NO782538L - PROCEDURE FOR PREPARING NEW 19-NOR PREGNAHEXANES - Google Patents

Description

New 19-nor-pregnahexanes, processes for their preparation and pharmaceutical compositions containing them

The present invention relates to 19-nor-pregna-1,3,5(10), 6,8,14-hexaen-20-ones, a method for producing these and pharmaceutical compositions containing them.

The invention is based on the observation that certain 19-nor-pregna-1,3,5(10),6,8,14-hexaen-20-ones which can be defined by general formula I in the following, exhibit anti-mitotic activity with minimal or no hormonal side effects and thus are applicable in the treatment of diseases characterized by rapid and/or abnormal cell proliferation, in particular in the treatment and control of psoriasis.

In general, the compounds of formula I are new compounds even if at least one compound is covered by this formula, i.e. 19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a-21- triol-20-one-3,21-diacetate [and optionally•by implication its 3-(free hydroxy) analogue]( has been described previously [Heller et al./j. Am. Chem. Soc. 89, 1919 et séqu. (1967)].The therapeutic activity thereof, or of related compounds, is, however, neither described nor proposed according to the state of the art.

Accordingly, the active compounds in the new therapeutically active compositions according to the invention are defined by the following general formula:

wherein A is hydrogen, lower alkyl, fluorine or fluorine-substituted methyl, R 1 is hydrogen, lower alkyl or an acyl radical of a carboxylic acid of up to 12 carbon atoms, W is (H,H); (H, lower alkyl); (H,a-0R2), where R- is hydrogen or an acyl radical of a carboxylic acid with up to 12 carbon atoms, or =CHT, where T is hydrogen, lower alkyl, fluorine or chlorine,

Q is OR 4 (where is hydrogen or an acyl radical of a carboxylic acid of up to 12 carbon atoms); hydrogen, provided that W is (H,H), or (H, lower alkyl); or together with W denotes a 16a,17a-lower alkylidenedioxy group,

Y is (H,H) , (H,OH) , or oxygen;.

Z is hydrogen, chlorine or bromine,

R 3 is hydrogen or an acyl radical of a carboxylic acid of up to 12 carbon atoms; or OR^ together with Q denotes an alkylidenedioxy or alkyl orthoalkanoate group; and when Q is hydroxy and R 3 is hydrogen, 17a,20; 20,21-bismethylenedioxy derivatives thereof.

Claimed as new compounds per se according to 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 and W are preferably those having up to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl and tertiary butyl, although higher homologues such as pentyl and hexyl falls within the scope of the invention.

The acyl radicals of carboxylic acids with up to 12 carbon atoms included within the definitions of , R^, R^.°9R^ may be saturated or unsaturated, straight-chain or branched aliphatic, cycloaliphatic or cycloaliphatic-aliphatic, aromatic, aryl^-aliphatic or alkyl-aromatic , and can be substituted, for example, with hydroxy, aryloxy, alkoxy containing from 1 to 5 carbon atoms or halogen. Typical ester groups of the 19-nor-pregna-hexanes in the formulations according to the invention are thus derived from carboxylic acids such as alkanoic acids exemplified by acetic acid, propionic acid, trimethylacetic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, tertiary butylacetic acid, enanthic acid, caprylic acid, capric acid . <1>,5'-dimethylbenzoic acids; arylalkanoic acids such as phenylacetic acid 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 R-^, R2, R3 and R^ in formula I are those derived from lower alkanoic acids with preferably up to 8 carbon atoms, such as the radicals obtained from acetic acid, propionic acid, butyric acid, valeric acid, caprylic acid, caproic acid , tertiary butyl acetic acid or the like, as well as acyl radicals derived from aromatic carboxylic acids with up to 8 carbon atoms, preferably from benzoic acid.

The alkylidene groups which are taken into account in the compounds according to the invention are preferably lower alkyladenes, i.e. hydrocarbon radicals with preferably up to 4 carbon atoms included from radicals such as methylene, ethylidene, n-propylidene, isopropylidene, n-butylidene and sec.-butylidene.

The 19-nor-pregnahexaén-20-ones according to the invention are crystalline solid materials, usually white to "off-white" in color which are insoluble in water and soluble in most organic solvents, in particular in acetone, dioxane, dimethylformamide and dimethylsulfoxide, although they have limited solubility in non-polar solvents such as dialkyl ethers and alkyl hydrocarbons.

The 19-nor-pregnahexaen-2o-ones of formula I exhibit anti-mitotic activity and are particularly useful in the treatment and control of psoriasis.

Useful 19-nor-pregnahexaen-20-ones of formula I include 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17a,21-triol-20 -one-21-acetate and the 6-methyl, 6-fluoro, 6-difluoromethyl and 6-trifluoromethyl derivatives thereof, as well as the 16-desmethyl analogues and 163-methylepimers thereof; 16a-hydroxy-substituted compounds of formula I and ester and 16a,17a-alkylidenedioxy derivatives thereof such as 19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,16a-17a,21 -tetrol-2-one-16,21-diacetate and 16a,17a-isopropylidenedioxy-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,21-diol-2o- one-21-acetate; 16-alkylidene-substituted compounds of formula I such as 16-raethylene-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-2o-one- 21-acetate and the 3-acetate and 3-methyl ether derivatives thereof; and the 15-chloro derivatives of the preceding.

Of the compounds of formula I, particularly useful for the treatment of psoriasis are 16α-alkyl-substituted compounds [i.e. compounds of formula I wherein W is (H,α-alkyl)], and preferred compounds are 16α-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-20-pn of general formula:

wherein R 1 , R 3 and R 4 are as defined for formula (I).

Among the compounds of formula II, particularly useful anti-psoriatic agents are those in which R 4 is hydrogen and among these in particular those in which R 1 is hydrogen or acetyl. Among the foregoing, a particularly preferred compound is 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a-21-triol-20-one-21-acetate which exhibits excellent 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 the 3-benzoate ester and 3-methylether derivatives of the former; 16α-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17α,21-triol-2o-one; and the 21-propionate, 17-propionate and 17,21-di-n-butyrate ester derivatives of the latter.

19-nor-pregnahexaen-20-ones of formula I are conveniently prepared from the corresponding 19-nor-pregna-1,3,5(10),6,8-pentaen-20-ones by dehydrogenation in the 14-position, conveniently 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. Alternatively, a suitable 11-unsubstituted pregna-1,4,6,8,14-pentaen-3-one can be subjected to aromatization - eg, by means of a weak base, preferably in the presence of a soluble halogen salt such as lithium chloride - , or a suitable 9a,113-dihalogenp-pregna-1,4,6-trien-3-one can be subjected to accompanying didehydrohalogenation and aromatization (a specific embodiment is the accompanying 6-dehydrogenation, didehydrochlorination and aromatization of a suitable 9a,113 -diclof-pregna-1,4-dien-3-one, conveniently in situ, at elevated temperatures using DDQ as dehydrogenating agent and in the presence of an acid in an aprotic solvent). Isolation of the respective 19-nor-pregnahexaen-20-ones is then carried out by well-known methods in steroid chemistry.

When the above-mentioned 14-dehydrogenation of a 19-nor-pregna-1, 3, 5 (10), 6, 8-pentaen-20-one precursor is carried out in the presence of at least one molar equivalent of hydrogen chloride and with approx. two molar equivalents of DDQ, the respective 15-chloro-19-nor-pregnahexaen-20-ones of formula I are formed. Thus, e.g. the reaction of 16α-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17α,21-triol-20-one-21-acetate in dioxane with at least one molar equivalent of hydrogen chloride and with approx. two molar equivalents of DDQ 15-chloro-16g-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a-21-triol-2o-one-21-acetate, with anti-mitotic activity. By similarly using hydrogen bromide instead of hydrogen chloride, the respective 15-bromo compounds are obtained. Alternatively, a 15-chloro or -bromo substituent can 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 (eg N-halo-succinimide), or hydrogen halide in the presence of DDQ.

The preceding process, which makes use of hydrogen chloride and DDQ for the preparation of the 15-chloro-substituted compounds according to the invention, is preferably carried out at room temperature (although temperatures in the range from 0 to 100° C can be used) and in dioxane (although other aprotic solvents can be used, in particular ethers such as tetrahydrofuran, diethyl ether and diglyme). When the reaction is carried out at room temperature it is usually complete within 30 minutes as determined by thin layer chromatography, although at lower temperatures it may take up to 24 hours for complete conversion of a 19-nor-pregna-1,3,5(10 ),6,8-pentaen-20-one to the corresponding 15-chloro-14-dehydro compound. Although the present method only requires one mblar equivalent of hydrogen chloride per moles of pregnapentaen-20-one starting compound, it is preferred to use large excesses of hydrogen chloride (eg, a saturated solution of hydrogen chloride in dioxane) as the reaction rate is thereby increased and the process is completed in 30 minutes or less.

Many of the 19-nor-pregna-1,3,5(10),6,8-pentaen-2-one intermediate products from which the 19-nor-pregnahexaen-20-ones according to the invention can be obtained are known in the art ( e.g. described in US Patent 3,182,057 and 3,182,075) and has been produced by reacting a 9a,113-dichloro-1,4-pregnadiene-17a,21-diol-3,20-dione-21 -alkanoate (e.g. 16α-methyl-9α, 11(3-dichloro-1, 4-pregnadiene-17α,21-diol-3,20-dione-21-acetate)) with a weak base, preferably in the presence of lithium chloride. Weak bases useful in this process are pyridine, collidine, lutidine and preferably dimethylformamide. Other 19-nor-pregnapentaen-20-one intermediates can also be prepared from the corresponding 9a,113-dichloro-1,4-pregna- diene-3,20-diones in a similar manner.

