triol-20-one 21-acetate, in a non-toxic pharmaceutically acceptable carrier, usually in concentrations from about 0.0001 percent to about 5 percent, preferably from about 0.1 percent to about one percent, is applied several times daily to skin affected by psoriasis until the psoriatic condition has improved. Topical applications may then be continued at less frequent intervals (e.g.
  • application is in any topical form including creams, lotions, aerosols and ointments, prepared by combining the active ingredient with conventional pharmaceutical diluents and carriers as used in topical formulations comprising steroids; conveniently in a liquid solvent, preferably in a water-miscible liquid carrier made up of hydrophylic liquids having a high solvating action, e.g. a solution of 16 ⁇ -methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17 ⁇ ,21-triol-20-one 21-acetate in polyethyleneglycol.
  • the pharmaceutical formulation aspect of this invention resides in the concept of a pharmaceutical composition, preferably for topical application, comprising an anti-psoriatically effective amount of a 19-nor-pregnahexaene-20-one of formula (I) together with a non-toxic pharmaceutically acceptable carrier.
  • a pharmaceutical composition preferably for topical application, comprising an anti-psoriatically effective amount of a 19-nor-pregnahexaene-20-one of formula (I) together with a non-toxic pharmaceutically acceptable carrier.
  • topical formulations comprising 16 ⁇ -methyl-19-nor-pregnahexaene-20-ones of formula (II), particularly 16a-methyl derivatives thereof having a free hydroxyl function at C-17, pharmaceutical formulations comprising 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17 ⁇ -21;triol-20-one 21-acetate being particularly valuable.
  • Typical formulations include ointments, lotions, creams, sprays, powders, drops (e.g. ear drops), suppositories, and aerosols.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • bases may, thus, for example, include water and/or an oil (such as liquid paraffin) or a vegetable oil (such as peanut oil or castor oil).
  • Thickening agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl-alcohol, polyethyleneglycols, woolfat, hydrogenated lanolin, beeswax, etc.
  • Lotions may be formulated with an aqueous or oily base and will, in general, also include one or more of the following, namely, stabilizing agents, emulsifying agents, dispersing agents, suspending agents, thickening agents, coloring agents, perfumes and the like.
  • Powders may be formed with the aid of any suitable powder base, e.g. talc, lactose, starch, etc.
  • Drops may be formulated with an aqueous base or non-aqueous base, also comprising one or more dispersing agents, suspending agents, solubilizing agents, etc.
  • the topical pharmaceutical compositions according to the invention may also include one or more preservatives or bacteriostatic agents, e.g. methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, etc. They may also contain other active ingredients such as antimicrobial agents, particularly antibiotics.
  • preservatives or bacteriostatic agents e.g. methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, etc.
  • bacteriostatic agents e.g. methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, etc.
  • active ingredients such as antimicrobial agents, particularly antibiotics.
  • inventive concept also includes pharmaceutical formulations for oral or parenteral administration, obtainable by standard procedures and comprising an anti-mitotic amount of a 19-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 %d 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.
  • Formulations exemplify some of the dosage forms in which the anti-mitotic agents of our invention may be employed.
  • the active ingredient is l6 ⁇ -methyl-19-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 1 5-chloro derivative.
  • the other ingredients are dissolved in sesame oil and brought to a total volume of 1 ml.
  • the other ingredients are dissolved in water and brought to a total volume of 1 ml.

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Claims (12)

