CA1266641A - 16-keto-17-substituted thia-17-alkyl (or alkenyl or alkynyl) androstenes - Google Patents

Abstract

ABSTRACT

A steroid having the formula:

or a 1,2-dehydro derivative thereof, wherein R1 is alkyl, mono-, di- or trifluoroalkyl, R6-?-O-(CH2)?, aryl or alkylthioalkyl, wherein R6 is alkyl or aryl and m is 1,2, 3 or 4;
R3 is carbonyl or .beta.-hydroxymethylene:
R4 is hydrogen or halogen;
R5 is hydrogen, methyl or fluorine; and R7, R8 and R9 are each independently hydrogen or alkyl of 1 to 4 carbon atoms:
which is useful as an intermediate in the preparation of related steroids having the formula:

Description

~6~4~

(OR ALKENYL OR ALKYNYL) ANDROSTENES

The or~sent invention relates to new steroids having the formula I

Rl S=()n R~

1~
have antiinflammatory activity. In formula I, and throughout the specification, the symbols are as defined below.
Rl is alkyl, mono-, di- or trifluoroalkyl,

2~ R
R6-C-O-(CH2)m~, aryl or alkylthioalkyl, wherein R6 is alkyl or aryl and m is 1, 2, 3 or 4;
IR7 R8 R~g ~7 R8 19 R7 ~8 Rlg R2 is -CH-C - CH, -C = C - CH2, or -C~-CH-CH2, wherein R7, R8 and Rg are each independently hydrogen or alkyl of 1 to 4 carbon atoms;
R3 is carbonyl or ~-hydroxymethylene;
R4 is hydrogen or halogen;
R5 is hydrogen, methyl or fluorinei and n is 0, 1 or 2;

.

~;

.
~: .

: ~ , . :. : - : :

~ 2 6 66fll K595 with the proviso that if Rl is alkylthioalkyl, n is 0. The dotted line in the 1,2-position of the structural formulas shown in this specification indicate the optional pressnce of ethylenic unsaturation.
The term "aryl", as used throughout the specification either individually or as part of a larger group, refers to phenyl or phenyl substituted with one, two or three alkyl, alkoxy or halogen groups.
The term "halogen", as used throughout the specification either individually or as part of a larger group, refers to fluorine, chlorine, bromine and iodine.
The terms "alkyl" and "alkoxy", as used throughout the specification either individually or as part of a larger group, refer to groups having 1 to 12 carbon atoms.
United States Patent 4,361,5S9, issued November 30, 1982, discloses (as antiinflammatory agents) 3-ketoandrostenes having in the 17-position the substituents A1-S- and A2-S-wherein Al and A2 are-the same or different and each is alkyl, cycloalkyl or aryl.
United States Patent 4,094,840, issued June 13, 1978, discloses (as antiinflammatory agents) androstenes having the partial structural formula ~A5 3_ ~2~

o wherein A3 is -S-, -S- or -~-, A4 is alkyl, aryl, acyloxyalkyl, and the A5 groups are halogen.
United States Patent 4,091,036, issued May 23, 1978, discloses (as antiinflammatory agents) androstenes having the partial structural formula ,A4 A6 ~ ,~ H