9α,113-dichloro-1,4-pregnadiene-17α,21-diol-3,20-dione the precursors of 19-nor-pregna-1,3,5(10), 6,8-pentaen-20-one The -intermediate products are also known in the art and can be prepared from corresponding 9(11)-dehydroderivatives according to procedures as described in US Patents 2,894,963 and 3,009,933.

In the preparation of a 16-alkylidene compound of formula. I (ie a compound where W is =CH.T) , one can start with a 9a,113-dichloro-16-alkylidene-1,4-pregnadiene-17a,21-diol-3,20-dione-21- lower-alkanoate precursor and converting this to a 16-alkylidene-19-nor-pregna-1,3,5(10),6,8-pentaene and from there to the 14-dehydroanalogue of formula I according to the method described above . In order to reduce the side reactions that take place when a 1,6-methylene-17a-hydroxy-1,4,9(11)-pregnatriene-3,20-dione is halogenated, one can alternatively protect the 17a-hydroxyl function thereof, e.g. by esterification after introduction of the 9(11) double bond. After preparation of the corresponding 9α,11β-dichloro derivative of the 17α-hydroxy-protected derivative of a 16-methylene-1,4,9(11)-pregna-triene-3,20-dione (e.g. 16- methylene-9a,113-dichloro-1,4-pregnadiene-17a,21-diol-3,20-dione-17,21-diacetate) and conversion thereof to a 16-alkylidene-19-nor-pregna-1,3 ,5(10),6,8,14-hexaen-3-ol of formula I [e.g. 16-methylene-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-tri6l-20-one-17,21-diacetate], the 17a- hydroxy-protecting groups are easily removed via known techniques (e.g. using ordinary sodium bicarbonate in methanol), forming a 16-alkylidene-19-nor-pregna-1,3,5(10) ,6,8,14-hexaen-3,17a,21-triol-20-one according to the invention [e.g. 16-methylene-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17a,21-triol-20-one].

In the conversion of a 19-nor-pregna-1,3,5(10),6,8-pentaen-20-one to the corresponding 19-nor-pregna-1,3,5(10),6,8, 14-hexaen-20-one when reacted with DDQ as described above, it is often necessary that the 21-hydroxyl group and any 16-hydroxyl group that may be present be protected, such as with an acyl function. It is preferred to use lower alkanoate ester derivatives (usually acetates) of the 19-nor-pregna-pentaen-20-one intermediates, thereby forming 19-nor-pregnahexaeh-20-ones of formulas I and II as 21-alkanoates, usually 21 -acetates; and the corresponding 21-free-hydroxy compound is then easily obtained from the 21-alkanoate by known hydrolytic procedures, such as with aqueous sodium bicarbonate in methanol or by using malt diastase enzyme in aqueous ethanol using known procedures.

When generally a 17,21-mono-lower alkanoate or a 17,21-dilower alkanoate derivative of a 3-(free-hydroxy)-19-nor-pregnahexaen-20-one of formula I is desired, it is advantageous to use as starting material a 19-nor-prégna-l, 3, 5 (10)., 6, 8-pentaen-20-one intermediate containing the desired 21-monoalkanoate or 17, 21-dialkanoate esterf unks j-one before the reaction with DDQ.

A 17-mono-lower alkanoate ester derivative of a 3-(free-hydroxy)-19-nor-pregnahexaen-20-one of formula I can be prepared by reacting the respective 17-free-hydroxy compound [e.g. 16α-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17α,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. triethylorthopropionate) in the presence of a strong acid (e.g. p-toluenesulfonic acid) followed by hydrolytic cleavage of the resulting 17α,21-orthoester using of one aqueous acid (e.g. aqueous acetic acid), and then separate and isolate the 17-monoester using known techniques, usually including chromatographic methods, whereby a 17-mono-alkanoate (e.g. 17- propionate). This procedure usually also forms some of the corresponding 21-morio-alkanoate derivatives (e.g. 21-propionate) which can also be isolated via chromatographic techniques.

A 3,17-diester derivative of the formula. I is conveniently prepared from a corresponding 3-(free-hydroxy)-17α,21-orthoester

(which can be obtained as described above) by reaction 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 using aqueous acetic acid gives 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 triesters can be prepared from the corresponding 17a,21 or 3,17a diesters using common esterification techniques.

To prepare a 3-monoester derivative of formula I is

it is often necessary to protect the 21-hydroxyl group (eg with an ether derivative such as 21-methoxyethoxymethylether) in the 9α,113~dichloro-1,4-pregnadiene-3,21-dione precursor. (e.g. by reaction of 16α-methyl-9α,113-dichloro-1,4-pregnadiene-17α,21-diol-3,20-dione with N,N,N-triethyl-N-methoxyethoxymethyl-ammonium chloride in acetonitrile) before reacting this with a weak base in the presence of lithium chloride to form the corresponding 3-(free-hydroxy)-19-nor-pregna-1,3,5(10),6,8-pentaene-20- on ff.eg 16a-methyl-19-nor-pregna-1,3,5(10) ,6, 8-pentaen-3 ,17a, 21-triol-20-one-21-methoxyethoxymethyl-r ether]. Reaction of such a 21-protected 19-nor-pregna-1,3,5-(10),6,8-pentaen-20-one with DDQ gives the corresponding 19-nor-pregna-1,3,5(10 ),6,8,14-hexaen-20-one [e.g. 16apmethyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one-21-methoxyethoxymethylether], as by treatment according to standard esterification -procedures (e.g. by reaction with acetic anhydride in pyridine) give the corresponding 3-monoester derivative. By deprotection of the 21-position (e.g. cleavage of the 21-ether function using zinc bromide in methylene chloride) the desired 3-monoester of formula I is then formed [e.g. 16α-methyl-19-nor-pregna-1,3,5(10)-6,8,14-hexaene-3,17α,21-triol-20-one-3-acetate].

The 3-alkoxy derivatives of formula I are conveniently prepared via known etherification techniques such as those which make use of a diazoalkane (eg diazomethane in ether). Thus, a 3-hydroxy-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, by reaction with a diazoalkane in ether . - A derivative of formula I with a 3-alkoxy group and free hydroxyl function at 17 and 21 can conveniently be obtained from a 3-alkoxy-21-monoester derivative via hydrolysis such as with aqueous sodium bicarbonate. in methanol. - To prepare a 3-Alkoxy-17-monoester derivative of a compound of formula I [e.g. 16α-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17α,21-triol-20-one-17-acetate-3-methylether] is advantageous first preparing a 17α,21-orthoester derivative of a 3,17α,21-triol of formula (I) according to the procedures described above, followed by reaction with a diazoalkane (e.g. diazomethane) to form the corresponding 3-Alkoxy-17a,21-orthoester derivative, followed by cleavage of the 17a,21-

the orthoester group by means of dilute acid to form the desired 3-Alkoxy-17-monoester derivative of formula (I).

For the preparation of a 16a,17a-alkylidenedioxy derivative of formula (I), the 16a,17a-alkylidenedioxy function can be introduced 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-o.n or at an earlier step in the synthesis; however, the 17a,21-alkylidenedioxy group is preferably introduced after preparation of the corresponding 17a,21-di-(free-hydroxy)-19-nor-pregna-1,3,5(10),6,8,14-hexaene-20- Wed. Both the 16a,17a- and 17a,21-alkylidenedioxy derivatives of the 19-nor-pregna-1,3,5 (10),6,8,14-hexaen-20-ones of formula (I) can be prepared from the corresponding 16a, 17α-di-(free-hydroxy)- or 17α,21-di-(free-hydroxy )-steroids by reaction with a ketone or aldehyde (e.g. acetone, acetaldehyde, acetophenone) in the presence of an inorganic acid ( eg hydrochloric acid). 17a, 20; The 20,21-bismethylenedioxy function can be introduced before or after introducing the 19-nor-pregnapentaene or the 19-nor'-pregnahexane system by known reactions such as by using formaldehyde in the presence of acid.

The following examples illustrate the invention: Example 1

16a- methyl- 19- nor- pregna- l, 3, 5( 10), 6, 8, 14- hexaene- 3, 17a, 21- triol-2 0- one- 21- acetate

A. 16a- methyl- 19- nor- pregna- l, 3, 5( 10), 6, 8- pentaene- 3, lia , 21-triol- 2 0- one- 21- acetate

Add to a solution under., reflux cooling of 120 g of lithium chloride and . 1.8 ml of concentrated sulfuric acid in 750 ml of dimethylformamide 3.0 g of 9a , 11p-dlchloro-1 6a-methyl-1, 4-pregnadiene-17a, 21-diol-3,20-dione-21-acetate. Heat the reaction mixture to the reflux temperature for 15 minutes, then pour into 6 liters of water/ice. Extract the aqueous mixture with ethyl acetate, wash the combined extracts with water and then evaporate to a volume of approx. 350 ml. Separate the resulting crystalline precipitate by filtration, wash the precipitate with ethyl acetate and air dry to give 16α-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17α,21-triol- 20-one-21-acetate (yield 9.6 g), m.p. = 235 - 240°C; [a]^<6>+101°.'(dioxa<n>)<;>^^s^<01>^ nm] = 230 (e 81 100), 258 (e = 3600),

269 (e = 4900), 280 (e =. 5600), 292' (e 4100), 326 (e = 2400),

346 (e = 800).

