3,135,743 United States Patent Office Patented June 2, 1964

2 The 18, 19-bisnorsteroid, 18,19-norsteroid and normal 3,135,743 Steroid moieties in the compounds of the invention con STERGIDOI2,3-dSOXAZOLES AND PREPARATION tain, respectively, seventeen, eighteen and nineteen car THEREOF bon atoms plus any carbon content which may be pro Raynorad O. Clinton, East Greenbisia, and Andrew John vided by one or more nuclearly substituted carbon con Maason, North Greenbush, N.Y., assignors to Sterling taining radicals, up to and including a total of about Drug Inc., New York, N.Y., a corporation of Delaware twenty-three carbon atoms, exclusive of ester radicals. No Drawing. Filed June 29, 1960, Ser. No. 39,458 When acyloxy radicals are present in the steroid moiety, 32 Claims. (C. 260-239.55) the acyl radicals are preferably derived from carboxylic This invention relates to heterocyclic substituted ste O acids having from one to about ten carbon atoms, con roids, and in particular it is concerned with steroido (2.3- ventionally employed in the steroid art, and having a disoxazoles and the preparation thereof. molecular weight less than about 200. Representative of It has been found that new and useful compounds are the acyl radicals which can be present are lower-alkanoyl produced when an isoxazole ring is fused through its 4 radicals, e.g., formyl, acetyl, propionyl, butyryl, isobutyr and 5-positions to the 2- and 3-positions, respectively, of 5 yl, caproyl, heptanoyl, octanoyl, trimethylacetyl, and the a steroid nucleus, said steroid having from seventeen to like; carboxy-lower-alkanoyl radicals, e.g., succinyl (B- about twenty-three carbon atoms exclusive of ester radi carboxypropionyl); cycloalkyl-lower-alkanoyl radicals, cals. e.g., g-cyclopentylpropionyl, 3-cyclohexylpropionyl, and The ring structure of the compounds of the invention is the like; monocarbocyclic aroyl radicals, e.g., benzoyl, p represented by the following structure: 20 toluyl, p-nitrobenzoyl, 3,4,5-trimethoxybenzoyl, and the like; monocarbocyclic aryl-lower-alkanoyl or -alkenoyl radicals, such as phenylacetyl, 3-phenylpropionyl, cin namoyl, and the like; and monocarbocyclic aryloxy lower-alkanoyl radicals, such as p-chlorophenoxyacetyl, 25 and the like. Esters of inorganic acids such as phosphoric acid are also contemplated. The compounds of the invention are prepared by react ing a 2-(1-hydroxyalkylidene)-3-oxo-steroid with hy droxylamine or an acid-addition salt thereof according to 30 the following equation: The exact nature of the steroid moiety is not critical, and it can be derived from any steroid of the general type R known to exhibit hormonal or other pharmacological or endocrinological properties. Such steroid moieties have 35 HNOH -- Hot-6Q --> N 4.YQ. -- 2:O from seventeen to about twenty-three carbon atoms, not -3 N counting carbon content which may be provided by esteri O fied hydroxy groups. Esterified hydroxy-steroids are in () (II) cluded within the scope of the invention, but the carbon content contributed by the acid moiety of the ester is not 40 In the above general Formulas I and II, Q represents considered part of the essential carbon content of the the remaining portion of the steroid moiety described steroid. above. In the above Formulas I and II, R represents a The steroid moiety can be any member of the estrane, hydrogen atom or a lower-alkyl radical, the latter hav 18-norestrane, androstane, etiocholane, pregnane or allo ing preferably from one to about four carbon atoms, thus pregnane series. The foregoing can contain varying de 45 including such groups as methyl, ethyl, propyl, isopropyl, grees of unsaturation and a variety of substituents in the butyl, and the like. form of hydrocarbon radicals or functional groups con The condensation of the hydroxylamine with a 2-hy ventionally employed in the steroid art. Representative droxyalkylidene-3-oxo-steroid is carried out by heating of the steroid moieties which make up the compounds Said steroid with at least one molar equivalent of hy of the invention are those having at position 17 a hy 50 droxylamine or acid-addition salt thereof in an inert sol droxy, acyloxy, oxo, or both a hydroxy and a lower-alkyl vent at a temperature between about 50° C. and 150° C. radical, characteristic of the androgenic and anabolic The inert solvent is preferably a lower-alkanol, e.g., meth steroids; or a lower-alkenyl, lower-alkynyl, acetyl, hy anol, or ethanol, or a lower-alkanoic acid, e.g., acetic droxyacetyl, 1,2-dihydroxyethyl, 1-hydroxyethyl, and the acid or propionic acid, or a mixture of an alcohol and like radicals, characteristic of the progestational and 55 an acid. The reaction is catalyzed by the presence of a adrenal cortical steroids. The steroid moiety can also weak or moderate acid such as acetic acid, although if a have one or more substituents at other positions of the strong acid is present it may cause dehydration of a hy nucleus, for example, hydroxy, acyloxy, or oxo radicals droxy group in the 17-position, followed by deep-seated at positions 6, 7, 11, 12, 14 or 16; halogen atoms, prefer rearrangement of the steroid nucleus. In the event an ably fluorine, chlorine or bromine, for example, at the 60 acid-addition salt of hydroxylamine, such as the hydro 4-, 6-, 7-, 9-, 12-, 16-, 17- or 21-positions; and lower-alkyl chloride, is used, an approximately equivalent amount of groups, for example, at the 4-, 5-, 6-, 7-, 11- or 16-posi a Salt of a strong base and a weak acid, e.g., sodium tions. The steroid moiety can also have one or more acetate, is added to convert the strong acid of addition double bonds, especially at the 4,5- and/or 1,2- and/or to a weak acid in order to prevent dehydration and re 6,7-positions. The steroid moiety usually possesses angu 65 arrangement. 17-hydroxy groups can also be protected lar methyl groups at C1 and C13, although 18- and 19 by esterification prior to isoxazole formation, norsteroids and 18, 19-bisphorsteroids, lacking one or both If the steroid moiety has a double bond already pres of the angular methyl groups at C13 and C10, respectively, ent in the 1,2-position, the essential steroid intermediate are also representative steroids. is a 2-formyl-A-steroid (III; R is H) or a 2-lower-alka 3,135,743 4. noyl-Al-steroid (III; R is lower-alkyl). The reaction is In the above general Formulas V, VI and VII, R', when represented by the following equation: it represents a lower-alkyl, lower-alkenyl, or lower-alkynyl R radical, has from one to about four carbon atoms and may be straight or branched, and thus includes such groups R d 5 as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary O=C- % - ? ? butyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, propargyl, HNOH + . Q. --> N Q. --2HO and the like. O= The compounds of Formulas V, VI and VII are pre O N pared by reacting the appropriate 2-(1-hydroxyalkyli (III) (IV) 0 dene)-3-oxo-steroid, viz.: The intermediate 2-acyl-Al-steroid (III) can be pre pared by bromination or chlorination of a 2-acyl steroid R (I) in the 2-position, followed by dehydrohalogenation Y Z. with collidine or with lithium chloride in dimethylform amide solution. R Y Compounds having an aromatic ring A characteristic of r estrogens (estratriene compounds), viz.: Ho-3- f O - C 20 (VIII) or the corresponding compounds where double bonds are ... present in the 4,5- or the 4,5- and 6,7-positions, with hy KCCN/ N droxylamine or an acid-addition salt thereof; R, R, X, Z, can be prepared by dehydrogenation of the correspond 25 Y and Y have the same meanings given above. When ing A-19-norsteroido-isoxazole by conventional proce the steroid moiety contains, oxo groups in addition to the dures, as by heating with palladium-on-carbon catalyst. one at position 3, they can be protected as a ketal derival A particularly preferred group of compounds, derived tive to prevent side reactions with the hydroxylamine from readily available starting materials, comprises those (oxime formation). For example, when compounds in having the structural formula which R' represents acetyl or hydroxyacetyl are desired, 30 these radicals can be ketalized by known methods, e.g., R - with ethylene glycol, prior to introduction of the hydroxy Vrz alkylidene radical at the 2-position and reaction with hy - X droxylamine. It has been found, however, that 3,20 d;f Y r 35 dioxo-steroids bearing hydroxy groups at the 17- and 21 N positions can be selectively formylated in the 2-position without protecting the 20-oxo group by ketalization. . The 20-monoketals of 3,20-dioxo-steroids are prepared from the 3,20-diketals by selective hydrolysis by known methods, e.g., by allowing the diketal to stand at room tem (V) perature in acetone solution containing a trace of p-tolu wherein R represents hydrogen or a lower-alkyl radical; enesulfonic acid. The ketal groups are readily cleaved by R’ represents hydrogen or a lower-alkyl, lower-alkenyl, dilute acid after the condensation with hydroxylamine. lower-alkynyl, the acetyl, the hydroxyacetyl, the 1,2-dihy An oxo group at the 11-position is relatively unreactive droxyethyl or the 1-hydroxyethyl radical; X is selected and need not be protected before reaction with hydroxyl from the group consisting of H2. (H) (OH) and O; Y amine. - and Y represent hydrogen or the methyl radical; and Z In addition to the other uses set forth below, the com represents hydrogen or the hydroxy radical, Z being re pounds of the invention are useful as intermediates in the stricted to hydroxy when R represents hydrogen, or a preparation of different species within the scope of the lower-alkyl, lower-alkenyl or lower-alkynyl radical. Also invention by introduction of new groups or alteration of representative of the invention are carboxylic acid esters, 50 groups already present, in the steroid nucleus by known acid-addition salts and quaternary ammonium salts of the methods. For example, a steroido (2.3-disoxazole having foregoing compounds, as well as those having one double a hydroxy group in the 17-position of the steroid nucleus bond in the 4,5-position (V), or two double bonds, one - (V, VI or VII; R is H, Z is OH) can be oxidized to the in the 4,5-position and the other in the 6,7-position (VI): corresponding 17-oxo compound. As another instance, a 55 steroido 2.3-disoxazole having a 1-hydroxyethyl radical R in the 17-position (V, VI or VI; R is CHCH(OH)- x=/N Z is H) can be oxidized to the corresponding 17-acetyl y compound (V, VI or VII;R is CH3CO-, Z is H). 60 The intermediate 2-hydroxyalkylidene-3-oxo-steroids N (I) are prepared by condensing a 3-oxo-steroid, a 3-oxo All A-steroid or a 3-oxo-A,6-steroid with a lower-alkyl lower alkanoate, RCOOR', wherein R is hydrogen or lower o/NA alkyl and R' is lower-alkyl, in the presence of a strong (VI) base under anhydrous conditions. The strong base is 65 preferably an alkali metal lower-alkoxide or amide (cf. R Ruzicka U.S. Patent 2,281,622), or hydride. An acyl Y' -z group enters the 2-position with elimination of a molecule . of an alcohol as follows: l Y H i? 70 H-Y R-co-Y RCO OR. -- Q + ROH O =N (VII) 75 In the case wherein the radical R is lower-alkyl an alter 3,135,743 red s 3. native and preferred method comprises treating the 3-oxo activity only about one-eighth that of testosterone propi Steroid with a lower-alkanoic acid anhydride in the pres onate. Anabolic agents are useful in the alleviation of ence of boron trifluoride. Steroids containing a 17-hy conditions arising from poor nitrogen utilization in various droxy group, particularly the 17-hydroxy-17-alkylsteroids, debilitating diseases by accelerating the growth of new can be protected against dehydration by prior esterifica healthy tissue. tion. Generally speaking, the common anabolic agents possess Although, by analogy with halogenation procedures, it a moderate to high degree of androgenic activity and their would be expected that ring A saturated compounds of us in females leads to undesirable side-effects such as the etiocholane series (ring juncture A/B cis) would form virilism and hirsutism. Therefore, the separation of these 4-hydroxyalkylidene derivatives rather than 2-hydroxy 0. activities, as found in the compounds of the present in aikylidene derivatives, it has been found that the latter are vention, which have high anabolic but low androgenic ac produced preponderantly. This was proved by preparing tivities, is a highly desirable feature. a A4-steroido[3.2-c pyrazole from a 2-hydroxymethylene The compounds of the invention can be prepared for 4-steroid, according to the method described in the co use by dispersing them in an aqueous suspension or by pending application of R. O. Clinton, Serial No. 723,148, dissolving them in a pharmacologically acceptable oil or filed March 24, 1958, hydrogenating the double bond to oil-water emulsion for parenteral administration; or by produce a mixture of saturated steroido 3.2-c pyrazoles of incorporation in tablet form with excipients for oral ad the androstane and etiochclane series, and showing that ministration. the etiocholane isomer was identical with that produced The structure of the compounds of the invention was by direct formation of the pyrazole from the hydroxy 20 established by the mode of synthesis, their ultraviolet and methylene derivative of the parent etiocholane compound. infrared spectra, and by the fact that the values found if the hydroxymethylene group had entered the 4-position, upon elementary analysis corresponded with the values cal the resulting prazole would have been fused to the 3,4- culated for the assigned structures. Further evidence is position of the steroid nucleus and would have been differ provided by the fact that the steroido2.3-disoxazoles of ent from the etiocholanopyrazole obtained by hydrogena 25 the invention are cleaved by strong base to produce 2 tion of the A-compound. Therefore, etiocholane as well cyano-3-oxo-steroids (IX) as androstane compounds are useful as starting materials in the preparation of the compounds of the invention. NC Isoxazoles are weakly basic substances and will form Q O Q acid-addition salts upon addition of strong acids and qua 30 O ternary ammonium salts upon addition of esters of strong N\, acids. (IX) (X) The quaternary ammonium salts of the compounds of This is analogous to the known cyclohexanodisoxazole the invention are prepared by causing a steroido 3.2-d- which is produced as the major product of the reaction of isoxazole to react with an ester of a strong inorganic or 35 2-hydroxymethylenecyclohexanone and hydroxylamine, organic sulfonic acid, said ester preferably having a molec and is cleaved by base to produce 2-cyanocyclohexanone. ular weight less than about 200. A particularly preferred If the hydroxylamine and 2-hydroxymethylene steroid had class of esters, because of their ready availability, are reacted in reverse fashion, the resulting product, a ste lower-alkyl, lower-alkenyl and lower-aralkyl esters, for ex roido (3.2-clisoxazole (X), would be stable to base as it ample, methyl iodide, ethyl iodide, ethyl bromide, propyl 40 is known that cyclohexano[c]isoxazole is stable to base. bromide, butyl bromide, allyl bromide, methyl sulfate, methyl benzenesulfonate, methyl p-toluene-sulfonate, In the 2-cyano-3-oxo-steroids (DX), the 2-cyano group as benzyl chloride, o-chlorobenzyl chloride, and the like. Sumes the Cz-configuration in steroids of the androstane The reaction of the steroido 2.3-disoxazole and the qua series and in A- and A5-steroids, whereas it assumes the ternizing agent takes place upon simple admixture of the 45 g-configuration in steroids of the etiocholane series. The components, preferably in the presence of an inert organic 2-cyano-3-oxo-steroids are also within the purview of the solvent, although heating may be applied to accelerate the invention and have been found to possess hormonal prop reaction. erties, for example, anabolic and adrenal inhibiting ac The acid-addition and quaternary ammonium salts pref tivities. erably have anions which are pharmacologically accepta 50 The following examples will further illustrate the inven ble, that is, the anions do not appreciably increase the tox tion without the latter being limited thereby. icity of the compound as a whole toward animal orga Example 1 nisins. Such anions include, for example, the chloride, bromide, iodide, sulfate or acid sulfate, methanesulfonate, (a) 2-hydroxymethylene-17a-methyl-4-androsten - 1 76 benzenesulfonate, and the like. Salts having toxic anions 5 5 ol-3-one.