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.