B. 16a-methyl-19-nor-pregna-l,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one-21-acetate

Add to a solution of 14.0 g of 16a-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21^triol-20-one-21-acetate in 2 liters of dioxane 9.98 g = 1.2 equivalents of 2,3-dichloro-5,6-dicyanobenzo-guinone and stir the reaction mixture at room temperature for .4 1/2 hours. Separate the precipitated solid material by filtration and

wash the precipitate with dioxane. Combine the filtrate and washings and evaporate to a small volume. Dissolve the residue in ethyl acetate, wash the ethyl acetate solution with water, then with aqueous sodium bicarbonate solution and then with saturated sodium chloride solution and then again with water. Evaporate the ethyl acetate solution in vacuo to a small volume and separate the resulting precipitate by filtration to give 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21 -triol-20-one-21-acetate (yield 6.48 g). Concentrate the filtrate to dryness, triturate the resulting residue with ether and filter to give an additional 4.47 g of 16α-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3, 17α,21-triol-20-one-21-acetate;

ta] l6=-95° (dioxane), m.p. = 218 - 221°C; ^^<ano1>(inm)

248 (e = 36,000), ' 257 (e = 46,400), 266 (e = 49,200), 288 (shoulder)

(e = 13,900), 298 (e = 19,000), 310 (e = 17,900).

Example 2

Other 19- nor- pregna- l, 3, 5( 10), 6, 8, 14- hexaen- 3, 17a, 21- triol- 20-one- derivatives

A. 19- nor- pregna-l, 3, 5( 10), 6, 8- pentaene- 3, 17a, 21- triol- 2 0-one- derivatives

Treat in a similar manner as described in Example IA each of the following 9a,113-dihalogeno-1,4-pregnadienes with lithium chloride in dimethylformamide: 1) 9a,113-dichloro-160-methyo-1,4-pregnadiene-17a,21- diol-3,20-dione-21-acetate, 2) 9a,113-dichloro-16a-methyo-1,4-pregnadiene-17a,21-diol-3,20-dione-17,21-di-n- butyrate,

3) 9α,110-dichloro-1,4-pregnadiene-17α,21-diol-3,20-

21-acetate.

Isolate and purify each of the resulting products in a similar manner as described in Example IA, forming respectively: 1) 163-methyl-19-nor-pregna-1,3,5(10),6,8-pentaen-3, 17α,21-triol-20-one-21-acetate, m.p. = 182 - 184° C, [a]26 = +122° (chloroform), x^thanol = 229 = 67,000) 258 (£ = 3,700)/ max 268 (e = 4,800), 279 (e 5,500), 291 (e - 4000), 327 (e = 2400) , 340 (e - 2700) , 2) 16a-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3, 17α,21-triol-20-one-17,21-di-n-butyrate, m.p. = 200 - 202° C, [a]<26>= -15° (dioxane), *JJa£san01 Unm]= 228 U = 67 °°0)'257 U=4000), 268 (e = 5100), 279 (e - 5700), 290 (e = 4000), 325 (e = 2300), 340 (e = 2700), 3) 19-nor-pregna-1,3,5(10),6,8-pentaene -3,17a,21-triol-20-one-21-acetate, m.p. = 185 - 190° C, [a]^6 = +91° (chloroform),

x<m>ethanol [ ±nm) = 22g (<£><=>66 40Q) 258 (£= 36Q0) f 268

max

(e = 4900), 281 (e= 5700), 291 (e = 4200), 327 (e = 2600), 340 (e - 3100).

B. 19-nor-pregna-l,3,5(10),6,8,14-hexaen-3,17a,21-triol-20-one derivatives

In a similar manner as described in Example IB, treat each of the 19-nor-pregna-1,3,5(10),6,8-pentanes obtainable from Example 2A with DDQ in dioxane and isolate and purify each of the resulting products in a similar manner as described under the formation of 1) 163-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17a,21-triol-20-one, respectively -21-acetate, m.p. = 177 - 179° C, [a]26<=><+>95°

(chloroform), AjJ<®>^<ano1>[in nm] = 253 (e = 51,300), 262

(e = 51,800), 284 (e = 13,400), 295 (e = 18,100), 306 (e = 16,800), 327 (e = 2,800), 354 (e = 1,700),

■2) 16α-methyl-19-nor-pregna-1,3",5(10),6,8,14-hexaen-3,17α,21-triol-2o-one-17,21-di- n-butyrate,' m.p. = 188 - 190° C, [a]D =

-201° (chloroform), *JJf£gan01 ^ nm) = 246 (£'= 38,700),

(e = 51,300), 264 (e = 51,300), 287 (e = 15,300), 297

(e .= 20,000), 309 (e =18,700), 339 (e = 2,000), 355 (e 1,500), ,

3) 19-nor-pregna-1,3,5(10),6,8,14)-hexaene-3,17a-triol-20-one-21-acetate, m.p. = 212 - 216° C, ta]26 = -30° (dioxane), *™a£gano1 ti nm] =245 (e = 38,000), 253 (e =,49,900), 262 (e = 46,700 ), 286 (e = 13,300), 295 (e 17,900), 307 (e = 16,500*), 338 (e = 2,000), 355 (e = 1,600).

Example 3

3- Alkoxy derivatives of 19- nor- pregna-l, 3, 5( 10), 6, 8, 14- hexaen-3, 17a, 21- triol.- 2-ones

A. 3-Methoxy-16a-methyl-19-nor-pregna-l,3,5(10),6,8,14-hexaén-17a,21-diol-20-one-21-acetate

Add to a solution, of 1 g of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one-21-acetate in 50 ml of ethyl acetate a solution of diazomethane in ether (the molar amount of diazomethane is greater than the molar amount of pregnahexane). Allow the reaction mixture to stand overnight at room temperature, then distill excess diazomethane and ether. Purify the resulting residue via chromatography on silica gel preparative plates using chloroform:ethyl acetate (4:1) as the solvent system. Remove the band containing the desired product as shown under ultraviolet light) by extraction with ethyl acetate. Evaporate the ethyl acetate and crystallize the resulting residue from petroleum ether/ether to give 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 - 188° C, fcc]^<6>= -109° (chloroform), XmakSan<01>(in nm) = 246 (e = 36,600)'254 (£= 46,300), 264

(e = 47,000), 283 (e = 14,700), 293 (e = 20,200), 306 (e

19,700), 335 (e = 1,700), 352 (e = 1,300). B. Other 3- methoxy- 19- nor- pregna-l, 3, 5( 10), 6, 8, 14- hexaen- 17a, 21-diol- 20-ones Treat in a similar way each of the 3-( free-hydroxy)-19-nbr-pregna-1,3,5(10),6,8,14-hexanes according to example 2B with diazomethane to form respectively 1) 3-methoxy-1 6 |3-methyl 1- 19-nor-pregna-1,3,5(10),6,8,14-hexaene-17a,21-diol-20-one-21-acetate, 2) 3-methoxy-16a-methy1-19- nor-pregna-1,3,5(10),6,8,14-hexaene-17a,21-diol-20-one-17a,21-di-n-butyrate, and 3 ) 3-meth"oxy- 19-nor-pregna-1,3,5(10),6,8,14-hexaene-17a,21-diol-20-one-21-acetate.

C. Other 3-Alkoxy derivatives

By following the procedures described in examples 3A and 3B but using other diazo-alkane solutions instead of diazomethane, e.g. diazoethane, the corresponding 3-alkyl derivatives are obtained, e.g. The 3-ethoxy derivatives, corresponding to the 3-methoxy products according to examples 3A and 3B.

Example 4

1 9- nor- pregna- l, 3, 5( 10), 6, 8, 14- hexaen- 3, 17a, 21- triol- 2 0-ones A. 16a- methyl- 19- nor- pregna- l, 3, 5( 10), 6, 8, 14- hexaene- 3, 17a, 21-triol- 20- one

Add to a solution of 1 g of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-tripl-20-one-21-acetate in 70 ml methanol under nitrogen atmosphere 5 ml 10% aqueous sodium carbonate. Heat to reflux temperature for 30 minutes, cool, add dilute acetic acid until the reaction mixture has a pH of approx. 7, pour into water and extract with ethyl acetate. Wash the combined extracts with water, dry over magnesium sulfate and evaporate. Crystallize the resulting residue from chloroform/ethyl acetate to give 16α-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17α,21-triol-20-one, yield =697 mg, [a]^<6>= -188°

(dioxane), m.p. = 220 - 225° C, xme^hano1 (in nm) = 246 (e =

. ■ max 3.5 000), 255 (e = 45 100), 2 64 (e = .4 5 900), 285 (e 13 800), 296 (e = 18 500), 308 (e = 17 900), 338 ( e = 2600), 355 (e = 1700)..

B. Other 19- nor-pregna-l, 3, 5( 10), 6, 8, 14- hexaen- 3, 17a, 21-triol-20-ones

Treat on. similarly each of 163'-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one-21-acetate and 19- nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one-21-acetate with aqueous sodium bicarbonate and isolate and purify the resulting products as described under formation of 163-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17a,21-triol-20-one and 19-nor-pregna-1,3 respectively ,5(10),6,8,14-hexaeh-3,17a,21-triol-2 O-one.