--To a dry 2 liter, 3-necked flask, fitted with a are, however, useful in that they serve as characterizing stopper, gas outlet stopcock and a condenser arranged for derivatives of the steroido 2.3-disoxazoles, and serve as distillation into a receiver equipped with a calcium chlo intermediates for non-toxic quaternary salts by conven ride tube, was added a solution of 50.0 g (0.165 mole) of tional ion exchange reactions. All acid-addition salts, re 17a-methyl-4-androsten-176-ol-3-one in 1200 ml. of ben gardless of the nature of the anions, are useful as interme 60 Zene. A portion of the benzene (200 ml.) was removed diates in the purification of the free bases. by distillation to insure anhydrous conditions. The dis Endocrinological studies of the compounds of the in tillation apparatus was replaced with an outlet tube con vention have shown that they possess useful metabolic, nected to a gas trap which consisted of a U-tube filled with hormonal and anti-hormonal properties. In particular, an amount of mercury that would allow the escape of any they exhibit one or more of the following activities: ana 65 positive pressure built up in the reaction flask. A slow bolic, androgenic, pituitary inhibiting, estrogenic, progesta stream of nitrogen was introduced into the reaction flask tional and adrenal cortical. through the gas outlet stopcock. Sodium hydride (10.0 The compounds of the invention further possess advan g., 0.42 mole) and 35 ml. (0.43 mole) of ethyl formate, tages in being anabolic (myotrophic and nitrogen reten previously dried over phosphorus pentoxide and distilled, tive) at dose levels at which they do not shown an appre 70 Were added. The reaction mixture was allowed to stand ciable degree of sex hormonal properties. For example, at room temperature under a nitrogen atmosphere for five 17,3-hydroxy-17a-methyl - 4 - androsteno2.3-disoxazole days, after which time an orange gel had formed and no was found to have a myotrophic activity in rats about further evolution of gas could be observed. The reaction one-fourth to one-half that of testosterone propionate flask was fitted with a mechanical stirrer, and 25 ml. of upon subcutaneous injection while having an androgenic 75 methyl alcohol was carefully added with stirring to de 3,135,743 ry compose excess sodium hydride. The reaction mixture 100 ml. of 5% sodium hydroxide was added. The latter was poured into 1500 ml. of water and shaken. The mixture was shaken, and the ether layer was separated, layers were separated, and the aqueous layer was extracted washed three times with 5% sodium hydroxide solution with ether, cooled to ice bath temperature and acidified and once with water. The combined aqueous layers and with concentrated hydrochloric acid containing ice. The undissolved material was cooled to 10° C. and acidified solid product was collected by filtration, washed with water with concentrated hydrochloric acid containing ice. The and dried at 60° C. for twenty-four hours in vacuo, giving acidified mixture was extracted twice with ethyl acetate, 49.1 g of 2-hydroxymethylene-17a-methyl-4-androsten and the extracts were dried over anhydrous sodium sul 176-ol-3-one. A sample when recrystallized from a meth fate, saturated with nitrogen and concentrated in vacuo anol-water mixture had the M.P. 178.5-180°C. (corr.), using a stream of nitrogen. The residue was recrystallized crld'8= --14.0 (1% in chloroform); ultraviolet maxima twice from an ether-hexane mixture and dried at 95 C. at 252 and 307 mu (E-12,000- and 6,030). -- ... in vacuo for eight hours to give 2c -cyano-17a-methyl-4- Analysis.-Calcd. for CHOs:- C, 76.32; H, 9.15. androsten-176-ol-3-one, M.P. 1672-171.0° C. (corr.), Found: C, 76.36; H, 9.19. alp?S= --93.0--0.1 (1% in chloroform); ultraviolet (b) 176 - Hydroxy - 17ox - methyl-4-androstenoI2.3-d 5 maxima at 243 and 310 mu (E=14,600 and 465). isoxazole VI; R is H, R' is CH, X is H. Z is OH, Y and Analysis.-Calcd. for CH3NO2: C, 77.02; H, 8.93; Y are CH3.- To a 500 ml, 3-necked flask, equipped with O, 9.77. Found: C, 76.98; H, 8.88; O, 9.90. a sealed Hershberg-type stirrer, a reflux condenser and a stopper, was added a solution of 20.0 g (0.0605 mole) of Example 2 2 - hydroxymethylene - 170-methyl-4-androsten-176-ol-3- 20 (a) 2 - hydroxymethylene - 17o-ethyl-4-androsten-176 one in 300 ml. of 95% ethanol. Stirring was commenced ol-3-one was prepared from 17.19 g. of 17c-ethyl-4-an- - and a slurry of 4.80 g. (0.0585 mole) of fused sodium ace drosten-17,3-ol-3-one, 17 ml, of ethyl formate and 5 g. of tate and 4.42 g. (0.0635 mole) of hydroxylamine hydro sodium hydride in 350 ml. of benzene according to the chloride in 100 ml. of glacial acetic acid was added. The manipulative procedure described above in Example 1, mixture was refluxed gently on a steam bath for one and 25 part. (a). The acidic product was obtained in the form one-half hours. Fifteen minutes after initiating the reac of a gum which was converted to its sodium salt and used: tion, the reaction mixture gave a negative ferric chloride directly in the next reaction without further purification. test. Most of the ethanol and acetic acid were removed by (b) 178 - hydroxy - 17cy - ethyl - 4-androsteno,2,3-d distillation in vacuo, 300 ml. of water and 300 ml. of isoxazole Vi; R is H., R is CH5, X is HZ is OH, Y ether were added to the concentrate, and the mixture was 30 and Y are CH was prepared from 7.32 g. of the sodium shaken. The layers were separated, the aqueous layer salt of 2-hydroxymethylene-17 oz-ethyl-4-androsten-176-ol extracted with fresh ether, and the combined ether ex 3-one, 2.1 g of hydroxylamine hydrochloride, 5.g. of tracts were washed with water, dried over anhydrous sodium acetate trihydrate and 50 mi. of acetic acid ac-. sodium sulfate, filtered and evaporated to dryness in cording to the manipulative procedure described above in vacuo. The residue was crystallized by trituration with 35 Example 1, part (b). The crude product was obtained ether, and the crystals were collected by filtration, washed in the form of a brown resin which was chromatographed with hexane and dried, giving 12.0 g., M.P. 164-175 C. on a column of silica gel in benzene solution. The column (uncorr.). The mother liquors were concentrated to dry was eluted with benzene containing increasing amounts ness and dissolved in a minimum amount of acetone, of ether, and 10% ether brought out 4.10 g. of 176-hy whereupon a second crop was obtained, 2.5 g., M.P. 40 droxy - 170 - ethyl - 4 - androsteno2.3-disoxazole, M.P. 164-175 C. (uncorr.). The two crops were combined, 145.0-148.2°C. (corr.) after recrystallization successively dissolved in ethyl acetate, decolorized with activated char from an ethyl acetate-ether mixture, benzene, and a ben coal, and recovered by concentration, yielding 11.8 g. of zene-ethyl acetate mixture and drying at 90-100° C. and 17B - hydroxy-17a-methyl-4-androstenoI2.3-disoxazole, 20 mm. for eight hours, ox25= --94.80.0 (1% in M.P. 177.0-179.6°C. (corr.) after a second recrystalliza 45 chloroform); ultraviolet maximum at 286 mu, (E= tion from acetone; op?5= --108.8+0.3 (1% in chloro 10,870). s - form); ultraviolet maximum at 285 mu (E=11,900). Analysis.-Calcd. for C2HNO: C, 77.37; H, 9.15; Analysis-Calcd. for CHNO: C, 77.02; H, 8.93; O, O, 9,37. Found: C, 77.33; H, 9.27; O, 9.33. 9.77. Found: C, 76.90; H, 8.77; O, 9.80...... 17,3 - hydroxy-17o-ethyl-4-androstenoI2.3-disoxazole When measured by its effect upon the growth of the was found to possess pituitary inhibitory activity. levator ani muscle in the rat, 179-hydroxy-17 oz-methyl-4- 50 androstenoi2.3-disoxazole was found to have a myo Example 3 trophic activity about one-fourth to one-half that of testos (a) 2 - hydroxymethylene - 17o-vinyl-4-androsten-176- . terone propionate upon subcutaneous administration ol-3-one.-A mixture of 12.04 g. of 17c-vinyl-4-an while having an androgenic activity only about one-eighth 55 rosten-176-ol-3-one, 12 ml. of ethyl formate and 4.0 g. that of testosterone propionate. In nitrogen retention of sodium hydride in 300 ml. of benzene was kept at studies in the rat, another measure of anabolic activity, room temperature for three days under a nitrogen atmos this compound was found to be about one-fourth as active phere. After this time about 2 g. of sodium methoxide as testosterone propionate. was added and the reaction mixture allowed to stand for 17(3-hydroxy-17o-methyl-4-androsteno2.3-disoxazole 60 seven days longer. The reaction mixture was worked up can be caused to react with hydrochloric acid, hydro according to the manipulative procedure described above bromic acid, sulfuric acid or methanesulfonic acid to give in Example 1, part (a), giving 11.46 g. of 2-hydroxy the hydrochloride, hydrobromide, sulfate (or bisulfate) methylene - 17 or - vinyl-4-androsten-176-ol-3-one in semi or methanesulfonate salt, respectively. crystalline form. 17(3-hydroxy-17a-methyl-4-androstenoI2,3-disoxazole 65 (b) 17,3-hydroxy-17c-vinyl-4-androstento2.3-disoxa can be caused to react with methyl iodide, ethyl bromide, zole VI: R is H, R is. CH=CH X is H. Z is OH, Y allyl bromide, methyl sulfate or benzyl chloride to give and Y are CH-1.01.g. of sodium acetate and 0.95 the methiodide, ethobromide, allobromide, methosulfate g. of hydroxylamine hydrochloride in 5 ml. of water or benzochloride salt, respectively. w was added to a solution of 4.45 g. of 2-hydroxymethyl (c) 2a -cyano-17a-methyl-4-androsten-17B-ol-3-one.-- 70 ene-17a-vinyl-4-androsten-176-ol-3-one in about 90 ml. A solution of 5.00 g. of 176-hydroxy-17a-methyl-4-an of ethanol, and the mixture was heated on a steam bath drosteno2.3-disoxazole in 500 ml. of absolute ether was for two hours. The reaction mixture was poured into added to a solution of sodium methoxide prepared from water, and the product was extracted with ether. The 0.5 g. of sodium and 5 ml. of absolute methanol. The ether extracts were dried and concentrated and the residue mixture was shaken for one hour, poured into water and 75 was recrystallized first from aqueous methanol and then 3,135,743 from an ethyl acetate-hexane mixture to give 17,3-hy Example 5 droxy - 17 a - vinyl-4-androsteno 2,3-disoxazole, M.P. (a) 2-hydroxymethylene-17a-methylandrostan-176-ol 139.2-145.2° C. (corr.), c.25- -82.1-0.1 (1% in 3-one.-A solution of 20.7 g. of 17a-methylandrostan chloroform); ultraviolet maximum at 285 mu (E= 173-ol-3-one in 500 mi. of benzene was added to sodium 10,600). methoxide (prepared by dissolving 15.0 g. of sodium in Analysis.-Calcd. for C2HNO2: C, 77.84; H, 8.61; 250 mi. of absolute methanol, concentrating the solution O, 9.43. Found: C, 77.82; H, 8.90; O, 9.15. and drying the residue for one hour at 150-160 C. and 15 mm.). Ethyl formate (48.8 g.) was then added with Example 4 stirring in a nitrogen atmosphere. The reaction mixture O was stirred for four hours longer at room temperature, (a) 2-hydroxymethylene-4-androsten-176-ol-3-one was allowed to stand for about fifteen hours, stirred for two prepared from 25 g. of testosterone, 7.5 g. of sodium hours longer and then poured into water. The reaction hydride and 25 ml. of ethyl formate in 500 ml. of dry mixture was extracted with benzene, the aqueous layer benzene according to the manipulative procedure de warmed until clear, filtered and cooled below room tem scribed above in Example 1, part (a). There was thus perature. Concentrated hydrochloric acid and ice were obtained 21.63 g. of 2-hydroxymethylene-4-androsten added to the filtrate until the mixture was acid to Congo 178-ol-3-one in crystalline form. red, and the product was extracted with chloroform. (b) 17B - propionoxy - 4 - androsteno2.3-disoxazole The chloroform extracts were washed with water, dried V; R and R are H, X is H. Z is OCCCHCH, Y and over anhydrous sodium sulfate, filtered and concentrated Y are CH-A mixture of 4.0 g. of 2-hydroxymethyl 20 in vacuo to a volume of 80 mi., whereupon there sep ene-4-androsten-17 3-ol-3-one, 1.3 g. of hydroxylamine arated 14.89 g, of 2-hydroxymethylene-17c-methylan hydrochloride and 180 m. of propionic acid was stirred drostan-176-ol-3-one, M.P. 179-183° C. (uncorr.). A for about eight hours at 70-80 C. The reaction mix sample when recrystallized from an ether-methanol mix ture was concentrated in vacuo, water was added to the ture and dried at 80° C. in vacuo had the M.P. 185 residue, and the mixture was extracted with benzene. 25 190.5 C. (corr.), c.25=-|-35.9° (1% in chloroform); The benzene extracts were washed twice with 10% sodi ultraviolet maximum at 282 mg (E=10,300). um bicarbonate solution, dried over anhydrous sodium Analysis.-Calcd. for CHOs: C, 75.86; H, 9.70. sulfate and concentrated. The residue was dissolved in Found: C, 76.10; H, 9.53. ether, the solution decolorized with activated charcoal, (b) 17,3-hydroxy-17 cy-methylandrostano 2.3-disoxa filtered, and treated with methanol to cause crystalliza 30 zole IV; R is H, R is CH, X is H, Z is OH, Y and Y’ tion of the product. There was thus obtained 2.1 g. - are CH3 (rings A/B trans). To a solution of 3.88 g. of 17g-propionoxy-4-androsteno2.3-disoxazole, M.P. of Sodium acetate trihydrate in 5 ml. of water was added 129.8-133.6 C. (corr.) when recrystallized from ethyl 2.09 g. of hydroxylamine hydrochloride, and methanol acetate; c.25=-103.1-0.2 (1% in chloroform); was added until solution resulted. This solution was ultraviolet maximum at 285 mu (E=11,319). added to a solution of 10.0 g. of 2-hydroxymethylene Analysis.-Calcd. for CHNO3: C, 74.76; H, 8.46; 17a-methylandrostan-17 (3-ol-3-one in 200 m. of absolute O, 13.0. Found: C, 74.80; H, 8.26; O, 13.0. methanol, and the combined solution was refluxed for 176 - propionoxy - 4-androsteno2.3-disoxazole was thirty minutes on a steam bath. The reaction mixture found to possess myotrophic activity accompanied by a was concentrated, the residue extracted with ethyl ace low degree of androgenic activity. 40 tate, and the ethyl acetate extracts were washed with (c) 17:3-hydroxy-4-androsteno2.3-disoxazole Vi; R ethyl acetate, and the ethyl acetate extracts were washed and R are H, X is H, Z is OH, Y and Y are CH was with 5% hydrochloric acid, dried over anhydrous sodi prepared by carrying out the procedure described above urn sulfate and concentrated to a volume of 40 ml, in Example 4(b) in ethanol instead of propionic acid. whereupon there separated 2.82 g. of solid material, M.P. It was obtained in the form of light brown crystals, M.P. 222-234 C. (uncorr.). The mother liquors were con 183.2-184.2° C. (corr.), cal25=-122.8 (1% in 95% centrated to dryness and the residue recrystallized from ethanol). ether to give 3.32 g. of solid product, M.P. 160-168 C. Analysis.-Calcd. for C2HNO2: C, 76.64; H, 8.68; (uncorr.). The latter was chromatographed on a col N, 4.47. Found: C, 76.95; H, 8.63; N, 4.56. umn of silica gel in benzene solution, recrystallized from 17,3 - hydroxy - 4 - androsteno2.3-disoxazole was 50 ethyl acetate and dried at 75° C. for twenty hours to found to possess anabolic activity (nitrogen retention) at give 17g-hydroxy-17c-methylandrostano 2.3-disoxazole, 0.5 mg/kg./day in the rat. M.P. 171.4-173.2° C. (corr.), c.25=-42.8-0.2 (1% (d) 17B - (4 - chlorophenoxyacetoxy)-4-androsteno in choroform); ultraviolet maximum at 228 mu (E= 2.3-disoxazole IV; R and R' are H, X is H, Z is 5,100). OCOCHOCHAC-4, Y and Y are CH was prepared 55 Analysis.