United States Patent (19) 11 4,277,468 Hofmeister et al. 45 Jul. 7, 1981 (54) 11-METHYLENESTEROIDS, THEIR 56) References Cited PREPARATION AND PHARMACEUTICAL U.S. PATENT DOCUMENTS PREPARATIONS CONTAINING THEM 3,927,046 12/1975 van den Broek ................ 260/.397.45 (75) Inventors: Helmut Hofmeister; Rudolf Wiechert; OTHER PUBLICATIONS Klaus Annen; Henry Laurent; Fried et al., JACS 83 (1961), pp. 4663-4464. Hermann Steinbeck, all of Berlin, Fed. Rep. of Germany Primary Examiner-Elbert L. Roberts Attorney, Agent, or Firm-Millen & White 73) Assignee: Schering Aktiengesellschaft, Berlin 57 ABSTRACT and Bergkamen, Fed. Rep. of 11-Methylene steroids of Formula I Germany OR 21 Appl. No.: 135,066 H2Cs Sesno CECC 22 Filed: Mar. 28, 1980 (30) Foreign Application Priority Data x1a Mar. 30, 1979 DE Fed. Rep. of Germany ....... 291.338 wherein m (51) Int. Cl. ................................................ CO7 1/OO R is hydrogen or acyl, and 52 U.S. C. ............................... 424/243; 260/397.45; X is oxygen or two hydrogen atoms 260/.397.5 have valuable pharmacological properties. 58) Field of Search ............. 260/.397.4, 397.45, 397.5; 424/243 10 Claims, No Drawings 4,277,468 2 acid, isonicotinic acid, furan-2-carboxylic acid, O 11-METHYLENE STEROIDS, THEIR tridecanoylglycolic acid, O-hexadecanoylglycolic acid, PREPARATION AND PHARMACEUTICAL g-tridecanoyloxypropionic acid, etc. Suitable sulfonic PREPARATIONS CONTAINING THEM acids include: methane-, ethane-, 3-chloroethane-, pro pane-, isopropane-, butane-, cyclopentane-, cyclohex BACKGROUND OF THE INVENTION ane-, benzene-, p-toluene- and p-chlorobenzenesulfonic The present invention relates to 11-methylene ste acids, etc.; and, furthermore, N,N-dimethyl-, N,N- roids, a process for their preparation, and pharmaceuti diethyl, bis(3-chloroethyl)-aminosulfonic acids, etc.; or cal preparations containing them. pyrrolidino, piperidino-, piperazino-, N-methyl It is known that ll-methylene steroids possess valu 10 piperazino-, morpholinosulfonic acids, etc. able biological properties. For example, DOS (German The compounds of this invention can be prepared by Unexamined Laid-Open Application) No. 2,361,120 reacting an 11-methylene-17-oxosteroid of formula II describes 11-methylene-17a-ethynyl-18-methyl-A- estrenes possessing strong progestational properties. O 15 (II) SUMMARY OF THE INVENTION It is an object of this invention to provide new steroi dal compounds having valuable pharmacological prop etles. Upon further study of the specification and appended 20 claims, further objects and advantages of this invention will become apparent to those skilled in the art. These objects have been attained by providing 11 wherein Y is a free or acid-hydrolyzable blocked oxo methylene steroids of Formula I group or two hydrogen atoms and 25 OR (I) H2C - CEC-Cl S 27 N 30 is a double bond in the 4,5-, 5,6- or 5, 10-position, or two double bonds emanating from the 3- and 5-positions, x112 according to methods known perse with an organo metallic chloroethynyl compound to produce a com wherein 35 pound of formula I wherein R is hydrogen; hydrolyzing R is hydrogen or acyl, and an initially introduced 3-oxo blocking group; and, de X is oxygen or two hydrogen atoms. pending on the finally desired groups for R, optionally esterifying the 17-hydroxy group before or after the DETAILED DISCUSSION splitting off of the blocking group. The steroids of Formula I contain the group OR in This process is conducted according to methods the 1713-position, wherein R is hydrogen or an acyl known perse by reacting the 17-oxosteroid in a suitable group. Suitable acyl groups R are those of acids which solvent with the organometallic chloroethynyl com form resultant physiologically compatible steroids, e.g., pound at a temperature of 0-50° C. for 0.1-0.5 hours. such acids which are C1-17 hydrocarbon carboxylic or The chloroethynyl compound may be formed in situ sulfonic acids. Preferred acids which are equivalent 45 from 1,2-dichloroethylene and an ethereal alkyl lithium include the former, e.g., organic carboxylic and sulfonic solution, such as, for example, methyl- or butyllithium acids of 1-17 carbon atoms belonging to the aliphatic, solution. Suitable solvents include tetrahydrofuran and cycloaliphatic, aromatic or aromatic-aliphatic series or diethyl ether. such acids belonging to the heterocyclic series. These When a 3-keto group is present in II, it is suitably acids can also be saturated or unsaturated, mono- or 50 protected prior to chloroethynylation. The protective polybasic and/or substituted in conventional fashion for blocking group is to be cleavable by acid hydrolysis. such acyl forming acids producing further equivalent The blocking group Y should form, with the double acids and resultant acyl groups. Examples of such sub bond or double bonds present in ring A or B, such an stituents include hydroxy, alkoxy, acyloxy, oxo, amino arrangement of atoms that the compound will be con and halogen. 