Example 5

17- mono- lower alkanoates and 21- mono- lower alkanoates from the corresponding 19- nor- pregna- l, 3, 5( 10), 6, 8, 14- hexaene- 3, 17a, 21- triol-2 0- oners

A. 2 The 1- propionate and 17- propionate of 16a- methyl- 19- nor- pregna-1, 3, 5 ( 10), 6, 8, 14- hexaen- 3, 17a, 21- triol- 20- one

(1) Add to a solution of 697 mg of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17a,21-triol-20-one in 9 .7 ml of dimethylsulfoxide and 0.97 ml of triethylorthopropionate and 97 mg of p-toluenesulfonic acid. Stir the reaction mixture at room temperature for 5 hours, then add 14 ml of acetic acid/

water (9:1) and stir the mixture at room temperature overnight. Pour the reaction mixture into water, separate the resulting precipitate by filtration and wash it with water, then chromatograph the precipitate over silica gel, eluting with methylene chloride/ether (19:1). Combine the equal early fractions as determined by thin layer chromatography, evaporate, crystallize the resulting residue from ether and filter to give 16α-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]<26>= -109° (chloroform), ^methanol (± nm) = 245 (£ = 3g 500) 255 (e = 47 400), 264 (e =

max

48,200), 286 (e = 13,900), 296 (e = 19,300), 309 (e = 18,200), 338 (e 2,000), 355 (e.= 1,500). (2) Continue the elution with the same solvent and combine the equal late fractions as determined by thin layer chromatography, evaporate, crystallize the resulting precipitate from ether/petroleum ether and filter to give 16a-methyl-19-nor-pregna-1,3,5 (10),6,8,14-hexaene-3,17a,21-triol-2 0 -one-17-2 6 propionate, yield = 41 mg, m.p. 115 - 120 C, t ot ] D =

-212° (chloroform).

B. 2 1- and 17- monoesters of other 19- nor-pregna-l, 3, 5( 10), 6, 8, 14-hexaen- 3, 17a, 21-triol- 20-ones

Treat each of 163-methyl-19^nor-pregna-1,3,5(10),6,8,14-hexaene-3 similarly. ,17a, 21-triol-20-one and 19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17a,21-triol-20-one with triethyl orthopropionate and p -toluenesulfonic acid, followed by treatment with aqueous acetic acid, and isolate and purify each of the resulting products, in a similar manner to that described above, forming 163-methyl-19-nor-pregna-1,3,5(10),6 respectively ,8,14-hexaene-3,17a,21-triol-20-one-21-propionate and 163-methyl-19-nor-pregna-1,3,5(10), 6,8,14-hexaene- 3,17a,21-triol-20-one-17-propionate, 19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one -17-propionate, 19-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.

Example 6

15- chlor- l 9- nor- pregna- l , 3, 5( 10) , 6, 8, 14- hexaen- 3 , 17a , 21- tr iol- 2o-^ oner A. 1 5- chlor- 16a- methyl- 19- nor- pregna- l, 3, 5( 10), 6, 8, 14- hexaene-3, 17a, 21- triol- 20- one- 21- acetate

Add to a saturated solution of hydrogen chloride gas i

50 ml dioxane 382 mg 16a-methyl-19-nor-pregna-1,3,5(10),6,8-L pentaene-3,17a,21-triol-20-one-21-acetate and heat gently to dissolved. To the resulting solution add 454 mg of 2,3-dichloro-5,6-dicyano-benzoquinone and stir the reaction mixture at room temperature for 30 minutes. Evaporate the dioxane, dissolve the resulting residue in ether and filter the ether solution through an aluminum oxide column.

Evaporate the combined eluates and chromatograph the resulting residue over silica gel and elute with petroleum ether/ether graded elution. Combine equal fractions containing the desired product as determined by thin layer chromatography and evaporate the combined eluates. Recrystallize the resulting residue from ether/petroleum ether and filter the resulting 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. oie ->oo° ✓v r 126 i o i-o _ \ ,methanol ,. >

225 - 228 C, [a]D = -185 (chloroform) , ^maj^s f1nm> =

258 (e = 44,700), 266 (e=49,200)', 290 (e = 12,500)., 303 (e =

15,000), 315 (e = 14,600), 336 (e = 3900), 354 (e =-2900). B. Other 15- chloro- 19- nor- pregna- l, 3, 5( 10), 6, 8, 14- hexaen- 3, 17a, 21-triol- 20-ones Treat in a similar manner each of the 19 -norTpregnapenta- ner obtainable from Example 2A with DDQ and hydrogen chloride and isolate and purify each of the resulting products in a similar manner as described here during the formation of respectively 1) 15-chloro-163-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-2 0- one-17,21-di-n-butyrate, 3) 15-chloro-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-2O -one-21-acetate

Example 7

Preparation of 3-carboxylate esters

A. 1 6a- methyl- 19- nor- pregna-l, 3, 5( 10), 6, 8, 14- hexaene- 3, 17a, 21-triol- 20-one- 3, 21- diacetate

Add to a solution of 450 mg of 16a-methyl-19-nor-pregna-1,3,5(10) ,6,8,14-hexaen-3 ,17a ,-21-tri iol-2 0-one-21 -acetate in 2 ral pyridine 1 ml acetic anhydride and let the reaction mixture stand at room temperature overnight. Pour the reaction mixture into the . dilute hydrochloric acid, separate the resulting precipitate by i.filtration, wash it with water, dry and crystallize from ether,

while forming 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17a,21-triol-20-.one-3,21-diacetate, yield = 232 mg, m.p. = 153 - 157° C, [a]^ = -93° (chloroform),

Xmaxan<01>(in nm) = 388 (e = 29,300), '246 (£= 32,600), 255

(e = 41,360), 264 (e = 41,600), 283 (e = 14,500), 293 (e = 18,000), 306 (e =16,700), 330 (e = 600).

B... 16 a- methy 1- 19- nor- pregna- l, 3, 5( 10) , 6, 8 , 14- hexaen- 3, 17 a , 21-triol- 20-one- 3- benzoate - 21- acetate

By using benzoyl chloride instead of acetic anhydride in the method according to example 7A, 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20 is obtained -one-3-benzoate-21-acetate, m.p. = 197 - 202° C, [a]26 = -68° (chloroform), xJ!Jaksan01 (in nm) = 238 (e = 39,300), 256 (e = 44,800), 265 (e = 45,500) ., 283 (e = 16,000), 295 (e = 17,900), 307 .(e = 17,000).

C. 3-carboxylate esters of other 19-nor-pregna-l, 3, 5(10), 6, 8, 14-hexaene derivatives

(1) Treat similarly each of 3-(free-hydroxy)- or 3,21-di-(free-hydroxy)-19-nor-pregna-1,3,5(10),6,8,14 -the hexaene compounds obtained from examples 2B, 5 and 6 (possibly containing an additional free hydroxyl group in the 17-position) with acetic anhydride in pyridine or benzoyl chloride in pyridine, forming the corresponding 3-acetate or 3-benzoate ester, or the corresponding 3,21 -diacetate or 3,21-dibenzoate. (2) Treat each of the 3,17a,21-tri-(free-hydroxy)-19-nor-pregna-1 , 3 , 5 (10 ), 6 , 8 , 14-hexanes prepared according to Example 4 with acetic anhydride in pyridine or benzoyl chloride in pyridine according to the methods according to examples 7A and 7B, forming 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-1 9-nor-pregna-l ,3,5(10),6-, 8,14-hexaen-3 ,17a , 21-triol-20-one-3,21-dibenzoate, 3) 163-methyl-1-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol -20-one-3,21-diaceatt, 4 ) 163:-methy 1-19-nor-pregna-l ,3,5(10) ,6,8 ,14-hexaen-3 ,17a , 21-tr iol -20-one-3 , 21-dibenzoate, 5) 19-nor-pregna-1,3,5(10),6,8,14-hexane-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.

Example 8

1 6a- methyl- 19- nor- pregna- l, 3, 5( 10), 6, 8, 14- hexaene- 3, 17a, 21- triol-11, 2 0- dione- 3- benzoate- 21- acetate

A. 16a- methyl- 19- nor- pregna- l, 3, 5( 10), 6, 8- pentaene- 3, 17a, 21-triol- 11, 20- dione- 3- benzoate- 21- acetate

Add to a solution of 30 g of 9α-bromo-16α-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-21-acetate in 240 ml of pyridine; 60 ml of benzoyl chloride and heat the reaction mixture to 60° C. for 20 hours, cool and pour into dilute hydrochloric acid. Extract the aqueous solution with ethyl acetate, wash the combined extracts with water and evaporate. Chromatograph the resulting residue over silica gel and elute with petroleum ether/ether gradient. Combine the equal fractions containing the desired product as determined by thin layer chromatography, then evaporate and crystallize the resulting residue from ether to give 16α-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3 ,17α,21-triol-11,20-dione-3-benzoate-21-acetate (yield 13.1 g); sm.p. = 183 - 184p C,

[a]<26>= +63° (dioxane), x<me>^<hano1>(in nm) = 215 (e = 40,600),

237 (e = 38,400) , 314 (e = 7,900).

B. 16a- methy1- 19- nor- pregna-l, 3, 5( 10), 6, 8, 14- hexaen- 3, 17a, 21-triol-ll, 20- dione- 3- benzoate- 21- acetate

Add to a solution of 10.4 g of 16α-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17α,21-triol-11,20-dione-3- benzoate-21-acetate in 500 mL dioxane 13.33 g = 2.4 equivalents of DDQ and heat the reaction mixture to reflux for 48 hours. Then evaporate in vacuo, dissolve the resulting residue in methylene chloride and filter through aluminum oxide ("activity V", i.e. annealed aluminum oxide whose activity has been modified by the addition of 15% water). Evaporate the combined eluates to a small volume and chromatograph over silica gel, elute with pétroleum ether/ether gradient. Combine the equal fractions containing the desired product as determined by thin-layer chromatography and vapor<p>and then recrystallize the resulting residue from ether to give 16α-methyl-19-rnor-pregna-1,3,5(10),6 ,8,14-hexaene-3,17a,21-triol-11,20-dione-3-benzoate-21-acetate, m.p. 144 -

!<rO „ , , 26 ,,o ,,. > ,methanoi ... , 145 C, taJD = +1 (dioxane), ^max (x nm) = 234 (e = 37 700)., 270 (e 42 900), 277 (shoulder) (e = 40 400 ), 312

(e =9000), 349 (e =6000), 365 (e 5300).