-Calcd. for C2H31NO2: C, 76.55; H, 9.48; from 17B-hydroxy-4-androsteno2.3-disoxazole and p O, 9.71. Found: C, 76.70; H, 9.55; O, 10.00. chlorophenoxyacetyl chloride in pyridine. It was ob 17,3 - hydroxy - 17o - methylandrostano 2.3 - disoxa tained in the form of straw-colored crystals, M.P. 172.8- Zoe was found to possess myotrophic activity accom 174.8 C. (corr.), (c.125=-|-92.9 (1% in chioroform). panied by a low degree of androgenic activity. Analysis.--Calcd. for CH3CNO: C, 69.77; H, 6.69; 60 176 - hydroxy - 17 c. - methylandrostano 2.3 - disoxa C1, 7.36. Found: C, 69.72; H, 6.48; C1, 7.48. Zole was rearanged with base to give 2c -cyano-17 cy-meth 175-(4-chlorophenoxyacetoxy) - 4 - androsteno 2,3-d ylandrostan-17(3-ol-3-one, M.P. 252.4-257.8° C. (corr.), isoxazole was found to possess anabolic activity (nitro olp25---50.7 (0.5% in pyridine). gen retention) at 1.0 mg./kg/day in the rat. Example 6 (e) 173 - (3 - cyclohexylpropionoxy)-4-aridrosteno 65 (a) 2 - hydroxymethylene - 17cz - methyletiocholan - 2.3-disoxazole VI; R and R are H, X is H, Z is 17g-ol-3-one.--To 4.8 g. (0.2 mole) of sodium hydride OCOCH2CH2C6H11, Y and Y are CHs was prepared Suspended in 75 ml. of benzene was added 3.2 g (0.1 from 17B-hydroxy-4-androsteno 2.3-disoxazole and 3 mole) of methanoi. After the reaction subsided, the cyclohexylpropionic anhydride in pyridine. It was ob mixture was heated to boiling, cooled, and treated with tained in the form of colorless crystals, M.P. 86.2-87.4 a mixture of 20.8 g. (0.068 mole) of 17a-methyletio C. (corr.), op?5=-|-93.3 (1% in chloroform). cholan-176-ol-3-one, 75 ml. of benzene, and 21 m. of Analysis.-Calcd. for C2HNO3: C, 77.12; H, 9.15; ethyl formate. The mixture was stirred vigorously for N, 3.10; O, 10.63. Found: C, 77.36; H, 8.97; N, 3.34; four hours, mixed with 200 ml. of water, and the layers O, 10.90. 75 Were separated. The water layer was washed with ether 3,135,743 A and then acidified with hydrochloric acid. The result the solid sodium salt and used directly in the next reac ing precipitate was collected by filtration and dried, giving tion. - . . . - 17.8 g. of 2-hydroxymethylene-17a-methyletiocholan-17F (b) 173 - hydroxy-17a-ethylandrostano[2.3-d isox ol-3-one, suitable for use in the succeeding reaction. A azole IV: R is H, R is CH5, X is H, Z is CH, Y and sample was further purified by chromatography on 100 5 Y are CH-A mixture of 3.18 g. of the sodium salt g. of silica gel in an equal volume mixture of ether and of 2-hydroxymethylene-17a-ethylandrostan-17f8-ol-3-one, pentane. The resulting solid was recrystallized from 1.1 g of hydroxylamine hydrochloride, 20 ml. of ethanol ether, giving colorless needles, M.P. 205.6-211.6. C. and 20 ml. of acetic acid was refluxed for two hours. The (corr.), 25=-0.3-0.2 (1% in chloroform); ultra product was separated and purified by chromatography violet maxima at 285 and 347 mu (E=7,200 and 1,500). O on silica gel in benzene solution. The resulting product Analysis.--Calcd. for Cai H3O3: C, 75.86; H, 9.70. was recrystallized from benzene and dried at 70 C. and Found: C, 75.69; H, 9.74. 20 mm. for eight hours to give 17,3-hydroxy-17a-ethylan (b) 178 - hydroxy - 17c. - methyletiochlolano.2.3 - d. drostano (2,3-d)-isoxazole, M.P. 144.4-148.6 C. (corr.), isoxazole IV; R is H, R is CH3, X is H2, Z is OH, Y and c25=-|-36.2-0.2 (1% in chloroform); ultraviolet Y are CH (Rings A/B cis)}-A stirred mixture of 3.32 5 maximum at 225 mu (E=4,410). - g. (0.01 mole) of 2-hydroxymethylene-17a-methyletio Analysis.-Calcd. for CH3NO2: C, 76.92; H, 9.68; cholan-176-ol-3-one, 1.31 g (0.016 mole) of fused so dium acetate, 1.01 g (0.015 mole) of hydroxylamine N, 4.08. Found: C, 76.77; H, 9.51; N, 4.05. hydrochloride and 100 ml. of acetic acid was heated at Example 9 60° C. for six and one-half hours. The mixture was 20 (a) Allopregnan - 36- ol - 20 - one 20 - ethylene glycol cooled and poured into 200 ml. of water, and the pre ketal.-A mixture of 27.4 g. (0.086 mole) of allopregnan cipitated solid was collected and chromatographed on 100 36-ol-20-one, 33 ml. of ethylene glycol, 700 ml. of ben g of silica gel in ether containing 20% pentane. The zene and 1.g. of p-toluenesulfonic acid was refluxed for resulting product was recrystailized from acetone to give 78 hours with a water separator in the system. The reac 1.01 g of 17g-hydroxy-170-methyletiocholano (2,3-d- 2 5 tion mixture was then cooled and shaken with 100 ml, of isoxazole in the form of colorless needles, M.P. 244.2- 2 N sodium hydroxide solution, and the resulting mixture 250.2° C. (corr.), c.25-37.9+0.2 (1% in chloro was filtered to collect. 20.5 g. of allopregnan-3,3-ol-20-one form); ultraviolet maximum at 226 mu, (E=4,300). 20-ethylene glycol ketal, M.P. 166-169° C. (uncorr.). Analysis.--Calcd. for CH3NO2: C, 76.54; H, 9.48; When the latter was recrystallized from acetone, the com N, 4.25. Found: C, 76.65; H, 9.53; N, 4.23. 30 pound was obtained in the form of colorless plates, M.P. 178 - hydroxy - 17c. - methyletiocholano[2.3 - disoxa 172.5-175 C. (uncorr.). - zole was found to possess anti-estrogenic activity. (b) Allopregnane - 5,20 - dione 20 - ethylene glycol 17B - hydroxy - 17c. - methyletiocholano[2.3 - disoxa ketal-Chromic oxide (26.6 g.) was added in small por zole was rearranged with base to give 2,3-cyano-17a-meth tions to 425 ml. of pyridine at 25-30 C. To this mix yietiocholan-17B-ol-3-one, M.P. 222.4-226.0° C. (corr.), 3 5 ture was added all at once a solution of 19.5 g. (0.054 a 25-30.8 (1% in ethanol). moie) of allopregnan-36-ol-20-one 20-ethylene glycol. ketal in 250 ml. of pyridine. The reaction mixture was Example 7 stirred at room temperature for 18 hours, diluted with 1 (a) 2. hydroxymethylene - 17c. - methyl-19 - noran liter of hot benzene and filtered. The filtered solid was drostan-17-ol-3-one was prepared from 4.35 g. of 17a 40 washed with 500 ml. of hot benzene, and the combined methyl-19-norandrostan-176-ol-3-one (Bowers et al., J. filtrates were washed with four 500 m. portions of water Am. Chem. Soc. 79,4556 (1957), 10 ml. of ethyl forfiliate followed by one 200 ml. portion of saturated sodium and 2.40 g. of sodium hydride according to the manipula chloride solution. The organic solvent was then concern tive procedure described above in Example 1, part (a). trated in vacuo, and the residue was triturated with 50 There was thus obtained 4.35 g. of 2-hydroxymethylene ml. of methanol. Filtration of the mixture and concen tration of the filtrate to a volume of 20 ml. gave a small 17-methyl-19-norandrostan-17B-ol-3-one, M.P. 190-200° additional amount of solid product. The combined solid C. (uncorr.). product was recrystallized from ethyl acetate using ac (b) 17B - hydroxy - 17c. - methyl - 19 - norandro tivated charcoal for decolorizing purposes to give 12.6 g. stano.2.3-disoxazole V: R is H, R' is CH3, X is H2, 50 of allopregnane-3,20-dione 20-ethylene glycol ketal in Z is OH, Y is H, Y is CH31-A mixture of 2.39 g, of the form of blades and plates, M.P. 190-191.5 C. (un 2-hydroxymethylene - 17cc - methyl - 19 - Ilorandrostan corr.). . 176-ol-3-one, 0.695 g. of hydroxylamine hydrochloride, (c) 2-hydroxymethyleneallopregnane-3,20-dione 20 1.50 g. of sodium acetate trihydrate and 75 ml. of acetic ethylene glycol ketal was prepared from 2.45 g. of allo acid was heated at 60° C. for five hours. The reaction 55 pregnane-3,20-dione 20-ethylene glycol ketal, 20 ml. of mixture was poured into 850 ml. of water, and the pre ethyl formate, and sodium methoxide (from 0.33.g. of cipitated solid was collected by filtration, washed with sodium and 15 m. of methanol) in 70 m. of pyridine water and dried at 65 C. The latter product was according to the manipulative procedure described below recrystallized successively from aqueous methanol, ethyl in Example 10, part (c). There was thus obtained 2.64 acetate and acetone to give 17f8-hydroxy-17c-methyl-19 60 g. of 2-hydroxymethyleneallopregnane-3,20-dione 20 norandrostano (2,3-disoxazole in the form of colorless ethylene glycol ketal, used in the next reaction without needles, M.P. 197.6-199.6 C. (corr.). - further purification. Analysis.--Calcd. for C20H23NO2: C, 76.39;H, 8.98; O, . . (d) 20-oxoallopregnano 2.3-disoxazole V: R is H, 10.18. Found: C, 76.02; N, 9.15; O, 10.40. R’ is COCH, X is H2, Z is H, Y and Y are CH (rings 178 - hydroxy - 170 - methyl - 19 - norandrostano (2.3- 65 A/B trans))-A mixture of 1.70 g. of fused sodium disoxazole was found to have myotrophic activity accom acetate, 1.52 g. of hydroxylamine hydrochloride and 300 panied by a low degree of androgenic activity. ml. of acetic acid was heated to 100° C. with stirring and Example 8 then cooled to 60° C. 2-hydroxymethyleneallopregnane 3,20-dione 20-ethylene glycol ketal (7.67 g.) was then (a) 17c. - ethyl-2-hydroxymethyleneandrostan - 179 70 added, and the mixture was heated at 60-65 C. for seven ol-3-one was prepared from 7.0 g. of 17c-ethylandrostan hours. The reaction mixture was cooled and diluted with 176-ol-3-one, 8 ml. of ethyl formate and 3.8 g. of so 1 liter of water, and the solid which precipitated was dium methoxide in 150 ml. of benzene according to the collected and warmed to 50 C, with 175 ml. of methanol manipulative procedure described above in Example 5, and 2 mi. of 0.5 N, hydrochloric acid for fifteen minutes. part (a). The product was obtained in the form of 75 The latter mixture was cooled and filtered to give 3.3g. 3. 4. of solid product, M.P. 193-206° C. (uncorr.), which was Example 11 chromatographed on 100 g. of silica gel in a solvent mix (a) 2- hydroxymethyleneandrostan - 176-ol-3-one was ture consisting of 30% ether, 10% methylene dichloride prepared from androstan-17B-ol-3-one and ethyl formate and 60% pentane. The resulting product was recrystal in the presence of sodium methoxide in benzene solution lized from methanol to give 20-oxoallopregnano2.3- according to the manipulative procedures described above disoxazole, M.P. 2040-209.4° C. (corr.), or D in Example 5, part (a). The product was recrystallized =-|-134.7-0.1 (1% in chloroform); ultraviolet maxi from acetone and ether, giving 2-hydroxymethyleneandro mum at 225 mu (E=4,500). stan-176-ol-3-one, M.P. 126-132 C. (uncorr.); ultra Analysis.-Calcd. for C2HNO2: C, 77.36; H, 9.15. violet maximum at 282 mu (E=8,400). Found: C, 77.15; H, 8.98. 10 (b) 17,3-acetoxyandrostano 2.3-disoxazole V: R and R’ are H, X is H2, Z is OCOCH3, Y and Y are CH Example 10 Equimolar quantities of 2-hydroxymethyleneandrostan 176-ol-3-one and hydroxylamine hydrochloride in glacial (a) Pregnan-3oz-ol-20-one 20-ethylene glycol ketal was acetic acid were caused to react as described hereinabove prepared from 30 g. of pregnan-3oz-ol-20-one, 30 g. of 5 for analogous procedures. The product was separated by ethylene glycol, 0.9 g of 1-toluenesulfonic acid mono the addition of water and filtration of the precipitated hydrate and 700 m. of benzene according to the manipu product. The product was recrystallized first from meth lative procedure described above in Example 9, part (a). anol and then from acetone and dried at 85-105 C. for The resulting product was recrystallized twice from sixteen hours to give 17B-acetoxyandrostano-2.3 isoxa methanol with a few drops of pyridine added to give 25.6 20 zole, M.P. 1640-166.0° C. (corr.), c.25= --39.6-0.2 g. of pregnan-3c-ol-20-one 20-ethylene glycol ketal in (1% in chloroform); ultraviolet maximum at 226 mu, the form of colorless needles, M.P. 147.0-149.2 C. (E-4,300). (corr.), Ia)= -28.5-0.2 (1% in chloroform). Analysis.--Calcd. for C2HNO3: C, 73.91; H. 8.74; Analysis.-Calcd. for C2H8O3: C, 76.19; H, 10.57. O, 13.43. Found: C, 73.66; H, 8.64; O, 13.15. Found: C, 76.13; H, 10.75. 25 178-acetoxyandrostano I2.3) isoxazole was found to have (b) Pregnane-3,20-dione 20-ethylene glycol ketal was myotrophic activity accompanied by a low degree of prepared from 25.3 g. of pregnan-3oz-ol-20-one 20-ethyl androgenic activity. ene glycol ketal, 33 g. of chromic oxide and 630 ml. of (c) 17,3-hydroxyandrostano 2.3-disoxazole V: R and pyridine according to the manipulative procedure de R are H, X is H2, Z is OH, Y and Y are CH, obtained scribed above in Example 9, part (b). The product was 30 by hydrolysis of 176-acetoxyandrostano 2.3-dl isoxazole, recrystallized from 400 ml. of methanol to give 17.5 g. of had the M.P. 179.8-182.0° C. (corr.), a 25---61.6 pregnane-3,20-dione 20-ethylene glycol ketal in the form (1% in chloroform); ultraviolet maximum at 228 mu, of colorless leaflets, M.P. 169.8-172.8 C. (corr.), (E=4,900). a 25---32.0--0.1 (1% chloroform). Analysis.-Calcd. for CHNO: C, 76.16; H, 9.27; Analysis.-Calcd. for C2H8O3: C, 76.62; H, 10.07. O, 10.15. Found: C, 75.93; H, 9.38; O, 9.90. Found: C, 76.93; H, 10.08. 173-hydroxyandrostano 2.3-disoxazole was found to (c) 2 - hydroxymethylenepregnane - 3,20 - dione.- possess anabolic activity and myotrophic activity with Sodium methoxide was prepared by dissolving 0.73 g. moderate to high degree of separation of myotrophic and (0.03 mole) of sodium hydride in 30 ml. of methanol and androgenic actvity. removing the excess methanol at 100° C. in vacuo. To 40 17(3-hydroxyandrostano2.3-disoxazole was rearranged the sodium methoxide were added 100 ml. of pyridine, 5.45 g. (0.0151 mole) of pregnane-3,20-dione 20-ethylene with base to give 2c -cyandrostan-17(3-ol-3-one, M.P. glycol ketal and then 30 ml. of ethyl formate. The re 250.0-252.0° C. (corr.). action mixture was allowed to stand at room temperature (d) The 176-(3-cyclohexylpropionate) of 17,3-hydroxy for twenty-one hours and concentrated to dryness in stano 2.3-disoxazole IV; R and R are H, X is H, Z is vacuo below 45 C. The residue was dissolved in water, 45 OCOCH2CH2C6H11, Y and Y are CH had the M.P. and carbon dioxide was passed into the solution until it 140.4-141.8 C. (corr.), o?= --40.6 (1% in chloro reached a pH of 8. The precipitated product was col form. lected by filtration and air dried, giving 5.9 g, of 2-hy Analysis.-Calcd. for C9H4NO3: C, 76.78; H, 9.56; droxymethylenepregnane-3,20-dione 20-ethylene glycol N, 3.09. Found: C, 76.54; H, 9.63; N, 3.12. ketal, suitable for conversion to the isoxazole derivative. 50 The 1713-(3-cyclohexylpropionate) of 176-hydroxyan A 1.5 g. portion of the 2-hydroxymethylenepregnane drostano (2,3-d) isoxazole was found to possess anabolic 3,20-dione 20-ethylene glycol ketal was dissolved in 10 activity and myotrophic activity of long duration with ml. of methanol, 2 ml. of 2 N hydrochloric acid was a high degree of separation of myotrophic and androgenic added, and the mixture was heated to boiling. The solu activities. tion was set aside and was allowed to cool for one hour, 55 (e) 17B - (4-chlorophenoxyacetoxy)androstano 2.3-d diluted with 6 ml. of water, and the precipitated solid isoxazole V: R and R are H, X is H2, Z is was collected by filtration and chromatographed on 25 g. OCOCHOCHCI-4 of silica gel in pentane containing 25% ether. There was thus obtained 0.57 g. of 2-hydroxymethylenepregnane Y and Y are CH3) was prepared from 178-hydroxyandro 60 Stano (2.3-disoxazole and p-chlorophenoxyacetyl chloride 3.20-dione, M.P. 139.8-146.0° C. when recrystallized in pyridine. It was obtained in the form of colorless from methanol, a 25- --114.2-i-0.3 (1% chloro needles, M.P. 152.2-153.2 C. (corr.), a 25- - -38.2 form). (1% in chloroform). Analysis.-Calcd. for C22H2O3: C, 76.70; H, 9.36. Analysis.-Calcd. for C2H4CINOA: C, 69.48; H. 7.08; Found: C, 76.65; H, 9.62. 65 Cl, 7.33. Found: C, 69.16; H, 7.11; C1, 7.70. (d) 20-oxopregnano 2.3-disoxazole V: R is H, R is . 