Steroidal 2,3-4 isoxazole

Intermediate 12, on heating in benzene, gives the isoxazole 13, whereas related compounds give, for example, pyrazolo[l,5-a] pyridines.33 Irradiation of the 6>nitrocholest-5-enes 14 in acetic acid at reflux gave the steroidal isoxazoles 15. It was proposed that the isoxazoles were formed via the labile intermediate 16, which was formed by hydrogen abstraction as shown in Scheme 1. The possible importance of this method for functionalizing a nonactivated carbon atom was pointed out.34 We are unaware of examples involving CCNOC and CNOCC synthons. 

Many of the reported transformations are of more theoretical than practical interest. However, ring contraction of condensed 4-pyrones continues to play a useful role in the synthesis of steroidal isoxazoles.38,39 The stepwise, polar addition of an electron-rich, multiply bonded component to an easily cleaved cyclic electron acceptor has been proposed as a strategy for the synthesis of a variety of heterocyclic systems.40 The formation of the isoxa-zolone 18 from the 1,3,5-dioxazolidone 17 and diethylaminopropyne exemplifies the principle. This reaction is also interesting in that compound 17 represents a cyclic NOC synthon. 

As a result of this first report, a large number of compounds containing an isocyclic or a heterocyclic ring fused tc the steroid skeleton were prepared and tested for androgenic and anabolic activity. Included are steroidal isoxazoles [205], thiazoles [94], pyrroles [206], pyrimidines [207,208], oxazines [209], thiazenone [92], quinoline [107], pyridine [122], and furazane [121], all prepared by the fusion of the heterocyclic ring to ring A. Several bis heterocyclic steroids were also prepared by... 

Synthesis and biological activity of steroid isoxazoles 00KGS291. 

The reaction of the steroidal )3-ketoaldehyde (293) with hydroxylamine hydrochloride in acetic acid gave a mixture of the 3- and 5-substituted isoxazoles (294) and (295a). In sodium acetate buffer the reaction provided exclusively the 5-substituted isomer (29Sb) (66JOC3193). 

Pharmacologically useful isoxazoles (B-82MI41600) include antibacterial sulfonamides (614), (615) and (616), semisynthetic penicillins (617), (618), (619) and (620), semisynthetic cephalosporin (621), anabolic steroid (622), the monoamine oxidase inhibitor (623) (used in psychotherapy), antiinflammatory agent (624) and antitumor agent (625). 

Novel steroids which contain an isoxazole fused ring within the structure have biological activity which is primarily contraceptive (74MI41604, 79MI41607, 79USP4160027) and a variety of other indications (75USP3869467, 75ZOB2090). 

Quite recently great attention has been focused on steroids involving an isoxazole ring in the 2,3-position because of their anabolic activity. ... 

Hydrogenolysis of methylenediisoxazoles have been useful in preparing substituted resorcinols and aminophenols (7). The isoxazole annelation reaction (71,89,90,91,103) is well suited to the synthesis of steroids and other complex molecules. 

Propiolaldehyde diethyl acetal has found numerous synthetic applications in the literature which may be briefly summarized. The compound has been utilized in the synthesis of unsaturated and polyunsaturated acetals and aldehydes by alkylation of metal-lated derivatives, " by Cadiot-Chodkiewicz coupling with halo acetylenes, " and by reaction with organocuprates. Syntheses of heterocyclic compounds including pyrazoles, isoxazoles, triazoles, and pyrimidines have employed this three-carbon building block. Propiolaldehyde diethyl acetal has also been put to use in the synthesis of such natural products as polyacetylenes " and steroids. ... 

A23-22-Oxo steroids 424 have been synthesized via 1,3-dipolar cycloaddition of steroidal nitrile oxides to low-molecular dipolarophiles. Cycloaddition of 2-propynyl bromide to 20-carbonitrile oxide, followed by hydrogenation of the isoxazole derivative, gives 22-enamino-24-keto steroid. The latter has then been converted into the target enones in several steps (465). 