E xample 9 16a-methy1-19-nor-pregna-l,3,5(10),6,8,14-hexaene-3,17a,21-triol-ll,20-dione

By subjecting 16α-methyl-19-nor-pregna-1,3,5(10),6-8,14-hexaene-3,17α,21-triol-11,20-dione-3-benzoate-21- acetate mainly, the same conditions as described in example 4A yield 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20 -dione, sm.p. = 163 - 165°.C, [a]<26>= -107° (dioxane), CakS31103, (in nm) = 236 (e = 24,100), 276 (e = 34,000), 317

(e = 5600) , 378 (e = 5700).

Example 10

Other ester derivatives of 16a-methy1-19-nor-pregna-l>3,5(10),6,8,14-hexaene-3,17a,21-triol-ll,20-dione

A. The 21- propionate and the 17- propionate of 16a- methyl- 19- nor- prégna-1, 3, 5( 10), 6, 8 , 14-. hexaene-3,17a,21-triol-ll,20-dione

By subjecting 100 mg of 16α-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17α,21-triol-11,20-dione to essentially the conditions which is described in example 5A, 25 mg of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexa'en-3,17a,21-triol-11,20- dione-21-propionate (the residue from the least polar band), and 25 mg of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21- triol-II, 20-dione-17-propionate (the residue from the most polar bond).

B. 1 6a- methyl- 19- nor-pregna-l, 3, 5( 10), 6, 8, 14- hexaene- 3, 17a, 21-triol-ll, 20-dione- 3, 17, 21- tripropionate

Add to a suspension of 2 g of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione in 20 ml propionic acid containing 200 mg p-toluenesulfonic acid at -5° C 8 ml. trifluoroacetic anhydride dropwise over a 40-minute period. Allow the reaction mixture to warm to room temperature, then stir for 24 hours. Pour the reaction mixture into ice/water and extract with ethyl acetate. Wash the combined extracts with aqueous sodium bicarbonate, then with water and evaporate in vacuo. Chromatograph the resulting residue over silica gel and elute with petroleum ether/ether gradient. Combine the equal fractions containing the desired product as determined by thin layer chromatography to give 16α-methyl-19-nor-pregna-1,3,5(10),6-8,14-hexaen-3,1'7a,21- triol-ll, 20-dione-3,17,21-tripropionate, yield 2.04 g, [a]<26.>-82° (dioxane), ^^<ano1>(inm) = 233

(e = 26,300), 260 (shoulder) (e = 30,700), 269 (e = 36,100),

278 (e = 34,800), 316 (e = 7,700), 345 (shoulder) (e = 5,400),

364 (e = 4600).

C. 16ct-methyl-l9-nor-pregna-l,3,5(10),6,8,14-hexaen-3,17a,21-triol-ll,20-dione-3,21-diacetate

Subject 16α-methyl-19-nor-pregna-1,3,5.(10),6,8,14-hexaene-3,17α,21-triol-11,20-dione to substantially the same conditions as described in Example 7A to form 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione-3,21-diacetate ,[a]<26>= -1° (dioxane),xmeth<anpl>(±nm) = 234 (e<=>

max

25,900), 269 (e = 33,300), 278 (e = 29,300), 315 (e =7,800), 348 (e = 5,300), 365 (e = 4,700).

D. 16a-methy1-19-nor-pregna-l,3,5(10),6,8,14-hexaene-3,17a,21-triol-ll,20-dione-3,21-dipropionate

By following the same procedure as described in example 10C but using an equivalent amount of propionic anhydride instead of acetic anhydride, 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14 is obtained -hexaene-3,17a,21-triol-11,20-dione-3,21-dipropionate, m.p. = 135 - 137° C, [a]26 = +2° (dioxane), ^^g31101(inm) = 233 (e = 24,000), 269 (e = 32,700)., 279 (shoulder) (e = 28,500), 315 (e = 7,100), 349 (e = 5,000), 365 (e = 4,300).

Example 11

16a- methyl- 19- nor- pregna-l, 3, 5( 10), 6 , 8 , 14- hexaen- 3, 11( 3 , 17a , 21-tetrol- 20-one- 3, 17, 21- tripropionate and 17, 21-dipropionate

Add to a solution of 1 g 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 in 50 ml tetrahydrofuran/methanol (1:1) - dried over an aluminum oxide column at 0° C, 220 mg = 3 equivalents of sodium borohydride in portions over a 5-minute period. Stir the reaction mixture- for a further 10 minutes and then neutralize it by adding glacial acetic acid dropwise. Pour the reaction mixture into water, extract with ethyl acetate, wash the combined extracts with water and evaporate. Chromatograph the resulting residue over a silica gel GF column, eluting with chloroform/ethyl acetate (9:1). Combine the like fractions as. determined by thin-layer chromatography and evaporate each of the three different combined fractions to residues comprising respectively 1) 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,lia,17a ,21-tetrol-2o-one-3,17a,21-tripropionate.(yield: 53 mg), 2) 16a-methy1-19-nor-pregna-1,3,5(10),6,8,14 -hexaene-3,113,17a,21-tetr.ol-20-one-3,17a,21-tripropionate (yield: 502 mg). After purification by recrystallization from petroleum ether/ether: [a]<26>= -136° (dioxane), -^^g*11<01>(in nm) = 237 (e = 30 200)'244 (e- = 34,000) , 253 (e = 45,100) , 262 (e 44,200) , 281

(e = 16,200), 291 (e■ 20,300), 304 (e = 18,500), 328

(e = 900), 344 (e = 500)

3). 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,113,17a,21-tetrol-2 0-one-17,21-dipropionate (yield: 93 mg ). After purification by recrystallization. from petroleum ether/ether: r ,26 , . co., j. > ,methanol ,.. „_^,11n .

[a]D = -145 (dioxa<n>), ^ma^s d nm) 236 (shoulder)

(e = 28,100), 244 (e= 33,800), 256 (e = 40,200), 265

(e = 40,200), 287 (shoulder) (e = 12,600), 297' (e = 16,400.) , 308 (e =15,500), 337 (e = 2,700).

JÉk* sample 12

6- f fluoro- 16g- methy 1- 19- nor- pregna- l, 3 , 5 ( 10)', 6 , 8 , 14- hexaene-3, 17a, 21- triol- 20- one- 2r- acetate

A. 6- fluoro- 16a- methy1- 19- nor- pregna- l, 3, 5( 10), 6, 8- pentaene-3, 17a, 21- triol- 20- one- 21- acetate

Add 4.2 g of 6a-fluoro-9'a,113-dichloro-16a-methyl-1,4-pregnadiene-17a,21-diol-3,20-dione-21-acetate to 200 ml of dimethylformamide under reflux and continued heating at reflux temperature for 30 minutes. Pour over the reaction mixture. in saturated aqueous sodium chloride solution, separate the resulting precipitate' by filtration. Dissolve the precipitate in the ethyl acetate and crystallize fractionally below; formation of both'6a-fluoro-16a-rhethyl-pregna-1,4,8(14),9(11)-tetraene-17a,21-diol-3,20-dione-21-acetate and 6-fluoro -16α-raethyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17α,21-triol-20-one-21-acetate. Purify the latter compound further by crystallization from methylene chloride to give 316 mg, [cx]<26>= +88°'(dioxane), m.p. = 238 - 241° C, Xmax<n01>(in nm) = 238 (e = 50 500)'270-(e = 5000), 281

(e = 5000), 293 (e =. 3400), 315 (shoulder) (e = 1700), 330

(e = 2400), 344 (e = 2600).

B. 6-fluoro-16a-methy1-19-nor-pregna-l,3,5(10),6,8,14-hexaen-3,17a,21-triol-20-one-21-acetate

Submit 200 mg of 6-fluoro-16a-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-20-one-21-acetate mainly under, same conditions as described in example IB to form 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 - 202° C, ^ak^anQl (in nm) 248 <shoulder) (e = 36 300),

255 (e = 48 100), 265 (e = 49 200), 288 (e = 13 900), - 29 9 (e = 19 5 00), 311 (e = 18 500), 34 2 (e = 2100) , 3 59 (e = 1500).

Example 13 163- methy 1- 19- nor- pregna-l, 3, 5( 10) , 6, 8 , 14- hexaen- 3, 11( 3 , 17 a , 21-tetrol- 2 0- one- 21- acetate

A. 1 6g- methyl- pregna- l , 4, 6, 8- tetraen- ll| 3 , 17a , 21-triol- 3 , 20-dione— 21- acetate

Add to a mixture of 3.44 g of 9a-chloro-163-methyl-pregna-1,4,6-trien-113,17a-,21-triol-3,20-dione-21-acetate in 700 ml of acetone 10 .3 g of potassium acetate and boil the reaction mixture under reflux and stirring for 48 hours. Filter the reaction mixture, evaporate the filtrate in vacuo to a small 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 approx. 100 ml. Separate the resulting crystalline solid by filtration bg dry to give 163-methyl-pregna-1,4,6,8-tetraene-llp,17a,21-triol-3,20-dione-21-acetate, yield: 1 .96 g, m.p. = 175 - 180° C, [a]<26>= +786° (pyridine), Xmak^<an>01 (in nm) 230 (shoulder) (e = 10,600), 264 (e = 10,000). , 388 (e 6500) .