175 - (4 - chlorophenoxyacetoxy)androstano 2.3 - d. COCH, X is H, Z is H, Y and Y are CH (rings A/B isoxazole was found to possess anabolic activity (nitrogen cis) was prepared from 2-hydroxymethylenepregnane retention) at 0.8 mg./kg/day subcutaneously in the rat. 3.20-dione 20-ethylene glycol ketal, hydroxylamine hydro (f) 17f8-(trimethylacetoxy)androstano 2.3-disorazole chloride, sodium acetate and acetic acid according to the 70 IV; R and R are H, X is Ha, Z is OCOC(CH), Y and manipulative procedure described above in Example 9, Y are CH3 was prepared from 176-hydroxyandro part (d). The compound was obtained in the form of Stano 2.3-disoxazole and trimethylacetyl chloride in pyri pale yellow crystals, M.P. 137.4-153.2 C. (corr.). dine. It was obtained in the form of colorless needles, Analysis-Calcd. for Ca2HNO2: C, 77.37; H, 9.15; M.P. 188.2-189.2 C. (corr.), ox25=-|-40.2 (1% in N, 4.10. Found: C, 77.60; H, 9.31; N, 4.00. 75 chloroform). - - . 3,135,748 15 3 Analysis.-Calcd. for CHNO: C, 75.17; H, 9.33; precipitated was collected by filtration and recrystallized O, 12.01. Found: C, 75.46; H, 9.20; O, 12.25. from aqueous methanol, giving 2.83.g. of solid, M.P.158 (g) 17:3 - (5-cyclopentylpropionoxy)androstano (2,3-d 194 C. (uncorr.). The total product, including the latter isoxazole V: R and R' are H, X is HZ is Solid, was dissolved in 80 ml. of ether, the solution diluted 5 to 800 ml. With pentane and chromatographed on a column OCOCHCHCH of 200 g., of silica gel. The column was eluted with Y and Y are CHI was prepared from 173-hydroxyan pentane containing gradually increasing amounts of ether. drostano[2.3-disoxazole and 6-cyclopentylpropionyl chlo Elution with 20% ether brought out 1.21 g. of crystalline ride in pyridine. It was obtained in the form of colorless product, M.P. 180-190° C. (uncorr.). Subsequentelu needles, M.P. 142.6-143.4° C. (corr.), a 25---41.2° O tion with 40% ether brought out 2.07 g. of solid product, (1% in chloroform). M.P. 176-204 C. (uncorr.). The latter was recrystal Analysis.--Calcd. for CHNO: C, 76.49; H, 9.40; lized successively from aqueous methanol, ethyl acetate O, 10.92. Found: C, 76.53; H, 9.37; O, 10.60. - and acetone and dried at 110° C. in vacuo for seven hours 17B - (3 - cyclopentylpropionoxy)androstano (2.3 - d. to give 17,3-hydroxyandrostano 2.3-dI-3-methylisoxazole isoxazole was found to possess anabolic activity and myo 5 in the form of blunt needles, M.P. 208.8-219.6°C. (corr), trophic activity of long duration with a high degree of sepa IoD=-|-56.4+0.1 (1% in chloform); ultraviolet maxi ration of myotrophic and androgenic activities. mum at 227 mu (E=5,500). 17 g (3 - phenylpropionoxy)androstano 2.3 - disoxa Analysis.--Calcd. for CHNO: C, 76.55; H, 9.48; Zole can be prepared by an analogous procedure. N, 4.25. Found: C, 76.33; H, 9.41; N, 4.14. Example 12 20 The material, M.P. 180-190 C. (uncorr.), eluted with (a) 2-acetyl-17f8-acetoxyandrostan-3-one.-A mixture 20% ether, was recrystallized from methanol and from of 9.6 g. (0.16 mole) of glacial acetic acid and 50 m. of hexane to give 17g-acetoxyandrostano (2.3-d-3'-methyl ethylene dichloride was cooled in an ice-bath, and dry isoxazole, M.P. 189.2-195.20° C. (corr.) borontrifluoride gas was passed into the solution until it [alp?S= +35.2+0.1 Was Saturated. With continued addition of boron tri 25 fluoride, a solution of 11.60 g (0.04 mole) of androstan (1% in chloroform). 17g-ol-3-one and 12.2 g. (11.14 ml, 0.12 mole) of acetic Example 13 anhydride in 75 ml. of ethylene dichloride was added. (a) 2-(n-butyryl)androstan-176-ol-3-one was prepared The reaction mixture was stirred in the ice-bath for thirty from 27.68 g. of 176-(n-butyryloxy-androstan-3-one (M.P. minutes and at room temperature for three hours, and 30 97-99 C.), 24.3 g of n-butyric anhydride and 27.1 g. then poured into a solution of 30 g. of sodium acetate of n-butyric acid in the presence of boron trifluoride ac trihydrate in 200 ml. of water. The organic solvent was cording to the manipulative procedure described above in distilled off, and the residue refluxed for forty-five min Example 12, part (a). The initial product obtained, 2-(n- utes and diluted with water. The solid product was col butyryl)-173-(n-butyryloxy)androstan-3-one was saponi lected by filtration, suspended in 200 mi. of methanol con 35 fied by treating a methanol solution of the compound taining 23 ml. of 35% sodium hydroxide solution with with 35% sodium hydroxide at room temperature, and the stirring, 25 ml. of water was added, and the solution al resulting 17f8-hydroxy compound was chromatographed lowed to stand for one hour. The solution was acidified on-silica gel to give 25.14 g. of 2-(n-butyryl)andro with glacial acetic acid, the methanol removed in vacuo, Stan-176-ol-3-one, M.P.130.8-132.8 C. (corr.), colorless and Water was added to precipitate a gummy product. 40 prisms from methanol, cyp25---55.8-0.1 (1% in The latter was separated and dissolved in 25 ml. of acetic chloroform); ultraviolet maximum at 290 mu (E-9,470). anhydride and 20 ml. of pyridine, and the solution was Analysis.--Calcd. for C2H6O: C, 76.62; H, 10,07. kept at room temperature and heated for one hour on a Found: C, 76.70; H, 10.10. Steam bath. The reaction mixture was added to cold, (b) 17,3-hydroxyandrostano (2,3-di-3 - (n-propyl) dilute sulfuric acid and the product collected, washed, isoxazole IV: R is (CH2)2CH3, R is H, X is H, Z is OH, dissolved in hot methanol, and the solution filtered. Water Y and Y are CH3) was prepared from 3.60 g of 2-(n- was added to the filtrate to the point of turbidity, and the butyryl)androstan-17B-ol-3-one, 0.73 g. of hydroxylamine product which separated upon cooling was collected and hydrochloride, 1.29.g. of sodium acetate trihydrate and dried at 70° C.; yield 11.59 g, M.P. 132-158 C. 50 ml. of absolute ethanol according to the manipulative (uncorr.). The latter was dissolved in n-hexane and 50 procedure described above in Example 1, part (b). The chromatographed on alumina. The fraction eluted with product was a colorless resin and gave a negative ferric 20% ether in n-pentane was recrystallized from acetone chloride test. and dried in vacuo at 110 C. for eight hours, giving The benzoate ester of 176-hydroxyandrostano 2,3-d- 6.98 g. of 2-acetyl-73-acetoxyandrostan-3-one, M.P. 3'-(n-propyl)isoxazole IV; R is (CH)CH, R is H, X 183.0-184.6 C. (corr.), c.25=-39.40.2 (1% in 55 is H2, Z is OCOCH5, Y and Y are CH was obtained in chloroform); ultraviolet maximum at 290 mu (E=9,100). the form of colorless prisms, M.P. 1994-202.6° C. Analysis.-Calcd. for Cash4O4: C, 73.76; H, 9.15. (corr.), op= -82.4 (1% in-chloroform); ultraviolet Found: C, 73.80; H, 9.55. maxima at 229, 273 and 281 mu (E=20,463, 925 and (b) 2-acetylandrostan-17B-ol-3-one.--A solution of 2 731). acetyl-17B-acetoxyandrostan-3-one in methanol was treat 60 Analysis.--Calcd. for CoHNO: C, 78.05; H, 8.52; ed with an excess of 35% sodium hydroxide solution, and N, 3.03. Found: C, 78.31; H, 8.77; N, 3.03. the mixture was allowed to stand at room temperature for one hour. The reaction mixture was neutralized with Example 14 acetic acid and diluted with water, and the product was (a) 2-hydroxymethylene-4,6-androstadien-176-ol-3-one isolated and purified by chromatography on silica gel, giv 65 was prepared from 12.41 g. of 4,6-androstadien-176-ol-3- ing 2-acetylandrostan-176-ol-3-one, M.P. 149.6-154.0° C. one, 14 m. of ethyl formate and 3.9 g, of sodium hydride (corr.), a D2- --62.3-0.1 (1% in chloroform), when . according to the manipulative procedure described above recrystallized from an ethyl acetate-petroleum ether mix in Example 1, part (a). There was thus obtained 13.15 ture. g. of 2-hydroxymethylene-4,6-androstadien-176-ol-3-one, (c) 17:3 - hydroxyandrostano 2.3-d3'-methylisoxazole 70 M.P. 80-100° C. (uncorr.). V; R is CH3, R is H, X is H, Z is OH, Y and Y are (b) 17,3-acetoxy-4,6- androstadieno.2.3-disoxazole CH3-A mixture of 3.32 g of 2-acetylandrostan-176-ol VII; R and R' are H, X is H. Z is OCOCH, Y and Y. 3-one, 0.73 g. of hydroxylamine hydrochloride and 25 ml. are CH3-A mixture of 5.73 g. of 2-hydroxymethylene of acetic acid was boiled for ten minutes. The reaction 4,6-androstadien-176-ol-3-one, 1.39 g. of hydroxylamine mixture was diluted with water, and the product which 75 hydrochloride and 100 ml. of acetic acid was boiled for 3,135,743 17 18 - ten minutes. The product was isolated by dilution with (1% in chloroform); ultraviolet maxima at 319, 253, 245 water and collection of the precipitated product, and the and 236 mu, (E=19,800, 2,500, 2,990 and 3,400). latter was chromatographed on silica gel in benzene solu Analysis.-Calcd. for CiiNO: C, 77.50; H, 8.36; tion. The column was eiuted with benzene containing O, 983. Found: C, 77.19; H, 8.29; O, 10.05. gradually increasing amounts of ether. The naterial 5 176-hydroxy - 17c-methyl-4,6- androstadieno 2.3-d- eluted with 5% ether in benzene was recrystallized from isoxazole was found to have myotrophic and pituitary benzene and from ethyl acetate, and dried at 70° C. in inhibiting activities accompanied by a low degree of vacuo for fifteen hours to give 17,3-acetcxy-4,6-aridro androgenic activity. stadieno 2.3-disoxazole, M.P. 157.4-161.4° C. (corr.), Example 16 a 25--182.6-0.3 (1% in chloroform) ultraviolet IO (a) 2-hydroxymethylene-17 oz-ethyl-4,6- androstadien maxima at 244, 252 and 319 mu (E=3,150, 2,740 and 17,3-ol-3-one was prepared from 8.83 g. of 17 oz-ethyl-4,6- 18,240). androstadien-176-ol-3-one, 10 ml. of ethyl formate and Analysis.--Calcd. for C2HNOa: C, 74.75; H, 7.70; 2.8 g. of sodium hydride in 200 ml. of benzene according N, 3.96; O, 13.58. Found: C, 73.97; H, 8.09; N, 3.92; to the manipulative procedure described above in Ex O, 13.25. ample 1, part (a). There was thus obtained 9.68 g. of The crystalline fraction eluted with 25% ether in bein 2-hydroxymethylene-17a-ethyl-4,6- androstadien-17 (3-ol Zeile from the chromatogram was recrystallized successive 3-one in the form of its sodium salt. ly from benzene, ethanol, ethyl acetate and ethanol and (b) 176-hydroxy-17o-ethyl - 4,6-androstadieno 2.3-d1 dried at 75° C. in vacuo for fifteen hours. There was isoxazole VI: R is H, R' is CH5, X is H2, Z is OH, thus obtained 17B-hydroxy-4,6-androstadieno 2.3-disoza 20 Y and Y are CH-A mixture of 3.64.g. of the sodium zole, M.P. 216.2-219.6 C. (corr.), c.25=-134.7-0.1 salt of 2-hydroxymethylene-17a-ethyl-4,6-androstadien (1% in chloroforin); ultraviolet maxiria at 235, 254 and 17 B-cl-3-one, 0.76 g. of hydroxylamine hydrochloride, 319 mu (E-2900, 2,500 and 17,800). 0.10 g. of sodium acetate and 50 ml. of acetic acid was Analysis.-Calcd. for CH5NO2: C, 77.13; H, 8.09; refluxed for five minutes. The product was isolated by N, 4.50. Found: C, 76.89; H, 7.85; N, 4.49. 25 dilution with water and collection of the resulting pre 17,3-hydroxy-4,6-androstadieno2.3-disoxazole and its cipitate, and was recrystallized successively from benzene, acetate were found to have myotrophic activity with a ethanol and ethyl acetate, and dried at 70° C. for three low degree of androgenic activity. days and then at 100° C. for eight hours to give 17.3- 17,3-hydroxy-4,6-androstadienc2.3-disoxazole can be hydroxy - 17c-ethyl-4,6-androstadieno (2.3-disoxazole in reacted with acetic anhydride, propionic anhydride, 30 caproyl chloride, succinic anhydride, 6-cyclopentylpro the form of yellow granules, M.P. 176.6-185.0 C. pionyl chloride, benzoyl chloride, p-nitrobenzoyl chloride, (corr.), c.25=-209.4-4-0.1 (1% in chloroform); 3,4,5-trimethoxybenzoyl chloride, phenylacetyl chloride, ultraviolet maxima at 243, 252 and 319 mu (E=2,900, 2,500 and 17,800). or cinnamoyl chloride, by heating in the presence of Analysis.-Calcd. for C22H23NO2: C, 77.84; H, 8.61; pyridine, to give, respectively, O, 9.43. Found: C, 77.74; H, 8.34; O, 9.60. 17,3-acetoxy-4,6-androstadieno 2.3-disoxazole, Example 17 176-propionoxy-4,6-androstadieno (2.3-disoxazole, 17cc, 176 - dinnethyl - 18 - nor - 12 - androsteno (2.3-d- 17,8-caproyloxy-4,6-androstadieno 2.3-disoxazole, isoxazole.-A raixture of 3.33 g. of 2-hydroxymethylene 17,3-(B-carboxypropionoxy)-4,6-androstadieno2.3-d- 40 17o-methylandrostan-176-ol-3-one, 0.70 g. of hydroxyl 176-(6-cyclopentylpropionoxy)-4,6-androstadienoisoxazole, amine hydrochloride and 30 ml. of glacial acetic acid 2,3-disoxazole, was refluxed for five minutes. The product was isolated 17,3-benzoyloxy-4,6-androstadieno (2.3-disoxazole, by dilution with water and collection of the resulting 176-(p-nitrobenzoyloxy)-4,6-androstadieno 2.3-dil precipitate, and the resulting 2.56 g. of material was 45 recrystallized several times from ethanol and dried at 173-(3,4,5-trimethoxybenzoyloxy)-4,6-androstadienoisoxazole, 40° C. for seventy-two hours in vacuo to give 170,176 dimethyl-18 - nor - 12 - androsteno I2.3-disoxazole, M.P. 175-phenylacetoxy-4,6-androstadienc2.3-disoxazole,I2.3-disoxazole, or 134.0-138.6° C. (corr.), c.25- -7.8--0.1 (1% in chloroform); ultraviolet maximum at 222 mu (E=5,800). 176-cinnamoyloxy-4,6-androstadieno (2.3-disoxazole. 50 Analysis.--Calcd. for CHNO: C, 80.98; H, 9.39; Example 15 O, 5.14. Found: C, 80.94; H, 9.39; O, 5.20. The foregoing product proved to be homogeneous (a) 2-hydroxymethylene-17c-methyl-4,6-androstadien upon chromatography, and the structure assigned is Sup 17B-ol-3-one was prepared from 11.4 g. of 17 cc-methyl ported by infrared data. There is no indication of 4,6-androstadien-176-ol-3-one, 12.0 ml. of ethyl formate 55 hydroxyl or carbonyl absorption, and an absorption and 3.7 g. of sodium hydride in 250 ml. of benzene maximum at 7.34 mu was assigned to a gem-dimethyl according to the manipulative procedure described above group after comparison with model compounds. in Example 1, part (a). There was thus obtained 5.3 g. of 2-hydroxymethylene-17a-methyl-4,6-androstadien-178 Example 18 60 17-oxo-4,6-androstadienoL2.3-disoxazole can be pre ol-3-one,(b) 17B-hydroxy-17c-methyl-4,6-androstadieno M.P. 117-123 C. (uncorr.). (2,3-d- pared by treating a solution of 17g-hydroxy-4,6-androsta isoxazole VII; R is H, R is CH3, X is H2, Z is OH, dieno 2.3-disoxazole Example 14, part (b)) in glacial Y and Y are CH-A mixture of 3.3 g. of 2-hydroxy acetic acid with a solution of chromic oxide in aqueous methylene-17c-methyl-4,6-androstadien-17B-ol-3-one, 1.0 acetic acid. The product is isolated by addition of Water g. of hydroxylamine hydrochloride, 1.3 g of fused scdium 65 and collection of the resulting precipitate. acetate and 150 mi. of glacial acetic acid was heated at Example 19 75-80° C. for seven hours. The reaction mixture was concentrated in vacuo, water was added to the residue (a) 17a-ethynyl-2-hydroxymethylene - 4 - androsten and the product was extracted with benzene. The ben 17,3-ol-3-one.--To a solution of 14.2 g. of 17a-ethynyl zene extracts were washed with sodium bicarbonate Solu 70 4-androsten-176-ol-3-one in 300 ml. of dry pyridine was tion and water, dried over anhydrous Scdium sulfate an added 23 ml. of dry ethyl formate and then a solution concentrated. The residue was triturated with ether to of sodium ethoxide in ethanol (from 2.1 g of sodium give 2.55 g. of 17p-hydroxy-17a-methyl-4,6-androsta and 35 mi. of absolute ethanoi). The reaction mixture dieno2.3-disoxazole, M.P. 1934-199.0° C. (corr.) was allowed to stand at room temperature for forty-two when recrystallized from acetone, Lolo'--187.8+0.2 75 hours and then poured onto ice-water. Glacial acetic 3,135,743 20 acid (218 ml.) was added and the gummy product was 20-oxo-4-pregneno2.3-disoxazole was found to pos separated and dissolved in ether. The ether solution sess progestational activity when injected intramuscularly was washed with a solution of 30 g. of potassium hydrox in rabbits at a dose level of 1.0 mg./kg. ide in 1.5 liters of water, and the aqueous layer was cooled to 5 C. and acidified with 6 N hydrochloric acid. Example 22 The precipitated product was collected by filtration and dried in vacuo over phosphorus pentoxide at 60° C., (a) 2-hydroxymethylene-4,4,17a-trimethyl-5-androsten giving 13.5 g. of 17 oz-ethynyl-2-hydroxymethylene-4- 17p-ol-3-one was prepared from 6.2 g of 4,4,17a-trimeth androsten-176-ol-3-one. yl-5-androsten-178-ol-3-one, 16 ml. of ethyl formate and (b) 17a-ethynyl-176-hydroxy - 4 - androsteno (2.3-d- 10 sodium methoxide (from 2.2 g of sodium and 40 ml. of isoxazole VI: R is H, R' is C=CH, X is H2, Z is OH, methanol) in 400 ml. of benzene according to the manipu Y and Y are CHI was prepared from 4.32 g. of 17a lative procedure described above in Example 5, part (a). ethynyl-2-hydroxymethylene - 4 - androsten-176-ol-3-one, There was thus obtained 5.54 g. of 2-hydroxymethylene 1.00 g. of hydroxylamine hydrochloride, 1.12 g. of fused 44-17a-trimethyl-5-androsten-17,3-ol-3-one. sodium acetate and 135 ml. of acetic acid according to (b) 17B-hydroxy-4,4,17a-trimethyl-5-androsteno (2,3-d the manipulative procedure described above in Example 15 isoxazole can be prepared from 4.5 g. of 2-hydroxymethyl 1, part (b). There was thus obtained 2.35 g. of 17a ene-44-17c-trimethyl-5-androsten-176-ol-3-one, 0.91 g. of ethynyl-17 3-hydroxy-4-androsteno2.3-d]isoxazole, M.P. hydroxylamine hydrochloride, 1.03 g. of sodium acetate 224.2-226.8 C. (corr.) when recrystallized from ace and 150 ml. of acetic acid according to the manipulative tone; oz25=-|-7.5-0.2 (in 95% ethanol); ultraviolet procedure described above in Example 1, part (b). The maximum at 286 mu, (E=11,300). 