United States Patent (19) 11 Patent Number: 4,559,332 Grob et al. (45) Date of Patent: Dec. 17, 1985 54) 20-SPIROXANES AND ANALOGUES 57 ABSTRACT HAVING AN OPEN RING E, PROCESSES FOR THEIR MANUFACTURE, AND Steroid compounds of the 20-spiroxane series and their PHARMACEUTICAL PREPARATIONS analogues having an open ring E of the formula, THEREOF Yi Y2 (I) 75 Inventors: Jirgen Grob, Giebenach; Jaroslav Kalvoda, Binningen, both of ill (CH2)2-C=X Switzerland 73) Assignee: Ciba Geigy Corporation, Ardsley, N.Y. (21) Appl. No.: 598,109 in which 22 Filed: Apr. 9, 1984 -A-A- represents the group -CH2-CH2- or -CH-CH-, (30) Foreign Application Priority Data R represents hydrogen, and Apr. 13, 1983 ICH) Switzerland......................... 1981/83 R2 represents an a-oriented lower alkoxycarbonyl radical, or 51 Int. Cl." ............................................ A61K 31/585 R and R2 together represent an a- or a £3-oriented 52 U.S.C. ............................... 514/175; 260/239.57; methylene radical, 260/239.55 R -B-B- represents the group -CH2-CH2- or an 58 Field of Search....................... 260/239.57, 239.55 a- or g-oriented group (56) References Cited - U.S. PATENT DOCUMENTS -CH-CH2-CH-, 3,729,491 4/1973 Klimstra et al. ................. 260/343.6 3,849,404 11/1974 Zawadzki et al. ............. 260/239.57 X represents two hydrogen atoms or oxo, Yi and Y2 together represent the oxygen bridge FOREIGN PATENT DOCUMENTS -O-, or 1041534 9/1966 United Kingdom ........... 260/239.57 Yl represents hydroxy, and Y2 represents hydroxy, lower alkoxy or, if X repre OTHER PUBLICATIONS sents H2, also lower alkanoyloxy, Fieser, Louis F. et al., Steroids, Reinhold Publishing and salts of compounds in which X represents oxo and Corp., New York, Chapman & Hall, Ltd., London (Ad Y2 represents hydroxy, are distinguished as effective renocortical Hormones), pp. 708, (1979). aldosterone-antagonists with minimal side-effects and, "Chemical Abstracts', vol. 79, (1973), Par. 105471 p. for that reason, are especially suitable for the treatment of all forms of hyperaldosteronism. Primary Examiner-Elbert L. Roberts Attorney, Agent, or Firm-Michael W. Glynn 17 Claims, No Drawings 4,559,332 1. 2 cal is preferably one derived from a straight-chain alkyl 20-SPIROXANES AND ANALOGUES HAVING AN having from 1 to 7 carbon atoms; especially preferred OPEN RING E, PROCESSES FOR THEIR are formyl and acetyl. MANUFACTURE, AND PHARMACEUTICAL A methylene bridge in the 6,7- and/or 15, 16-position PREPARATIONS THEREOF is preferably g-oriented. Preferred compounds of the formula I are those in The invention relates to novel 20-spiroxanes and ana which Y and Y2 together represent the oxygen bridge logue compounds having an open oxygen-containing -O-. ring E of the general formula Especially preferred compounds of the formula I are those in which X represents oxo. (I) Of compounds of the formula I in which R1 repre sents hydrogen, R2 represents lower alkoxycarbonyl and X represents oxo there are most especially pre ferred those in which Yl together with Y2 represents the 15 oxygen bridge -O-. As already mentioned, 17(3-hydroxy-21-carboxylic acids may also be in the form of their salts. There come into consideration especially metal and ammonium salts, 20 such as alkali metal and alkaline earth metal salts, for in which example sodium, calcium, magnesium and, preferably, -A-A-represents the group -CH2-CH2- or potassium, salts, and ammonium salts derived from an -CH=CH-, monia or a suitable, preferably physiologically tolera R represents hydrogen, and ble, organic nitrogen-containing base. As bases there R2 represents an a-oriented lower alkoxycarbonyl 25 come into consideration not only amines, for example radical, or lower alkylamines (such as triethylamine), hydroxy R and R2 together represent an a- or a 6-oriented lower alkylamines such as 2-hydroxyethylamine, di-(2- methylene radical, hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, -B-B-represents the group -CH2-CH2- or an cycloalkylamines (such as dicyclohexylamine) or ben a- or g-oriented group Zylamines (such as benzylamine and N,N'-dibenzyle thylenediamine), but also nitrogen-containing heterocy clic compounds, for example those of aromatic charac -CH-CH-CH-, ter (such as pyridine or quinoline) or those having an at least partially saturated heterocyclic ring (such as N X represents two hydrogen atoms or oxo, 35 ethylpiperidine, morpholine, piperazine or N,N'-dime Y and Y2 together represent the oxygen bridge thylpiperazine). -O-, or Also included amongst preferred compounds are Y represents hydroxy, and alkali metal salts, especially potassium salts, of com Y2 represents hydroxy, lower alkoxy or, if X repre pounds of the formula I in which R1 and R2 together sents H2, also lower alkanoyloxy, represent