H

wherein A3 and A4 are as defined above, and A6 and A7 are the same or different and ars hydrogen, alkyl, alkoxy, carboalkoxy, formyl, alkyl-C-, alkyl-~-O, hydroxy, halogen, phenyl or cyano, with the proviso that when A6 and A7 are different, one of A6 and A7 i~ hydrogen.
United States Patent 4,146,538, issued March 27, 1979, discloses (as antiinflammatory agents) androstene~ having the partial structural fo~mula " ~;266~1 wherein A3 and A4 are as defined above,and ~8 and Ag are the same or different and are hydrogen, halogen, alkyl, or alkoxy, or A8 and Ag together with the benzene ring to which they are attached form a naphthalene group.
United States Patent 4,265,815, issued May 5, 1981 discloses (as chemical intermediates) androstenes having the partial structural for~ula Alo ,~All wherein Alo is alkyl, aryl, arylalkyl or acyloxy-alkyl and All is chloro, bromo, alkoxy, aryloxy, alkylthio or arylthio.
United States Patent4,252,733, issued February 24, l9al, discloses (as antiinflammatory agents) androstenes having the partial structural ormula ~A12 lso2 ~A13 A14 ~I D I A13-A14 wherein A12 is alkyl or aryl, A13 is oxygen or sulfur and A14 is al~yl or arylalkyl, or together the A14 groups are (C~2) 20r 3 United States Patent 4,420,428, issued December 13, 1983 discloses (as antiinflammatory agents) androstenes having the partial structural formula S
:~ ~0 wherein A13 and A14 are the same or different and each.is alkyl, cycloalkyl or aryl.
United States Patent 4,427,592, issued January 24, 1984, discloses (as antiinflammatory agents) androstenes having the partial structural formula A15~ ~A16 S S
~ Al~

wherein one of A15 and A16 is alkyl, aryl, arylalkyl, or cycloalkyl, and the other is alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, mono-, di- or tr fluoroalkyl, cyanoalkyl !

al~anoylalkyl or -(CH2)p-~-NY4Y5 wherein p is 1, 2, 3 or 4 and Y4 and Y5 are the same or differ~nt and each is hydrogen or alkyl, and A17 is hydrogen, hydroxy, alkoxy, aryloxy, oxo, methylene, alkyl-thio, arylthio, alkanoyl, alkanoyloxy or 1uorine.
. United States Patent 4,447,426, issued ~ay 8, 1984, discloses (as antiinflammatory agents) androstenes having the partial structural formula A18~ ~Alg S ,S

¦ D ¦
wherein one of A18 and Alg is alkyl, cycloalkyl, aryl, arylalkyl, or -CH2X3 wherein X3 is alkylthio, alkoxy, aroyloxy, alkanoyloxy or alkoxycarbonyl, and the other is alkylthioalkyl, alkoxyalkyl, alkanoyloxyal~yl, aroyloxyalkyl, alkoxycarbonyl-alkyl, carboxylalkyl or arylalkyl and A20 is hydrogen, hydroxy, alXoxy, aryloxy, oxo, methylene, alkylthio, arylthio, alkanoyl, alkanoyloxy, orhalogen.
-126664c~ K595 United States Patent 4,481,144, issuedNovember 6, 1984, discloses (as antiinflammatory agents) andro~tenes having the partial structural formula S C~
S
~ 2 wherein X is hydrogen, alkyl or aryl; X1 is l hydrogen, alkyl, Yl-C-O-(C~2)p-, alkylthio, alkoxy, fluoro, hydroxyalkyl, cyanoalkyl, alkoxy-carbonyl-(C~2)p)-~ mono-, di- or trifluoroalkyl, or Y2Y3N-~-(CH2)p-, wherein p is O, 1, 2, 3 or 4, Y1 is alkyl or aryl, and Y2 and Y3 are the same or diferent and each is hydrogen or alkyl; and X2 is alkyl, alkenyl or alkynyl.

~S6~4~
_7 K595 The steroids of formula I, and the 1,2-dehydro and 6,7-dehydro derivatives thereof, are topical antiinflammatory agents that can be used to treat skin conditions such as dermatitis, psoriasis, sunburn, eczema, neurodermatitis, or anogenital pruritus, and inhalation therapy for topical treatment of allergy and asthma.
For the treatment of skin conditions, the topical antiinflammatory steroids of this invention may be administered in a conventional pharmaceutical carrier in the form of a cream, ointment, lotion or the like. The steroids will preferably be used in the range of 0.01 to 5.0% by lS weight of the vehicle, preferably 0.05 to 2.0% by weight o the vehicle.
For the topical treatment of allergy and asthma, the topical antiinflammatory steroids o~
this invention may be administered in the conven-tional manner, e.q., as solid medicament which has been atomized. United States Patents 3,948,264 and 4,147,166 are exemplary of the literature which describes devices that can be used to administer solid medicaments for inhalation therapy.
The steroids of formula I can be prepared using the corresponding steroid having the formula ~l2~i6~