20 crude product was chromatographed on silica gel in ben Analysis.--Calcd. for C2HNO: C, 78.30; H, 8.07; zene solution, eluted with benzene containing 5% of ether O, 9.48. Found: C, 78.00; H, 8.06; O, 9.10. and recrystallized from ethanol to give 17g-hydroxy-4,4, 17ox - ethynyl - 176 - hydroxy - 4 - androsteno2.3-d- 17a-trimethyl-5-androstenoI2.3-disoxazole, M.P. 177.6 isoxazole has been found to possess anabolic and myo 180.8° C. (corr.), c.25-66.9-0.1 (1% in 95% trophic activity with a low degree of androgenic activity. ethanol); ultraviolet maximum at 229 m.p. (E=6,200). It also was found to possess estrogenic and pituitary in Analysis.--Calcd. for C23H3NO2: C, 77.70; H, 9.36; hibitory activity. O, 9.00. Found: C, 77.71; H, 9.17; O, 9.30. Example 20 17B-hydroxy-4,4,17a-trimethyl - 5 - androsteno (2.3-di isoxazole was found to possess a blocking action on the (a) 2-hydroxymethylene-4-pregnen-203-ol-3-one was 30 adrenal response to ACTH in castrated male rats. prepared from 4.97 g. of 4-pregnen-203-ol-3-one, 5 ml. of 176-hydroxy-44,17a-trimethyl - 5 - androstenoI2.3-d- ethyl formate and 1.0 g. of sodium hydride in 100 ml. of isoxazole was rearranged with base to give 20-cyano-4,4, benzene according to the manipulative procedure described 17a-trimethyl-5-androsten-176-ol-3-one, M.P. 226.8- above in Example 1, part (a). 229.6° C. (corr.), c.25- -24.8 (0.5% in ethanol). (b) 208-hydroxy-4-pregneno2.3-disoxazole VI: R is 35 H., R is CH(OH) CH, X is H. Zis H, Y and Y are CH Example 23 was prepared from the 2-hydroxymethylene-4-pregnen (a) 2-hydroxymethylene-4,4-dimethyl - 5 - androsten 203-ol-3-one obtained above in part (a) and 1.20 g. of 176-ol-3-one was prepared from 6.69 g. of 4,4-dimethyl hydroxylamine hydrochloride in 200 ml. of ethanol ac 40 5-androsten-176-ol-3-one, 9.5 ml. of ethyl formate, 0.95 cording to the manipulative procedure described above in g. of sodium and 18-20 ml. of ethanol in 65 ml. of pyri Example 1, part (b). There was thus obtained 203-hy dine according to the manipulative procedure described droxy-4-pregneno2.3-disoxazole, M.P. 129.2-147.8° C. above in Example 19, part (a). There was thus obtained (corr.), ox25- --105.0--0.2 (1% in chloroform); 5.21 g. of 2-hydroxymethylene-4,4-dimethyl-5-androsten ultraviolet maximum at 286 mu, (E=10,050). 45 17,3-ol-3-one. Analysis.--Calcd. for C2HNO: C, 77.37; H, 9.15; (b) 4,4-dimethyl-17 (3-hydroxy - 5 - androsteno (2.3-d- O, 9.37. Found: C, 77.16; H, 9.21; O, 9.70. isoxazole can be prepared from 2-hydroxymethylene-4,4- Example 21 dimethyl-5-androsten-176-ol-3-one and hydroxylamine hydrochloride according to the manipulative procedure de 20-oxo-4-pregneno.2.3-disoxazole VI; R is H, R' is 50 scribed above in Example 1, part (b). COCH, X is H, Z is H, Y and Y are CH-To a solu tion of 1.10 g. of 2013-hydroxy-4-pregneno2.3-d isoxa Example 24 zole in 80 ml. of acetone was added 8.46 ml. of oxidizing (a) 2-hydroxyniethylene - 4,4,17a; - trimethylandrostan solution (prepared from 26.7 g. of chromic oxide, 23 ml. 17,3-ol-3-one was prepared from 6 g. of 4,4-17 oz-trimethyl of concentrated sulfuric acid and 40 ml. of water, diluted 55 to 1000 ml. with water) dropwise during ten minutes. androstan-176-ol-3-one, 10 ml. of ethyl formate, 0.85g. The reaction mixture was kept at room temperature for of sodium and 15 ml. of ethanol in 125 ml. of pyridine ten minutes, poured into 200 ml. of water and extracted according to the manipulative procedure described above with ethyl acetate. The ethyl acetate extracts were washed in Example 19, part (a). There was thus obtained 5.0 g. with water, dried over anhydrous sodium sulfate and con 60 of 2-hydroxymethylene-4,4,17a-trimethylandrostan - 176 centrated. The residue was dissolved in acetone, retreated ol-3-one, M.P. 150-154 C. (uncorr.). with 14.25 ml. of the oxidizing solution, and the product (b) 4,4,17a-trimethyl-176 - hydroxyandrostano 2.3-d worked up as before. The crude product was dissolved in isoxazole was prepared from 2.8 g. of 2-hydroxymethyl benzene and chromatographed on a column of silica gel. ene-4,4,17a-trimethylandrostan-17f8-ol-3-one, 0.57 g. of The column was eluted successively with pentane-benzene hydroxylamine hydrochloride, 0.64 g. of sodium acetate (1:1), benzene, and benzene-ether (19:1). The last and 90 ml. of acetic acid according to the manipulative named solvent mixture brought out the desired product procedure described above in Example 1, part (b). The which was recrystallized from an acetone-ether mixture, product was recrystallized from ethanol to give 44,17a giving 20-oxo-4-pregneno2.3-d]isoxazole, M.P. 182.5- trimethyl-17f8 - hydroxyandrostano 2.3-disoxazole, M.P. 187 C. (uncorr.). A purified sample of the compound 210-214 C. (uncorr.); ultraviolet maximum at 228mg had the M.P. 181.4-183.0 C. (corr.), a 25- - -220.9 (E=5,456). A purified sample had the M.P. 207.2- -E0.2 (1% in chloroform); ultraviolet maximum at 285 209.8 C. (corr.), IceD25= --7.07-0.25 (1% in etha mu (E=11,000). nol). Analysis.--Calcd. for C2HNO2: C, 77.83; H, 8.61; Analysis.--Calcd. for CHNO: C, 77.27; H, 9.87; O, 9.43. Found: C, 78.09; H, 8.91; O, 9.47. 75 O, 8.95. Found: C, 77.58; H, 9.98; O, 9.03. 2. 22 Example 25 Y and Y are CHI can be prepared by replacement of (a) 2-hydroxymethylene-5oz,17a-dinnethyl-4-androsten the 2-hydroxymethylene-17a-methyl-4- androsten-176-ol 17,3-ol-3-one was prepared from 5.0 g. of 6a, 17 cz-dimethyl 3-one in Example 1, part (b) by a molar equivalent 4-androsten-17 (3-ol-3-one, 5.0 m. of ethyl formate and amount of 2-hydroxymethylene-17 co-propargylandrostan 1.5 g. of sodium hydride in 100 ml. of benzene according 17(3-ol-3-one. - to the manipulative procedure described above in Ex Example 29 ample 1, part (a). (a) 2 - hydroxymethylene-4-pregnene-20,21-diol-3-one (b) 6a, 17a-dimethyl-17B-hydroxy-4-androstero 2.3-d can be prepared by replacement of the 17c-methyl-4- isoxazole was prepared from 2-hydroxymethylene-6c.,17a androsten-17f8-oi-3-one in Example 1, part (a) by a molar dimethyl-4-androsten 17B-ol-3-one and hydroxylamine hy 0 equivalent amount of 4-pregnene-20,21-diol-3-one. drochloride according to the manipulative procedure de (b) 20,21-dihydroxy-4-pregneno 2.3-disoxazole VI; scribed above in Example 1, part (b). It had the M.P. R is H, R’ is C(OH)CHOH, X is H, Z is H, Y and Y' 177.0-182.2° C. (corr.), cy25=-|-90.2-0.5 (1% in are CHI can be prepared by replacement of the 2-hy chloroform); ultraviolet maximum at 285 mu (E=10,- droxymethylene-17a-methyl-4-androsten-17 3-ol-3-one in 700). Example 1, part (b) by a molar equivalent amount of 2 Analysis.--Caicod. for C23H31NO2: C, 77.3 7; H, 9.15; hydroxymethylene-4-pregnene-20,21-diol-3-one. N, 4.10. Found: C, 77.58; H, 8.97; N, 3.93 Example 30 Example 26 (a) 2 - hydroxyinethylene-9-fluoro-4-pregnene-113,17a, (a) 2 - hydroxymethylene-4-pregnene-17a,21-diol-3,11, 20 21-triol-3,20-dione 20-inonoethylene glycol ketal can be 20-trione was prepared from 2.0 g. (0.005 mole) of 21 prepared by replacement of the 17c-methyl-4-androsten acetoxy-4-pregnen-17a-ol-3,11,20-trione (cortisone ace 17,3-ol-3-one in Example 1, part (a) by a molar equiva tate) and 1.0 g. of sodium hydride in 100 ml. of pyridine lent amount of 9-fluoro-4-pregnene-1,1,3,17a,21-triol-3,20 according to the manipulative procedure described above dione 20-monoethylene glycol ketal. in Example 19, part (a), all operations being carried (b) 9 - fluoro - II 3,17c.,21-trihydroxy-20-oxo-4-preg out in a nitrogen atmosphere. In the process the 21-ace neno (2.3-d-isoxazole ethylene glycol ketal can be pre toxy group was saponified to give 1.3 g. of 2-hydroxy pared by replacement of the 2-hydroxymethylene-17a methylene - 4 - pregnene-17C,21-diol-3,11,20-trione; ultra methyl-4-androsten-17f8-ol-3-one in Example 1, part (b) violet maxima at 246 and 293 mu (E=8,000 and 4,300), by a molar equivalent amount of 2-hydroxymethylene-9- characteristic of the 2-hydroxymethylene-A-3-oxo group fluoro - 4-pregnene-116,17a,21-triol-3,20-dione 20-mono ig. ethylene glycol ketal. (b) 17a,2I - dihydroxy-11,20-dioxo-4-pregneno 2.3-d isoxazole VI: R is H., R is COCHOH, X is O, Z is OH, Example 31 Y and Y are CH was prepared from 2-hydroxymethyl (a) 2 - hydroxymethylene-4-pregnene-I6a, 17 oz,21-triol ene-4-preghene-17a,21-diol-3,11,20-trione and hydroxyl 3. 5 5,20-dione-98,116-oxide 20-monoethylene glycol ketal can amine hydrochloride according to the manipulative pro be prepared by replacement of the 17c-methyl-4-andro cedure described above in Example 1, part (b). The stem-17(3-ol-3-one in Example 1, part (a) by a molar product was purified in the form of its 21-acetate which equivalent amount of 4-pregnene-16cz,17a,21-triol-3,20 was obtained in the form of colorless prisms, M.P. 246.2- 40 dione-96,116-oxide 16cz,21-diacetate 20-monoethylene gly 254.2 C. (corr.), c.125= --215.7 (1% in chloro col ketal. form); ultraviolet maximum at 287 mu (E=10,600). (b) 16oz,17a,21 - trihydroxy - 20-oxo-98, IIf3-oxido-4- Analysis.--Calcd. for C2H23NOs: C, 67.42; H, 6.84; pregneno.2.3-d-isoxazole ethylene glycol ketal can be N, 3.28. Found: C, 67.65; H, 6.58; N, 3.23. prepared by replacement of the 2-hydroxymethylene-17a methyl-4-androsten-176-ol-3-one in Example 1, part (b) Example 27 by a molar equivalent amount of 2-hydroxymethylene-4- (a) 2 - hydroxymethylene-17 oz-ethynylandrostan-17f8 pregnene - 160,17a,21-triol-3,20-dione-96,116-oxide 20 ol-3-one was prepared from 7.54 g. of 17 cc-ethynylandro monoethylene glycol ketal. stan-176-ol-3-one, 11.5 ml. of ethyl formate and sodium methoxide (from 1.10 g. of sodium and 20 ml. of meth Example 32 anol) in 250 ml. of pyridine according to the manipula (a) 2 - formyl-1,4-pregnadiene-17cz,21-diol-3,11,20-tri tive procedure described above in Example 19, part (a). one 20-monoethylene glycol ketal can be prepared by re The crude product had a melting point of 171-177.5 C. placement of the 17 cz-methyl-4-androsten-176-ol-3-one in (uncorr.). Example 1, part (a) by a molar equivalent amount of 1,4- (b) 176 - hydroxy-17a-ethynylandrostano (2.3-disova pregnadiene-17c,21-diol-3,11,20-trione 20-monoethylene zole IV: R is H, R’ is C=CH, X is H2, Z is OH, Y and glycol ketal. Y are CHJ.-A mixture of 3.42 g. of 2-hydroxymethyl (b) 17c,21-dihydroxy-11,20-dioxo-(1,3)5-pregnatrieno ene-17o-ethynylandrostan-17 3-ol-3-one and 0.76 g. of hy 2.3-disoxazole 20-monoethylene glycol ketal can be droxylamine hydrochloride in 50 ml. of acetic acid was prepared by replacement of the 2-hydroxymethylene-17cz boiled for five minutes. The product was isolated and methyl-4-androsten-176-ol-3-one in Example 1, part (b) recrystallized successively from acetone, a benzene-ace 60 by a molar equivalent amount of 2-formyl-1,4-pregnadi tone mixture, ethanol and ethyl acetate to give 17,3-hy ene-17 ca,21a-diol-3,11,20-trione 20-monoethylene glycol droxy - 17cz - ethynylandrostano 2.3-disoxazole, M.P. ketal, and then hydrolyzed with dilute hydrochloric acid 1972-198.8° C. (corr.), c.125=-8.0-0.2 (1% in to give 17a,21-dihydroxy-11,20-dioxo-(1,3)5-pregnatri chloroform); ultraviolet maximum at 227 mu (E=5,100). eno2.3-disoxazole. Analysis.--Calcd. for C22H2NC: C, 77.83; H, 8.61; Example 33 O, 9.43. Found: C, 77.55; H, 8.39; O, 9.70. (a) 2 - hydroxymethylene-17cz-propynyl-6-methyl-4-an Example 28 droster-17 (8-ol-3-one can be prepared by replacement of (a) 2 - hydroxymethylene - 17a - propargylandrostan the 170-methyl-4-androsten-176-ol-3-one in Example 1, 17B-ol-3-one can be prepared by replacement of the 17a O part (a) by a molar equivalent amount of 17a-propynyl methyl-4-androstan-17B-ol-3-one in Example 1, part (a) 6-methyl-4-androsten-176-ol-3-one. by a molar equivalent amount of 17 ce-propargylandro (b) 176-hydroxy-17a-propynyl-6-methyl-4-androsteno stan-176-ol-3-one. 2.3-disoxazole can be prepared by replacement of the (b) 176 - hydroxy - 17oz - propargylandrostano 2.3-d 2 - hydroxymethylene-17a-methyl-4-androsten-176-ol-3- isoxazole IV: R is H, R is C=CCH3, X is H2, Z is OH, one in Example 1, part (b) by a molar equivalent amount 3,135,743 23. 24. of 2 - hydroxymethylene-17a-propynyl-6-methyl-4-andro Example 38 stem-17f8-ol-3-one. (a) 2-hydroxymethylene-21-acetoxy-6-methyl-4 - preg Example 34 men-17a-ol-3,11,20-trione 20-monoethylene glycol ketal can be prepared by replacement of the 17 oz-methyl-4- (a) 2-hydroxymethylene - 17cz - methyl - 4 - androsten androsten-176-ol-3-one in Example 1, part (a) by a molar 176-ol-3-one in the form of the copper chelate (2.07 g., equivalent amount of 21-acetoxy-6-methyl-4-pregnen-17a M.P. 205-220 C.) was brominated with 1.46 g. of ol-3,11,20-trione 20-monoethylene glycol ketal. - bromine in 100 ml. of carbon tetrachloride to give 2 (b) 21-acetoxy-17c-hydroxy-11,20-dioxo-6-methyl - 4 bromo-2-hydroxymethylene-17a-methyl-4-androsten - 17B pregneno2.3-disoxazole 20-monoethylene glycol ketal ol-3-one. The latter can be dehydrobrominated by heat 0 can be prepared by replacement of the 2-hydroxymethyl ing with collidine to give 2-formyl-17 cy-methyl-1,4-an ene-17a-methyl-4-androsten-17 3-ol-3-one in Example 1, drostadien-17f8-ol-3-one. part (b) by a molar equivalent amount of 2-hydroxymeth (b) 173-hydroxy - 17c. - methyl-(1,3)5-androstatrieno ylene-21-acetoxy-6-methyl-4-pregnen - 17 or - ol - 3,11,20 (2,3-disoxazole can be prepared by replacement of the trione 20-monoethylene glycol ketal, and then hydrolyzed 2-hydroxymethylene-17a-methyl-4-androsten-17(3 - oil - 3 5 one in Example 1, part (b) by a molar equivalent amount with dilute hydrochloric acid to give 21-acetoxy-17a-hy of 2-formyl-17c-methyl-1,4-androstadien-17(3-ol-3-one. droxy-11,20-dioxo-6-methyl-4-pregneno (2.3-disoxazole. Example 35 Example 39 (a) 2-hydroxymethylene-21-acetoxy-9-fluoro-6 - meth (a) 2-hydroxymethylene-21-acetoxy-4-pregnene - Ilg, 20 yl-4-pregnen-17a-ol-3,11,20-trione 20-monoethylene glycol 17 oz-diol-3,20-dione 20-monoethylene glycol ketal can be ketal can be prepared by replacement of the 17 oz-methyl prepared by replacement of the 17 oz-methyl-4-androsten 4-androsten-17 (8-ol-3-one in Example 1, part (a) by a 17,3-ol-3-one in Example 1, part (a) by a molar equivalent molar equivalent amount 21-acetoxy-9-fluoro-6-methyl-4- amount of 21-acetoxy-4-pregnene-116,17a-diol-3,20-dione pregnen-17a-ol-3,11,20-trione 20-monoethylene glycol 20-monoethylene glycol ketai (hydrocortisone acetate 20 25 ketal. monoethylene glycol ketal). - (b) 21-acetoxy-11B,17a-dihydroxy-20-oxo-4 - pregneno (b) 21-acetoxy-17a-hydroxy-11,20-dioxo-9 - fluoro - 6 (2.3-dl isoxazole 20-monoethylene glycol ketal can be methyl-4-pregneno?2.3-dl isoxazole 20-monoethylene gly prepared by replacement of the 2-hydroxymethylene-17a col ketal can be prepared by replacement of the 2-hy methyl-4-androsten-176-ol-3-one in Example 1, part (b) 30 droxymethylene-17 oz-methyl-4-androsten-173-ol-3-one in by a molar equivalent amount of 2-hydroxymethylene-21 Example 1, part (b) by a molar equivalent amount of acetoxy-4-pregnene-116,17a-diol - 3,20 - dione 20-mono 2-hydroxymethylene-21-acetoxy-9-fluoro - 6 - methyl-4- ethylene glycol ketal, which can be hydrolyzed with meth pregnen-17a-ol-3,11,20-trione 20-monoethylene glycol anolic potassium hydroxide to saponify the 21-acetate ketal, and then hydrolyzed with dilute hydrochloric acid and then with dilute hydrochloric acid to cleave the to give 21-acetoxy-17a-hydroxy-11,20-dioxo-9-fluoro - 6 ketal group, giving 116,170,21-trihydroxy-20-oxo-4-preg methyl-4-pregneno.2.3-disoxazole. neno[2.3-dl isoxazole VI; R is H, R is COCHOH, X Example 40 is (H) (OH), Z is OH, Y and Y are CH. (a) 2-formyl-21-acetoxy-2-methyl-4-pregnen-17cy - ol Example 36 3,11,20-trione. 