a methylene group or, especially, Rl repre and salts of such compounds in which X represents oxo sents hydrogen and R2 represents lower alkoxycar and Y represents hydroxy, that is to say of correspond bonyl, with X representing oxo and each of Y1 and Y2 ing 17.3-hydroxy-21-carboxylic acids. representing hydroxy. The invention relates also to processes for the manu Especially preferred compounds of the formula I are, facture of these compounds and to pharmaceutical com 45 for example, the following: positions containing these compounds, and also to pro 9a,11a-epoxy-7a-methoxycarbonyl-20-spirox-4-ene cesses for the preparation of such compositions. The 3,21-dione, invention relates also to the therapeutic use of the com 9a,11a-epoxy-7a-ethoxycarbonyl-20-spirox-4-ene-3,21 pounds and compositions mentioned, especially as al dione, dosterone-antagonistic diuretics, and to the correspond 50 9a,11a-epoxy-7a-isopropoxycarbonyl-20-spirox-4-ene ing medical method for the treatment of a warm 3,21-dione, blooded animal, especially a human, with a therapeuti and the 1,2-dehydro analogue of each of the com cally effective amount of such a compound on its own pounds, or in the form of a pharmaceutical composition to cure 9a,11a-epoxy-6a,7a-methylene-20-spirox-4-ene-3,21 or alleviate pathological conditions connected with 55 hyperaldeosteronism. dione, Unless stated otherwise, organic radicals referred to 9a,11a-epoxy-6p3,7(3-methylene-20-spirox-4-ene-3,21 as "lower' in the present disclosure contain at most 7, dione, and preferably from 1 to 4, carbon atoms. 9a,11a-epoxy-6p3,7(3;15A, 16,3-bismethylene-20-spirox A lower alkoxycarbonyl radical is preferably one 60 4ene-3,21-dione, derived from an alkyl radical having from 1 to 4 carbon and the 1,2-dehydro analogue of each of these com atoms, such as methyl, ethyl, propyl, isopropyl, butyl, pounds, isobutyl, sec.-butyl and tert-butyl; especially preferred 9a,11a-epoxy-7a-methoxycarbonyl-17G-hydroxy-3- are methoxycarbonyl, ethoxycarbonyl and isopropox oxo-pregn-4-ene-21-carboxylic acid, ycarbonyl. A lower alkoxy radical is preferably one 65 9a,11a-epoxy-7a-ethoxycarbonyl-1713-hydroxy-3-oxo derived from one of the above-mentioned C1-C4 alkyl pregn-4-ene-21-carboxylic acid, radicals, especially from a primary C1-C4 alkyl radical; 9a,11a-epoxy-7a-isopropoxycarbonyl-17(3-hydroxy-3- especially preferred is methoxy. A lower alkanoyl radi oxo-pregn-4-ene-21-carboxylic acid, 4,559,332 3 4. 9a,11a-epoxy-17(3-hydroxy-6a,7a-methylene-3-oxo in the 9,11-position. Thus, for example, 9a,11a-epoxy pregn-4-ene-21-carboxylic acid, 66,743-methylene-20-spirox-4-ene-3,21-dione displays in 9a,11a-epoxy-17A-hydroxy-6.6,743-methylene-3-oxo pregn-4-ene-21-carboxylic acid, adrenal-ectomised male rats in the Kagawa test Ka 9a,11a-epoxy-1713-hydroxy-66,743; 15(3,166-bismethy 5 gawa et al.: Proc. Soc. Exptl. Biol. Med. (N.Y.), 115, lene-3-oxo-pregn-4-ene-21-carboxylic acid, and alkali 837-840 (1964)), in the entire dosage range of from 1 to metal salts, especially the potassium salt, of each of 10 mg/kg which was tested, an aldosterone-antagonistic these acids, and also a corresponding 1,2-dehydro activity that is equally as great as, if not greater than, analogue of each of the mentioned carboxylic acids that of the corresponding 9,11-unsubstituted compari or of a salt thereof, 10 9a,11a-epoxy-15?,1613-methylene-3,21-dioxo-20 son substance 66,743-methylene-20-spirox-4-ene-3,21 spirox-4-ene-7a-carboxylic acid methyl ester, ethyl dione (J. F. Zawadzki et al.: U.S. Pat. No. 3,849,404). In ester and isopropyl ester, contrast, however, in a specific quantitative test in vitro 9a,11a-epoxy-15As, 1613-methylene-3,21-dioxo-20 in which, as a measure of the antiandrogenic action, the spiroxa-1,4-diene-7a-carboxylic acid methyl ester, 15 binding of the test substance to androgen-receptors in ethyl ester and isopropyl ester, homogenates of ventral prostate glands of rats is mea and also 9a,11a-epoxy-3-oxo-20-spirox-4-ene-7a-car sured, the binding of the former compound is found to boxylic acid methyl ester, ethyl ester and isopropyl be approximately 20 times (after a 2-hour test period) to ester, 9a,11a-epoxy-6p3,7f8-methylene-20-spirox-4-en-3-one, 20 as much as 27 times (after a 20-hour test period) weaker 9a,11a-epoxy-66,713;156,166-bismethylene-20-spirox than in the case of the above-mentioned comparison 4-en-3-one, compound. and also 9a,11a-epoxy-1713-hydroxy-17a-(3-hydroxy The chemical names of the compounds of the formula propyl)-3-oxo-androst-4-ene-7a-carboxylic acid methyl I and of analogue compounds having the same charac ester, ethyl ester and isopropyl ester, 25 teristic structural features are derived according to 9a,11a-epoxy-17(3-hydroxy-17a-(3-hydroxypropyl)- 6a,7a-methylene-androst-4-en-3-one, current