1. Dérivés de 19-Nor-pregnahexaène de la formule générale:
Figure imgb0030
dans laquelle A représente l'hydrogène, un alcoyle inférieur, un fluoro ou un méthyl fluoro-substitué;
Ri représente l'hydrogène, un alcoyle inférieur, ou un radical acyle d'un acide carboxylique ayant jusqu'à 12, de préférence jusqu'à 8, atomes de carbone;
W représente (H,H); (H, alcoyle inférieur); (H, α-OR2), avec R2 étant l'hydrogène ou un radical acyle d'un acide carboxylique ayant jusqu'à 12, de préférence jusqu'à 8, atomes de carbone; ou = CHT, avec T représentant l'hydrogène, un alcoyle inférieur, du fluor, ou du chlore;
Q représente OR4, avec R4 étant l'hydrogène ou un radical acyle d'un acide carboxylique ayant jusqu'à 12, de préférence jusqu'à 8, atomes de carbone; l'hydrogène, pourvu que W représente (H,H) ou (H, alcoyle inférieur); ou avec W représente un groupement 16α,17α-alcoylidène inférieur dioxy;
Y représente (H,H), (H, OH) ou l'oxygène;
Z représente l'hydrogène, du chlore ou du brome;
R3 représente l'hydrogène ou un radical acyle d'un acide carboxylique ayant jusqu'à 12, de préférence jusqu'à 8, atomes de carbone; ou OR3 avec Q représente un groupement alcoylidènedioxy ou alcoylorthoalcanoate;
et lorsque Q représente un hydroxy et R3 représente l'hydrogène, les dérivés 17cr,20; 20,21- bisméthylènedioxy de ceux-ci;
à l'exception du 21-acétate et du 3,21-diacétate de la 19-Nor-pregna-1,3,5(10),6,8,14-hexaène-3.17α.21-triol-20-one.
2. Compositions pharmaceutiques contenant, comme ingrédient actif, un composé de la formule générale (I), tel que défini à la revendication 1, y compris les composés rapportés dans cette revendication comme étant exceptés.
3. Les composés et compositions des revendications 1 et 2, respectivement, dans lesquelles W dans la formule (I) représente (H, a-méthyle).
4. Les composés et compositions de la revendication 3, dans lesquels
Q représente OR4 (R4 étant tel que défini à la revendication 1);
chacun de A et Z représente l'hydrogène;
Y représente (H,H);
Ri est tel que défini à la revendication 1 ; et
R3 représente l'hydrogène ou un radical acyle d'un acide carboxylique ayant jusqu'à 12, de préférence jusqu'à 8, atomes de carbone.
5. Le l6α-méthyl-19-nor-pregna-1,3,5(10),6,8,14-hexaène-3.,17α,21-triol-20-one 21-acétate, et les compositions pharmaceutiques le contenant.
6. Composition pharmaceutique selon l'une quelconque des revendications 2 à 5, contenant également un support pharmaceutique approprié, pour l'emploi de l'obtention d'une réponse inhibitoire mitotique dans un animal à sang chaud ayant une maladie caractérisée par une prolifération cellulaire rapide, spécialement pour le traitement de psoriasis.
7. Procédé de préparation des dérivés 19-nor-pregnahexaène de la revendication 1, caractérisé en ce que:
(A) un dérivé de 19-nor-pregna-1,3,5(10),6,8-pentaène approprié est soumis à une déshydrogénation en position 14(15); ou
(B) une 11-non-substituée pregna-1,4,6,8,14-pentaène-3-one appropriée est soumise à une aromatisation; ou
(C) une 9α,11β-dihalogéno-pregna-1,4,6-triène-3-one appropriée est soumise à une didéshydrohalogénation et aromatisation concomitante;

étant entendu que l'aromatisation selon (B) et (C) inclut de manière inhérente l'enlèvement du méthyle angulaire en C-10; et le dérivé 19-nor-pregna-1,3,5(10),6,8,14-hexaène résultant, si désiré, est soumis à une ou plusieurs des étapes finales facultatives suivantes:
(i) une dé-estérification et/ou estérification aux fonctions hydroxyle dans une ou plusieurs des positions 3, 1 1 β, 16a, 17a et 21;
(ii) une alcoylation et/ou une déalcoylation à la fonction hydroxyle en position 3;
(iii) l'introduction ou l'enlèvement d'un 16α,17α- ou 17α,21-alcoylidènedioxy ou d'une fonction 17a,20; 20-21-bisméthylènedioxy;
(iiii) la réduction ou l'oxydation d'une fonction 11-oxygène
(iiiii) la chloration ou la bromation en position 15.
8. Procédé selon la revendication 7A, caractérisé en ce que la déshydrogénation est réalisée en utilisant au moins un équivalent molaire de 2,3-dichloro-5,6-dicyanobenzoquinone comme agent de déshydrogénation, dans un solvant aprotique.
9. Procédé selon la revendication 8, pour la préparation des composés de la formule (I) dans laquelle Z est un atome de chlore ou de brome, caractérisé en ce que la déshydrogénation du composé de départ 19-nor-pregna-1,3,5(10),6,8-pentaène non substitué en position 14 est réalisée, en utilisant au moins deux équivalents molaires de 2,3-dichloro-5,6-dicyanobenzoquinone, en présence d'au moins un équivalent molaire de chlorure d'hydrogène ou de bromure d'hydrogène, de façon à réaliser une 15- halogénation concomitante.
10. Procédé selon la revendication 7B, caractérisé en ce que l'aromatisation est réalisée au moyen d'une base faible, de manière désirable en présence d'un sel d'halogénure soluble tel que du chlorure de lithium, de préférence au moyen de chlorure de lithium/diméthylformamide.
11. Procédé selon la revendication 7C, caractérisé en ce qu'une 9α,11β-dichloro-pregna-1,4- diène-3-one appropriée est soumise à une 6-déshydrogénation, didéshydrochloration et aromatisation concomitante.
12. Procédé selon la revendication 11, caractérisé en ce que les reactions sont réalisées in situ à des températures élevées, au moyen de 2,3-dichloro-5,6-dicyanobenzoquinone comme agent de déshydrogénation et en présence d'un acide dans un solvant aprotique.
EP78200112A 1977-07-26 1978-07-20 19-Nor pregnahexaènes, procédé pour leur préparation et compositions pharmaceutiques les contenant Expired EP0000609B1 (fr)

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