20-monoethylene glycol ketal can be pre (a) 2-hydroxymethylene-21-acetoxy-4,6-pregnadien pared by replacement of the 17a-methyl-4-androsten-17B 17a-ol-3,11,20-trione 20-monoethylene glycol ketal can ol-3-one in Example 1, part (a) by a molar equivalent be prepared by replacement of the 17a-methyl-4-an amount of 21-acetoxy-2-methyl-4-pregnen-17cc-ol-3,11,20 drosten-176-ol-3-one in Example 1, part (a) by a molar trione 20-monoethylene glycol ketal. equivalent amount of 21-acetoxy-4,6-pregnadien-17c-ol (b) 21-acetoxy-17a-hydroxy-2-methyl-11,20-dioro - 4 3,11,20-trione 20-monoethylene glycol ketal. pregneno (2.3-disoxazole 20-monoethylene glycol ketal . (b) 21-acetoxy-17a-hydroxy-11,20-dioxo - 4,6 - preg can be prepared by replacement of the 2-hydroxymethyl nadieno (2.3-disoxazole 20-monoethylene glycol ketal can ene-17c-methyl-4-androsten-176-ol-3-one in Example 1, be prepared by replacement of the 2-hydroxymethylene part (b) by a molar equivalent amount of 2-formyl-21 17 oz-methyl-4-androsten-17 3-ol-3-one in Example 1, part 50 acetoxy-2-methyl-4-pregnen-17a-ol-3,11,20-trione 20 (b) by a molar equivalent amount of 2-hydroxymethyl monoethylene glycol ketal, and then hydrolyzed with ene-21-acetoxy-4,6-pregnadien-17a-ol-3,11,20-trione 20 dilute hydrochloric acid to give 21-acetoxy-17a-hydroxy monoethylene glycol ketal, and then hydrolyzed with 2-methyl-11,20-dioxo-4-pregneno (2,3-disoxazole. dilute hydrochloric acid to give 21-acetoxy-17 oz-hydroxy Example 41 11,20-dioxo-4,6-pregnadieno2.3-disoxazole Vi; R is 55 (a) 2-hydroxymethylene-21-acetoxy-4-pregnene - 11p, H, R' is COCHOCOCH, X is O, Z is OH, Y and Y are 16oz,17a-triol-3,20-dione 20-monoethylene glycol ketal. CH3. can be prepared by replacement of the 17c-methyl-4- Example 37 androsten-17f8-ol-3-one in Example 1, part (a) by a molar equivalent amount of 21-acetoxy-4-pregnene-116,160,17a (a) 2-hydroxymethylene-21-acetoxy-4 - pregnen - 17o 60 triol-3,20-dione 20-monoethylene glycol ketal. ol-3,20-dione 20-monoethylene glycol ketal can be pre (b) 21-acetoxy-116,16c.,17a-trihydroxy - 20 oxo - 4 pared by replacement of the 17a-methyl-4-androsten-17 (3- pregneno.2.3-disoxazole 20-monoethylene glycol ketal ol-3-one in Example 1, part (a) by a molar equivalent can be prepared by replacement of the 2-hydroxymethyl amount of 21-acetoxy-4-pregnen-17a-ol-3,20-dione 20 ene-17c-methyl-4-androsten-176-ol-3-one in Example 1, monoethylene glycol ketal. 65 (b) 21-acetoxy-17a-hydroxy-20-oxo-4-pregneno.2.3-d part (b) by a molar equivalent amount of 2-hydroxy isoxazole 20-monoethylene glycol ketal can be prepared methylene-21-acetoxy-4-pregnene-116,160,17a-triol. 3,20 by replacement of the 2-hydroxymethylene-17a-methyl-4- dione 20-monoethylene glycol ketal, and then hydrolyzed androsten-17(3-ol-3-one in Example 1, part (b) by a molar with dilute hydrochloric acid to give 21-acetoxy-116,16, equivalent amount of 2-hydroxymethylene-21-acetoxy-4- 17a-trihydroxy-20-oxo-4-pregneno[2.3-dl isoxazole. pregnen-17a-ol-3,20-dione 20-monoethylene glycol ketal, 70 Example 42 and then hydrolyzed with dilute hydrochloric acid to (a) 2-hydroxymethylene-21-acetoxy-4-pregnene - 16oz, give 21-acetoxy-17c-hydroxy-20-oxo-4-pregneno (2.3 - d - 17o-diol-3,11,20-trione 20-monoethylene glycol ketal can isoxazole VI; R is H., R is COCHOCOCH, X is O, Z be prepared by replacement of the 17a-methyl-4-an is OH, Y and Y are CH1. 75 drosten-17f8-ol-3-one in Example 1, part (a) by a molar. 8,135,743 25 26 equivalent amount of 21-acetoxy-4-pregnene-16c.,17a-diol Example 48 3,11,20-trione 20-monoethylene glycol ketal. (a) 2-hydroxymethylene-4-androsten-176-ol-3,11-dione (b) 21-acetoxy-16c.,17a-dihydroxy-11,20-dioxo-4-preg can be prepared by replacement of the 17a-methyl-4- neino 2,3-d-isoxazole 20-monoethylene glycol ketal can androsten-17(3-ol-3-one in Example 1, part (a) by a molar be prepared by replacement of the 2-hydroxymethylene equivalent amount of 4-androsten-17,3-ol-3,11-dione. 17a-methyl-4-androsten-17B-ol-3-one in Example 1, part (b) 17,3-hydroxy-11-oxo-4-androsteno2.3-disoxazole (b) by a molar equivalent amount of 2-hydroxymethyl Vi; R and R' are H, X is O, Z is OH, Y and Y are ene-21-acetoxy-4-pregnene-16c.,17a-diol - 3,11,20 - trione CHs can be prepared by replacement of the 2-hydroxy 20-monoethylene glycol ketal, and then hydrolyzed with methylene - 17a - methyl-4-androsten-176-ol-3-one in Ex dilute hydrochloric acid to give 21-acetoxy-160,17a-dihy O ample 1, part (b) by a molar equivalent amount of 2 droxy-11,20-dioxo-4-pregaeno2.3-d isoxazole. hydroxymethylene-4-androsten-17,3-ol-3,11-dione. Example 43 Example 49 (a) 2-hydroxymethylene-4,17(20)-pregnadiene-116,21 diol-3-one can be prepared by replacement of the 17cz (a) 2-hydroxymethylene-4-androstene-66,176-diol-3- methyl-4-androsten-17f8-ol-3-one in Example 1, part (a) orie can be prepared by replacement of the 17a-methyl-4- by a molar equivalent amount of 4,17(20)-pregnadiene androsten-17 (3-ol-3-one in Example 1, part (a) by a molar lig,21-diol-3-one. equivalient amount of 4-androstene-66,176-diol-3-one. (b) IIB,21-dihydroxy - 4,17(20) - pregnadieno 2.3-d (b) 66,17B-dihydroxy-4-androsteno (2.3-disoxazole can isoxazole can be prepared by replacement of the 2-hy 20 be prepared by replacement of the 2-hydroxymethylene droxymethylene - 17 oz - methyl-4-androsten-176-ol-3-one 17c-methyl-4-androsten-17 (8-ol-3-one in Example 1, part in Example 1, part (b) by a molar equivalent amount of (b) by a molar equivalent amount of 2-hydroxymethyl 2-hydroxymethylene - 4, 17 (20) - pregnadiene-1,3,21-diol ene-4-androstene-66,175-diol-3-one. 3-one. Example 50 Example 44 25 (a) 2 - hydroxymethylene-17a-methyl - 4 - androstene Ilg,17a,21 - trihydroxy - 20 - oxo-4-pregneno2.3-d 6,3,176-diol-3-one can be prepared by replacement of the isoxazole (Example 35) can be caused to react with 17c-methyl-4-androsten-176-ol-3-one in Example 1, part p-toluenesulfonyl chloride in pyridine under mild condi (a) by a molar equivalent amount of 17a-methyl-4-an tions to give 21-tosyloxy-11 (3,17a-dihydroxy-20-oxo-4- 30 drostene-6(3,17B-diol-3-one. pregneno2.3-disoxazole. The latter can be caused to (b) 17a-methyl-63,176-dihydroxy-4-androsteno2.3-d react with sodium bromide, sodium iodide, sodium chlo isoxazole can be prepared by replacement of the 2-hy ride or Sodium thiocyanate to give, respectively, 21-bromo, droxymethylene-17c-methyl-4-androsten-176-ol-3-one in 21-iodo, 21-chloro or 21-thiocyano derivatives of 116,17a Example 1, part (b) by a molar equivalent amount of 2 dihydroxy-20-oxo-4-pregneno (2,3-disoxazole. hydroxymethylene - 17a - methyl-4-androstene - 63,176 Example 45 diol-3-one. Example 51 (a) 2-hydroxymethyleneandrostane-6B,173-diol-3-one can be prepared by replacement of the 17c-methyl-4- 40 (a) 2-hydroxymethylene-4-androstene-14c.,176-diol-3- androsten-17f8-ol-3-one in Example 1, part (a) by a one can be prepared by replacement of the 17a-methyl molar equivalent amount of androstane-63,173-diol-3-one. 4-androsten-176-ol-3-one in Example 1, part (a) by a (b) 65,176-dihydroxyandrostano (2.3-disoxazole can molar equivalent amount of 4-androstene-140,17(3-diol-3- be prepared by replacement of the 2-hydroxymethylene One. 17c-methyl-4-androsten-17 3-ol-3-one in Example 1, part (b) 14a,176-dihydroxy - 4 - androsteno.2,3-disoxazole (b) by a molar equivalent amount of 2-hydroxymethylene can be prepared by replacement of the 2-hydroxymethyl ene-17a-methyl-4-androsten-173-ol-3-one in Example 1, androstane-6,3,176-diol-3-one. part (b) by a molar equivalent amount of 2-hydroxy Example 46 methylene-4-androstene-14c., 17,3-diol-3-one. (a) 2-hydroxymethylene-17a-ethynyl-4-androsten-17 3 Example 52 ol-3,11-dione can be prepared by replacement of the 17a methyl-4-androsten-176-ol-3-one in Example 1, part (a) (a) 2 - hydroxymethylene-166-methyl-4-androsten-17B by a molar equivalent amount of 17a-ethynyl-4-androsten ol-3-one can be prepared by replacement of the 17a 17 (3-ol-3,11-dione. methyl-4-androsten-176-ol-3-one in Example 1, part (a) (b) 17a-ethynyl-17 3-hydroxy-11 - oxo - 4 - androsteno 55 by a molar equivalent amount of 16.6-methyl-4-androsten 2,3-disoxazole V; R is H, R is C=CH, X is O, Z is 176-ol-3-one. OH, Y and Y are CH can be prepared by replacement (b) 16:3-methyl - 173 - hydroxy - 4 - androsteno.2.3-d of the 2-hydroxymethylene-17 cc-methyl-4-androsten-17(3- isoxazole can be prepared by replacement of the 2-hy ol-3-one in Example 1, part (b) by a molar equivalent droxymethylene-17a-methyl-4-androsten-176-ol-3-one in amount of 2-hydroxymethylene-17a-ethynyl-4-androsten 60 Example 1, part (b) by a molar equivalent amount of 2 17.3-ol-3,11-dione. hydroxymethylene-163-methyl-4-androsten - 176 - oil - 3 Example 47 OC. Example 53 (a) 2 - hydroxymethylene-17a-methyl-4-androsten-17 3 ol-3,11-dione can be prepared by replacement of the 17a (a) 2 - hydroxymethylene-4-androstene-IIa,176-diol-3- Inethyl-4-androsten-17B-ol-3-one in Example 1, part (a) One can be prepared by replacement of the 17a-methyl by a molar equivalent amount of 17a-methyl-4-androsten 4-androsten-176-ol-3-one in Example 1, part (a) by a 176-ol-3,11-dione. molar equivalent amount of 4-androstene-11a, 17B-diol (b) 17cy - methyl-173-hydroxy-11-oxo - 4 - androsteno 3-one. 2,3-disoxazole VI; R is H, R is CH3, X is O, Z is (b) II c.179 - dihydroxy-4-androsteno.2.3-disoxazole OH, Y and Y are CH can be prepared by replacement V; R and R are H, X is (H) (OH), Z is OH, Y and Y of the 2-hydroxymethylene-17a-methyl-4-androsten-17B are CHI can be prepared by replacement of the 2-hy ol-3-one in Example 1, part (b) by a molar equivalent droxymethylene - 17a-methyl-4-androsten-176-ol-3-one in amount of 2-hydroxymethylene-17 oz-methyl-4-androsten Example 1, part (b) by a molar equivalent amount of 2 17,3-ol-3,11-dione. 5 ilydroxymethylene-4-androstene-11 oz-176-diol-3-one. 3,135,743 27 28 Example 54 68,17a,21-triol-3,20-dione 20-monoethylene glycol ketal, (a) 2 - hydroxymethylene-19-nor-4-androstene-63,176 and then hydrolyzed wtih dilute hydrochloric acid to give diol-3-one can be prepared by replacement of the 17a 66,170,21 - trihydroxy - 20 - oxoallopregnano 2.3-disox methyl-4-androsten-17f8-ol-3-one in Example 1, part (a) azole. by a molar equivalent amount of 19-nor-4-androstene-66, Example 60 176-diol-3-one. (a) 2 - hydroxymethylene - 21-acetoxy-4-pregnene-12c, (b) 66,176 - dihydroxy - 19 - nor-4-androsteno.2.3-d 17a-diol-3,20-dione 20-monoethylene glycol ketal can be isoxazole can be prepared by replacement of the 2-hy prepared by replacement of the 17 oz-methyl-4-androsten droxymethylene - 17 oz-methyl-4-androsten-176-ol-3-one in 17,3-ol-3-one in Example 1, part (a) by a molar equivalent Example 1, part (b) by a molar equivalent amount of 2 O amount of 21acetoxy-4-pregnene-12c,17a-diol-3,20-dione hydroxymethylene-19-nor-4-androstene-63,176-diol-3-one. 20-monoethylene glycol ketal. Example 55 (b) 21 - acetoxy-12o.,17a-dihydroxy-20-oxo-4-pregneno (a) 2 - hydroxymethylene - 4-bromo-17a-methyl-4-an 2.3-disoxazole 20-monoethylene glycol ketal can be pre drosten-176-ol-3-one can be prepared by replacement of 5 pared by replacement of the 2-hydroxymethylene-17a the 17a-methyl-4-androsten-17 (8-ol-3-one in Example 1, methyl-4-androsten-176-ol-3-one in Example 1, part (b) part (a) by a molar equivalent amount of 4-bromo-17a by a molar equivalent amount of 2-hydroxymethylene-21 methyl-4-androsten-17f8-ol-3-one. acetoxy - 4 - pregnene-120,17a-diol-3,20-dione 20-mono (b) 4 - bromo - 17a-methyl-17,3-hydroxy-4-androsteno ethylene glycol ketal, and then hydrolyzed with dilute 2,3-disoxazole can be prepared by replacement of the 20 hydrochloric acid to give 21-acetoxy-120,17a-dihydroxy 2 - hydroxymethylene - 17 oz-methyl-4-androsten-17f8-ol-3- 20-oxo-4-pregneno2.3disoxazole. one in Example 1, part (b) by a molar equivalent amount Example 61 of 2-hydroxymethylene-4-bromo-17 oz-methyl-4-androsten (a) 2 - hydroxymethylene-21-acetoxyallopregnan-17a 17(3-ol-3-one. ol-3,12,20-trione 20-monoethylene glycol ketal can be pre Example 56 25 pared by replacement of the 17a-methyl-4-androsten-176 (a) 2 - hydroxymethylene - 4-methyl-4-androsten-176 ol-3-one in Example 1, part (a) by a molar equivalent ol-3-one can be prepared by replacement of the 17a amount of 21 - acetoxyallopregnan-17a-ol-3,12,20-trione methyl-4-androsten-176-ol-3-one in Example 1, part (a) 20-monoethylene glycol ketal. by a molar equivalent amount of 4-methyl-4-androsten 30 (b) 21 - acetoxy-17c-hydroxy-12,20-dioxoallopregnano 176-ol-3-one. 2.3-disoxazole 20-monoethylene glycol ketal can be pre (b) 4 - methyl - 173-hydroxy-4-androsteno (2.3-disox pared by replacement of the 2-hydroxymethylene-17a azole can be prepared by replacement of the 2-hydroxy methyl-4-androsten-176-ol-3-one in Example 1, part (b) methylene-17a-methyl-4-androsten-176-ol-3-one in Exam by a molar equivalent amount of 2-hydroxymethylene-21 ple 1, part (b) by a molar equivalent amount of 2-hy 35 acetoxyallopregnan - 17a-ol-3-12,20-trione 20-monoethyl droxymethylene-4-methyl-4-androsten-17f8-ol-3-one. ene glycol ketal, and then hydrolyzed with dilute hydro chloric acid to give 21-acetoxy-17a-hydroxy-12,20-dioxo Example 57 allopregnano2.3-d-isoxazole. (a) 2 - hydroxymethylene-4,17a-dimethyl-4-androsten 17,3-ol-3-one can be prepared by replacement of the 17a Example 62 methyl-4-androsten-176-ol-3-one in Example 1, part (a) (a) 2 - hydroxymethylene-4,11-pregnadiene-3,20-dione by a molar equivalent amount of 4,17a-dimethyl-4-an 20-monoethylene glycol ketal can be prepared by replace drosten-176-ol-3-one. ment of the 17c-methyl-4-androsten-17 3-ol-3-one in Ex (b) 4,17 - dimethyl-176-hydroxy-4-androsteno.2.3-d ample 1, part (a) by a molar equivalent amount of 4,11 isoxazole can be prepared by replacement of the 2-hy pregnadiene-3,20-dione 20-monoethylene glycol ketal. droxymethylene - 17 cc-methyl-4-androsten-17.3-ol-3-one in (b) 20 - Oxo - 4, 11 - pregnadieno 2.3-disoxazole 20 Example 1, part (b) by a molar equivalent amount of 2 monoethylene glycol ketal can be prepared by replace hydroxymethylene - 4,17a-dimethyl-4-androsten-17f8-ol-3- ment of the 2-hydroxymethylene-17a-methyl-4-androsten OC. 17,3-ol-3-one in Example 1, part (b) by a molar equiv Example 58 50 alent amount of 2-hydroxymethylene-4,11-pregnadiene-3, (a) 2-hydroxymethylene-17 oz-ethynyl-4,6-androstadien 20-dione 20-monoethylene glycol ketal, and then hydro 176-ol-3-one can be prepared by replacement of the 17a lyzed with dilute hydrochloric acid to give 20-oxo-4,11 methyl-4-androsten-176-ol-3-one in Example 1, part (a) pregnadieno (2.3-disoxazole. by a molar equivalent amount of 17 oz-ethynyl-4,6-andro Example 63 stadien-176-ol-3-one. 55 (b) 17a-ethynyl-17 3-hydroxy-4,6-androstadieno 2.3-d (a) 2 - hydroxymethylene - 4 - pregnen - 17o - ol-3,- isoxazole VII; R is H, R is C=CH, X is H2, Z is OH, 20-dione 20-monoethylene glycol ketal can be prepared Y and Y are CHI can be prepared by replacement of by replacement of the 17a-methyl-4-androsten-176-ol-3- the 2-hydroxymethylene-17a-methyl-4-androsten-176-ol-3- one in Example 1, part (a) by a molar equivalent amount 60 of 4-pregnen-17a-ol-3,20-dione 20-monoethylene glycol one in Example 1, part (b) by a molar equivalent amount ketal. of 2-hydroxymethylene-17a-ethynyl-4,6-androstadien-17B (b) 17a - hydroxy - 20 - oxo - 4 - pregneno2.3-disox ol-3-one. azole 20-monoethylene glycol ketal can be prepared by Example 59 replacement of the 2-hydroxy-methylene-17a-methyl-4- (a) - 2 - hydroxymethyleneallopregnane-6p3,17a,21-triol 65 androsten-176-ol-3-one in Example 1, part (b) by a molar 3,20-dione 20-monoethylene glycol ketal can be prepared equivalent amount of 2-hydroxymethylene-4-pregnen-17a by replacement of the 17 oz-methyl-4-androsten-176-ol-3- ol-3,20-dione 20-monoethylene glycol ketal; and then hy one in Example 1, part (a) by a molar equivalent amount drolyzed with dilute hydrochloric acid to give 17a-hy of allopregnane-63,170,21-triol-3,20-dione 20-monoethyl droxy-20-oxo-4-pregneno2.3-disoxazole VI: R is H, R' ene glycol ketal. - 70 is COCH, X is H2, Z is OH, Y and Y are CHI. (b). 