The fused pyrrole ring system (204) has been obtained by the reaction of 17/3-hydroxy-17-methylandrosta-l,4-dien-3-one with tosylmethyl isocyanide in the presence of sodium hydride in DMSO,92 and 17/3-hydroxy-17-methyl-7-oxa-5o -androstano-[3,2-c]- (205) or -[2,3-d]-isoxazoles (206 X = O) have been prepared by treating 7-oxa-2-(hydroxymethylene)-17/3 -hydroxy-17-methyl-5 a -androstan-3-one with hydroxylamine hydrochloride.93 In the presence of pyridine, the isox-azole (206 X = O) is formed, but when the reaction is catalysed by sodium acetate in acetic acid the isomeric steroid (205) results. Cycloaddition of hydrazine hydrate to the same 2-hydroxymethylene-7-oxa-steroid results in the [3,2-c]pyrazole (206 X = NH). A similar addition is encountered in the reactions between 3/3-hydroxy-16-(hydroxymethylene)-5a-androstan-17-one and the substituted hydrazines RNHNH2 (R = H, o-COC6H4NH2, or p-COQHUNH ,) when the corresponding [17,16-c]pyrazoles (207) are formed after cyclization of the intermediate hydrazones.94... 

Changes in reaction conditions may cause marked changes in the degree of regiospecificity. Thus, the steroidal j8-ketoaldehyde, which mainly exists as the enol 6, has afforded either a mixture of the 3- (7) and 5-substituted (8) isoxazoles (in acetic acid) or exclusively the 5-substituted isomer (9) (in... 

Oi-Methyl-17Q-hydroxy-5oi-androstan [3,2-c ]isoxazole. Evaluation of this derivative (Androisoxazole, D-33) for anabolic activity by means of nitrogen balance studies gave an oral anabolic activity of 155% of that of 17o -methyltestosterone. At the same time, the androgenic activity (oral administration) was found to he 22% of that of 17a-methyltestosterone on the basis of weight increase of the ventral prostate. In spite of the fact that this compound has found therapeutical application [131,283-285], it soon became apparent that the steroidal [2,3-c/]isoxazoles possessed more noteworthy endrocinological activities [11] than the steroidal [3,2-c ]isoxazoles. 

A series of new substituted oestradiols has been synthesized. The reaction of oestradiol with acetyl chloride gave the 2-acetyl derivative (133a). Condensation with ethyl formate (see Scheme 11), followed by brief exposure to acid, afforded the steroidal chromone (134). Whereas treatment of (134) with hydrazine hydrate provided the 3 -phenylpyrazole (135), reaction with hydroxylamine yielded a mixture of the 5 -phenylisoxazole (136) and of the isomeric 3 -phenyl-isoxazole (137). When the oxime (133b) was allowed to react with benzenesul-phonyl chloride in pyridine solution, the methylbenzoxazole (138) was obtained. 

Diosgenin has been converted into [3,2-c]pyrazole and [2,3-d]isoxazole derivatives of types (452) and (453). Pyrazolines (454), prepared from the corresponding 2-benzylidine-3-oxo-steroid and phenylhydrazine, were dehydrogenated to give the substituted pyrazole (455). ... 

TA Williams, J Edelson, RW Ross, Jr. A radioimmunoassay for danazol 17-alpha pregna-2,4-dien-20-yno 2 3-d-isoxazol-17-ol. Steroids 31 205, 1978. 

Fused Heterocycles The /8-dicarbonyl system in the formyl derivative of 17-methyltestosterone shows much the same reactivity as the same array in simpler compounds. Thus, reaction of the formyl derivative 17-1 with hydrazine fuses apyrazolering onto the steroid at positions 2,3 (21-1) (Scheme 5.21). This compound, stanazol, is one of the more frequently abused anabolic agents. Reaction of the same formyl derivative with hydroxylamine goes on to add an isoxazole ring to give danazol (21-2). 

Other new but conventional radioimmunoassays have involved oestra-l,3,5(10)-triene-3,15a,16a,17/S-tetrol ( oestetrol ), as its 6-(0-carboxy-methyloximino)-derivative, the 16-carboxymethyloximino-derivative of androst-5-ene-3/S,17 8-diol, the 15-hemisuccinate of 15a-hydroxy-testosterone, some oestriol monoglucoside derivatives, the 6-carboxy-methyloximino- and 3-hemisuccinate derivatives of the synthetic oestrogen 17a-ethynyloestradiol, the 3-carboxymethyloximes of the contraceptive steroids norethindrone and norgestrel , and the pituitary gonadotropin inhibitor, the isoxazole derivative Danazol (25), which was effectively bound by an antiserum for the corresponding 17-carboxymethyloxime (26)7°... 

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