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United States Patent (19) 11 Patent Number: 4,584,288 Nickish Et Al

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United States Patent (19) 11 Patent Number: 4,584,288 Nickish Et Al United States Patent (19) 11 Patent Number: 4,584,288 Nickish et al. (45) Date of Patent: Apr. 22, 1986 (54) 6,6-ETHYLENE-15,16-METHYLENE-3-OXO 17a-PREGN-4-ENE-21,17-CARBOLACTONES, PROCESSES FOR THE PRODUCTION O (I) THEREOF, AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM 75 Inventors: Klaus Nickish; Dieter Bittler; Henry Laurent; Rudolf Wiechert; Sybille Beier; Walter Elger, all of Berlin, Fed. Rep. of Germany 73) Assignee: Schering Aktiengesellschaft, Berlin and Bergkamen, Fed. Rep. of Germany (21) Appl. No.: 692,489 22 Filed: Jan. 18, 1985 30 Foreign Application Priority Data Jan. 20, 1984 DE Fed. Rep. of Germany ....... 3402329 51) Int, Cl." ....................... CO7J 19/00; A61K 31/58 is a CC-single of CC-double bond, 52 U.S. C. ................................ 514/172; 260/239.57 R1 is a hydrogen atom or a methyl group, 58) Field of Search .................... 260/239.57; 514/172 R2 is a methyl or ethyl group, and 56) References Cited U.S. PATENT DOCUMENTS 3,422,097 1/1969 Kerwin ........................... 260/239.57 Na 4,500,522 2/1985 Nickish et al. ................. 260/239.57 is " > OT l D Primary Examiner-Elbert L. Roberts Attorney, Agent, or Firm-Millen & White exhibit strong gestagen potency and an aldosterone 57) ABSTRACT antagonistic activity. 6,6-ethylene-15, 16-methylene-3-oxo-17a-pregn-4-ene 21,17a-carbolactones of general Formula I 18 Claims, No Drawings 4,584,288 1. 2 tagen effects, but wherein the gestagen activity is not so 6,6-ETHYLENE-15,16-METHYLENE-3-OXO-17a strongly pronounced (DOS No. 3,022,337). PREGN-4-ENE-21,17-CARBOLACTONES, In a test for antialdosterone activity, the novel com PROCESSES FOR THE PRODUCTION THEREOF, pounds of Formula I have proven to be up to five times AND PHARMACEUTICAL PREPARATIONS more effective than spironolactone. CONTAINING THEM In the modified Clauberg test for gestagen activity, positive results are achieved with quantities of 0.03 mg BACKGROUND OF THE INVENTION of the compounds of this invention upon subcutaneous This invention relates to 6,6-ethylene-15, 16-methy 10 administration. lene-3-oxo-17a-pregn-4-ene-21, 17-carbolactones, pro In the pregnancy-maintaining test on rats and mice, cesses for the production thereof, and pharmaceutical the minimum amount required for attaining a positive preparations containing them. effect ranges around 0.1 mg. SUMMARY OF THE INVENTION The novel compounds of Formula I can be utilized by 15 themselves or in combination with estrogens in prepara It is an object of the invention to provide compounds tions for contraception in fully conventional fashion, having valuable pharmacological properties. e.g., analogous to the use of conventional gestagens in Upon further study of the specification and appended these contraceptive preparations. According to this claims, further objects and advantages of this invention invention, the novel compounds are to be used particu will become apparent to those skilled in the art. 20 larly by women desiring contraception and prone to These objects have been achieved by providing 6,6- hypertension on account of risk factors present, such as ethylene-15, 16-methylene-3-oxo-17a-pregn-4-ene advanced age, obesity, or smoking. Considering the 21, 17-carbolactones of Formula I profile of these compounds which is comparable to that of natural progesterone, they are apt to improve well (I) being and compatibility over conventional preparations even in women who cannot be classified as hish-risk patients. The dosage of the compounds of this invention on contraceptive preparations is to be preferably 0.5-5 30 mg per day. The gestagen and estrogen active agent components are administered in contraceptive prepara-, tions preferably orally in combination. The daily dose is administered preferably all at once as usual. The estro gen is administered daily in a quantity corresponding to 35 that of 0.03-0.05 mg of ethynylestradiol. wherein The novel compounds of general Formula I can also be utilized in preparations for the treatment of gyneco logical disorders. Because of their favorable activity profile, the compounds of this invention are especially well suited for the treatment of premenstrual com plaints, such as headaches, depressive moods, water retention, and mastodynia. The daily dose when treat is a CC-single or CC-double bond, ing premenstrual difficulties is about 1-20 mg, e.g., R1 is a hydrogen atom or a methyl group, 45 analogously to Duoluton (R). They can also be used, R2 is a methyl or ethyl group, and analogously to spironalactone as diuretics and antihy pertensives in the same dosis range as spironolactone. The pharmaceutical preparations based on the novel compounds are formulated conventionally by