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United States Patent (19) 11) 4,183,924 Green Et Al

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United States Patent (19) 11) 4,183,924 Green Et Al United States Patent (19) 11) 4,183,924 Green et al. 45 Jan. 15, 1980 (54) 17a-CHLORO-179-HYDROCARBONSULFI 58) Field of Search .................... 260/239.55 R, 397.3, NYL-1,4-ANDROSTADENES AND THE 260/.397.45; 424/242; Steroids MS File/ CORRESPONDING 176-HYDROCARBONSULFONYL 56 References Cited DERVATIVES AND THEIR USE AS U.S. PATENT DOCUMENTS ANT-ACNE AGENTS 4,091,036 5/1978 Varma ........................... 260/.397.3 X 75 Inventors: Michael J. Green, Kendall Park; Primary Examiner-Ethel G. Love Robert Tiberi, Englishtown, both of Attorney, Agent, or Firm-Elizabeth A. Bellamy; Mary N.J. S. King 73 Assignee: Schering Corporation, Kenilworth, N.J. 57 ABSTRACT Novel 17a-chloro-1743-hydrocarbonsulfinyl and 17a 21) Appl. No.: 881,217 chloro-17 (3-hydrocarbonsulfonyl derivatives of 3-oxo (22 Filed: Feb. 27, 1978 1,4-androstadienes and their use as anti-acne agents are 51) Int. C.? ...................... A61K 31/565; C07J 31/00 described. 52 U.S.C. ........................... 424/242; 260/239.55 R; 260/.397.3; 260/.397.45 18 Claims, No Drawings 4,183,924 1. 2 Preferred compounds of our invention are those de 17a-CHLORO-176-HYDROCARBONSULFINYL fined by the following formula II: 1,4-ANDROSTADIENES AND THE CORRESPONDING II 176-HYDROCARBONSULFONYL DERIVATIVES 5 AND THER USE AS ANT-ACNE AGENTS FIELD OF THE INVENTION This invention relates to novel compositions-of-mat ter, to methods for their manufacture and methods for 10 their use as anti-acne agents. Specifically, this invention relates to novel 17a chloro-176-hydrocarbonsulfinyl and 17a-chloro-1718 hydrocarbonsulfonyl derivatives of 3-oxo-1,4-andros 15 tadienes useful as anti-acne agents. Further, this inven wherein X is as defined for Formula I, and Z and Z are tion relates to pharmaceutical compositions comprising hydrogen, methyl or chlorine. said derivatives, to methods for their manufacture, and Exemplary compounds of this formula are: to methods for their use in the treatment and control of (a) 17a-chloro-1713-(R)-benzylsulfinyl-1,4-androstadi acne vulgaris via topical, intralesional and oral routes. 20 ene-3,11-dione, Particularly, this invention relates to novel 17a (b) 17a-chloro-1743-(p-chlorobenzylsulfinyl)-1,4- chloro-1743-hydrocarbonsulfinyl and 17a-chloro-176 androstadiene-3,11-dione, hydrocarbonsulfonyl derivatives of 3-oxo-1,4-andros (c) 17a-chloro-1713-(2',4'-dichlorobenzylsulfinyl)-1,4- tadienes among which are included such compounds as androstadiene-3,11-dione, 17a-chloro-17G-R-benzylsulfinyl-1,4-androstadiene 25 (d) 17a-chloro-1713-(3',4'-dichlorobenzylsulfinyl)-1,4- 3,11-dione; 17a-chloro-1713-(p-chlorobenzylsulfinyl)- androstadiene-3,11-dione, 1,4-androstadiene-3,11-dione; 9a-fluoro-17a-chloro (e) 17a-chloro-1743-(2-methylbenzylsulfinyl)-1,4- 176-R)-benzylsulfinyl-1,4-androstadiene-3,11-dione; androstadiene-3,11-dione, 17a-chloro-17B-R-benzylsulfonyl-1,4-androstadiene (f) 9a-fluoro-17a-chloro-176-R-benzylsulfinyl-1,4- 3,11-dione and the like. 30 androstadiene-3,11-dione. This invention also relates to the process for the prep Still other preferred compounds of this invention are aration of the 17a-chloro-176-hydrocarbonsulfinyl de those having the following Formula III: rivatives of the 3-oxo-1,4-androstadienes. GENERALDESCRIPTION OF THE INVENTION 35 III COMPOSITION-OF-MATTERASPECT In its composition-of-matter aspect, this invention relates to novel 17a-chloro-1713-hydrocarbonsulfinyl and 17a-chloro-1713-hydrocarbonsulfonyl derivatives of 3-oxo-1,4-androstadienes. Particularly, this invention relates to novel steroids defined by the following For mula I: wherein X, Z and Z are as defined in Formula II. Ex emplary of such compounds is 17a-chloro-1713-benzyl sulfonyl-1,4-androstadiene-3,11-dione. Yet another embodiment of this invention are com 50 pounds having the following Formula IV: IV wherein R is benzyl, phenethyl, methylbenzyl, dimeth SEO ylbenzyl, chlorobenzyl, dichlorobenzyl, and an alkyl 55 group having up to 8 carbon atoms; X is hydrogen or fluorine; Y is oxygen, or hydrogen when X is hydrogen; and n is or 2. The compounds of our invention wherein R is meth ylbenzyl, dimethylbenzyl, chlorobenzyl or dichloro benzyl are defined as those wherein the substituents methyl, dimethyl, chloro or dichloro can be in any wherein R is as previously defined and wherein A is position on the benzene ring. Furthermore, alkyl groups hydrogen, o-fluoro, ot-bromo; B is hydroxyl, or to included in the definition of R may be straight or 65 gether A and B form a 93,116-epoxy group or a 9(11) branched chain, e.g., methyl, ethyl, propyl, isopropyl, bond. Exemplary compounds of this formula are: butyl, tert-butyl and higher homologs such as pentyi, (a) 17a-chloro-176-R-benzylsulfinyl-1113-hydroxy hexyl, heptyl and octyl. 