B. 16P- methyl- 19- nor- pregna- l, 3, 5( 10), 6, 8- pentaene-3, IIP , 17a, 21- tetrol- 2 0- one- 21- acetate

Add to a solution of 850 mg 160-methyl-pregna-1,4,6,8-tetraene-113,17a,21-triol-3,20-dione-21-acetate in 200 ml tetrahydrofuran 20 ml 1N hydrochloric acid. 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 to a volume of approx. 25 ml. Separate the resulting crystalline precipitate by filtration and dry to give 163-methyl-19-nor-pregna-1,3,5(10),6,8-pentaen-3,113,17a,21-tetrol-20-one -21-acetate, yield: 368 mg, m.p. = 203 - 207° C, [a]26 = +172° (pyridine), A ^s^O1 (in nm) = 233 (e 69 100)'267

.Ce = 4800), 278 (e = 5400), 315 (e = 1900),' 327 (e = 2300), 340 (e = 2700). C. 163:- methyl- 19- nor- pregna-l, 3, 5(10), 6 , 8 , 14- hexaen- 3, 113 , 17a , 21-t etrol- 2 0-one- 21- acetate Subcast 199 mg of 163-methyl-19-nor-pregna-1,3,5(10),6,8-pentaene-3,113,17a,21-tetrol-20-one-21-acetate essentially the same conditions as described in example IB in the formation of 163-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,113,17a,21-tetrol-20-one-21-acetate, yield: 91 mg, m.p. 185 - 195° C, X ^^ an01 (in nm) = 244 (e = 35^ 100), 254 (e = 44,000), 263 (e = 44,000), 285 (shoulder), (e = 12,400 ), 295,(e = 16,000), 306 (e = 14,900), 337 (e = 2,600)., 354 (e = 2,200).

Example 14

163- methyl- 19- nor- pregna-l, 3, 5( 10), 6, 8, 14- hexaene- 3, 17a, 21- triol-ll, 20- dione- 21- acetate

A. 163- methyl- pregna- l, 4, 6, 8- tetraene- 17a, 21- diol- 3, 11- 20-trione- 21- acetate

Add to a solution of 500 mg of 16,3-methyl-pregna-1,4,6,8-tetraene-113,17a,21-triol-3,20-dione-21-acetate in 50 ml of methylene chloride 5 g of finely powdered manganese dioxide and stir at room temperature for 20 hours. Separate the manganese dioxide by filtration and wash with methylene chloride. Evaporate the combined filtrate and methylene chloride washes and crystallize the resulting residue from ether to give 163-methyl-pregna-1,4,6,8-tetraene-17a,21-diol-3,11,20-trione-21-acetate, mp, = 185 - 188 C, [α]26 = +1164° (chloroform).

B. 163- methyl- 19- nor- pregna-l, 3, 5( 10), 6, 8- pentaene- 3., Ila , 21-triol-ll, 20- dione- 21- acetate

Subject 163-methyl-pregna-1,4,6,8-tetraene-17a,21-diol-3,11,20-trione-21-acetate to substantially the same conditions as described in Example 13B to form 163-methyl- 19-nor-pregna-1,3,5(10),6,8-pentaene-3,17a,21-triol-11,20-dione-21-acetate.

C. 1 63- methy1- 19- nor- pregna-l, 3, 5( 10), 6, 8, 14- hexaene- 3, 17a, 21-triol-ll, 20- dione- 21- acetate

Treat in a similar manner as described in Example 13C 163-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 resulting product in a similar manner as described to give 163-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a, 21-triol-11,20-d ion-21-acetate.

Example 15

16g- methy1- 19- nor- pregna- l, 3, 5( 10), 6, 8, 14- hexaen- 3, 113, 17a, 21-, tetrol- 2Q- one

A. 16g- methyl- 17a, 20;20, 21- bismethylenedioxy- 19- nor- pregria-1, 3, 5( 10), 6, 8, 14- hexaen- 3- one- ll- one

Add to a solution of 4.3 g of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-11,20-dione in 200 ml of methylene chloride under a nitrogen atmosphere, 200 ml of a 37% aqueous solution of formaldehyde and 200 ml of concentrated hydrochloric acid. Stir the mixture at room temperature for 4 hours, separate the two layers, extract the aqueous layer with methylene chloride, combine the organic layer and the methylene chloride extracts, and wash with aqueous sodium bicarbonate, then with water. Evaporate the organic solution and chromatograph the resulting residue over silica gel, eluting with one petroleum ether/ether gradient. Combine equal fractions containing the desired product as determined by thin-layer chromatography and evaporate and crystallize the resulting residue from ether to give 16α-methyl-17α,20;20,21-bismethylenedioxy-19-nor-pregna-1,3,5(10 ),6,8,14-hexaen-3-ol-11-one.

B. 16a-methyl-17a,20;20,21-bismethylenedioxy-19-nor-pregna-1, 3, 5( 10), 6, 8, 14- hexari- 3, 113- diol

Subject 16a-methyl-17a,20;20,21-bismethylenedioxy-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3-ol-ll-one mainly to the conditions that are described in Example 11 to form 16α-methyl-17α,20;20,21-bismethylenedioxy-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,lla-dione ( from the combined previous fractions) and 16α-methyl-17α,20;20,21-bismethylenedioxy-19-nor-pregna-1,3,5(10), 6,8,14-hexaene-3,113-diol (from the combined equal late fractions). Purify by crystallization from ether.

C. 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3, liP, 17a, 21- tetrol 20- one

Add a suspension -of 990 mg = 2.5 mmol 16a-methyl-17a,20;20,21-bismethylenedioxy-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,113 -diol to 2.5 ml of aqueous 45% hydrochloric acid at 0°C and stir the resulting suspension at 0°C for 1 1/2 hours. Neutralize the reaction mixture by adding aqueous 5% potassium bicarbonate and then extract with ethyl acetate, wash the combined extracts and evaporate to a small volume. Separate the resulting crystals by filtration and dry to give 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,113,17g,21-tetrol 20-one .

Example 16 Alternative preparation of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,113,17a,21-tetrol-20-one

Add to a solution of 271 mg of 16a-methyl-19-nor-: pregna-1,3,5(10),6,8,14-hexaene-3,113,17a,21-tetrol-20-one 3,17a, 21-tripropionate in 25 ml methanol 3.0 ml 5% aqueous sodium bicarbonate solution and stir overnight at room temperature. Add dilute hydrochloric acid until the reaction mixture has a pH of approx. 7, then remove the methanol in vacuo. Add water to the resulting residue and extract with ether. Wash the combined ether extracts with water, dry over magnesium sulfate and evaporate. • Crystallize the resulting residue from methyl chloride/ether to form 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hex-'aene-3,113,17a,21,tetrol- 20-on; yield 44 mg; m.p.= 160-163°C;

. [a]26 -161° (dioxane),^\met<hano1>[ ± nm] = 263 (shoulder)

D max

24,600), 245 (£= 31,000), 255 (£=38,000), 264 (1= 38,700), 286 (shoulder) (1=12,800), 296 (£. =16,200), 308 U =15,100) , 338 ( £=2,700).

Example 17 Other 19,nor-pregna-1,3,5(10),6,8,14-hexaen-3, 17a, 21-trlol-20-ones

A. Other 19-nor-pregna-1,3,5(10),6,8-pentaen-3,17a,21-triol-20-ones

In a similar manner to Example IA, treat each of the following 9α,113-dihalbgen-1,4-pregnadienes with lithium chloride in dimethylformamide. 1) 6α,16α-dimethyl-9α,113-dichloro-1,4-pregnadiene-17α,21-diol-3,20-dione 21-acetate; 2) 6α-fluoro-9α,113-dichloro-1,4-pregnadiene-17α,21-diol-3,20-dione 21-acetate; 3) 6α-fluoromethyl-9α,113-dichloro-1,4-pregnadiene-17α,'21-diol-3,20-dione 21-acetate; 4) 6α-difluoromethyl-9α,113-dichloro-1,4-pregnadiene-17α,21-diol-3,20-dione 21-acetate; 5) 6α-trifluoromethyl-9α,113-difluoro-1,4-pregnadiene-17α,21-diol-3,20-dione 21-acetate; 6) 9α,113-dichloro-1,4-pregnadiene-16α,17α-21-triol-3,20-dione 16,21-diacetate; 7) 6α-fluoro-9α,113-dichloro-16α,17α-isopropylidenedioxy-1,4-pregnadien-21-ol-3,20-dione 21-acetate; 8) 6α-fluoro-9α,113-dichloro-16d-methyl-1,4-pregnadiene-17α,21-diol-3,20-dione 21-acetate; 9). 6α-methyl-9α,113-dichloro-1,4-pregnadiene-17α,21-diol-3,20-dione 21-acetate; 10) 6α, 163-dimethyl-9α, 113-dichloro-1-, 4-pregnadiene-17α, α-diol-3,20-dione 21-acetate; Isolate and purify each of the resulting products in a similar manner as described, forming respectively 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-pentaen-3,17a,21-triol-20-one 21-acetate; 3) 6-fluoromethy1-19-nor-pregna-1,3,5(10),6,8-pentaen-3,17a,21-triol-20-one 21-acetate; 4) 6-difluoromethyl-19-nor-pregna-1,3,5(10),6,8-pentaen-3,17a,21-tropl-20-one 21-acetate; 5) 6-trifluoromethyl-19-nor-pregna-1,3,5(10),6,8-peritaen-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-pentaen-3,21-diol-20-one 21-acetate; 8) 8-fluoro-16α-methyl-19-nor-pregna-1,3,5(10),6,8-pentaen-3,17α,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; LO) 6,163-dimethyl-19-nor-pregna-i,3,5(10),6,8-pentaene-3,17a,21- triol-20-20-one 21 acetate. B. Treat each of them in a similar manner as in example IB 19-nor-pregna-1,3,5(10),6,8-pentanenes obtained from Example 8A with DDQ in dioxane and isolate and purify each of the resulting products, forming respectively 1) 6,16a- dimethyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-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-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate; 4). 6-difluoromethyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-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; 7) 6-fluoro-16α,17α-isopropylidenedioxy-19-nor-pregna-1,3,5(10), 6,8,14-hexaene-3,21-diol-20-one 21-acetate; 8) 6-fluoro-16α-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17α,21-triol-20-one 21-acetate; 9) 6-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-. triol-20-one 21-acetate;

LO) 6,163-dimethyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17a,21-triol-20-one 21-acetate.

