17-ALPHA-(ARYLOXY OR ALKOXY) ANDROSTENES

Abstract: Antiglucocorticoid activity is exhibited by new steroids having the formula and the 1,2-dehydro derivatives thereof, wherein R₁ is aryl or alkyl; R₂ is hydrogen, hydroxy, alkyl, alkoxy, aryloxy, oxo, methylene, alkylthio, arylthio, alkanoyl, alkanoyloxy, or halogen; R₃ is carboxyl or β-hydroxymethylene; R₄ is hydrogen or halogen; and R₅ is hydrogen, fluorine or methyl, wherein the term «aryl» refers to phenyl and phenyl substituted with 1,2 or 3 alkyl, alkoxy or halogen atoms.

Description: 1 7a - (ARYtOXY OR ALKOXY)ANDROSTENES This invention relates to new steroids having the formula EMI1.1 which have antiglucocorticoid activity. In formula I, and throught the specification, the symbols are as defined below: R1 is aryl or alkyl; R2 is hydrogen, hydroxy, alkyl, alkoxy, aryloxy, oxo (=0), methylene (=cm2), alkylthio, arylthio, alkanoyl, alkanoyloxy, or halogen; R3 is carbonyl or ss-hydroxymethylene; R4 is hydrogen or halogen; and Rs is hydrogen, fluorine or methyl. The dotted line in 1,2-position of the structural formulas herein represents the optional presence of ethylenic unsaturation. The terms "alkyl" and "alkoxy" as used throughout the specification, refer to straight and branched chain alkyl groups having 1 to 10 carbon atoms. The term "aryl", as used throughout the specification, refers to phenyl and phenyl substituted with 1, 2 or 3 alkyl, alkoxy or halogen atoms. The term "halogen", as used throughout the specification, refers to fluorine, chlorine, bromine and iodine. The steroids of this invention can be prepared utilizing as starting materials androstenes having the formula EMI2.1 wherein R3, is carbonyl, ss-hydroxymethylene or 8-(acetyloxy)methylene. Sequential reaction of a steroid of formula II with a phosphine such as triphenylphosphine, an azodicarboxylate such as diethylazodicarboxylate and a compound having the formula III R1-OH yields the corresponding steroid having the formula EMI3.1 If the product of formula IV is an 11ss-(acetyloxy)- androstene, deprotection can be accomplished using conventional techniques; e.g., treatment of the protected steroid with an inorganic base. The steroids of formula I have antiglucocorticoid activity and can be used in mammals to treat conditions caused by the presence of too high a level of administered or endogenous glucocorticoids. One such condition is Cushing's syndrome, and another is the retardation of growth in children. The steroids of this invention can be administered either orally or by injection, the dosage being adjusted for the relative potency of the particular steroid. The daily range will be between about 0.01 and 1 gram for a 70 killogram mammal. The following example is a specific embodiment of this invention. Example 1 (llss,17a)-9-Fluoro-11-hydroxy-17-(phenoxy)androsta- 1,4-dien-3-one A) (11S,17a)-11-(Acetyloxy)-9-fluoro-17-(phenoxy)- androsta-1,4-dien-3-one (11B,17B)-ll-(Acetyloxy)-9-fluoro-17- hydroxyandrosta-1,4-dien-3-one (365 mg, 1.0 mmole) and triphenylphosphine (288 mg, 1.1 mmole) were dissolved in 5.0 ml of dry tetrahydrofuran under a nitrogen atmosphere with magnetic stirring. Phenol (97 mg, 1.1 mmole) dissolved in 5.0 ml of tetrahydrofuran followed by diethylazodicarboxylate (.134 ml, 1.1 mmole) dissolved in 5.0 ml of tetrahydrofuran was added to the stirred solution. The mixture had a yellow color. After 67 hours, TLC (7:3 chloroform:ethyl acetate) showed little product formation. An additional 576 mg (2.2 mmole) of triphenylphosphine, 194 mg (2.2 mmole) of phenol, and 0.258 ml (2.2 mmole) of the diethylazodicarboxylate were added to the reaction mixture and it was refluxed. After 22.0 hours of reflux, TLC showed little starting material left. The mixture was added to cold water and extracted with chloroform. The pooled chloroform extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated to an oil. This was preadsorbed on Baker silica gel (60-200 mesh) and flash-chromatographed on a column of silica gel (LP-1). The desired product was successfully eluted with a 2% ethyl acetate:98% chloroform mixture. The desired fractions were combined and evaporated in vacuo to yield a foamy solid which showed an NMR spectrum consistent with the expected structure. B) (llss,17&alpha;)-9-Fluoro-11-hydroxy-17-(phenoxy)- androsta-1,4-dien-3-one (11ss,17&alpha;)-11-(Acetyloxy)-9-fluoro-17- (phenoxy)androsta-1,4-dien-3-one was dissolved in tetrahydrofuran (12.0 ml) and methanol (6.0 ml) with magnetic stirring under a nitrogen atmosphere. A 12% sodium hydroxide solution (1.0 ml) was added and the mixture was stirred for 1.5 hours at room temperature before the addition of water and extraction with chloroform. The pooled extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated to yield an oil. Two recrystallizations from a dichloromethanepetroleum ether mixture yielded 129 mg of an analytical specimen with consistent spectral data, melting point of 210 -212 C, [&alpha;]D25 -13.7 (c, 1.0; chloroform). Anal. Calc'd. for C25H29O3F1: C, 75.73; H, 7.37; F, 4.79. Found: C, 75.76; H, 7.54; F, 4.76.

Claims: What we claim is: 1. A steroid having the formula EMI6.1 or 1,2-dehydro derivative thereof, wherein R1 is aryl or alkyl; R2 is hydrogen, hydroxy, alkyl, alkoxy, aryloxy, oxo, methylene, alkylthio, arylthio, alkanoyl, alkanoyloxy, or halogen; R3 is carboxyl or (3-hydroxymethylene; R4 is hydrogen or halogen; and R5 is hydrogen, fluorine or methyl, wherein the term "aryl" refers to phenyl and phenyl substituted with 1, 2 or 3 alkyl, alkoxy or halogen atoms. 2. A steroid in accordance with claim 1 having the formula EMI6.2 3. A steroid in accordance with claim 1 or 2 wherein R2 is hydrogen. 4. A steroid in accordance with claim 1, 2 or 3 wherein R1 is aryl. 5. A steroid in accordance with claim 1, 2 or 3 wherein R1 is alkyl. 6. A steroid in accordance with claim 1, (llss,17a)-9-fluoro-11-hydroxy-17-(phenoxy)androsta- 1 ,4-dien-3-one.

Inventors: HAUGWITZ, RUDIGER D.
Applicants: E.R. SQUIBB & SONS, INC.
Application year: 1985
Main classification: C07J1
IPC codes: A61K31, A61P5, C07J1