1,4-androstadiene-3-one, 4,183,924 3 4. (b) 17a-chloro-1713-R)-benzylsulfinyl-11 (3-hydroxy lizing separation techniques known in the art, the 17a 1,4,9(11)-androstatriene-3-one, chloro-176-sulfinyl derivative of the 3-oxo-1,4-andros (c) 9a-bromo-17a-chloro-17.6-R-benzylsulfinyl-11 (3- tadiene is isolated (e.g., 17a-chloro-17 (3-R-benzylsulfi hydroxy-1,4-androstadiene-3-one, nyl-1,4-androstadiene-3,11-dione). (d) 96,113-epoxy-17a-chloro-17 (3-R)-benzylsulfinyl Within the scope of our invention is included any 1,4-androstadiene-3-one, chlorine or "positive' chlorine source; for example, (e) 9a-fluoro-17a-chloro-176-R)-benzylsulfinyl-11g chlorine gas, iodobenzene dichloride, N-chlorosuccini hydroxy-1,4-androstadiene-3-one. mide, 1-chlorobenzotriazole. It will be obvious to one skilled in the art that when At least two equivalents of the chlorine source are n is 1 in Formula I, and in Formulae II and IV, there is 10 an asymmetric center present at the sulfur atom. There necessary for optimization of the process, albeit 2 to fore, our 17a-chloro-17g-hydrocarbonsulfinyl com about 5 equivalents of said chlorine source can be uti pounds may be in the RS-form, in the R form, in the S lized. We have found that about 3 equivalents of the form, or a mixture thereof. Where X-ray crystallo chlorine source maximize the yields of the desired con graphic techniques have confirmed the presence of 15 pounds. Utilization of more than 5 equivalents of the specific stereochemistry, we have so indicated in the chlorine source increases the possibility of producing nomenclature of the compounds. excessively chlorinated compounds. The physical embodiments of the compounds of this The solvent system is water and a water soluble base. invention are characterized as being crystalline solids, If, however, solubility problems are encountered, or usually white to off-white in color, which are insoluble ganic diluents such as tetrahydrofuran, dioxane and the in water and soluble in most organic solvents, particu like may also be employed. Nitrogenous bases such as larly in acetone, dioxane, dimethylformamide, and di pyridine, trialkylamines, collidine and the like are pre methylsulfoxide, although of limited solubility in non ferred as the water soluble bases. However, inorganic polar solvents such as dialkylethers and alkylhydrocar water soluble bases such as sodium hydroxide, sodium bons. 25 methoxide, calcium hydroxide can also be used. Any The 17a-chloro-176-hydrocarbonsulfinyl and 17a amount of base used in the reaction will produce the chloro-17(3-hydrocarbonsulfonyl derivatives of the 3 17a-chloro-17(3-hydrocarbonsulfinyl compounds of our oxo-1,4-androstadienes (Formulae I-III) inhibit seba invention. However, to maximize the yields of product ceous gland activity thereby making them useful as a minimum of 2 equivalents of base must be utilized. topical or oral anti-acne agents. Compounds of formula 30 Obviously, since pyridine is preferentially used as the IV are useful as intermediates in the preparation of part of the solvent system, excessive quantities of base compounds of Formulae I-III. are not deleterious to the reaction. PROCESS ASPECT OF THE INVENTION The temperature range wherein the process can be conducted is about -78° C. to about ambient tempera The process aspect of this invention resides in the 35 tures, preferably from about - 40 C. to about O' C. and concept of preparing 3-oxo-1,4-androstadienes having usually at around -40 C. Prolonged reaction times at substituents at C-17 of the following partial formula: higher temperatures can produce excessive chlorination on the steroid molecule. The reaction can be carried out over a period of 40 12-60 hours, but usually is completed in 18-36 hours. Absence of the starting material as determined by TLC indicates the conclusion of the reaction. The 17a-thio derivatives of the 3-oxo-1,4-androstadi wherein R is benzyl, phenethyl, methylbenzyl, dimeth enes utilized as the starting compounds in the process ylbenzyl, chlorobenzyl, dichlorobenzyl, and an alkyl 45 described hereinabove, although not specifically de group having up to 8 carbon atoms; which comprises scribed in the prior art are derived by known chemical reacting a 3-oxo-1,4-androstadiene having a substituent reactions. That is, nucleophilic substitution reactions by at C-17 of the following partial formula: sulfides on leaving groups at C3, C4 and C6 are known in 50 the literature and analogous procedures may be applied R to effect C17 sulfide displacements. In one such proce dure, sodium metal is dissolved in ethanol to which is S added benzyl mercaptan and 17.6-methanesulfonyloxy 1,4-androstadiene-3,11-dione, the mixture being re 55 fluxed for 72 hours. The resulting 17a-benzylthio-1,4- wherein R has the same meaning as above; with excess androstadiene-3,11-dione is isolated via standard tech equivalents of a chlorine source in a mixture of water niques.
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