55 verted into a 4,5-unsaturated ketone by subsequent acid The following equivalent carboxylic acids can be hydrolysis. In a preferred embodiment, the keto group mentioned as examples: formic acid, acetic acid, propi is blocked by ketal formation. The ketal residues are onic acid, butyric acid, isobutyric acid, valeric acid, derived from the alcohols and thioalcohols convention isovaleric acid, caproic acid, enanthic acid, caprylic ally utilized for the blocking of free oxo groups; exam acid, pelargonic acid, capric acid, undecylic acid, lauric ples in this connection include: ethylene glycol, 2,2- acid, tridecylic acid, myristic acid, pentadecylic acid, dimethyl-1,3-propanediol, 1,2-ethanedithiol, etc. The trimethylacetic acid, diethylacetic acid, tert-butylacetic 3-keto group, however, can also be partially blocked by acid, g-cyclopentylpropionic acid, cyclohexylacetic enol ether, enol ester, or enamine formation. acid, cyclohexanecarboxylic acid, phenylacetic acid, The splitting off of the 3-keto blocking group, which phenoxyacetic acid, mono-, di-, and trichloroacetic 65 can be conducted before or after the optional esterifica acid, aminoacetic acid, diethylaminoacetic acid, tion, can be effected according to methods known to piperidinoacetic acid, morpholinoacetic acid, lactic those skilled in the art. Suitable agents for splitting acid, succinic acid, adipic acid, benzoic acid, nicotinic purposes include, for example, mineral acids, e.g., per 4,277,468 3 4. chloric acid, sulfuric acid, or hydrochloric acid, or Contraception: The Chemical Control of Fertility, ed organic acids, e.g., oxalic acid. The splitting step is ited by Daniel Lednicer, 1969, Marcel Dekker, Inc. preferably carried out in an alcoholic solution or in New York, whose disclosure is incorporated by refer another polar solvent, such as, for example, acetone, at ence herein), or as the sole active ingredient. However, temperatures of about 20-100° C. 5 the compounds can also be utilized in preparations for For the optionally subsequent esterification, fully the treatment of gynecological disturbances, such as conventional processes normally employed in steroid cycle irregularities in case of inadequate function of the chemistry for esterification can be used. One example is corpus luteum, climacteric complaints, endometriosis, reaction with an acid or acid anhydride in the presence etc, of strong acids, e.g., trifluoroacetic acid or p-toluenesul O fonic acid, at room temperature or slightly elevated For pharmaceutical usage, the novel compounds can temperature. Another example is reaction with an acid be conventionally processed, together with the addi anhydride in the presence of a tertiary amine while tives, vehicles, and flavoring agents customary in ga heating at about 20-200 C. If pyridine and 4-(dime lenic pharmacy, into the usual medicines. Especially thylamino)pyridine are used together as the tertiary 15 suitable for oral administration are tablets, dragees, amines, the esterification can be conducted at room capsules, pills, suspensions, or solutions. Particularly temperature. suitable for parenteral application are oily solutions, The starting compounds of Formula II used in the e.g., Sesame oil or castor oil solutions which can option process of this invention are described in DOS No. ally additionally contain a diluent, such as, for example, 2,361,120 or can be prepared analogously to the meth 20 benzyl benzoate or benzyl alcohol. The concentration ods disclosed therein. of active ingredient (unit dosage) is dependent on the For example, a preferred starting material, 3,3-(2,2'- form of administration. Thus, for example, tablets for dimethyl-trimethylenedioxy)-18-methyl-11-methylene oral administration contain preferably 0.01-0.5 mg of 5-estren-17-one can be prepared as follows. active ingredient, and solutions for parenteral adminis 1.0 g of 18-methyl-11-methylene-4-estrene-3,17-dione 25 tration contain preferably 1-100 mg of active agent per in 10 ml of methylene chloride is combined at room 1 ml of solution. temperature with 1 ml of triethyl orthoformate, 2.0 g of The pharmacologically active compounds of For 2,2-dimethyl-1,3-propanediol and 5 mg of p-toluenesul mula I can be processed in accordance with conven fonic acid. After 5 hours, the reaction mixture is diluted tional methods of galenic pharmacy to provide medici with methylene chloride, washed neutral, and dried. 30 nal agents to patients, e.g., mammals including humans. The crude product is chromatographed on silica gel Conventional excipients are pharmaceutically