II Rl /alkyl \S S
~ i OH
R

as a starting material. These steroids are disclosed in United States Patents 4,361,559, issued November 30, 1982, 4,427,592, issued January 24, 1984, and 4,447,426, issued May 8, 1984.
Reaction of a steroid of formula II with a compound having the formula III
Rg R8 R7 halogen-C~-C = C~
in the presence of an inorganic base (e.q., sodium hydride) yields the corresponding steroid having the formula IV Rl alkyl \S S Rg R18 IR7 \,' _, O-~-C=C~I

,~
~
~, , S
The steroids of formula IV are novel intermediates, and as such, form an integral part of thisinvention.

- . : , . .: .

_g_ K595 Thermolysis of an intermediate of formula IV, preferably in an aromatic solvent (e.~., diethylbenzene) yields the corresponding sterold product having the formula ~1~ R7 R8 Rg S C~-C=C~

R ~ O
~,~
~ .
~5 Troatment of a product of formula V with a tran3ition metal cataly~t (e.q., palladium on carbon or rhodium chloride) or an acid catalyst yields the isomeric product having the formula V~ R1 ~ R7 R8 Rg S Ca~C~-C~2 R

~ydrogenation of a product of formula V in th~ pr~enco of a catalyst 3uch a~ triphenyl~
phosphino rhodium chlorid~ yield~ the corresponding product having the for~ula ~6~;~1 VII R1 R7 R8 Rg ,~c~ c~2 R ~ 0 Tho ~ulfides of for~ula I (n is 0) can be oxidized to the corresponding sulfinyl steroids (products of for~ula I, n is 1) or sulfonyl steroids (producta o formula I, n is 2) with peracid~ ., m-chloroperoxybenzoic acit or pcriodic acid). The u~e of one equivalent o oxidizing agent will yield predominantly a ~ul-foxide and the U80 of two or more cguivalent~ o oxitizing agent will yielt pr~dominantly a sulone.
$ho oxidation reaction can ~o run in an organic solvont, a.q., a halog~nated hydrocarbon such as chlorofor~. Alt-rnativQly, the sulonyl steroids of formula I can be prepared by oxidizing the corre~ponding sulfinyl ~teroid.
Tho following e~a~pl6 i3 a specific embodim-nt of thi~ invention.

Example 1 (11~,17~)-9-Fluoro-11-hydroxy-17-(methylthio)-17-(2-pro~enYl)androsta-1,4-dien-3,16-dione A) (11~,16a)-11-(Acetyloxy)-9-fluoro-17,17-bis-(methylthio)-16-(2-propenyloxy)androsta-1,4-dien-

3,16-dione A solution of 11~-(acetyloxy)-9-fluoro-16a-hydroxy-17,17-bis(methylthio)androsta-1,4-dione-3-one (1.0 g, 2.2 mmole) in dry tetrahydrofuran(15.0 ml) was cooled in an ice bath and a 1.7M
solution of n-butyl lithium in hexane (1.35 ml, 2.30 mmole) was added. After 5.0 minutes, dry dimethylformamide (5.0 ml) was added, followed by allyl bromide (1.0 ml). After 2.~ hours, tlc examination of an aliquot showed es~entially comple~e absence of the starting steroid. The mi~ture was then added into water and extracted with chloroform. The extracts were combined, washed with water, dried (anhydrous magnesium sulfate) and evaporated to afford the crude product. This was subjected to a preparative tlc on four 2.0x200x200 mm silica gel plates (using chloroform-ethyl acetate (9:1) for development and chloroform-methanol (3:1) for extraction of the bands) to isolate, in the order of increasing polarity, the following compounds: two minor components which were not characterized (95 mg), the title compound (630 mg), (11~,16a)-9-fluoro-11-hydroxy-17,17-bis(methylthio)-16-(2-propenyloxy)-androsta-1,4-dien-3-one (180 mg) and unreacted starting material (110 mg). The (11~,16~)-9-~luoro-11-hydroxy-17,17-bis(methylthio)-16-(2-propenylo~y)androsta-1,4-dien-3-one presuma~ly resulted because of moisture present in the ~266~

solvents. The title compound showed an ~H NMR
spectrum consistent with the structure.