66,17a,21 - trihydroxy-20-oxoallopregnano.2.3-d isoxazole 20-monoethylene glycol ketal can be prepared Example 64 by replacement of the 2-hydroxymethylene-17 oz-methyl-4- (a) 2 - hydroxymethylene - 17o - methyl - 4 - pregnene androsten-176-ol-3-one in Example 1, part (b) by a molar 3,20-dione 20-monoethylene glycol ketal can be prepared equivalent amount of 2-hydroxymethyleneallopregnane 75 by replacement of the 17a-methyl-4-androsten-176-ol-3- 3,135,743 29 30 one in Example 1, part (a) by a molar equivalent amount to give 20-oxo-18, 19-bisnor-4-pregneno2.3-d isoxazole of 17a-methyl-4-pregnene-3,20-dione 20-monoethylene VI: R is H, R' is COCH, X is H, Z is H, Y and Y glycol ketal. are H. (b) 17a - methyl- 20 - Oyo - 4 - pregneno.2.3 - disox Example 69 azole 20-monoethylene glycol ketal can be prepared by re 5 placement of the 2-hydroxymethylene-17a-methyl-4-an (a) 2 - hydroxymethylene - 21 - acetoxy - 4 - bronzo drosten-17B-ol-one in Example 1, part (b) by a molar 4-pregnen-17 cc-ol-3,11,20-trione 20-monoethylene glycol equivalent amount of 2-hydroxymethylene-17a-methyl-4- ketal can be prepared by replacement of the 17 cc-methyl pregnene-3,20-dione 20-monoethylene glycol ketal, and 4-androsten-176-ol-3-one in Example 1, part (a) by a then hydrolyzed with dilute hydrochloric acid to give 17 cy O molar equivalent amount of 21-acetoxy-4-bromo-4-preg methyl-20-oxo-4-pregneno.2.3-disoxazole. nen-17a-ol-3,11,20-trione 20-monoethylene glycol ketal. (b) 21 - acetoxy - 4 - brono - 17o - hydroxy - 11,20 Example 65 dioxo-4-pregnenoL2.3-disoxazole 20-monoethylene glycol (a) 2 - hydroxymethylene - 4 - pregnen - 63 - ol - 3,20 ketal can be prepared by replacement of the 2-hydroxy dione 20-monoethylene glycol ketal can be prepared by 5 methylene-17 cy-methyl-4-androstan-17(3-ol-3-one in Exam replacement of the 17f8-methyl-4-androsten-17 3-ol-3-one ple 1, part (b) by a molar equivalent amount of 2-hy in Example 1, part (a) by a molar equivalent amount of droxyinethylene - 21 - acetoxy - 4 - bromo - 4 - pregnen 4-pregnen-63-ol-3,20-dione 20-monoethylene glycol ketal. 17a-ol-3,11,20-trione 20-monoethylene glycol ketal, and (b) 6,3 hydroxy - 20 - Oxo - 4 - pregneno (2.3 - disox then hydrolyzed with dilute hydrochloric acid to give azole 20-monoethylene glycol ketal can be prepared by re 21 - acetoxy - 4 - bromo - 17 cc - hydroxy - 1 1,20 - dioxo placement of the 2-hydroxygnethylene-17 cy-methyl-4-an 4-pregneno 2.3-disoxazole. drosten-17f8-ol-3-one in Example 1, part (b) by a molar equivalent amount of 2-hydroxymethylene-4-pregnen-68 xample 70 ol-320-dione 20-monoethylene glycol ketal, and then hy (a) 2 - hydroxymethylene - 4 - pregnene - 7a, 12cy drolyzed with dilute hydrochloric acid to give 6,3-hydroxy 25 diol-3,20-dione 20-monoethylene glycol ketal can be pre 20-oxo-4-pregneno 2.3-disoxazole. pared by replacement of the 17a-methyl-4-androsten-17 3 Exampie 66 ol-3-one in Example 1, part (a) by a molar equivalent amount of 4-pregnene-7c, 12cy-diol-3,20-dione 20-mono (a) 2 - Hydroxymethylene - 4 - pregnene - 78,116 ethylene glycol ketal. diol-3,20-dione-20-monoethylene glycol ketal can be pre (b) 7 c.12c - dihydroxy - 20 - oxo - 4 - pregneno2.3- pared by replacement of the 17 oz-methyl-4-androsten-17 3 disoxazole 20-monoethylene glycol ketal can be pre ol-3-one in Example 1, part (a) by a molar equivalent pared by replacement of the 2-hydroxymethylene-17a amount of 4-pregnene-75,13-diol-3,20-dione 20-mono methyl-4-androsten-176-ol-3-one in Example 1, part (b) ethylene glycol ketal. by a molar equivalent amount of 2-hydroxymethylene-4- (b) 7B, IIB - dihydroxy - 20- ovo - 4 - pregnenoL2.3- 35 pregnene-7a, 12c-diol-3,20-dione 20-monoethylene glycol disoxazole 20-monoethylene glycol ketal can be prepared ketal, and then hydrolyzed with dilute hydrochloric acid by replacement of the 2-hydroxymethylene-17 oz-methyl-4- to give 7 oz,12a-dihydroxy-20-oxo-4-pregneno2.3-disox androstan-17 3-ol-3-one in Example 1, part (b) by a molar equivalent amount of 2-hydroxymethylene-4-pregnene azole. 7(3,116-diol-3,20-dione 20-monoethylene glycol ketal, and 40 Example 71 then hydrolyzed with dilute hydrochloric acid to give (a) 2 - hydroxymethyleneallopregnane - 3,720 - trione 7f8,11.f3-dihydroxy-20-oxo-4-pregneno2.3-d)-isoxazole. 7.20-bis(ethylene glycol ketal) can be prepared by re Example 67 placement of the 17c-methyl-4-androsten-17,3-ol-3-one in Xample 1, part (a) by a molar equivalent amount of (a) 2- hydroxymethylene - 12c - chloro - 4 - pregnetie 45 allopregnane-3,7,20-trione 7,20-bis(ethylene glycol ketal) 17a,21-diol-3,11,20-trione 20-monoethylene glycol ketal (prepared by ketalization of allopregnan-3-3-ol-7,20-dione can be prepared by replacement of the 17ty-methyl-4-an and oxidation by the Oppenalier procedure). drosten-17 3-ol-3-one in Example 1, part (a) by a molar (b) 7,20-dioxoallopregnano 2.3-disoxazole 7,20-bis equivalent amount of 12a-chloro-4-pregnene-17 cc,21-diol (ethylene glycol ketal) can be prepared by replacement 3,11,20-trione 20-monoethylene glycol ketal. 50 (b). I2c - chloro - 17c.,2I - dihydroxy - II,20 - dioxo of the 2-hydroxyethylene-17 cy-methyl-4-androsten-176 4-pregneno.2.3-d)-isoxazole 20-monoethylene glycol ol-3-one in Example 1, part (b) by a molar equivalent ketal can be prepared by replacement of the 2-hydroxy amount of 2-hydroxymethyleneallopregnane-3,7,20-trione methylene-17a-methyl-4-androsten-17 3-ol-3-one in Exam 7.20-bis(ethylene glycol ketal), and then hydrolyzed with ple 1, part (b) by a molar equivalent amount of 2-hy diliate hydrochloric acid to give 7,20-dioxoailopregnano droxymethylene - 12c - chloro - 4 - pregnene - 17 c.21 2,3-disoxazole. dioi-3,11,20-trione 20-monoethylene glycol ketal, and Example 72 then hydrolyzed with dilute hydrochloric acid to give 120 (a) 2-formyl-9cv-fluoro-16cc - methyl-1,4- pregnadiene chloro - 17 c.21 - dihydroxy - 11.20 - dioxo - 4 - pregneno Ilg,17a,21-triol-3,20-dione 20-monoethylene glycol ketal 2.3-disoxazole. 60 can be prepared by replacement of the 17 oz-methyl-4-an Example 68 drosten-17B-ol-3-one in Example 1, part (a) by a molar equivalent amount of 9ce-fluoro-16cy-methyl-1,4-pregna (a)2 - hydroxymethylene - 18, 19 - his nor - 4 - preg diene-116,17a,21-triol-3,20-dione 20-monoethylene glycol nene-3,20-dione 20-monoethylene glycol ketal can be pre ketal. pared by replacement of the 17 cy-methyl-4-androsten-17 3 (b) 9cz-fluoro-16cy-methyl-11 (3,17a,21- trihydroxy-20 ol-3-one in Example 1, part (a) by a molar equivalent oxo-(1,3)5-pregnatrieno 2.3-disoxazole 20-ethylene gly amount of 18, 19-bisnor-4-pregnene-3,20-dione 20-mono col ketal can be prepared by replacement of the 2-hy ethylene glycol ketal. (b) 20 - oxo - 18.19 - bisnor - 4 - pregneno I2.3-d droxymethylene-17a-methyl-4-androsten-17 3-ol-3- one in isoxazole 20-monoethylene glycol ketal can be prepared 70 Example 1, part (b) by a molar equivalent amount of by replacement of the 2-hydroxy-methylene-17 oz-methyi 2 - formyl - 90 - fiuoro - 16c - methyl - 14 - pregnadiene 4-androsten-17 3-ol-3-one in Example 1, part (b) by a 11f8, 17cz,21-triol-3,20-dione 20-monoethylene glycol ketal, molar equivalent amount of 2-hydroxymethylene-18, 19 and then hydrolyzed with dilute hydrochloric acid to give bisnor-4-pregnene-3,20-dione 20-monoethylene glycol 9c-fluoro-16oz-methyl-118, 7c., 21 - trihydroxy-20 - oxo ketal, and then hydrolyzed with dilute hydrochloric acid 1,3)5-pregnatrieno 2.3-disoxazole. 3,135,743 3. 32 Example 73 Analysis.--Calcd. for Citias NO2-CH5OH: C, 75.52; (a) 2-formyl-6c.,9a-difluoro-1,4-pregnadiene-11b, 17a, H, 8.87; O, 12.07. Found: C, 75.50; H, 8.53; O, 12.30. 21-triol-3,20-dione 20-monoethylene glycol ketal can be Example 80 prepared by replacement of the 17a-methyl-4-androsten 17f8-ol-3-one in Example 1, part (a) by a molar equivalent 5 17,3-hydroxy-17a-propylandrostano 2.3-disoxazole IV; amount of 6a,9oz-difluoro-1,4-pregnadiene-1118,17a,21-tri R is H, R is CHCHCH3, X is H. Z is OH, Y and Y ol-3,20-dione 20-monoethylene glycol ketal. are CH3, colorless elongated prisms, M.P. 163.2-168.2 (b) 6a,9oz - difluoro - 116,17c,21 - trihydroxy-20-oxo C. (corr.), cD2- --31.9 (1% in chloroform); ultra (1,3)5-pregnatrieno 2.3-disoxazole 20-ethylene glycol violet maximum at 224 mu (E=4,000). ketal can be prepared by replacement of the 2-hydroxy O Analysis.-Calcd. for CHNO: C, 77.27; H, 9.87; methylene - 17ox - methyl-4-androsten-17f8-ol-3-one in Ex O, 8.95. Found: C, 77.55; H, 9.69; O, 8.65. ample 1, part (b) by a molar equivalent amount of 2 Example 81 formyl-6oz,9oz-difluoro-1,4-pregnadiene-116, 17a,21- triol 3,20-dione 20-monoethylene glycol ketal, and then hy 17,3-hydroxy - 17a - methyl-19 - nor - 4 - androsteno 15 2.3-disoxazole VI: R is H., R is CH3, X is H. Z is drolyzed with dilute hydrochloric acid to give 6a,9oz-diflu OH, Y is H, Y is CH3, pale yellow needles, M.P. 158.0- oro - 11 g,17a,21- trihydroxy - 20 - oxo - (1,3)5 - pregna 165.4° C. (corr.), al?5=-449 (1% in chloroform). trieno (2.3-disoxazole. Analysis.-Calcd. for CHNO: C, 76.64; H, 8.69; The following compounds were prepared according to N, 4.47. Found: C, 76.57; H, 8.63; N, 4.44. the methods previously described: 20 17 (3-hydroxy - 17oz - methyl - 19 - nor - 4 - androsteno Example 74 I2.3-dl isoxazole was found to possess anabolic activity 6oz,17a - dimethyl - 176 - hydroxyandrostano (2.3 - d - and myotrophic activity with a low degree of androgenic isoxazole, M.P. 1614-166.2° C. (corr.), c.25-47.8 activity; and it also was found to possess a high degree -0.4' (1% in chloroform); ultraviolet maximum at 228 of progestational activity when administered intramus mpg (E=4,800). 25 cularly to estrogen-primed immature female rabbits at a Analysis.--Calcd. for C2HNO: C, 76.92; H, 9.68; dose level of 2.0 mg./kg. N, 4.08. Found: C, 77.04; H, 9.75; N, 3.99. Example 82 Example 75 17,3 - hydroxy-17 oz-propynylandrostano (2.3-disoxazole 17,3 - hydroxy - 17 or - propyl - 4 - androsteno (2.3 - d - 30 IV; R is H, R is C=CCH, X is H2, Z is OH, Y and Y isoxazole Vi; R is H, R is (CH2)2CH3, X is Ha, Z is are CH), M.P. 124.6-135.4 C. (corr.), a 25- -18.5 OH, Y and Y are CH, M.P. 122.6-127.8° C. (corr.), (1% in chloroform); ultraviolet maximum at 227 mu o:25= -79.7-0.2 (1% in chloroform); ultraviolet (E=5,300). maximum at 286 mu, (E=10,200). Analysis.-Calcd. for C23H3NO2: C, 78.14; H, 8.84; Analysis.-Calcd. for C23H3NO2: N, 3.94; C, 9.00. 35 C, 9.05. Found: C, 77.85; H, 9.13; O, 9.15. Found: N, 3.82; O, 9.15. Example 83 Example 76 (a) 2 - hydroxymehylene - 9a - fluoro - 4 - pregnene IIB,17a,21-triol - 3.20 - dione 17,2020,21-bismethylenedi 17a-allyl-176 - hydroxy-4- androsteno (2.3-disoxazole 40 oxy derivative was prepared from 8.54 g. of 9o-fluoro VI; R is H, R is CHCH=CH, X is H, Z is OH, Y hydrocortisone 17,20:20,21-bismethylenedioxy derivative, and Y are CH, M.P. 152.2-156.0° C. (corr), c.125 24 ml. of ethyl formate and 1.2 g. of sodium hydride in =85.0-0.1 (1% in chloroform); ultraviolet maximum benzene according to the manipulative procedure de at 286 mu, (E=12,200). scribed above in Example 1, part (a). Analysis.-Calcd. for C2HNO2: C, 78.14; H, 8.84; 45 (b) 9a - fluoro - I 16,170,21 - trihydroxy - 20 - oxo-4- O, 9.05. Found: C, 78.37; H, 8.82; O, 9.10. pregneno2.3-disoxazole 17,2020,21-bismethylenedioxy Example 77 derivative was prepared from 6.2 g. of 2-hydroxymethyl ene-9 oz-fluoro-4-pregnene-116,17a,21-triol-3,20-dione. 17, 17,3 - hydroxy - 17ox - propargyl - 4 - androstenoI2.3-d- 20:20,21-bismethylenedioxy derivative, 2.00 g. of hydrox isoxazole VI: R is H, R is CHC=CH, X is H2, Z is OH, 50 ylamine hydrochloride and 2.00 g. of fused sodium acetate Y and Y are CH, pale yellow prisms, M.P. 182.0-187.6 in acetic acid according to the manipulative procedure de C. (corr.), IoD25=-|-72.6 (1% in chloroform); ultra scribed above in Example 1, part (b). The product was violet maximum at 285 mu (E=11,227). obtained in the form of a pale yellow solid, M.P. 280 Analysis.--Calcd. for C2HNO2: C, 78.59; H, 8.32; 290 C. (uncorr.) when recrystallized from a benzene N, 3.99. Found: C, 78.27; H, 8.06; N, 3.97. 55 ethanol mixture. Example 78 Analysis.--Calcd. for CHFNOs: C, 64.43; H, 6.76. 44,17,17-tetramethyl-18-nor-5,12-androstadieno2.3-d Found: C, 64.78; H, 6.70. (c) 21 - acetoxy - 9a - fluoro - 116,17a - dihydroxy isoxazole, M.P. 164.2-166.2° C. (corr.), or D25=-175 20-oxo-4-pregneno.2.3-disoxazole was prepared from (1% in chloroform); ultraviolet maximum at 225 mp. 60 1.25 g. of 9oz-fluoro-116,170,21-trihydroxy-20-oxo-4-preg (E=6,400). This compound was formed by reacting neno2.3-disoxazole 17,20:20,21-bismethylenedioxy de 2-hydroxymethylene - 4.4,17a - trimethyl - 5 - androsten rivative, 40 ml. of acetic acid and 4 ml. of perchloric acid, 176-ol-3-one with hydroxylamine hydrochloride in acetic seven hours at room temperature. The product was iso acid, rearrangement occurring in a manner analogous to lated and acetylated with acetic anhydride in pyridine and that of Example 17. 65 recrystallized from methanol to give 21-acetoxy-9o-fluo Analysis.-Calcd. for CH3NO: C, 81.85; H, 9.26; ro - 116,17a-dihydroxy - 20 - oxo - 4 - pregneno2.3-d- O, 4.74. Found: C, 81.93; H, 9.29; O, 5.10. isoxazole, yellow crystals, M.P. 204-227.2° C. (dec.) Example 79 (corr.), c.25=-|-157.6° (1% in chloroform). 176 - hydroxy - 17ox - propynyl - 4 - androsteno2.3-d- Analysis.--Calcd. for CH30FNOs: C, 64.43; H, 6.76; isoxazole VI: R is H, R is C=CCH, X is H, Z is OH, 70 F, 4.25; N, 3.13. Found: C, 64.27; H, 6.80; F, 4.34; N, Y and Y are CH, obtained with one molecule of ethanol 3.02. of crystallization, M.P. 138.6-144.2 C. (corr.), ox25 Example 84 = -8.3 (1% in chloroform); ultraviolet maximum at (a) 2-hydroxymethylene - 4 - pregnene - 116,17a - tri 284 mu (E=9,600). 75 ol-3,20-dione 17,20:20,21 -bismethylenedioxy derivative 3,185,743 33 34 was prepared from 12.6 g. of hydrocortisone 17,20:20,21 Example 88 bismethylenedioxy derivative, 22 ml. of ethyl formate and 18 - formyl - IIB,21 - dihydroxy - 20 - oxo - 4 - preg 2.2 g. of sodium hydride in benzene according to the manipulative procedure described above in Example 1, neno.2.3-d-isoxazole 11, 18-lactol from aldosterone. part (a). Example 89 (b) 11,3,17a,21 - trihydroxy - 20 - oxo - 4 - pregneno 6cy-fluoro-20-oxo-4-pregneno.2.3-disoxazole from 6cy 2.3-disoxazole 17,2020,21-bismethylenedioxy deriva fluoro-4-pregnene-3,20-dione. tive was prepared from 10.6 g. of 2-hydroxymethylene-4- pregnene - 116,17a,21 - trio - 3,20-dione 17,20:20,21-bis Example 90 methlenedioxy derivative, 2.5 g. of hydroxylamine hy 0. 6-fluoro-20-oxo-4,6-pregnadieno2.3-disoxazole from drochloride and 2.5 g. of fused sodium acetate in acetic 6-fluoro-4,6-pregnadiene-3,20-dione. acid according to the manipulative procedure described Example 91 above in Example 1, part (b). There was thus obtained 5.1 g. of 11B, 17 ca,21-trihydroxy-20-oxo-4-pregnenoI2.3- 17a - methyl - 176 - hydroxy - 19 - nor -4.9 - androsta disoxazole 17,20;20,21 - bismethylenedioxy derivative, 5 dieno (2.3-disoxazole from 17 oz-methyl-19-nor-49-an M.P. 271-274 C. (uncorr.) when recrystallized from a drostadien-176-ol-3-one. benzene-ethanol mixture. Example 92 (c) 116,17a,21 - trihydroxy - 20 - oxo - 4 - pregneno 2.3-disoxazole VI: R is H., R is COCHOH, X is 75,17a-dimethyl-17B - hydroxy - 4 - androsteno.2.3- (H) (OH), Z is OH, Y and Y are CH was prepared 20 disoxazole from 7p,17a-dimethyl-4-androsten-176-ol-3- from 5.1 g. of 11.f3,17a,21-trihydroxy-20-oxo-4-pregneno one (76,17a-dimethyltestosterone). 