Example 18 Alternative preparation of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21 acetate

To a solution of 31 g of 9α,113-dichloro-16α-methyl-1,4-pregnadiene-17α,21-diol-3,20-dione 21-acetate in 1.8 liters of dioxane, add a solution of hydrogen chloride gas (66 g ) i.dioxane (420 mL) and 18.75 g DD". Stir the reaction mixture on a steam bath for 48 hours, then at room temperature for 40 hours. Concentrate the reaction mixture in vacuo to a small volume, then chromatograph the resulting residue over aluminum oxide (activity V), and elute with ether. Evaporate the combined eluates and recrystallize the resulting residue from acetone:hexane to give 16α-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene -3,17a,21-triol-20-one 21 acetate.

Example 19 Alternative preparation of 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17a,21-triol-20-one,3,21-diacetate

To a solution of 0.075 g of 16α-methyl-19-nor-pregna-1,4,6,8,14-pentaene-17α,21-diol-3,20-dione 21-acetate and 0.075 g of lithium chloride add one drop of concentrated hydrochloric acid and reflux for 1/2 hour, then remove the solvent in vacuo, dissolve the residue in a small amount of acetone, and add a large amount of water. Purify the resulting product by thin layer chromatography, eluting the least polar band with acetone and removing the solvent. Treat 16 hours with 1 ml pyridine and 0.5 ml acetic acid, add water and crystallize the resulting precipitate from acetone/hexane to give 16a-methyl-19-nor-pregna-1,3,5(10),6,8 ,14-hexaene-3,17a,21-triol-20-one 3,21-diacetate.

The application aspect of the present invention lies in eliciting a mitotic inhibitory response in a warm-blooded animal which has a disease characterized by rapid cell proliferation, which method comprises administering to the animal a non-toxic, mitotic-inhibitory effective amount of a 19-nor-pregnahexaene- 20-one of formula (I), usually together with a non-toxic, pharmaceutically acceptable carrier, particularly in the treatment and control of skin proliferative diseases, primarily for the treatment of psoriasis via topical administration.

Psoriasis is characterized by increased epidermipoiesis associated with a high reproduction rate, rapid cell rearrangement and altered keratinization. Psoriasis over the skin can be normalized by reducing cell growth through inhibition of proliferation. All drugs frequently 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 as simulated psoriasis in laboratory animals. Topically effective anti-psoriatic agents, including corticosteroids, anthralin, coal tar and 5-fluorouracil cause local side effects although they are relatively free of systemic side effects. Thus, corticosteroid therapy causes skin atrophy, dilation of the small veins in the skin and formation of stripes, while anthralin and 5-fluorouracil are skin irritants and require careful clinical monitoring for optimal therapeutic effect. Anthralin can also cause spotting on the skin.

It has now been found that compounds according to general formula (I) [especially 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20 -on 21 acetate] reduces epidermal mitotic activity without producing significant local or systemic hormonal or toxic effects when applied topically to the skin of mice in which epidermal mitosis has been stimulated.

When mice are treated by a procedure modified from

S. Belman and W. Troll, Cancer Research 3_2:450-454 (1972), the 19-nor-pregnahexaen-20-ones of the invention, particularly the 16a-methyl derivatives of formula (II) croton oil, reduce stimulated epidermal mitosis in mice when applied topically.'Furthermore, they are non-irritating without causing hormonal side effects which is surprising in light of the 19,nor-pregnahexaen-20-one structure containing an aromatic A-ring like this. as in many estrogens, and a corticoid side chain as in powerful topical anti-inflammatory agents.

In the preceding test, croton oil is applied topically to shaved mice, which thus accelerates mitosis. A 19,nor-pregna-1,3,5 (10),6,8,14-héxaén-3,17a,21-triol-20-one according to the invention is applied topically to the stimulated site, after which parts of the treated skin is excised 24 hours later for histological processing, mitotic parts per 1000 basal interfollicular epiderm cells are counted in a light microscope. Epidermal, mitotic counts from treated mice were compared with counts from controls for statistical differences with analysis of variance. The mitotic count for each compound tested is expressed as a percent reduction of mitoses compared to the number of mitoses on the skin of mice treated with croton oil. In general, it was found that

19-nor-pregnahexaen-20-ones according to the invention (formula I) significantly reduce croton oil-stimulated epidermal mitosis. E.g. the 16α-methyl-19-nor-pregnahexaen-20-ones of formula (II) typically exhibit over 60% inhibition of mitoses at a 2 mg topical dose. 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaene-3,17a,21-triol-20-one ql-acetate (a preferred compound according to the invention) exhibits approx. . 80% reduction in mitosis (even at a topical dose as low as 0.2 mg) which is approximately 10-fold greater than the mitotic reduction exhibited by an equal amount (ie 0.2 mg) of beta-methasone dipropionate (a known .tipsoriatic agent) in the same animal model..

The anti-mitotic activity was also shown in similar tests in mice, whereby an increased epidermal mitosis was induced by ultraviolet irradiation according to procedures modified from A. DuVivier and R.B. Stoughton, J. Investigative Dermatology, 6^:233-237 ( 1975). In these tests, it was demonstrated that the 19-nor-pregnahexaen-20-ones according to the invention, especially 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17a ,21-triol-20-one 21-acetate, significantly reduces epidermal mitotic rate after 1.5 or.

9 topical administrations (each with 0.02 mg, 0.10 mg and 0.5 mg doses) on ultraviolet-stimulated hairless mouse epidermis, and advantageously an epidermal thinning effect after several applications when the effect became similar to that exhibited by steroidal anti-psoriatic agents such as betamethasone valerate. Since the compounds according to the invention, as formulated by formulas (I) and (II), do not exhibit estrogenic or other hormonal or toxic effects when applied topically as shown by tests on mice, continued applications of 19, nor-pregnahexaen-20-one does not cause irritation or spotting on the skin or skin atrophy as is caused by known anti-psoriatic agents. The foregoing anti-psoriatic mode of activity of the 19,nor-pregnahexaen-20-ones of the invention differs from that exhibited by known steroid anti-psoriatic agents such as betamethasone valerate which, when applied topically to ultraviolet-stimulated hairless mouse epidermis at doses similar to which was used with i9-nor-pregnahexaen-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 causes an epidermal thinning without. reduction of mitoses.

The 19-nor-pregnahexaen-20-ones according to the invention, in particular 16a-methyl^19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17a,21-triol-20- on 21-acetate, has also been found to exhibit antimitotic activity when administered orally or parenterally to mice, without causing significant local or systemic hormonal or toxic effects.

In view of the anti-mitotic and anti-acanthotic (i.e. reduction of epidermal thickening) activity (as tested in mice) of the 19-nor-pregnahexaen-20-ones of the invention, especially when applied topically, the invention also includes treatment and control of psoriasis involving topical application to the affected area,

in a concentration effective for the treatment of psoriasis, of a 19-nor-pregnahexaen-20-one of formula (I), useful together with a non-toxic pharmaceutically acceptable carrier. Preferred anti-psoriatic agents according to the invention are 16-methyl-19-nor-pregnahexaen-20-ones, especially the 16a-methyl compounds of formula (II), especially 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.

Included within the term "topical administration" are applications to the skin surface, whereby the compounds according to the invention are effective in the treatment and control of skin diseases characterized by rapid and/or abnormal cell proliferation, e.g. psoriasis; aerosol administration; and subcutaneous injection, whereby they are effective in the treatment of local skin disorders.

Suitably, a pharmaceutical formulation is applied comprising a 19-nor-pregnahexaeh-20-one of formula (I), preferably a 16a-methyl compound of formula (II), such as 16a-methyl-19-nor-pregna-1,3 ,5(10),6,8,14-hexaene-3,17a,21-triol-20-one 21-acetate, in a non-toxic pharmaceutically acceptable carrier, usually in concentrations from about 0.0001% to approx. 5%, preferably from 0.1% to 1%, several times a day on the skin affected by psoriasis until the psoriatic condition has improved. Topical administrations may then be continued at less frequent intervals (eg once daily) to control mitosis to prevent recurrence of severe psoriatic conditions. In general, the application is made in any suitable topical form including creams, lotions, aerosols and ointments, prepared by combining the active ingredient with conventional pharmaceutical diluents and carriers used in topical formulations comprising steroids, conveniently in a liquid solution agent, preferably in a water-miscible liquid carrier consisting of hydrophilic liquids with a high solvating effect, e.g. a solution of 16α-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17α,21-triol-20-one 21-acetate in polyethylene glycol.

The present invention thus also relates to a pharmaceutical composition, preferably for topical administration, comprising an anti-psoriatic effective amount of 19-nor-pregnahexaen-20-one of formula (I) together with a non-toxic pharmaceutically acceptable carrier. Topical formulations comprising 1,6a-methyl-19-nor-pregnahexaen-20-ones of formula (II), especially 16a-methyl derivatives thereof with a free hydroxyl function at C-17, are preferred, pharmaceutical formulations comprising 16a-methyl -19-nor-pregna-1, 3 , 5 (10) , 6 , 8 ,14-hexaen-3,, 17a , 21-triol-20-one 21-acetate are particularly valuable.