B) (11~,16~)-9-Fluoro-11-hydroxy-17,17-bis(methyl-S thio) 16-t2-proPenYloxy)androsta-l~4-dien-3-one _ A solution of (I1~,16a ) -11- ( acetyloxy)-9-fluoro-17,17-bis(methylthio)-16-(2-propenyloxy)-androsta-1,4-dien-3,16-dione (594 mg, 1.2 mmole) in a mixture of methanol (15 ml) and tetrahydrofuran (15 ml) was stirred with 3M sodium hydroxide (2.0 ml) under an atmosphere of nitrogen for 1.0 hour. A slight excess of glacial acetic acid was then added and the mixture was concentrated in vacuo;
The residue was diluted with water and extracted with chloroorm. The chloroform extracts were combined, washed with water, dried (anhydrous magnesium sulfate), evaporated and mixed with the material (180 mg) isolated earlier (see part A) to afford a homogeneous (tlc) ~olid (700 mg). One Z0 crystallization of this from ethyl acetate and drying (110C, 0.3mm of Hg, 6.0 hours) afforded the analytical specimen of the title compound (520 mg) as heavy white prisms, melting point 2Z6-227C (dec.), with consistent spectral data.
Anal. Calc'd. for C24~33FO352 S, 14.17; F, 4.20 Found: C, 63.96; ~, 7.52; S, 14.22i F, 4.32 C) (11~,17~)-9-Fluoro-ll-hydroxy-17-(methylthio)-17-(2-~ro~envl)androsta-1,4-dien-3,16-d one _ A suspension of (11~,16a)-9-fluoro-11-hydroxy-17,17-bis(methylthio)-16-(2-propenyloxy)-androsta-1,4-diene-3-one (460 mg, 1.02 mmole~ in distilled, dry diethylbenzene (20 ml) was refluxed under a drying tube. A solution resulted, which , ' .

1266~4~

turned yellow in color. After less than one-half hour, examination of an aliquot of the solution by tlc showed the absence of the starting steroid.
The solution was then cooled to room temperature and was iltered through a column of silica gel (10 g) using chlorofo~m-hexane ( 1:1 ) for the filtration. This filtrate was discarded~ Sub-sequent elution of the column with chlorofoxm-ethyl acetate ~9:1) followed by evaporation of the eluates furnished the title compound as a slightly contaminated solid (367 mg). This was once cr~stallized from ethyl acetate and dried (110C, 0.3mm of Hg, 6.0 hours) to afford the analytical specimen as white heavy prisms (238 mg), melting point 223-224C, with consistent spectral data.
r C23~29FO35: C, 68.29; H, 7.23;
F, 4.70; S, 7.93 Found: C, 68.06; H, 7.18; F, 4.76; S, 7.88

Claims (6)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A steroid having the formula:

or a 1,2-dehydro derivative thereof, wherein R1 is alkyl, mono-, di- or trifluoroalkyl, , aryl or alkylthioalkyl, wherein R6 is alkyl or aryl and m is 1,2, 3 or 4;
R3 is carbonyl or .beta.-hydroxymethylene;
R4 is hydrogen or halogen;
R5 is hydrogen, methyl or fluorine; and R7, R8 and R9 are each independently hydrogen or alkyl of 1 to 4 carbon atoms.

2. A steroid in accordance with claim 1 wherein R1 is alkyl.

3. A steroid in accordance with claim 1 wherein R1 is mono-, di- or trifluoroalkyl.

4. A steroid in accordance with claim 1 wherein R1 is .

5. A steroid in accordance with claim 1 wherein R1 is aryl.

6. A steroid in accordance with claim 1 wherein R1 is alkylthioalkyl.