process 50 ing the active agent, optionally in combination with an estrogen for contraception, with the excipients, dilu ents, if desired flavoring agents, etc., customary in ga DETAILED DISCUSSION lenic pharmacy, and converting this preparation into The novel compounds of Formula I have, besides a the desired form of administration. Tablets, dragees, high aldosterone-antagonistic activity, a strong gesta 55 capsules, pills, suspensions, or solutions are especially gen potency. The combination of aldosterone-antago suitable for the preferred oral administration. Particu nistic and gestagen activities is not found in any of the larly suited for parenteral administration are oily solu known synthetic gestagens of the ethynylnortestoster tions, e.g. solutions in sesame oil, castor oil, and cotton one or hydroxyprogesterone series, but it does exist in seed oil. To enhance solubility, solubilizers can be the natural gestagen, namely progesterone. Since the added, such as, for example, benzyl benzoate or benzyl novel compounds possess the progesterone-like profile alcohol. of activity, they will not cause, when used as contracep Suitable hosts include mammals, including humans. tives, the otherwise occurring side effects, such as in The compounds of this invention according to gen creases in blood pressure and edemas. 65 eral Formula I can be prepared by conventionally intro By replacing the ethylene group in the 6-position by ducing a 6a-hydroxy-methyl group into 15, 16-methy a 63,713-methylene group, compounds are obtained lene-3-oxo-17a-pregn-4-ene-21,17-carbolactones of gen which likewise show aldosterone-antagonistic and ges eral Formula II 4,584,288 4. for example, dioxane, tert-butanol, tetrahydrofuran, (II) toluene, benzene and/or mixtures of these solvents. The reaction is finished after several hours. It is recom mended to control the conversion by thin-layer chro matography. The reaction mixture is worked up once the starting material has been converted. The starting materials of Formula II are all known or readily preparable from known starting materials using conventional reactions, e.g., analogously to the prepara o?a 10 tions reported in Examples 5 and 6 below. Without further elaboration, it is believed that one wherein skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, there 15 fore, to be construed as merely illustrative, and not 15 limitative of the remainder of the disclosure in any way y whatsoever. In the following examples, all temperatures are set forth uncorrected in degrees Celsius. unless oth R1 and R2 are as defined for Formula I, by way of the erwise indicated, all parts and percentages are by 3,5-diene-3-amines using formalin, followed by reconsti 20 weight. tution of the 4-ene-3-oxo system forming the 6-methy lene compound from the 6a-hydroxymethyl compound. EXAMPLE 1. and methyenating this 6-methylene compound to the 6,6-ethylene compound, and optionally introducing the (a) A solution of 4.1 g of 15,3,166-methylene-3-oxo Al-double bond. 25 17a-pregn-4-ene-21,17-carbolactone in 31 ml of metha First of all, the A-3-ketone is converted, with a sec nolisheated under reflux with 2.05 ml of pyrrolidine for ondary base, into the corresponding A-3-amine. Suit 15 minutes. After cooling in an ice bath, the thus able secondary bases are, for example, diethylamine, formed precipitate is suctioned off, washed with a small aniline, pyrrolidine, and morpholine. amount of methanol, and dried, thus obtaining 4.5g of ... For the introduction of the 6a-hydroxymethyl group, 30 1513,16p3-methylene-3-pyrrolidino-17a-pregna-3,5- ... the A35-3-amine is treated with formalin in an alcoholic diene-21,17-carbolactone, mp 234'-237 C. (with de ... solution (Helv. Chim. Acta 56 (1973) 2396). composition). Water is split off from the 6a-hydroxymethyl com UV: e276=22,900. pound with hydrochloric acid in dioxane, to obtain the (b) At room temperature, 4.5 ml of 37% strength corresponding 6-methylene compound. The water 35 formalin solution is added dropwise within 5 minutes to cleavage can also be performed by first introducing a a solution of 4.5g of 1513,166-methylene-3-pyrrolidino fugacious group and splitting it off again. Suitable fuga 17a-pregna-3,5-diene-21, 17-carbolactone in 90 ml of “...cious groups are, for example, mesylate, tosylate, and ethanol and 45 ml of benzene. After a reaction period of *:benzoate. 30 minutes, the reaction solution is evaporated to dry : The methylenation of the 6-methylene compound to ness under vacuum. The residue is chromatographed on it form the 6,6-ethylene compound can be effected in silica gel, thus producing 3.15g of 6a-hydroxymethyl dimethylsulfoxonium methylide. For this purpose, the 1543,166-methylene-3-oxo-17a-pregn-4-ene-21, 17-car 6-methylene steroid is added to a suspension of trime bolactone as an oil. thylsulfoxonium iodide with sodium hydride in mineral UV: €241 = 14,500.
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