The pharmaceutical formulations can be prepared according to known methods, some of which are described in detail in the following. Typical formulations include ointments, lotions, creams, sprays, powders, drops (eg, ear drops), suppositories, and aerosols. Ointments and creams can e.g. formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Such bases can thus include water and/or an oil (such as liquid paraffin) or a vegetable oil (such as peanut oil or castor oil). Thickeners-which may be used according to the nature of the base include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols, wool grease, hydrogenated lanolin, beeswax, etc. Lotions may be formulated with an aqueous or oily base, and will generally also include one or more of the following , namely stabilizers, emulsifiers, dispersants, suspending agents, thickeners, coloring agents, perfumes and the like. Powders can be formulated using any suitable powder base, e.g. talc, lactose, starch, etc. Drops can be formulated with an aqueous or non-aqueous base, and also include one or more dispersing agents, suspending agents, solvents, 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, chlorcresol, benzalkonium chloride, etc. They may also contain other active ingredients such as antimicrobial agents, especially antibiotics.

The invention thus also relates to pharmaceutical formulations for oral or parenteral administration which can be obtained by standard procedures and which comprise 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 amount of active steroid in the topical composition according to the invention depends on the exact type of formulation to be produced, but will generally be within the range from 0.0001 to 5% by weight. For most types of topical preparations, however, the amount of active steroid will be in the range of 0.1 to 3%, and preferably 0.1 to 1%. Based on studies of mice, by systematic administration, preferably parenterally, the necessary dose to induce an anti-mitotic response is in the range from 1 to 100 mg per kg body weight.

The following formulations exemplify some of the dosage forms in which the anti-mitotic agents according to the invention can be used. In this formulation, the active ingredient is 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17a,21-triol-20-one 21 -acetate. However, it will be understood that this compound is only a representative example and can be replaced with equivalent amounts of other active compounds according to the invention, e.g. with its 3-acetate, 3-benzoate or 15-chloro derivative.

FORMULATIONS

Formulation I: Ointment

Formulation

Procedure

Mix and heat to 65°C a balanced amount of white petrolatum, mineral oil, benzyl alcohol and cool to 50 - 55°C with stirring. Disperse the 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

Formulation

Procedure

Heat the stearic acid, glyceryl monostearate and polyethylene sorbitan monopalmitate to 70°C. Dissolve in a separate vessel sorbitol solution, benzyl alcohol, water and half the amount of propylene glycol and heat to 70°C. Add the aqueous phase to the oil phase with vigorous stirring, allowing the resulting emulsion to gradually cool. Dissolve the active ingredient in the remaining amount of propylene glycol and add the resulting solution to the above emulsion when the temperature of the latter is 37 - 40°C. Mix evenly while stirring and cool to room temperature.

Formulation III: Gel

Formulation

Procedure

Prepare a 1% solution of the sodium hydroxide in propylene glycol. and set this aside.. Mix separately approx.

half of the remaining amount of propylene glycol and polyethylene glycol .400, then dissolve the butylated hydroxytoluene in this mixture. Disperse the Carbomer 940 into the previous mixture with vigorous stirring, then add the sodium hydroxide solution with vigorous stirring to bring the pH of the solution up to 7 . Continue stirring until a thick gel forms. Dissolve the active ingredient in the remaining amount of propylene glycol. and add the resulting solution to the gel slowly and with continuous stirring.

x) see CFTA Dictionary

Formulation IV: Lotion

Formulation

Procedure

Prepare a 4% aqueous sodium hydroxide solution. Heat the purified water to 60°C, add Carbomer 940 and mix at high speed until these are dispersed. Cool the dispersion to room temperature and slowly add the sodium hydroxide solution until uniform mixing is achieved. Add 80% of the isopropanol to the above solution with stirring. Dissolve the active ingredient in the remaining amount of isopropanol and add to the mixture while stirring. Adjust pH to 5.0 - 5.5 with additional sodium hydroxide if necessary.

Formulation V: Tablets

Procedure

Prepare a slurry consisting of active ingredient, lactose and polyvinylpyrrolidone. Spray dry the slurry. Add the cornstarch and magnesium stearate. Mix and press into tablets.

Formulation VI: Parenteral Compositions

A. Intramuscular or subcutaneous oil injection

Formulation.

Procedure

The other ingredients are dissolved in sesame oil and brought to a total volume of 1 ml.

B. Intramuscular or subcutaneous aqueous suspension

Formulation

Procedure

The other ingredients are dissolved in water and brought to a total volume of 1 ml.

x) see CTFA Dictionary

Claims (1)

!• 19-nor-pregnahexaene derivatives of the general formula in which ; . - A is hydrogen, lower alkyl, fluorine or fluorine-substituted methyl; ^ is hydrogen, lower alkyl or an acyl radical of a carb oxylic acid of up to 12, preferably 8, carbon atoms; W is (H,H); (H, lower alkyl); (H,a-OR 2 ), where R 2 is hydro gene or an acyl radical of a carboxylic acid with up to 12, preferably up to 8 carbon atoms; or =CHT, where T is hydrogen, lower alkyl, fluorine or chlorine; Q is 0R4 , where R4 is hydrogen or an acyl radical of one carboxylic acid with up to 12, preferably up to 8 carbon atoms; hydrogen, provided that W is (H,H) or (H, lower alkyl); or together with W represents a. 16a,17d-lower. alkylidenedioxy group; Y is (H,H), (H,OH), or oxygen; Z is hydrogen, chlorine or bromine; R 1 is hydrogen or an acyl radical of a carboxylic acid with up to 12, preferably 8 carbon atoms; or OR^ together with Q denotes an alkylidenedioxy or alkylorthoalcaryo-ate group; and when Q is hydroxy and R 3 is hydrogen, 17a,20; 20,21-bismethylenedioxy derivatives thereof; except the 21-acetate and 3,21-diacetate of 19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17a,21-tridl-20-one." 2. Pharmaceutical compositions containing as active ingredient general formula (I) as defined in claim 1, including the compounds which in said claim are stated as exempt. 3. Compounds and compositions according to claims 1 and 2, wherein W in formula (I) denotes (H, α-methyl). 4. Compounds and compositions according to claim 3, characterized in that Q is OR^ (where R^ is as defined in claim 1); wherein each of A and Z is hydrogen; Y denotes (H,H) ; R^ is as defined in claim 1; and R 1 is hydrogen or an acyl radical of a carboxylic acid with up to 12, preferably up to 8, carbon atoms. 5. 16a-methyl-19-nor-pregna-1,3,5(10),6,8,14-hexaen-3,17a,21-triol-20-one 21 acetate and pharmaceutical compositions containing this. 6. Pharmaceutical compositions according to any one of claims 2-5, also containing a suitable pharmaceutical carrier, for use in eliciting a mitotic-inhibitory response in a warm-blooded animal with a disease characterized by how- . tig cell proliferation, especially for the treatment of psoriasis.-7. Process for the production of 19,nor-pregnahexaene derivatives according to claim 1, characterized in that (A) a suitable 19,nor-pregna-1,3,5(10),6,8-pentaene derivative is subjected to dehydrogenation at the 14(15) position; or (B) a suitable 11-unsubstituted pregna-1,4,6,8,14-pentaen-3-one is subjected to aromatization; or (C) a suitable 9α,113-dihalo-pregna-1,4,6-trien-3-dn is subjected to concomitant didehydrohalogenation and aromatization; it being understood that the aromatization as set forth in (B) and (C) naturally includes removal of the angled, methyl at C-10; and that the resulting 19-nor-pregna-1,3,5(10), 6,8,14-hexaene derivative is, if desired, subjected to one or more of the following optional final steps: (i) de-esterification and/or esterification by hydroxyl functions in one or more of the 3, 113, 16a, 17a and 21 positions; (ii) alkylation and/or dealkylation at the hydroxyl function in the 3-position; (iii) introducing or removing a 16α, 17α or 17α,21-alkylidenedioxy or a 17α,20;20,21-bismethylenedioxy function; (iv) reduction or oxidation of an 11-oxygen function; (v) chlorination or bromination in the 15-position. 8. Method according to claim 7A, characterized in that the dehydrogenation is carried out using at least one molar equivalent of 2,3-dichloro-5,6-dicyanobenzoquinone as dehydrogenating agent, in an aprotic solvent. 9. Process according to claim 8 for the preparation of such compounds of formula (I) in which Z is a chlorine or bromine atom, characterized in that the dehydrogenation of 19-nor-pregna-1,3,5(10),6,8-pentaene the starting compound which is unsubstituted in the 14-position is carried out using 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 to achieve accompanying 15-halogenation. 10. Method according to claim 7B, characterized in that the aromatization is carried out using a weak base, preferably in the presence of a soluble halogen salt such as lithium chloride, preferably using lithium chloride/diethylformamide. 11. Method according to claim 7C, characterized in that a suitable 9a,113-dichloro-pregna-1,4-dien-3-one is subjected to accompanying 6-dehydrogenification, didehydrochlorination and aromatization. 12. Method according to claim 11, characterized in that the reactions are carried out in situ at elevated temperatures using 2,3-dichloro-5,6-dicyanobbenzoquinone as dehydrogenating agent and in the presence of an acid in an aprotic solvent. 13.. 19-nor-pregnahexaene derivatives according to claim 1, obtained by the method according to any one of claims 7 - 12..