2,3-disoxazole 17,20:20,21-bismethylenedioxy deriva Example 93 tive, 200 ml. of acetic acid and 20 ml. of perchloric acid, five hours at room temperature. The resulting product 5 - methyl-116,17a,21 - trihydroxy - 20 - oxopregnano was treated with a solution of potassium bicarbonate in 25 {2.3-disoxazole from 5-methyl-17a,20:20,21-bismethyl aqueous methanol to hydrolyze any 21-ester produced, enedioxypregnan-11g-ol-3-one. and the product purified by chromatography on silica gel Example 94 to give 116,17a,21-trihydroxy-20-oxo-4-pregneno (2.3-d- 10oz - methyl - 93 - H - 20 - oxo - 19 - nor-4,6-preg isoxazole, pale cream prisms from ethyl acetate-benzene, nadieno (2.3-disoxazole from 10a-methyl-93-H-19-nor M.P. 226.8-236 C. (Corr.), oxi5= --146.4 (1% in 30 4,6-pregnadiene-3,20-dione. chloroform). Analysis.-Calcd. for C22H2NOs: C, 68.19; H, 7.54; Example 95 N, 3.62. Found: C, 67.99; H, 7.59; N, 3.77. 10oz - methyl -98 - H - 17B - hydroxy - 19 - nor - 4,6- Example 85 androstadieno (2.3-disoxazole from 10a-methyl-93-H-19 35 nor-4,6-androstadien-176-ol-3-one. (a) 2 - hydroxymethylene - 4.4 - dimethyl - 5 - preg Also within the purview of the invention are isoxazole nene-3,20-dione 20-monoethylene glycol ketal was pre derivatives of D-homosteroids. The following such com pared from 4,4-dimethyl-5-pregnene-3,20-dione 20-mono pounds can be prepared by procedures analogous to those ethylene glycol ketal, ethyl formate and sodium hydride described hereinabove: in benzene according to the manipulative procedure de 40 scribed above in Example 1, part (a). The product was Example 96 recrystallized from ethyl acetate as a peach-colored solid and had the M.P. 182.2-183.4 C. (corr.), al?--14.6 17a-Oxa-17-oxo-D-homo-4-androsteno 2.3-d) isoxazole (1% in chloroform). from testololactone. Analysis.--Calcd. for Cash;804: C, 75.32; H, 9.24; O, 45 Example 97 15.44.(b) 4,4-dimethyl-20Found: C, 75.00; - H,oxo-5-pregneno.2.3-disoxazole 9.55; O, 15.70. 20-oxo-D-homo-4-pregneno2.3-disoxazole from D was prepared from 2-hydroxymethylene-4,4-dimethyl-5- homo-4-pregnene-3,20-dione (D-homoprogresterone). pregnene-3,20-dione 20-monoethylene glycol ketal and Example 98 hydroxylamine hydrochloride according to the manipula tive procedure described above in Example 1, part (b), 50 17f8-hydroxy-D-homo - 4 - androsteno2.3-disoxazole followed by cleavage of the ketal group by heating with from D-homo-4-androsten-17 3-ol-3-one (D-homotestos dilute ethanolic hydrochloric acid. The product was ob terone). tained in the form of colorless crystals, M.P.161.2-163.8 Example 99 C. (corr.) when recrystallized from ethylene acetate, 55 17 oz-methyl-17,3-hydroxy-D-homoandrostano 2.3-dis ox25=-|-31.6 (1% in colorform). oxazole from 17a-methyl-D-homoandrostan-176-ol-3-one. Analysis.--Calcd. for CH3NO2: C, 78.43; H, 9.05; N, 3.81. Found: C, 78.34; H, 8.92; N, 3.82. Example 100 Example 86 17-hydroxy-(1,3)androstadieno 2.3-d-3'- methylisoxa 178 - hydroxy - 17cy - methyl-1,3,5 - estratrieno (2.3- 60 zole can be prepared from 2-acetylandrostan-176-ol-3-one d-isoxazole can be prepared by heating 17.3-hydroxy (Example 12(b)) by brominating the latter with bromine 17c-methyl-19-nor-4-androstenoI2.3-disoxazole (Exam in pyridine to give the 2-bromo derivative, M.P. 119.0- ple 81) with palladium catalyst; or by bromination of 121.0° C. (corr.). Ia D25= --163.8 (1% in chloroform), the latter compound at the 10-position by means of N dehydrobrominating the latter with collidine to give 2 bromosuccinimide, followed by dehydrobromination by 65 acetyl-1-androsten-17 3-ol-3-one, followed by reaction with heating with collidine or with lithium chloride in dimeth hydroxylamine in the usual manner. ylformamide solution. This application is a continuation-in-part of our prior The following compounds can also be prepared by the copending application, Serial No. 750,289, filed July 23, 1958, now abandoned. procedures descriped hereinabove: 70 We claim: Example 87 1. A steroido 2.3-disoxazole, the steroid moiety hav 7oy - acetylthio - 17a. - (B - carboxyethyl) - 176 - hy ing from seventeen to about twenty-three carbon atoms droxy-4-androsteno (2.3-disoxazole 17-lacetone from 3 exclusive of ester radicals and being selected from the (3 - oxo - 7c. - acetylthio - 176 - hydroxy - 4 - androsten group consisting of the estrane, 18-norestrane, androstane, 17a-yl)-propionic acid lactone. 75 etiocholane, pregnane and allopregnane series. 3,135,743 35 36 - 2. A compound selected from the group consisting of the acetyl radical, the hydroxyacetyl radical, the 1,2-di (A) compounds having the formula hydroxylethyl radical and the 1-hydroxyethyl radical; X represents a member of the group consisting of H2, (H) (OH) and O; Y and Y' represent a member of the group consisting of hydrogen and the methyl radical; and R Z represents a member of the group consisting of hydro r gen and the hydroxy radical, Z being restricted to hydroxy when R represents a member of the group consisting of hydrogen, lower-alkyl, lower-alkenyl and lower-alkynyl O radicals; (B) carboxylic acid esters thereof derived from carboxylic acids having from one to about ten carbon wherein R represents a member of the group consisting atoms and having a molecular weight less than about 250; of hydrogen and lower-alkyl radicals; R represents a (C) acid-addition salts thereof; and (D) quaternary am member of the group consisting of hydrogen, lower-alkyl monium salts thereof. radicals, lower-alkenyl radicals, lower-alkynyl radicals, 5 5. A 176-substituted androst-4-eno (2,3-d)-isoxazole the acetyl radical, the hydroxyacetyl radical, the 1,2-di represented by the formula hydroxylethyl radical and the 1-hydroxyethyl radical; X represents a member of the group consisting of H2, (H)(OH) and O; Y and Y represent a member of the group consisting of hydrogen and the methyl radical; and 20 Z represents a member of the group consisting of hydro gen and the hydroxy radical, Z being restricted to hydroxy when R represents a member of the group consisting of hydrogen, lower-alkyl, lower-alkenyl and lower-alkynyl radicals; (B) carboxylic acid esters thereof derived from 25 carboxylic acids having from one to about ten carbon atoms and having a molecular weight less than about 250; wherein R represents a member of the group consisting (C) acid-addition salts thereof; and (D) quaternary am of hydrogen and the alkanoyl radicals of lower hydro monium salts thereof. carbon carboxylic acids. 3. A compound selected from the group consisting of 30 6. 176-hydroxy-17a-methyl-4-androsteno2.3-d-isoxa (A) compounds having the formula zole. - 7. 17,3-propionoxy-4-androsteno2.3-disoxazole. 8. 176-hydroxy-17o-methylandrostano 2.3-disoxazole. Y tz 9. 173-hydroxy-4,4,17a-trimethyl-5-androstenoI2.3-d J 35 isoxazole. 10. 176-hydroxy-17a-methyl-19-norandrostano[2.3-d- isoxazole. 11. 176-acetoxyandrostano 2.3-d-isoxazole. 5. ? 12. 173-acetoxy-4,6-androstadieno 2.3-disoxazole. 40 13. 17,3-hydroxy-4,6-androstadieno 2.3-disoxazole. NN/ 14. 176-hydroxy-17o-methyl-4,6-androstadieno2.3-d- wherein R represents a member of the group consisting isoxazole. of hydrogen and lower-alkyl radicals; R represents a 15. 17a-ethynyl-176-hydroxy-4-androsteno2.3-disoxa member of the group consisting of hydrogen, lower-alkyl Zole. radicals, lower-alkenyl radicals, lower-alkynyl radicals, 45 16. 20-oxo-4-pregneno2.3-disoxazole. the acetyl radical, the hydroxyacetyl radical, the 1,2-di 17. 6oz,17a-dimethyl-17 3-hydroxy-4-androsteno2.3-d- hydroxylethyl radical and the 1-hydroxyethyl radical; X isoxazole. represents a member of the group consisting of H2, 18. 17,3-hydroxy-17cy - ethynylandrostano 2.3-disoxa (H) (OH) and O'; Y and Y' represent a member of the zole. group consisting of hydrogen and the methyl radical; and 50 19. 17a-allyl-17,3-hydroxy - 4 - androsteno2.3-disoxa Z represents a member of the group consisting of hydro Zole. gen and the hydroxy radical, Z being restricted to hydroxy 20. 1713-hydroxyandrostano 2.3-disoxazole. when R represents a member of the group consisting of 21, 17B-hydroxy-17a-propynyl-4-androsteno 2.3-dis hydrogen, lower-alkyl, lower-alkenyl and lower-alkynyl oxazole. radicals; (B) carboxylic acid esters thereof derived from 55 22. 176-hydroxy-17c-methyl-19-nor-4-androsteno I2.3- carboxylic acids having from one to about ten carbon disoxazole. atoms and having a molecular weight less than about 250; 23. 17.6-(3-cyclohexylpropionoxy)androstano 2.3-dis (C) acid-addition salts thereof; and (D) quaternary am oxazole. - monium salts thereof. - 24. 176-hydroxy-4-androsteno2.3-disoxazole. 4. A compound selected from the group consisting of 60 25. 176-(4-chlorophenoxyacetoxy)-4-androsteno2.3- (A) compounds having the formula disoxazole. 26, 173-(4-chlorophenoxyacetoxy)androstano 2.3-dis oxazole. 27. 11 (3,17a,21-trihydroxy-20-oxo-4-pregneno.2,3-dis R 65 oxazole. Y 28. The process for preparing an isoxazole compound fused through its 4- and 5-positions to the 2- and 3-posi tions, respectively, of a steroid nucleus, which comprises reacting a 2-(1-hydroxyalkylidene)-3-oxo-steroid with a 70 member of the group consisting of hydroxylamine and acid-addition salts thereof, the steroid moiety having from wherein R represents a member of the group consisting seventeen to about twenty-three carbon atoms exclusive of of hydrogen and lower-alkyl radicals; R represents a ester radicals and being selected from the group consist member of the group consisting of hydrogen, lower-alkyl ing of the estrane, 18-norestrane, androstane, etiocholane, radicals, lower-alkenyl radicals, lower-alkynyl radicals, 75 pregnane and allopregnane series. 3,135,743 (9.37 29. The process for preparing a compound selected less than about 250, which comprises reacting a com from the group consisting of (A) compounds having the pound having the formula formula Y tz x-/NY, ? l-Z R Xe ? R Y d Y EO-Cat K O Oc NN/ wherein R, R, X, Z, Y and Y are identical with their wherein R represents a member of the group consisting . selection above, with a member of the group consisting of hydrogen and lower-alkyl radicals; R represents a of hydroxylamine and acid-addition salts thereof in the member of the group consisting of hydrogen, lower-alkyl absence of a strong acid. radicals, lower-alkenyl radicals, lower-alkynyl radicals, 31. The process for preparing a compound selected ketalized acetyl radicals, ketalized hydroxyacetyl radicals, from the group consisting of (A) compounds having the the 1,2-dihydroxyethyl radical and the 1-hydroxyethyl formula radical; X represents a member of the group consisting of H. (H) (OH) and O; Y and Y represent a member 20 of the group consisting of hydrogen and the methyl radi cal; and Z represents a member of the group consisting x-/N O of hydrogen and the hydroxy radical, Z being restricted y to hydroxy when R' represents a member of the group / consisting of hydrogen, lower-alkyl, lower-alkenyl and N lower-alkynyl radicals; and (B) carboxylic acid esters ( ) thereof derived from carboxylic acids having from one to NN/ about ten carbon atoms and having a molecular weight wherein R represents a member of the group consisting less than about 250, which comprises reacting a com 30 of hydrogen and lower-alkyl radicals; R' represents a pound having the formula member of the group consisting of hydrogen, lower-alkyl R radicals, lower-alkenyl radicals, lower-alkynyl radicals, Y/ Z. ketalized acetyl radicals, ketalized hydroxyacetyl radicals, the 1,2-dihydroxyethyl radical and the 1-hydroxyethyl radical; X represents a member of the group consisting of H., (H)(OH) and O; Y and Y' represent a member HO-C-f of the group consisting of hydrogen and the methyl radi cal; and Z represents a member of the group consisting Os of hydrogen and the hydroxy radical, Z being restricted O 40 to hydroxy when R represents a member of the group wherein R, R, X, Z, Y and Y are identical with their consisting of hydrogen, lower-alkyl, lower-alkenyl and selection above, with a member of the group consisting lower-alkynyl radicals; and (B) carboxylic acid esters of hydroxylamine and acid-addition salts thereof in the thereof derived from carboxylic acids having from one to absence of a strong acid. about ten carbon atoms and having a molecular weight 30. The process for preparing a compound selected 45 less than about 250, which comprises reacting a com from the group consisting of (A) compounds having the pound having the formula formula

Y 50 R d Y 4 N/Nir x 55 wherein R, R, X, Z, Y and Y are identical with their NN/ selection above, with a member of the group consisting wherein R represents a member of the group consisting of hydroxylamine and acid-addition salts thereof in the of hydrogen and lower-alkyl radicals; R represents a absence of a strong acid. member of the group consisting of hydrogen, lower-alkyi 60 32. The process for preparing 176-hydroxy-17a-methyl radicals, lower-alkenyl radicals, lower-alkynyl radicals, 4-androsteno (2.3-disoxazole which comprises reacting ketalized acetyl radicals, ketalized hydroxyacetyl radicals, 2-hydroxymethylene - 17c. - methylandrostan-176-ol-3-one the 1,2-dihydroxyethyl radical and the 1-hydroxyethyl with a member of the group consisting of hydroxylamine radical; X represents a member of the group consisting and acid-addition salts thereof in the absence of a strong of H. (H)(OH) and O; Y and Y' represent a member of the group consisting of hydrogen and the methyl radi acid. cal; and Z represents a member of the group consisting References Cited in the file of this patent of hydrogen and the hydroxy radical, Z being restricted to hydroxy when R represents a member of the group UNITED STATES PATENTS consisting of hydrogen, lower-alkyl, lower-alkenyl and 3,035,068 Bowers et al. ------May 15, 1962 lower-alkynyl radicals; and (B) carboxylic acid esters 3,052,693 Engelfried et al. ------Sept. 4, 1962 thereof derived from carboxylic acids having from one to 3,063,990 Kuehne ------Nov. 13, 1962 about ten carbon atoms and having a molecular weight 3,100,771 Manson ------Aug. 13, 1963 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 135,743 June 2, 1964 Raymond O. Clinton et al. It is hereby certified that error appears in the above numbered pat correctedent requiring below. correction and that the said Letters Patent should read as Column 2 lines 31 to 39, formula (II) should appear as shown below instead of as in the patent :

2 column 4 lines 9 to 20, the lower left-hand portion of theformula patent (VIII) : should appear as shown below instead of as in

HO-C O column 9 linee 73 for C2H11NO3 read - C29H11NO3 -- a g column 10 lines 4l and 42 strike out 'ethyl acetate and linethe ethyl63 foracetate "N, 915extracts read were Hsi5washed with";column column 13, llline 16, for 'll-toluene sulfonic" read -- p-toluenesulfonic --; column 14 line 4l for "2d -cyandro stan-' read -- 2c -cyanoandro Stan - --;

3 l35,743 lines 43 and 44 for "l -hydroxy stano 2.3-disoxazole", in italics read -- l7 B-hydroxyandrostano 2.3-disoxazole ---, in italics; column 2l line 7l for "--andro Stan-" read -- -androsten- --; column 29 line l6 for "lTB-methyl-" read -- 17a-methyl- --; line 38 for "androstan-" read -- and rosten- --; column 30 line ls for "-andro Stan-" read -- -androsten- --; column 32 line 74 for "-ll B17d, in italics, read -- ll B, l7a, 21- -- in italics; column, 33 line 54 for "ethylene" read -- ethyl --. . . ; Signed and sealed this 6th day of April 1965.

(SEAL) Attest : ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents