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 nomenclature in the following manner: for com 9a,11a-epoxy-176-hydroxy-17a-(3-hydroxypropyl)- pounds in which Yi together with Y2 represents -O-, 66,713-methylene-androst-4-en-3-one, from 20-spiroxane (for example a compound of the 9a,11a-epoxy-17A-hydroxy-17a-(3-hydroxypropyl)- 30 formula I in which X represents oxo and Y1 together 66,743;15As, 16,3-bismethylene-androst-4-en-3-one, with Y2 represents -O- is derived from 20-spiroxan including 17a-(3-acetoxypropyl) and 17a-(3-formylox 21-one); for those in which each of Y and Y2 represents ypropyl) analogues of the mentioned androstane com hydroxy and X represents oxo, from 17(3-hydroxy-17a pounds, pregnene-21-carboxylic acid; and for those in which and also 1,2-dehydro analogues of all the mentioned 35 compounds of the androst-4-en-3-one and 20-spirox-4- each of Yl and Y2 represents hydroxy and X represents en-3-one series. two hydrogen atoms, from 176-hydroxy-17a-(3- The compounds according to the invention are distin hydroxypropyl)-androstane. Since the cyclic and open guished by favourable biological properties and are, chain forms, that is to say lactones and 17(3-hydroxy-21 therefore, valuable pharmaceutical active ingredients. 40 carboxylic acids and their salts, respectively, are so For example, they have a strong aldosterone-antagonis closely related to each other that the latter may be tic action in that they reduce and normalise unduly high considered merely as a hydrated form of the former, sodium retention and potassium excretion caused by aldosterone. They therefore have, as potassium-saving there is to be understood hereinbefore and hereinafter, diuretics, an important therapeutic application, for ex 45 unless specifically stated otherwise, both in end prod ample in the treatment of hypertension, cardiac insuffi ucts of the formula I and in starting materials and inter ciency or cirrhosis of the liver. mediates of analogous structure, in each case all the 20-Spiroxane derivatives having an aldosterone mentioned forms together. antagonistic action are known, cf., for example, Fieser The compounds of the formula I characterised at the and Fieser: Steroids; page 708 (Reinhold Publ. Corp., 50 beginning can be manufactured by processes analogous New York, 1959) and British Patent Specification No. to those known per se, for example as follows: 1,041,534; also known are analogously active 179 hydroxy-21-carboxylic acids and their salts, cf., for (a) a compound of the formula example, U.S. Pat. No. 3,849,404. Compounds of this kind that have hitherto been used in therapy, however, 55 (II) have a considerable disadvantage in that they always possess a certain sexual-specific activity which has trou blesome consequences sooner or later in the customary long-term therapy. Especially undesirable are the trou blesome effects that can be attributed to the anti-andro genic activity of the known anti-aldosterone prepara t1OnS. It has now been found that the above-characterised 9a,11a-epoxy compounds of the formula I surprisingly exhibit these undesirable side-effects to a substantially 65 in which A-A, B-B, R1, R2, X, Y1 and Y2 have lesser degree although they completely retain the the meanings given above, is treated with a peroxy favourable anti-aldosterone action of compounds that acid, or have an analogous structure but that are not substituted (b) a compound of the formula 4,559,332

(III) (VI)

10 in which A-A, B-B, X, Y and Y2 have the in which A-A, B-B, R, R2, Yl and Y2 have the meanings given above, R represents hydrogen and meanings given above and at least one of the sym Ro represents free carboxy, or a reactive derivative bols Z1 and Z2 represents hydroxy together with 15 or salt of such a compound, is converted into an hydrogen and the other has the same meaning or ester, or represents oxo or, in the case of the symbol Z, may (f) for the manufacture of a compound in which RI also represent two hydrogen atoms, is treated with and R2 together represent a methylene bridge and an oxidising agent, or the other symbols have the meanings given above, (c) for the manufacture of a compound in which Yl 20 the methylene group is added to a compound of the represents hydroxy and the other symbols have the formula meanings given above, a compound of the formula Y2 (VII) s (CH2)2-CeO, (IV)

in which A-A, B-B, Y1 and Y2 have the mean ings give above, and, if desired, 35 (g) a resulting compound of the formula I in which -A-A- represents -CH2-CH2- is treated in which A-A, B-B, R1, R2, X and Y2 have the with a dehydrogenation agent to introduce the meanings given above, Y represents hydroxy and 1,2-double bond, and/or m W represents a group -CH=CH- or -C=C-, (h) a resulting compound of the formula I in which is hydrogenated to saturate the multiple bond in the each of Yi and Y2 represents a hydroxy group is side chain, or cyclised by removing the elements of water to (d) for the manufacture of a compound of the formula form a compound of the formula I in which Yland I in which Yland Y2 together represent the oxygen Y2 together represent the oxygen bridge, and/or bridge -O- and the other symbols have the (i) a resulting compound of the formula I in which X 45 represents two hydrogen atoms is oxidised to a meanings given above, a compound of the formula corresponding compound in which X represents oxo, and/or (j) in a resulting compound of the formula I in which

X represents two hydrogen atoms and each of Y SO and Y2 represents a free hydroxy group the termi nal hydroxy group is acylated, and/or (k) a resulting compound of the formula I in which X represents oxo, Y1 represents hydroxy and Y2 rep resents hydroxy or lower alkoxy, or the two to 55 gether represent the oxygen bridge -O-, is con verted into a salt of the corresponding 17.3- hydroxy-21-carboxylic acid of the formula I in which X represents oxo and each of Yi and Y2 in which A-A, B-B, R, R2 and X have the represents hydroxy, and/or such a salt is converted meanings given above, Yl represents hydroxy and 60 into the free acid and/or the free acid or a salt Yo represents a leaving group, is cyclised with the thereof is converted into a lower alkyl ester. group Yo being removed, or Process variant (a), i.e. the epoxidation of the 9(11)- double bond, is carried out in a manner known perse by (e) for the manufacture of a compound of the formula treating the starting material of the formula II with a I in which R1 represents hydrogen and R2 repre 65 peroxy acid, preferably an organic peroxy acid, for sents a lower alkoxycarbonyl group and the other example an aliphatic peroxy acid, such as, especially, symbols have the meanings given above, a com performic acid or peracetic acid, or preferably an aro pound of the formula matic peroxy acid. Of the last-mentioned acids there is 4,559,332 7 8 advantageously used perbenzoic acid or a substituted a starting material of the formula III in which Z repre perbenzoic acid, such as m-chloroperbenzoic acid or sents oxo and each of Y1, Y2 and Z2 represents hydroxy monoperoxyphthalic acid (perphthalic acid). The reac (the last-mentioned symbol containing, in addition, a tion is carried out especially in an inert organic solvent, hydrogen atom) is obtained by reacting a corresponding for example, in an alkane, such as pentane, hexane or 17-oxo compound, while temporarily protecting the heptane, a halogenated lower alkane, such as, espe 3-oxo group, with an organometal derivative of the cially, methylene chloride, chloroform or 1,2- formula dichloroethane, or an open-chain or cyclic ether, such as, especially, diethyl ether, dioxan or tetrahydrofuran, R-O or an appropriate mixture thereof. The reaction temper 10 N ature should not, as a rule, exceed the temperature at CH-(CH2)2-Met which the spontaneous decomposition of the reactant proceeds more rapidly than the epoxidation reaction, R-O and the reaction is carried out especially at room tem perature or, preferably, below that to approximately 15 in which Met represents an alkali metal or the halomag -20 C., more especially at from -10 to +10 C. nesium group of a corresponding Grignard reagent, and Starting materials of the formula II can, if they are each Ra represents lower alkyl or the two together not known, be manufactured by processes analogous to represent CH2-CH2 or trimethylene, and removing the those known per se, for example analogously to one of oxo-protecting groups. The resulting product is present the process variants (b)-(k) described hereinbelow or a 20 as a mixture of several tautomeric, in part also hydrated, combination thereof, starting from known starting ma forms corresponding to the partial formulae terials, for example correspondingly substituted 17-oxo derivatives of the androstane series, by the conventional OH OH ph formation of the 3-hydroxypropyl side chain or the (CH2)2-CH-OH and spiro ring. Alternatively, a compound that is analogous 25 - (CH2)2-CH=O; - to a compound of the formula I but that contains an 11a- or 11,3-hydroxy group in place of the 9,11-epoxy (A) (B) ring can be dehydrated; the 11-hydroxy compound can be obtained, for example, by microbiological hydroxyl ation of a 9,11-unsubstituted compound. 30 "A" Process variant (b) is likewise carried out in a manner o1 Y CH known per se using conventional oxidising agents and oxidation processes that are customary for the conver - ...... H. sion of a hydroxy group into an oxo group. As preferred (C) oxidising agents there are used compounds of hexava 35 lent chromium, such as chromium trioxide, chromic which, however, behave uniformly in oxidation. Com acid and their metal salts, especially alkali metal salts, pounds of the formula III in which Z represents -OH and as preferred reaction medium there are used lower together with hydrogen are obtained whenever a corre alkanecarboxylic acids, such as acetic and propionic sponding 3-oxo compound is subjected to the action of acid, or pyridine or acetone, optionally with dilution 40 with a halogenated lower alkane, such as dichlorometh a customary reducing agent, for example simulta ane or chloroform. The reaction conditions can be neously with the 21-formyl in the reduction of the last finely adapted to the specific character of the hydroxy mentioned 21-carbaldehyde with a complex hydride. group in the starting material and of the oxo group in Process variant (c) also is carried out in a manner the product: for the oxidation of an allylic 3-hydroxy 45 known per se using conventional hydrogenation agents group mild conditions, such as cooling to a temperature under generally known reaction conditions of catalytic below room temperature, for example to approximately hydrogenation. The reaction is carried out with hydro - 10 to -10 C., are preferred; for the oxidation to the gen gas at normal or elevated pressure under conditions carboxy group, whether it be the free or the lactonised of heterogeneous or homogeneous catalysis. Especially carboxy group, more energetic conditions are expedi 50 suitable as catalysts for the former are finely divided ent, such as prolonged reaction time, reaction tempera metals, for example Raney metals, such as Raney nickel, tures in the range of or above (up to approximately 50 or nobel metals, such as palladium, platinum or rho C.) room temperature and/or aqueous sulphuric acid as dium, which are optionally distributed on a carrier, solvent for the oxidising agent (for example in the form such as calcium carbonate or barium sulphate. For ho of an 8N solution as so-called Jones reagent). Alterna 55 mogeneous catalysis there are used especially complex tively, the oxidiation of an allylic 3-hydroxy group can rhodium compounds, for example tris(triphenylphos also be carried out with manganese dioxide in a haloge phine)-rhodium(I) chloride. The conditions are to be so nated lower alkane, such as chloroform, attemperatures chosen that the 1,2- and/or 4,5-double bond is not re of from room temperature to the boiling temperature of duced at the same time. the reaction mixture, or with aluminium isopropoxide 60 Starting materials of the formula IV can, if they are and a ketone, such as, especially, acetone or cyclohexa not known, be obtained by processes analogous to those none, at temperatures of from room temperature to the of steroid chemistry that are known perse, for example boiling temperature of the mixture. by the methods described under process variants (a), (b) Starting materials of the formula III can, if they are and/or (d) to (k), and by advantageous combination not known, be obtained by processes of steroid chemis 65 thereof. Thus, for example, a starting material of the try that are known per se, for example by the methods formula IV in which W represents the radical described under process variants (a) and/or (c)-(k), and -C=C- is obtained by reacting a suitable 17-oxo by appropriate combination thereof. Thus, for example, compound with an ethynyl-organometal compound, 4,559,332 10 especially an ethynylalkali metal compound, for exam sents an alkali metalion, especially a lithium ion, and Re ple sodium or potassium acetylide or, especially, lithium represents a di-lower alkylamino group, preferably the acetylide. In the latter case, it is especially advantageous dimethylamino group. A 1713-hydroxy-17a-(3-di-lower to use the lithium acetylide in the form of its complex alkylaminopropyl) compound produced in that manner with ethylenediamine. The ethynyl radical introduced is then converted into a corresponding quaternary tri can then be carboxylated in a second step by exchang lower alkylammonium salt by the addition of a lower ing the terminal hydrogen atom in it for a carboxy alkyl ester of a strong acid, for example a lower alkyl group by treatment with a Grignard compound and Sulphate or a lower alkyl halide, such as, especially, subsequent reaction of the resulting co-magnesium hal methyl iodide. From that salt the corresponding quater ide with carbon dioxide. The 3-oxo group is, as a rule, 10 nary base is freed by treatment with a strong base, pref. protected in the usual manner during this reaction. Al erably a metal hydroxide, for example silver hydroxide, ternatively, a suitable organometal derivative of propio or an alkali metal or alkaline earth metal hydroxide, lic acid can also be used in analogous manner. such as potassium, sodium or barium hydroxide. In a purely formal sense, irrespective of the reaction Another advantageous leaving group Yo in com mechanism, process variant (d) is effected by simulta 15 pounds of the formula V in which X represents two neously removing the leaving group Yo and the hydro hydrogen atoms is a reactive esterified hydroxy group. gen atom of the 17g-hydroxy group Yl, with the oxy The ester-forming component is, for example, an oxy gen bridge -O-being formed. When carrying out the gen-containing inorganic acid, such as sulphuric acid, reaction in practice, there are used processes analogous Sulphurous acid, phosphoric acid, phosphorous acid or to those known per se in organic chemistry that are 20 a substitution derivative thereof in which one or more customary for closing a saturated furan ring, whilst of the hydroxy groups has been replaced by halogen, taking into account in each case the specific properties especially chlorine (i.e. an acid radical of the type of the leaving group Ya when choosing the reaction CISO2-, CISO-, Cl2P-, Cl2P(=O)- or Cl4P-), or conditions and reactants. an oxygen-free inorganic acid, especially a hydrohalic A preferred leaving group Yo in compounds of the 25 acid, such as hydrochloric, hydrobromic or hydriodic formula V in which X represents oxo is an amino group acid, or alternatively a strong organic acid, for example Am. The amino group Am is preferably a tertiary amino oxalic acid or, especially, a sulphonic acid, such as an group, especially a di-lower alkylamino group, such as, aliphatic or aromatic carbocyclic sulphonic acid, for above all, the dimethylamino and diethylamino group, example, especially, methane-, ethane- or trifluorome and forms with the adjacent carbonyl group an option 30 thane-Sulphonic acid and benzene-, p-toluene- or p ally N,N-disubstituted 21-carboxamide grouping -CO bromobenzene-sulphonic acid, respectively. The cycli =O)-Am in which Am has the meaning given above. sation by removal of such a reactive esterified hydroxy The conversion of such a starting material into a lactone group is effected by treatment with an inorganic or of the formula I in which Yland Y2 together represent organic basic agent. Inorganic basic agents for this pur the oxygen bridge -O- and X represents oxo is ef. 35 pose are, for example, hydroxides of alkali metal and fected in a manner known perse by acidic agents, espe alkaline earth metals, such as sodium or potassium and cially by treatment with an acidic ion exchanger in barium or calcium, respectively, and salts thereof with H-cycle. The amidic starting material can be manufac weak inorganic or organic acids, such as, especially, tured in a manner known perse, for example by reacting carbonates and bicarbonates, and acetates and formates, a corresponding 17-oxo compound, while temporarily respectively. Organic basic agents for this purpose are, protecting the 3-oxo group in conventional manner (for for example, tertiary bases of aliphatic character, such example as ketal or thioketal), in dimethylsulphonium as tertiary amines derived from lower alkyl and benzyl methylide, for example in accordance with the process radicals (for example triethylamine, benzyldimethyla described in U.S. Pat, No. 3,320,242, and condensing mine, diisopropylethylamine, diisopropylbenzylamine, the resulting 1713,20-epoxy-17a-methylsteroid in a man 45 dibenzylmethylamine or dimethylbutylamine) and their ner known per se with the d-carbanion of an N,N-di heterocyclic saturated analogues (for example N lower alkyl acetamide (or an N,N-di-lower alkyl acta methylpyrrolidine, N-methylpiperidine, N-benzyl mide metallated at methyl by an alkali metal, such as piperidine or N,N'-dimethylpiperazine), or especially sodium or lithium). aromatic heterocyclic bases, such as pyridine and its Another advantageous leaving group Yo, which is SO C-methylated analogues (for example collidine) or quin suitable especially for compounds in which X repre oline. An especially advantageous method of carrying sents two hydrogen atoms, in a quaternary ammonium out this process variant consists of removing a reactive group Am in the form of the base; the group Am is esterified hydroxy group, formed in the reaction mix preferably a tri-lower alkylammonium group, such as, ture, in situ, that is to say immediately after it has been especially, the trimethylammonium group. The cyclisa 55 produced in the same reaction medium by esterification tion of the quaternary base of the formula V in which X of the terminal hydroxy group (i.e. the group denoted represents two hydrogen atoms and Ya represents An by the symbol Y2) in a compound of the formula I by OH to form a compound of the formula I in which means of a reactive acid derivative in a basic medium. A Yi and Y2 together represent the oxygen bridge is ef. reactive acid derivative is especially an acid halide, such fected by heating the base, optionally in a high-boiling 60 as an acid chloride, which is derived from one of the organic solvent, such as ethylene glycol, to decomposi above-mentioned oxygen-containing inorganic and or tion temperature. The corresponding starting material ganic acids. As a typical reactant of this type there is can be manufactured in a manner known perse. For this preferred methane-sulphonyl chloride and, most espe purpose, a corresponding 17-oxo compound is treated, cially, p-toluene-sulphonyl chloride, and, as the reac while temporarily protecting the 3-oxo group in con 65 tion medium, there comes into consideration, above all, ventional manner, with an organometal compound of an aromatic heterocyclic base, such as pyridine. In this the formula Re-(CH2)3-M in which M represents the manner, end products of the formula I in which X rep grouping Mgxin which X is a halogen atom, or repre resents two H atoms and each of Yi and Y2 represents 4,559,332 11 12 hydroxy are cyclised to end products of the formula I in by dehydrogenation of corresponding 6,7-saturated which X represents two H atoms and Yl together with intermediates. Y2 represents -O-. According to the end product-end product conver Process variant (e) is also carried out in a manner sion (g), which may be carried out if desired, 1,2- known perse. The conversion of the acid of the formula 5 saturated compounds are dehydrogenated in a manner VI into the desired ester of the formula I is usually known perse to the corresponding 1,2-dehydro deriva effected by one of the numerous conventional esterifica tives. It is possible to use for this purpose biological tion methods, for example by treatment with a lower dehydrogenation methods, for example to dehydroge alkanol or a reactive derivative thereof, optionally in nate by means of the microorganisms Corynebacterium the presence of catalysts, especially acidic catalysts, 10 simplex or Septomyxa affinis or their enzyme systems, or and/or agents that remove water, for example a sym to treat with selenium dioxide in an organic solvent, for metrically substituted carbodiimide, such as, especially, example tert-butyl alcohol. Preferably, however, dehy N,N'-dicyclohexyl carbodiimide. Of the acidic catalysts drogenation is carried out with 2,3-dichloro-5,6- there come into consideration above all strong inor dicyano-1,4-benzoquinone over several, for example ganic acids, such as sulphuric, phosphoric and perchlo 15 from 6 to 24, hours and optionally at boiling tempera ric acid, and also organic sulphonic acids, such as me ture, in organic solvents, for example aromatic hydro thane-, benzene- or p-toluene-sulphonic acid; the corre carbons, such as benzene or xylene, lower aliphatic sponding alcohol is used in excess, in most cases simul alcohols, such as ethanol, propanol or tert.-butyl alco taneously as solvent. Alternatively, it is also possible to hol, lower aliphatic ketones, such as acetone or 2-buta esterify in a manner known per se with a diazoalkane, 20 none, aliphatic esters, such as ethyl acetate, or cyclic above all diazomethane, or convert the free acid into a ethers, such as dioxan or tetrahydrofuran. reactive derivative thereof, such as a chloride or anhy The cyclisation of an open-chain end product to a dride, for example a mixed anhydride with trifluoroace cyclic end product according to process variant (h), tic acid, and react that derivative with the correspond which may be carried out if desired, is also effected in a ing lower alkanol. Starting materials of the formula VI, 25 manner known per se. Cyclisation of compounds of the if they are not known, are manufactured by processes formula I in which X represents two hydrogen atoms is analogous to those that are known per se, for example effected, for example, in the manner described in pro by adding hydrocyanic acid to the 6,7-double bond of a cess variant (d). End products of the formula I in which suitable 3-oxo-4,6-diene compound (see below) and by X represents oxo and each of Yi and Y2 represents hy conventional conversion of the cyano group into a car 30 droxy, that is to say free 1743-hydroxy-21-carboxylic ...boxy group (for example by hydrolysis or by reduction acids, are cyclised (lactonised) in a manner known per to the formyl group and subsequent oxidation). se by treating them, for example, with a water-remov Process variant (f) is also carried out in a manner ing agent, for example acetic anhydride, anhydrous known per se by processes analogous to those conven copper sulphate, molecular sieves or dicyclohexyl car tionally used for adding the methylene group to a dou 35 bodiimide, in an inert organic solvent. Lactonisation ble bond. The addition is effected, for example accord may also occur spontaneously, especially under acidic ing to a preferred variant, by reacting a 6,7-dehydro conditions and/or at elevated temperature, and is con ... compound of the formula VII with a dimethyloxosul pleted, for example, by azeotropic water removal. phonium methylide. This variant also has the consider The oxidation of the methylene group in the spiro able advantage that it has a very high stereospecificity ring E to the carbonyl group in accordance with pro and provides predominantly 6,7-methylene compounds cess variant (i), which may be carried out if desired, is of one configuration, in most cases the a-configuration, also effected by means of methods that are known perse of the methylene group. The reaction is advantageously for the oxidation of a tetrahydrofuran ring to the corre carried out, for example, by bringing together, under an sponding lactone ring. For this purpose there are used inert gas, such as in a nitrogen atmosphere, and with the 45 especially compounds of hexavalent chromium and the exclusion of moisture, a mineral oil dispersion of sodium reaction is carried out under conditions analogous to hydride and trimethylsulphoxonium iodide and adding those described above, for example, under process vari dimethyl sulphoxide, whereupon the formation of the ant (b) for the oxidation of corresponding open-chain dimethyloxosulphonium methylide takes place. To this compounds in which Y2 represents hydroxy and X rep reagent which has been manufactured in situ there is 50 resents two hydrogen atoms to free carboxylic acids. added the 6,7-unsaturated steroid starting material in a Process variant (), which may be carried out if de molar ratio (reagent:steroid) of approximately from 1:1 sired, is effected in accordance with generally known to 5:1. The reaction is left to proceed at approximately customary esterification processes, preferably by treat room temperature and the reaction mixture is treated ment with a lower alkanoic acid, such as, especially, with water, after which the steroid is isolated according 55 formic acid, on its own, or alternatively with a reactive to customary methods. In such end products, which derivative thereof, such as an anhydride or halide, espe contain alkali-sensitive groups, such as lactone or ester cially the chloride, preferably in the presence of an groups, the decomposition of the reaction mixture is organic base, especially a tertiary amine, such as trieth advantageously to be steered in such a manner that the ylamine, dimethylbenzylamine or N,N-dimethylaniline, pH remains as far as possible in the neutral or weakly 60 a saturated tertiary heterocyclic base, such as N-ethyl acidic range. This method is also suitable for introduc piperidine or N,N'-dimethylpiperazine, or an aromatic ing the methylene group into various intermediates in heterocyclic base, such as quinoline, collidine, lutidine the manufacture of the starting materials of the formu and, above all, pyridine. It is also possible to employ, in lae II to VI. The starting materials of the formula VII addition, inert aprotic organic solvents as the reaction required for this variant can, if they are not known, be 65 medium. obtained by processes analogous to those known perse, The conversions in accordance with process variant for example by removal of water (dehydration) from (k), which may be carried out if desired, are carried out the corresponding 11a- or 11g-hydroxy compounds or by means of generally known, conventional methods. 4,559,332 13 14 Resulting lactones and 22-esters can be converted in a ents according to the invention on its own or in admix manner known per se into the corresponding 17,3- ture with one or more carriers, especially those in solid hydroxy-21 -carboxylic acids and salts thereof, for ex form. ample by hydrolysing them with an alkali metal or The invention relates especially to medicaments in alkaline earth metal base, whereupon these are option the form of tablets (including tablets for sucking, gran ally freed, if the free acid is desired, by acidifying, ules and pastilles), dragées, capsules, pills, ampoules, As alkali metal and alkaline earth metal bases there dry-filled phials or suppositories containing the above are used, for example, corresponding hydroxides, such defined active ingredient on its own or in admixture as sodium and, especially, potassium hydroxide, carbon with one or more carriers. ates, such as sodium and potassium carbonate, or bicar 10 As a special form of these pharmaceutical composi bonates, such as sodium and potassium bicarbonate; as tions and medicaments according to the invention there reaction medium there are advantageously used mix come into consideration also those which contain, in tures of water and one or more organic solvents, prefer addition to the aldosterone-antagonistic compound of ably those which are miscible with water, for example the formula I (including salts) according to the inven lower alkanols, such as methanol, ethanol or isopropyl 15 tion, which is referred to as component A in this con alcohol, cyclic ethers, such as tetrahydrofuran or di text, also a diuretic component B which is non-specific oxan, lower alkanones, such as acetone or 2-butanone, with regard to electrolytes. or lower alkyl amides of lower aliphatic carboxylic There come into consideration as such a diuretic acids and, among these, especially N,N-dimethylforma component B which is non-specific with regard to elec mide. Preferably, not more than an equivalent amount 20 trolyte excretion conventional "classic' diuretics or of the base is used and energetic reaction conditions mixtures thereof which increase diuresis both by renal which could impair other oxygen functions are avoided. and by extrarenal action on tissue, especially substances If an ester group is present in the 7-position, it can, as a having an inhibiting action on the reabsorption in the rule, be retained intact under the mild conditions de tubules, such as saluretics or ethacrynic acid and ana scribed above since it is hydrolysed considerably more 25 logues thereof. Especially suitable as the electrolyte slowly than the esterified or lactonised 21-carboxy non-specific component B are benzothiadiazine deriva group. tives, such as thiazides and hydrothiazides, also ben The alkali metal and alkaline earth metal salts ob Zenesulphonamides, phenoxyacetic acids, benzofuran-2- tained in that manner can be converted into the corre carboxylic acids and 2,3-dihydrobenzofuran-2-carboxy sponding free 17(3-hydroxy-21-carboxylic acids by acid 30 lic acids. The electrolyte-non-specific component B ifying a solution or suspension of a salt in water or in a may consist of a single active ingredient or an advanta water-containing organic solvent. The salts can also be geous combination of several active ingredients, it being converted into esters, for example with a di-lower alkyl possible also for the active ingredients to belong to sulphate or lower alkyl halide. Free 1713-hydroxy-21 several of the groups of substances mentioned. Most carboxylic acids can, if desired, also be converted into 35 especially, there come into consideration as the compo salts by treatment with a corresponding base, for exam nent B the following conventional diuretics: ple into ammonium salts and salts of organic bases, or 1-oxo-3-(3-sulphamyl-4-chloro-phenyl)-3-hydroxyisoin alternatively esterified, for example in a manner de doline, 6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-ben scribed under (e). zothiadiazine 1,1-dioxide, 3-cyclopentylmethyl-6- The invention relates also to those forms of the above chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadia processes in which a compound obtainable as an inter zine 1,1-dioxide, 4-(2-methylenebutyryl)-2,3- mediate at any stage is used as starting material and the dichloro-phenoxyacetic acid, 4-thenoyl-2,3-dichloro remaining steps are carried out, or in which a starting phenoxyacetic acid, material is formed under the reaction conditions. (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)- Pharmaceutical preparations of the present invention 45 acetic acid, 2-chloro-4-furfurylamino-5-carboxyben containing a compound of the formula I, or a salt zenesulphonamide, 2-phenoxy-3-butylamino-5-car thereof, can be used especially for the treatment of boxybenzenesulphonamide and 2-phenoxy-3-3-(1- hyperaldosteronism of very varied forms. They contain pyrrolyl)-propyl-5-carboxybenzenesulphonamide. an effective amount of the active ingredient on its own In such pharmaceutical compositions and medica or in admixture with inorganic or organic, solid or liq 50 ments according to the invention the ratio of compo uid, pharmaceutically acceptable carriers and, if de nent A to component B, based on the particular mean sired, also in admixture with other pharmacologically effective dose, is from approximately 4:1 to approxi or therapeutically valuable substances, and are suitable mately 1:4, preferably from approximately 3:2 to ap especially for enteral, for example oral or rectal, admin proximately 2:3. Since the mean effective dose of each istration or for parenteral administration. 55 specific component is a known value or a value that can Unless more specific information is given, the term easily be determined by known pharmacological test “active ingredient' is intended throughout the follow methods, it is easy for the person skilled in the art to ing text to mean a compound of the formula I, or a salt prescribe a suitable ratio of the two components, within thereof, as defined at the beginning. the limits mentioned above, for each patient according The present invention relates especially to pharma 60 to the specific complaint, general state of health, indi ceutical compositions containing as active ingredient a vidual responsiveness and age, and also the sex of the compound of the formula I (including salts) according patient. to the invention in the form of a sterile and/or isotonic For example, such combination preparations contain, aqueous solution, or alternatively in admixture with at per dosage unit, from 5 to 150 mg, especially from 10 to least one solid or semisolid carrier. 65 50 mg, of a compound of the formula I or a salt thereof The present invention relates also to medicaments, as component A and, as component B, for example from and especially to medicaments in the form of dosage 10 to 100 mg, especially from 25 to 50 mg, of 2-chloro-5- units, which contain at least one of the active ingredi 3-hydroxy-1-oxo-isoindolyl-(3)-benzenesulphonamide 4,559,332 15 16 or 4-(2-methylenebutyryl)-2,3-dichlorophenoxyacetic its own or together with one or more carriers or in a acid, from 5 to 50 mg, especially from 12 to 25 mg, of medicament form. The active ingredients according to 6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadia the invention are administered enterally, for example zine 1,1-dioxide or 2-chloro-4-furfurylamino-5-carbox rectally or, above all, orally, or parenterally, such as, ybenzenesulphonamide, from 2 to 20 mg, especially especially, intravenously. A special method of carrying from 5 to 10 mg, of 2-phenoxy-3-3-(1-pyrrolyl)- out the present treatment according to the invention is propyl-5-carboxybenzenesulphonamide, from 0.1 to 1.0 characterised in that a compound of the formula I ac mg, especially from 0.25 to 0.5 mg, of 3-cyclopentyl cording to the invention, or a salt thereof, as the aldost methyl-6-chloro-7-sulphamoyl-3,4-dihydro-1,2,4-ben erone-antagonistic steroid component A, and a diuretic zothiadiazine 1,1-dioxide or 2-phenoxy-3-butylamino-5- 10 component which is non-specific with regard to elec carboxybenzenesulphonamide, from 100 to 400 mg, trolyte excretion (component B) are administered simul especially 200 mg, of 4-thenoyl-2,3-dichlorophenoxya taneously or together, especially in the form of a corre cetic acid and from 5 to 25 mg, especially 10 mg, of sponding pharmaceutical composition or in the form of racemic (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5- a medicament. indanyloxy)-acetic acid, or half the amount of the laevo 15 In the following Examples, which further illustrate form of this acid. the invention without limiting the scope thereof, the For the treatment of oedema in a moderately severe temperatures are given in degrees Centigrade. All melt case, for example, from 1 to 3 dosage units are taken ing points are uncorrected. daily which contain the active ingredients in amounts by weight that are near the higher limit of the especially 20 EXAMPLE preferred dosage mentioned above; a moderately severe 75 mg of 90% m-chloroperbenzoic acid are added to case of essential hypertonia is, for example, treated with a solution of 100 mg of 7a-methoxycarbonyl-20-spirox from 1 to 3 dosage units the active ingredient content of a-4,9011)-diene-3,21-dione in 2 ml of methylene chloride which is near the lower limit of the especially preferred and the whole is left to stand for 18 hours at approxi range. 25 mately 4' and then for a further 7 hours at room temper The term 'medicament' is used to denote individual ature. After diluting with methylene chloride, the mix separate portion of uniform composition which are ture is washed in succession with 10% potassium iodide suitable for medical administration. The expression solution, 10% sodium thiosulphate solution, ice-cold "medicament in unit dosage form' is used in this de saturated sodium bicarbonate solution and water, dried scription to denote individual separate portions of uni 30 and concentrated by evaporation in a water-jet vacuum. form composition which are suitable for medical admin The amorphous crude product is separated by prepara istration and which each contain individually a specific tive thin-layer chromatography over silica gel in the - amount of the active ingredient according to the inven system methylene chloride/acetone (85:15). The main tion corresponding to from approximately 0.05 to ap zone is eluted with 100 ml of ethyl acetate and concen proximately 2, preferably from approximately 0.1 to 35 trated by evaporation. The resulting crystalline 9a,11a approximately 1, daily dose(s). epoxy-7a-methoxycarbonyl-20-spirox-4-ene-3,21-dione The carriers for use in the pharmaceutical composi is dissolved and allowed to crystallise from methylene tions are generally known materials. chloride/ether. M. p. 239-241. The pharmaceutical compositions according to the In an analogous manner, 7a-methoxycarbonyl invention contain preferably from approximately 0.1 to 40 15,3,1613-methylene-20-spiroxa-4,9011)-diene-3,21-dione ... approximately 99.5% by weight, and especially from is converted into 9a,11a-epoxy-7a-methoxycarbonyl approximately 1 to approximately 90% by weight, of 156,166-methylene-20-spirox-4-ene-3,21-dione. the active ingredient. The starting material can be manufactured in the The recommended daily dosage of the active ingredi following manner: ent of the formula I (including salts) for a warm 45 (a) A solution of 3.54 ml of triethylaluminium in 9.66 ml blooded animal weighing 75 kg is approximately from 5 of benzene is added over a period of 1.5 hours while to 200 mg, preferably approximately from 10 to 100 mg, cooling with ice and stirring with the exclusion of but may vary within wide limits depending on the spe moisture to an ice-cold solution of 0.636 ml of anhy cies, age and individual responsiveness and may exceed drous hydrocyanic acid in 6.44 ml of benzene, and the the upper amount. 50 whole is then stirred for 16 hours at room tempera The pharmaceutical compositions, preparations, ture. The resulting diethylaluminium cyanide solu medicaments and medicaments in unit dosage form tion is added to a solution of 2.0 g of 20-spiroxa according to the invention which are mentioned above 4,6,9(11)-triene-3,21-dione cf. J. Med. Chem., 6, are prepared by means of conventional preparation 732-735 (1963) in 40 ml of tetrahydrofuran, and the processes of the pharmaceutical industry that are 55 whole is heated under reflux for 30 minutes and known per se, for example by means of customary mix cooled. The reaction solution is poured, while stir ing, granulating, tabletting, confectioning, dissolving ring, into 40 ml of 1N sodium hydroxide solution and and lyophilising processes, it being possible, if desired, extracted twice with ethyl acetate. The organic phase for these processes to be carried out under aseptic con is washed in succession with saturated sodium chlo ditions or for an intermediate or a finished product to be 60 ride solution and ice-cold dilute hydrochloric acid, sterilised. dried and concentrated by evaporation in a water-jet The present invention relates also to the use of the vacuum. The resulting oily crude product yields, compounds of the formula I (including salts) for con after chromatography over silica gel by eluting with trolling very varied forms of hyperaldosteronism in a mixture of hexane/ether/methanol (2:9:1), 7a humans and other warm-blooded animals, and also to a 65 cyano-20-spiroxa-4,9011)-diene-3,21-dione. M.p. corresponding therapeutic method that is characterised 241-243. by the administration of an effective dose of at least one In an analogous manner, 15,6,1613-methylene-20 of the active ingredients according to the invention on spiroxa-4,6,9(11)-triene-3,21-dione (see Example 7, 4,559,332 17 18 manufacture of the starting materials) is converted into perature for 2 hours, diluted with further methylene 7a-cyano-15As, 16?s-methylene-20-spiroxa-4,9011)-diene chloride, washed in succession with 10% potassium 3,21-dione. iodide solution, 10% sodium thiosulphate solution, ice (b) 400 mg of 7a-cyano-20-spiroxa-4,9011)-diene-3,21 cold saturated sodium bicarbonate solution and water, dione from stage (a) are dissolved in 16 ml of benzene dried and concentrated by evaporation in a water-jet and, at a temperature of 10, 4.8 ml of a 20% (w/v) vacuum. The amorphous crude product is separated by solution of diisobutylaluminium hydride in toluene preparative thin-layer chromatography over silica gel are added thereto and the whole is stirred for 30 in the system methylene chloride/acetone (85:15). The minutes while cooling with ice. The mixture is heated main zone is eluted with 100 ml of ethyl acetate and to room temperature, stirred for a further 10 minutes, O concentrated by evaporation. The resulting crystalline diluted with 8.0 ml of benzene and stirred again for a 9a,11a-epoxy-7a-methoxycarbonyl-20-spirox-4-ene further 20 minutes at room temperature. While cool 3,21-dione of melting point 239-241 is identical to the ing with ice/sodium chloride, there are added drop product of Example 1. wise to the reaction mixture, at an internal tempera ture of not more than 10, first 4.8 ml of ethyl alcohol 15 EXAMPLE 3 and then 48 ml of water, and the mixture is heated (a) A suspension of 13.0 g of 3,21-dioxo-20-spiroxa under reflux for 5 hours and then cooled. The mixture 4,9(11)-diene-7a-carboxylic acid (cf. Example 1c), 5.2 is acidified with ice-cold dilute hydrochloric acid and ml of 1,5-diazabicyclo(5,4,0)-undec-5-ene and 9.5 ml of extracted with chloroform, and the organic phase is isopropyl bromide in 80 ml of benzene is stirred under concentrated by evaporation in a water-jet vacuum. 20 reflux for 3 hours. After cooling, 800 ml of saturated In an analogous manner, there is obtained from 7a cyano-156,166-methylene-20-spiroxa-4,9011)-diene NaCl solution are added to the reaction mixture and the 3,21-dione the corresponding 7a-formyl-1543,16,3- whole is extracted twice with ethyl acetate. The or methylene-20-spiroxa-4,9011)-diene-3,21-dione. ganic phases are washed in succession with dilute hy (c) The crude 7a-formyl-20-spiroxa-4,9011)-diene-3,21 25 drochloric acid, dilute sodium hydroxide solution and dione from stage (b) is dissolved in 20 ml of acetone saturated NaCl solution, dried and concentrated by and, at a temperature of 7-10, 1.2 ml of an 8N solu evaporation. The crude product is chromatographed in tion of chromium trioxide in aqueous sulphuric acid chloroform over 30 times the amount by weight of silica are added thereto and the whole is stirred for 1 hour gel. The uniform fractions yield, after being dissolved while cooling with ice. The mixture is diluted with 30 and allowed to crystallise from methylene chlori it. ice-water and extracted with chloroform, and the de/ether, 3,21-dioxo-20-spiroxa-4,9011)-diene-7a-car organic phase is washed once with water and ex boxylic acid isopropyl ester. :: tracted twice with 40 ml of saturated sodium bicar M. p. 138-139. bonate solution each time. The combined alkaline (b) 0.5 ml of a solution of 1.1 g of dipotassium hydro extracts are acidified with 4N hydrochloric acid 35 gen phosphate in 2.5 ml of 30% hydrogen peroxide while cooling with ice and left to stand for 10 min solution is added to a solution of 0.2 g of 3,21-dioxo-20 utes. The product is taken up from the milky mixture spiroxa-4,9011)-diene-7a-carboxylic acid isopropyl ester in chloroform and, after being dried, concentrated by in 1.6 ml of methylene chloride and 0.4 ml of tri evaporation in a water-jet vacuum. chloroacetonitrile, and the whole is stirred for 5 hours The resulting amorphous 3,2-dioxo-20-spiroxa 40 at 40'. After the addition of a further 0.4 ml of 30% 4,9(11)-diene-7a-carboxylic acid is further processed hydrogen peroxide solution, stirring is continued for 21 without additional purification. hours at 40. Customary working up yields an amor In an analogous manner, there is obtained from 7a phous crude product which is chromatographed over formyl-15g,1613-methylene-20-spiroxa-4,9011)-diene 50 times the amount by weight of silica gel in the system 3,21-dione3,21-dioxo-15As, 16,3-methylene-20-spiroxa 45 methylene chloride/acetone (98:2). By crystallisation of 4,9011)-diene-7a-carboxylic acid. the uniform fractions from methylene chloride/ether (d) An ethereal diazomethane solution is added drop 9a,11a-epoxy-7a-isopropoxycarbonyl-20-spirox-4-ene wise to a solution of 235 mg of 3,21-dioxo-20-spiroxa 3,21-dione, 4,9011)-diene-7a-carboxylic acid in 2.35 ml of methy m.p. 207-209, is obtained. lene chloride until the evolution of nitrogen ceases. 50 EXAMPLE 4 After 20 minutes at room temperature, the yellow reaction solution is carefully concentrated by evapo (a) A suspension of 7.2 g of 3,21-dioxo-20-spiroxa ration and the residue is dissolved and allowed to 4,9(11)-diene-7a-carboxylic acid (cf. Example 1c), 2.88 crystallise once from methylene chloride/ether/pe ml of 1,5-diazabicyclo(5,4,0)-undec-5-ene and 5.6 ml of troleum ether to yield 7a-methoxycarbonyl-20 55 ethyl bromide in 43 ml of benzene is stirred under reflux spiroxa-4,9011)-diene-3,21-dione. for 3 hours. After cooling, 400 ml of saturated NaCl M. p. 205-206'. solution are added to the reaction mixture and the In an analogous manner, using 3,21-dioxo-15A,166 whole is extracted twice with ethyl acetate. The or methylene-20-spiroxa-4,9011)-diene-7a-carboxylic acid ganic phases are washed in succession with dilute hy as starting material the corresponding methyl ester 60 drochloric acid, dilute sodium hydroxide solution and thereof is obtained. saturated NaCl solution, dried and concentrated by evaporation. The crude product is chromatographed in EXAMPLE 2 chloroform over 30 times the amount by weight of silica A mixture of 3.9 g of 7a-methoxycarbonyl-20-spirox gel. The uniform fractions yield, after being dissolved a-4,9011)-diene-3,21-dione, 1.95 g of dipotassium hydro 65 and allowed to crystallise from methylene chlori gen phosphate, 5.85 ml of trichloroacetonitrile, 17.5g of de/ether, 3,21-dioxo-20-spiroxa-4,9011)-diene-7a-car 30% aqueous hydrogen peroxide solution and 89 ml of boxylic acid ethyl ester. methylene chloride is intensively stirred at room tem M. p. 128-129. 4,559,332 19 20 (b) A mixture of 1.93 g of 3,21-dioxo-20-spiroxa mixture is washed in succession, once in each case, with 4,9(11)-diene-7a-carboxylic acid ethyl ester, 19.3 ml of 10% potassium iodide solution, 10% sodium thiosul methylene chloride, 2.89 ml of trichloroacetonitrile, 365 phate solution and ice-cold dilute sodium hydroxide ml of dipotassium hydrogen phosphate and 8.68 ml of solution, and the organic phase, after being dried, is 30% hydrogen peroxide solution is stirred for 6 hours at 5 concentrated by evaporation in a water-jet vacuum. By 40. Customary working up yields an amorphous crude chromatography over 150 times the amount by weight product which is chromatographed over 50 times the of silica gel and elution with a mixture of toluene/ethyl amount by weight of silica gel in the system methylene acetate (80:20) 9a,11a-epoxy-66,743-methylene-20 chloride/acetone (95:5). By crystallisation of the uni spirox-4-ene-3,21-dione is obtained which, after being form fractions from methylene chloride/ether 9a,11a- 10 dissolved and allowed to crystallise once from methy epoxy-7a-ethoxycarbonyl-20-spirox-4-ene-3,21-dione, lene chloride/ether, has a melting point of 299-301. m.p. 177-179, is obtained. In an analogous manner, 6(3,743; 156,1613-bis-methy lene-20-spiroxa-4,9011)-diene-3,21-dione can be con EXAMPLE 5 verted into 9a,11a-epoxy-6p3,7(3;15,3,166-bis-methy 430 mg of 90% m-chloroperbenzoic acid are added to 15 lene-20-spirox-4-ene-3,21-dione. a solution of 570 mg of 3,21-dioxo-20-spiroxa-4,9011)- The necessary starting materials can be manufactured diene-7a-carboxylic acid (see Example 1c) in 11.4 ml of in the following manner: methylene chloride and the whole is left to stand at With the stringent exclusion of moisture, 4.37 g of a room temperature for 3 hours. While cooling with ice, 72% (w/v) suspension of sodium hydride in mineral oil an ethereal diazomethane solution is added to this mix- 20 are added to a mixture of 30.4 g of trimethylsulphox ture until no more nitrogen evolution can be seen. The onium iodide and 102 ml of dimethylsulphoxide and the reaction solution, diluted with methylene chloride, is whole is stirred for 1 hour at room temperature. 7.80 g washed in succession with a 10% potassium iodide solu of 20-spiroxa-4,6,9(11)-triene-3,21-dione cf. J. Med.- tion, 10% sodium thiosulphate solution and ice-cold Chem., 6, 732-735 (1963) are added to this mixture and, saturated sodium bicarbonate solution, dried and con 25 after rinsing with 7.8 ml of dimethyl sulphoxide, the centrated by evaporation in a water-jet vacuum. The whole is stirred for 2 hours at room temperature. While gel-like crude product is chromatographed over 100 stirring well, the reaction mixture is poured into ice times the amount by weight of silica gel with a mixture water, acidified with dilute hydrochloric acid and ex of methylene chloride/acetone (96:4). The resulting tracted twice with ethyl acetate. The organic phase is 9a,11a-epoxy-7a-methoxycarbonyl-20-spirox-4-ene 30 washed in succession with a saturated sodium chloride 3,21-dione is identical to the product of Example 1. solution, ice-cold dilute sodium hydroxide solution and M. p. 239-241 (after being dissolved and allowed to again with the sodium chloride solution, dried and con crystallise twice from methylene chloride/ether). centrated by evaporation in a water-jet vacuum. The crude product is then chromatographed over 50 times EXAMPLE 6 35 the amount by weight of silica gel and eluted with a A solution of 980 mg of 3,21-dioxo-20-spiroxa mixture of toluene/ethyl acetate (85:15). After evapo 4,9(11)-diene-7a-carboxylic acid (cf. Example 1c) and rating off the solvents, 66,713-methylene-20-spiroxa 735 mg of 90% m-chloroperbenzoic acid in 19.6 ml of 4,9(11)-diene-3,21-dione, m.p. 174-178 (after being methylene chloride is left to stand at room temperature dissolved and allowed to crystallise twice from methy for 3 hours. After being diluted with methylene chlo- 40 lene chloride/ether), is obtained. ride, the mixture is washed in succession with 10% In an analogous manner, 6(3,74;15(3,166-bis-methy potassium iodide solution and 10% sodium thiosulphate lene-20-spiroxa-4,9011)-diene-3,21-dione is also obtained solution and extracted with an ice-cold 0.5N sodium using 15(3,166-methylene-20-spiroxa-4,6,9(11)-triene carbonate solution. The aqueous phase is washed with 3,21-dione as starting material; the latter can be ob ether and freeze-dried. The pulverulent sodium salt of 45 tained in the following manner: the 7a-carboxylic acid is suspended in 4.9 ml of dimeth (a) A solution of 20g of 17a,20:20,21-bismethylenediox ylformamide, 1.9 ml of isopropyl iodide are added ypregn-5-ene-3,6,11(3-diol (U.S. Pat. No. 3,409,610) in thereto and the whole is stirred for 16 hours at 40. 150 ml of pyridine and 150 g of acetic anhydride is Having been cooled, the reaction mixture is diluted heated under reflux for 1 hour. The cooled reaction with ice-water and acidified with dilute hydrochloric 50 solution is poured onto 3000 g of ice flakes while acid. The precipitate which forms is filtered with suc stirring and further stirred until thawing occurs. The tion, washed with water and dissolved in methylene precipitate is filtered with suction and dried in air, chloride; after being dried, the solution is concentrated and the crude 3(3,1118-diacetoxy-17a,20:20,21-bisme by evaporation in a water-jet vacuum. The oily crude thylenedioxypregn-5-ene is further processed without product yields, after being dissolved in methylene chlo 55 being purified. ride, filtered through aluminium oxide (neutral) and (b) 20.3 g of the 3,11-diacetate which has been dried in concentrated by evaporation, amorphous 9a,11a air are introduced in portions, while stirring and with epoxy-7a-isopropoxycarbonyl-20-spirox-4-ene-3,21 external cooling with ice-water, into 71 ml of a solu dione which, after being dissolved and allowed to crys tion prepared beforehand by passing, at approxi tallise from methylene chloride/ether, melts at 60 mately 0, 141 g of gaseous hydrogen fluoride into a 207-209. solution consisting of 100 ml of isopropyl alcohol, 48 g of urea and 9.6 ml of water. EXAMPLE 7 The reaction mixture is stirred for 1 hour while cool 11.3 g of 80% p-nitroperbenzoic acid are added to a ing with ice-water, carefully poured into an ice-cold solution of 15.7 g of 6,3,7(3-methylene-20-spiroxa 65 solution of 142 g of sodium sulphite in 1015 ml of water 4,9(11)-diene-3,21-dione in 628 ml of chloroform and and stirred for 20 minutes. The mixture is extracted with the whole is left to stand at room temperature for 2 ethyl acetate and washed in succession with saturated hours. After being diluted with methylene chloride, the sodium chloride solution, ice-cold dilute hydrochloric 4,559,332 21 22 acid, ice-cold dilute sodium hydroxide solution and temperature for 2 hours. The reaction mixture is di again with dilute sodium chloride solution, dried and luted with 100 ml of water and concentrated at ap- . concentrated by evaporation in a water-jet vacuum. proximately 45 in a water-jet vacuum. The residue is The residue is chromatographed over 10 times the taken up in ethyl acetate and washed in succession amount by weight of silica gel. By elution with a mix with saturated sodium chloride solution, ice-cold ture of methylene chloride/acetone (95:5) uniform frac dilute hydrochloric acid, ice-cold dilute sodium hy tions are obtained which, after being dissolved and droxide solution and again with saturated sodium allowed to crystallise once from methylene chloride/- chloride solution and dried over sodium sulphate. By methanol/ether, yield 3,6,1113-diacetoxy-17a,21-dihy distilling off the solvents in a water-jet vacuum an droxypregn-5-en-20-one of melting point 231-233. O amorphous residue of crude 16a-bromo-17, 17-ethy (c) To a solution of 13.8g of the last-mentioned com lenedioxy-androst-5-ene-3,6,11A-diol is obtained. The pound in 207 ml of dioxan there are added 69 g of resulting crude product (13 g) is dissolved in 143 ml finely pulverulent manganese dioxide and the whole of dimethyl sulphoxide and, in the course of 30 min is boiled under reflux for 3 hours. After cooling to utes at 45 while stirring, a mixture of 7 g of potas room temperature, the solid portion is removed by 15 sium tert-butoxide in 13 ml of dimethylsulphoxide is filtering with suction and is washed well with chloro added thereto and the whole is stirred for 20 hours at form. The filtrate is concentrated by evaporation, 50" (bath temperature). The mixture is cooled to dissolved in methylene chloride and filtered through room temperature, diluted with approximately 1300 10 times the amount by weight of neutral aluminium ml of a saturated ammonium chloride solution and oxide. By evaporating off the solvent, crystalline 20 taken up in ethyl acetate; the organic phase is washed 3p3,11g-diacetoxy-androst-5-en-17-one is obtained three times with a saturated sodium chloride solution which, after being recrystallised once from methy and dried over sodium sulphate. By distilling off the lene chloride/petroleum ether, melts at 177-179. solvents in a water-jet vacuum amorphous 17, 17 (d) A mixture of 7.5 g of 36,1143-diacetoxy-androst-5- ethylenedioxy-androsta-5,15-diene-3,6,11g-diol is ob en-17-one and 150 mg of p-toluenesulphonic acid in 25 tained the purity of which is adequate for further 450 ml of benzene and 7.5 ml of ethylene glycol is processing. boiled under reflux for 16 hours on a water separator. (g) 4 ml of a solution of 100 mg of p-toluenesulphonic After cooling, the solution is diluted with ethyl ace acid in 10 ml of water are added to a solution of 800 tate and immediately washed with 225 ml of ice-cold mg of . 17, 17-ethylenedioxy-androsta-5,15-diene saturated sodium chloride solution. The organic 30 343,1 i?s-diol in 40 ml of acetone and the whole is phase, after being dried, is concentrated by evapora stirred for 6 hours at room temperature. After dilut tion in a water-jet vacuum and the oily 3,3,1113 ing with 40 ml of water, the acetone is distilled offin diacetoxy-17, 17-ethylenedioxy-androst-5-ene is used a water-jet vacuum and the oily residue is taken up in for the next stage without being purified. chloroform and washed once with ice-cold saturated (e) To a stirred suspension of 2.35 g of lithium alumin 35 sodium bicarbonate solution. After evaporating off ium hydride in 95 ml of tetrahydrofuran there is the organic solvents, amorphous 36,11A-dihydroxy added dropwise, at an internal temperature of 5-10, androsta-5,16-dien-17-one is obtained which can be a solution of 4.7 g of 36,11A-diacetoxy-17, 17-ethy used for the next stage without further purification. lenedioxy-androst-5-ene in 140 ml of tetrahydrofuran, (h) 1.52 g of 55-60% strength sodium hydride (as a rinsing out is effected with 9 ml of tetrahydrofuran mineral oil suspension) and 7.57 g of trimethylsul and the mixture is boiled under reflux for 12 hours. phoxonium iodide are added under a nitrogen atmo The reaction mixture is then decomposed at an inter sphere to dimethyl sulphoxide (64 ml) and the whole nal temperature of not more than 5 by the careful is stirred first at room temperature for 30 minutes and dropwise addition of a mixture of 9 ml of tetrahydro then at an external temperature of 34-40 for a fur furan and 14 ml of ethyl acetate and then a mixture of 45 ther 30 minutes. There are added to the reaction 9 ml of tetrahydrofuran and 14 ml of water, and, after mixture, which has been cooled to room temperature, the addition of 70g of anhydrous sodium sulphate, is 8 g of 36,116-dihydroxy-androsta-5,15-dien-17-one stirred for a further 30 minutes without cooling. Solid and rinsing out is effected with 26 ml of dimethyl portions are removed by filtration with suction over sulphoxide. The reaction mixture is stirred for 3 hours a layer of kieselguhr (washing with tetrahydrofuran), 50 at room temperature, poured onto 1 liter of ice-cold and the filtrate is concentrated in a water-jet vacuum. saturated sodium chloride solution, rinsed out with a The amorphous residue is chromatographed over 50 little methyl alcohol and water, acidified with dilute times the amount by weight of silica gel. By elution hydrochloric acid and stirred for 30 minutes. The oil with a mixture of methylene chloride/acetone (93:7) which has separated is taken up in ethyl acetate and and evaporation of the solvent uniform 17, 17-ethy 55 the organic phase is washed in succession with satu lenedioxy-androst-5-ene-3,6,1113-diol is obtained rated sodium chloride solution, ice-cold dilute so which, after being dissolved and allowed to crystal dium hydroxide solution and again with saturated lise once from methylene chloride/ether, melts at sodium chloride solution. After drying, the solvents 23-125. are evaporated off in a water-jet vacuum and the (f) 36.3 g of pyridine hydrobromide perbromide are 60 resulting amorphous 3,3,1113-dihydroxy-15p3,166 added to a solution of 16.8g of 17, 17-ethylenedioxy methylene-androst-5-en-17-one is subjected to the androst-5-ene-3,6,11g-diol in 102 ml of tetrahydrofu subsequent acetylation without being purified. ran and the whole is stirred at room temperature for (i) A solution of 7.9 g of 36,116-dihydroxy-15(3,166 2 hours. 26.9 g of sodium iodide are added to the methylene-androst-5-en-17-one in 39.5 ml of pyridine mixture, stirring is carried out for a further 30 min 65 and 39.5 ml of acetic anhydride is left to stand at utes, a solution of 36.3 g of sodium thiosulphate in room temperature for 5 hours, diluted with 800 ml of 50.4 ml of water and 100 ml of pyridine are added in ice-water and, after standing for 1 hour, extracted succession and the whole is again stirred at room with ethyl acetate. The organic phase is washed in 4,559,332 23 24 succession with saturated sodium chloride solution, phase is washed with ice-cold saturated sodium bicar ice-cold dilute hydrochloric acid, ice-cold dilute so bonate solution and dried. By distilling off the sol dium hydroxide solution and again with saturated vents in a water-jet vacuum a crystalline crude prod sodium chloride solution, dried and concentrated in a uct is obtained which, in a solution in methylene water-jet vacuum. By chromatography of the crude 5 chloride, is filtered through 5 times the amount by product over 30 times the amount by weight of silica weight of neutral aluminium oxide. By distilling off gel and elution with a mixture of methylene chloride the solvent from the main fraction crystals are ob /acetone (98:2) 313-acetoxy-11 (3-hydroxy-1513,166 tained which, after being dissolved and allowed to methylene-androst-5-en-17-one is obtained which, crystallise once from methylene chloride/ether, yield after being dissolved and allowed to crystallise once 10 36-acetoxy-1513,166-methylene-20-spiroxa-5,9(11)- from methylene chloride/ether/petroleum ether, dien-21-one of melting point 241-243. melts at 209-211. (1) 19 ml of a 1N sodium hydroxide solution are added (j) 2.6 ml of a solution of 5% by weight sulphur dioxide to a suspension of 1.9 g of 3,6-acetoxy-15?,166 in methanesulphonic acid chloride are added to a methylene-20-spiroxa-5,9(11)-dien-21-one in 26.6 ml solution of 1.75 g of 3,3-acetoxy-11 (3-hydroxy- 15 of chloroform and 190 ml of methyl alcohol. The 1543,166-methylene-androst-5-en-17-one in 10.5 ml of mixture is stirred for 1 hour at room temperature, dimethylformamide and 3.5 ml of y-collidine and the diluted with 190 ml of water and extracted with one whole is stirred for 20 minutes, the internal tempera portion of chloroform and one portion of a mixture of ture being allowed to increase to approximately 45. chloroform/methanol (90:10). The combined organic The mixture together with the precipitate which has 20 phase, after being dried, are concentrated in a water separated is poured, while stirring, onto 17.5 ml of jet vacuum and the crystalline crude product is re ice-water and stirred for a further 10 minutes. The oil crystallised once from methylene chloride/ether/pe which has separated is taken up in ethyl acetate and troleum ether. The reslting 36-hydroxy-15p3,166 washed in succession with saturated sodium chloride methylene-20-spiroxa-5,9(11)-dien-21-one melts at solution, ice-cold dilute hydrochloric acid, ice-cold 25 244-246. dilute sodium hydroxide solution and again with satu (m) 4 ml of solvent are distilled off under normal pres rated sodium chloride solution. After evaporating off sure from a suspension of 400 mg of 36-hydroxy the solvents, 343-acetoxy-15As, 16.6-methylene-andros 1543,166-methylene-20-spiroxa-5,9(11)-dien-21-one in ta-5,9(11)-dien-17-one that is uniform according to 20 ml of toluene and 3 ml of cyclohexanone. Cooling thin-layer chromatography is obtained and is further 30 is effected to an internal temperature of approxi processed without being purified. mately 80, 480 mg of aluminium propoxide are (k) While cooling with ice-water, there are added to a added and the whole is stirred under reflux for 2 solution of 5.2 g of 3,3-acetoxy-15(3,166-methylene hours. The solution is cooled to room temperature, a androsta-5,9(11)-dien-17-one in 127.5 ml of tetrahy solution of 0.4 ml of acetic acid in 0.8 ml of toluene is drofuran 1.78 g of lithium wire (pieces of approxi 35 added thereto and the solution is evaporated to dry mately 5 mm in length) and then, over a period of 10 ness four times in a water-jet vacuum with 5 ml of minutes, a solution of 12.75 ml of the cyclic ethylene water each time. The oily residue is taken up in chlo acetal of 6-chloropropionaldehyde in 12.75 ml of roform and washed in succession with ice-cold dilute tetrahydrofuran is added dropwise thereto; the whole hydrochloric acid, water, ice-cold sodium hydroxide is then stirred for 1 hour while cooling with ice and 40 solution and again with water, and the organic phase for 16 hours at room temperature. 330 ml of ethyl is dried and evaporated in a water-jet vacuum. The acetate are added to the reaction mixture which is amorphous crude product is applied to 50 times the stirred for 45 minutes, then diluted with further ethyl amount by weight of silica gel an chromatographed acetate, washed in succession with saturated sodium with a mixture of methylene chloride/acetone (98:2). chloride solution, ice-cold dilute hydrochloric acid, 45 The resulting 1543,16p3-methylene-20-spiroxa-4,9011)- ice-cold dilute sodium hydroxide solution and again diene-3,21-dione melts at 172-174 after being dis with saturated sodium chloride solution, dried and solved and allowed to crystallise once from methy concentrated in a water-jet vacuum. The oily crude lene chloride/ether/petroleum ether. product is dissolved in a mixture of toluene/ethyl (n) A solution of 3.27 g of 15,6,166-methylene-20 acetate (90:10) and filtered through 10 times the 50 spiroxa-4,9011)-diene-3,21-dione in 16.35 ml of dioxan amount of weight of silica gel. After evaporating off and 6.54 ml of orthoformic acid trimethyl ester is the solvents, the filtrate yields 4.84 g of amorphous mixed with 0.654 ml of a solution of 900 mg of p-tol substance. This is dissolved in 363 ml of chloroform, uenesulphonic acid in 10 ml of dioxan and 2 ml of 242 g of acidic aluminum oxide (activity stage 1) are ethyl alcohol, the mixture is stirred for 4 hours at added and the whole is stirred at reflux temperature 55 room temperature, poured, while stirring, into 430 ml for 2 hours, diluted with a further 363 ml of chloro of an ice-cold 0.2N sodium hydroxide solution and form, stirred for a further 5 minutes and cooled. The intensively stirred for 15 minutes. The precipitate is mixture is filtered with suction over kieselguhr, the filtered with suction, washed with water and dried on filter cake is washed with chloroform and the filtrate the suction filter. The resulting crude 3-ethoxy is concentrated in a water-jet vacuum. The resulting 60 15A,16p3-methylene-20-spiroxa-3,5,9(11)-trien-21-one crude 21-carbaldehyde (4 g) is dissolved in 20 ml of is dissolved in 105 ml of acetone and treated in suc methylene chloride and 80 ml of acetone, and 8 ml of cession with a solution of 1.13 g of sodium acetate an 8N chromium(VI)-sulphuric acid solution are (trihydrate) in 8.84 ml of water and, while cooling to added thereto at 5 over a period of 5 minutes and the -5, with 1.55g of N-bromoacetamide and 1.13 ml of mixture is stirred for 45 minutes while cooling with 65 acetic acid. The mixture is stirred for 30 minutes at an ice. The mixture is diluted with 80 ml of ice-cold internal temperature of approximately -3 and sub water, stirred for 10 minutes without cooling and sequently for a further 15 minutes without cooling, a extracted with methylene chloride. The organic solution of 0.88 g of potassium iodide in 17.7 ml of 4,559,332 25 26 water and a solution of 5.58 g of sodium thiosulphate ice-water and stirred for 15 minutes. The precipitate in 17.7 ml of water are added in succession thereto, - which has separated is filtered with suction, washed out and the mixture is stirred for a further 5 minutes and with water and dissolved in chloroform and the organic diluted with 88 ml of water. The mixture is extracted phase, after being dried, is concentrated by evaporation with chloroform and the organic phase is washed 5 in a water-jet vacuum. The amorphous crude product is with ice-cold saturated sodium bicarbonate solution. applied to 30 times the amount by weight of silica gel Drying and concentration of the organic phase pro and eluted with a mixture of methylene chloride/ace duces the amorphous residue which, dissolved in 78 tone (95:5). The combined uniform fractions yield, after ml of dimethylformamide, has added to it 3.89 g of being dissolved and allowed to crystallise once from lithium carbonate and 3.89 g of lithium bromide and is 10 methylene chloride/ether, 9a,11a-epoxy-176-hydroxy stirred for 3 hours at 100'. Having been cooled, the 66,743-methylene-3-oxo-17a-pregn-4-ene-21-carboxylic mixture is poured, while stirring, onto 750 ml of ice acid methyl ester. M. p. 189-191'.. water, and the precipitate is filtered with suction and In an analogous manner, in place of methyl iodide, washed with water. The filter cake is dissolved in reaction can be carried out with an equivalent amount chloroform, dried with sodium sulphate and evapo- 15 of dimethyl sulphate. rated to dryness in a water-jet vacuum. A solution of the resulting residue in methylene chloride is filtered EXAMPLE 10 through a column of neutral aluminium oxide (activ A solution of 1.3 g of 9a,11a-epoxy-66,743-methy ity II) and eluted with further portions of the same lene-20-spirox-4-ene-3,21-dione and 1.3 g of DDQ (2,3- solvent. The eluates are concentrated and the desired 20 dichloro-5,6-dicyanobenzoquinone) in 26 ml of dioxan 1543,166-methylene-20-spiroxa-4,6,9(11)-triene-3,21 is stirred for 15 hours at 100'. The dark reaction mixture dione is precipitated in amorphous form by the addi is concentrated by evaporation three times with toluene tion of ether. The product is uniform according to in a water-jet vacuum, and the residue is dissolved in thin-layer chromatography and is suitable for further methylene chloride and filtered through 10 times the processing. 25 amount by weight of aluminium oxide (neutral). The resulting crystals yield, after being dissolved and al EXAMPLE 8 lowed to crystallise once from methylene chlori A mixture of 2.0 g of 9a,11a-epoxy-6p3,713-methy de/ether, the desired 9a,11a-epoxy-66,743-methylene lene-20-spirox-4-ene-3,21-dione, 40 ml of methyl alco 20-spiroxa-1,4-diene-3,21-dione of melting point hol and 2.45 ml of a 2N aqueous solution of potassium 30 295-296. hydroxide is stirred for 16 hours at 60. The reaction solution is concentrated by evaporation in a water-jet EXAMPLE 11 vacuum and freed of residual water by being concen A mixture of 1.3 g of 9a,11a-epoxy-7a-methoxycar trated by evaporation three times with absolute ethyl bonyl-20-spirox-4-ene-3,21-dione, 17 ml of methyl alco alcohol. The residue is dissolved in hot methanol and 35 hol and 1.41 ml of a 2N aqueous solution of potassium precipitated in crystalline form with ethyl acetate. The hydroxide is stirred for 16 hours at room temperature resulting potassium 9a,11a-epoxy-1713-hydroxy-66,743 and then for 20 minutes at 60. The reaction solution is methylene-3-oxo-17a-pregn-4-ene 21-carboxylate is concentrated by evaporation in a water-jet vacuum and dried in a high vacuum at 80'. freed of residual water by being concentrated by evapo Analysis: calculated 8.83% K.; found 8.76% K. 40 ration three times with absolute ethyl alcohol. The The same potassium salt is obtained with an analo crystalline residue is stirred with 40 ml of ethyl acetate, gous procedure and using, as starting material, an equiv filtered with suction and washed out on the filter with alent amount of 9a,11a-epoxy-1713-hydroxy-66,713 ethyl acetate and ether. The resulting flaky potassium methylene-3-oxo-17a-pregn-4-ene-21-carboxylic acid 9a,11a-epoxy-17A-hydroxy-7a-methoxycarbonyl-3- methyl ester. 45 oxo-17a-pregn-4-ene-21-carboxylate is dried in a high In an analogous manner, 9a,11a-epoxy vacuum at 80. 6p3,713; 156,166-bis-methylene-20-spirox-4-ene-3,21 Analysis: calculated 8.31% K; found 8.02% K. dione or 9a,11a-epoxy-1713-hydroxy-66,743; 15(3,163 The same salt is also obtained by analogous reaction bis-methylene-3-oxo-17a-pregn-4-ene-21-carboxylic of an equivalent amount of 9a,11a-epoxy-1719-hydroxy acid methyl ester can also be converted into the potas- 50 3-oxo-17A-pregn-4-ene-7a,21-dicarboxylic acid di sium salt of the last-mentioned acid. methyl ester. EXAMPLE 9 EXAMPLE 12 1.5 ml of 4N methanolic potassium hydroxide solu A mixture of 1.25 g of 9a,11a-epoxy-7a-isopropox tion are added to a suspension of 1.8g of 9a,11a-epoxy- 55 ycarbonyl-20-spirox-4-ene-3,21-dione, 15.6 ml of 66,713-methylene-20-spirox-4-ene-3,21-dione in 18 ml of methyl alcohol and 1.27 ml of a 2N aqueous solution of methyl alcohol and the whole is boiled under reflux for potassium hydroxide is stirred for 16 hours at room 1 hour. At normal pressure, approximately 12 ml of the temperature and then for 20 minutes under reflux. The solvent are distilled off, 18 ml of ethyl acetate are added reaction solution is concentrated by evaporation in a and the mixture is concentrated to approximately 12 ml 60 water-jet vacuum and freed of residual water by being in a water-jet vacuum. After adding a further 18 ml of concentrated by evaporation three times with absolute ethyl acetate, the crystalline precipitate which has ethyl alcohol. The crystalline residue is stirred with 40 formed is stirred for a further 10 minutes, filtered with ml of ethyl acetate, filtered with suction and washed out suction, washed with ethyl acetate and ether and dried on the filter with ethyl acetate and ether. The resulting on the suction filter. The yellowish powder is dissolved 65 flaky potassium 9a,11a-epoxy-17G-hydroxy-7a-iso in 9 ml of dimethylformamide, 0.9 ml of methyl iodide propoxycarbonyl-3-oxo-17a-pregn-4-ene 21-carboxy is added thereto and the mixture is stirred at room tem late is dried in a high vacuum at 80'. perature in a closed vessel. The mixture is diluted with Analysis: calculated 7.66% K.; found 7.15% K. 4,559,332 27 28 In an analogous manner, using an equivalent amount of 9a,11a-epoxy-7a-ethoxycarbonyl-20-spirox-4-ene EXAMPLE 1.5 3,21-dione or .9a,11a-epoxy-1713-hydroxy-3-oxo-17A Tablets, each containing approximately 20 mg of pregn-4-ene-7a,21-dicarboxylic acid 7-ethyl ester 21 active ingredient, for example 9a,11a-epoxy-7a methyl ester as starting material, the potassium salt of 5 methoxycarbonyl-20-spirox-4-ene-3,21-dione or 9a, 1 9a,11a-epoxy-7a-ethoxycarbonyl-17G-hydroxy-3-oxo 1a-epoxy-6p3,743-methylene-20-spirox-4-ene-3,21-dione, 17 g-pregn-4-ene-21-carboxylic acid is obtained the are prepared as follows: analysis (potassium content) of which corresponds to the theoretical analysis. 10 Composition for 1000 tablets EXAMPLE 13 active ingredient, very finely ground 200 g powdered sugar (saccharose) 79.0 g With the stringent exclusion of moisture, a mixture of gum arabic 4.75 g 5.7 g of trimethylsulphoxonium iodide in 19 ml of di sorbitol 3.75 g methylsulphoxide is stirred for 1 hour at room tempera talc 2.5 g. ture with 0.82 g of a 72% (wt/v) suspension of sodium 15 magnesium stearate 4.9 g hydride in mineral oil, and 1.46 g of 9a,11a-epoxy-20 mineral oil 0.1 g spiroxa-4,6-diene-3,21-dione cf. J. Med. Chem., 6, carboxymethylcellulose (sodium salt) 5.0 g 732-735 (1963) are added thereto, rinsing out is ef fected with 1.46 ml of dimethyl sulphoxide and stirring Preparation is continued for 3.5 hours at room temperature. The 20 reaction mixture is diluted with 146 ml of ice-water, The active ingredient is mixed with the powdered acidified with dilute hydrochloric acid and extracted sugar and gun arabic, sieved and granulated by means with ethyl acetate. The organic phase is washed in suc of an approximately 35 percent aqueous sorbitol solu cession with saturated sodium chloride solution, ice tion. The granulate is forced through a sieve, dried and cold dilute sodium hydroxide solution and again with 25 again sieved, and intimately mixed with the remaining saturated sodium chloride solution, dried over sodium adjuncts (talc, magnesium stearate, mineral oil and car sulphate and concentrated by evaporation in a water-jet boxymethylcellulose sodium salt). The mixture is vacuum. The resulting amorphous crude product is pressed in the usual manner to form tablets of 120 mg. chromatographed over 100 times the amount by weight of silica gel. By eluting with a mixture of toluene/ace 30 EXAMPLE 16 tone (95:5) and concentrating by evaporation 9a,11a Gelatine capsules, each containing approximately 25 epoxy-6a,7a-methylene-20-spirox-4-ene-3,21-dione, mg of active ingredient, for example 9a,11a-epoxy m.p. 262-264 (after being dissolved and allowed to 66,79-methylene-20-spirox-4-ene-3,21-dione, are pre crystallise once from methylene chloride/ether), is ob pared in the following manner: tained. 35 EXAMPLE 14 Composition for 1000 capsules A mixture of 10 g of 9a,11a-epoxy-7a-methoxycar active ingredient, very finely ground 25g bonyl-20-spirox-4-ene-3,21-dione, 100 ml of methyl al lactose, very finely ground 25g cohol and 7.5 ml of a 4N methanolic solution of potas 40 sium hydroxide is boiled under reflux for one hour. At The active ingredient and the lactose are intimately normal pressure, approximately 80 ml are distilled off mixed, triturated and sieved, and the resulting powder is from the reaction mixture, 60 ml of ethyl acetate are introduced into gelatine capsules in portions of 50 mg added and the suspension is concentrated to approxi each. mately 20 ml in a water-jet vacuum. After diluting again 45 with 60 ml of ethyl acetate, the mixture is left to stand EXAMPLE 1.7 at room temperature for 30 minutes, whereupon the Tablets, each containing approximately 25 mg of precipitate is filtered with suction and washed out twice component A and approximately 25 mg of component with ether. The pulverulent residue is suspended in 46 B, are prepared in the following manner: ml of dimethylformamide and, after the addition of 4.6 SO ml of methyl iodide, stirred in a closed vessel for 40 hours at room temperature. After diluting with 300 ml Composition of one tablet: of ice-water, the precipitate is separated off, washed component A, micronised 25.0 mg component B, micronised 25.0 mg with water, dissolved in ethyl acetate and the solution, corn starch 50.0 mg after being dried, is concentrated by evaporation in a 55 silica, colloidal 5.0 mg water-jet vacuum. The resulting crude product is chro gelatine 5.0 mg matographed over 30 times the amount of silica gel. The cellulose, microcrystalline 75.0 mg uniform fractions eluted with a mixture of methylene sodium carboxymethyl 20.0 mg starch chloride/acetone (92:8) yield, after sprinkling with magnesium stearate 1.5 mg ether and precipitation of the resulting precipitate once 60 from methylene chloride with ether, the desired 9a, 1 306.5 mg 1a-epoxy-17A-hydroxy-3-oxo-17a-pregn-4-ene-7a,21 dicarboxylic acid dimethyl ester in amorphous form. In an analogous manner, 9a,11a-epoxy-7a-methoxy Preparation of 100,000 tablets 15,3,16p3-methylene-20-spirox-4-ene-3,21-dione can be 65 2.5 kg of component A, micronised, 2.5 kg of compo converted into 9a,11a-epoxy-17A-hydroxy-15A, 166 nent B, micronised, and 5.0 kg of corn starch are mixed methylene-3-oxo-17a-pregn-4-ene-7a,21-dicarboxylic with 0.5 kg of colloidal silica and worked up with a acid dimethyl ester. solution of 0.5 kg of gelatine in 5.0 kg of distilled water 4,559,332 29 30 (30 C) to form a moist mass. This is forced through a X represents two hydrogen atoms or oxo, sieve of 3 mm mesh width and dried at 45 C. (fluidised Y and Y2 together represent the oxygen bridge bed drier). The granulate is forced through a sieve of 0.8 -O-, or mesh width, mixed with a previously sieved mixture of Yl represents hydroxy, and 7.5 kg of microcrystalline cellulose and 2.0 kg of sodium 5 Y represents hydroxy, lower alkoxy or, if X repre carboxymethyl starch and also 0.15 kg of magnesium sents H2, also lower alkanoyloxy, stearate and pressed to form tablets weighing 306.5 mg. and salts of compounds in which X represents oxo and As component Athere is used, for example, 9a,11a Y2 represents hydroxy. epoxy-7a-(methoxycarbonyl or isopropoxycarbonyl)- 2. A compound according to claim 1, in which R2 20-spirox-4-ene-3,21-dione, 9a,11a-epoxy-6(3,7(3- 10 represents methoxycarbonyl, ethoxycarbonyl or iso methylene-20-spirox-4-ene-3,21-dione or 9a,11a-epoxy propoxycarbonyl. 66,743;156,163-bis-methylene-20-spirox-4-ene-3,21 3. A compound according to claim 1, in which R1 and dione and, as component B, 6-chloro-7-sulphanyl-3,4- R2 together represent a 6-oriented methylene radical. dihydro-1,2,4-benzothiadiazine 1,1-dioxide. 4. A compound according to claim 1, in which In an analogous manner, the following active ingredi 15 -B-B- represents the 3-oriented group ents may also be used in equivalent amounts: as component A: the potassium or sodium salt of 9a,11a-epoxy-17f -CH-CH2-CH-. hydroxy-6p3,7f8-methylene-3-oxo-17a-pregn-4-ene 20 21-carboxylic acid (50 mg) or 9a,11a-epoxy-17f 5. A compound according to claim 1, in which X hydroxy-7a-methoxycarbonyl-3-oxo-17a-pregn represents oxo. 4-ene-21-carboxylic acid (30 mg); 6. A compound according to claim 1, in which Yland as component B: Y? together represent the oxygen bridge -O-. 2-chloro-5-(3-hydroxy-1-oxo-isoindolyl-3)-benzenesul 25 7. A compound according to claim 1, in which R and phonamide or 4-(2-methylenebutyryl)-2,3-dichloro R2 together represent a methylene group, X represents phenoxyacetic acid (50 mg of each), 6-chloro-7-sul oxo and each of Yl and Y2 represents hydroxy. phamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-diox 8. An alkali metal salt of a compound according to ide (25 mg), 2-phenoxy-3-butylamino-5-carboxyben claim 7. zenesulphonamide (0.5 mg), (1-oxo-2-methyl-2-phe 30 9. A potassium salt of a compound according to claim nyl-6,7-dichloro-indanyl-5-oxy)-acetic acid (as race 7. mate 20 mg, as the laevo-form 10 mg) or 3-cyclopen 10. A compound according to claim 1, which is 9a, 1 tylmethyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4- 1a-epoxy-7a-methoxycarbonyl-20-spirox-4-ene-3,21 benzothiadiazine 1,1-dioxide (0.5 mg). dione. We claim: 35 11. A compound according to claim 1, which is 9a, 1 1. A steroid compound of the formula 1a-epoxy-7a-isopropoxycarbonyl-20-spiroX-4-ene-3,21 dione.

12. A compound according to claim 1, which is 9d, 1 (I) 1a-epoxy-6a,7a-methylene-20-spirox-4-ene-3,21-dione. 13. A compound according to claim 1, which is 9d, 1 1a-epoxy-66,7f8-methylene-20-spirox-4-ene-3,21-dione. 14. A pharmaceutical composition containing as ac tive ingredient one of the compounds defined in claim 1. 15. A pharmaceutical composition containing an ef 45 fective amount of an aldosterone-antagonistic com pound according to claim 1, and at least one diuretic which is non-specific with regard to electrolytes and in which which increases diuresis by renal and by extrarenal -A-A- represents the group -CH2-CH2- or action on tissue. -CH=CH-, 50 16. A therepeautic method for controlling hyperaldo R represents hydrogen, and steronism in humans and other warm-blooded animals, R2 represents an a-oriented lower alkoxycarbonyl comprising the administration of an effective amount of radical, or a compound according to claim 1, in the presence or R1 and R2 together represent an a- or a g-oriented absence of a pharmaceutically acceptable carrier. methylene radical, 55 17. A therapeutic method for controlling hyperaldo -B-B- represents the group -CH2-CH2- or an steronism in humans and other warm blooded animals, a- or 3-oriented group comprising the simultaneous administration of an effec tive amount of a compound according to claim i, to gether with at least one diuretic which is non-specific 60 with regard to electrolytes and which increases diuresis -CH-CH2-CH-, by renal and by extrarenal action on tissue. s e k se s

65 UNITED STATES PATENT ANDTRADEMARK OFFICE Commissioner for Patents United States Patent and Trademark Office P.O. Box 1450 Alexandria, VA 22313-1450 www.uspto.gov

MAR - 9 2007 Scott A. Williams In Re: Patent Term Extension Pharmacia Corporation of Pfizer Inc. Application for . P.O. Box 1027 - U.S. Patent No. 4,559,332 St. Louis MO 63006

Dear Mr. Williams:

A certificate under 35 U.S.C.S 156 is enclosed extending the term of U.S. Patent No. 4,559,332 for a period of 1,219 days. While a courtesy copy of this letter is being forwarded to the Food and Drug Administration (FDA), you should directly correspond with the FDA regarding any required changes to the patent expiration dates set forthin the Patent and Exclusivity Data Appendix of the Orange Book (Approved Drug Products with Therapeutic Equivalence Evaluations) or in the Patent Information set forth in the Green Book (FDA Approved Animal Drug Products). Effective August 18, 2003, patent submissions for publication in the Orange Book and Docket '95S-01 17 need to be submitted on form FDA-3542 http://www.fda.gov/opacom/morechoices/fdaforms/default.htmlwhich may be downloaded from FDA's Electronic Forms Download . Website: (http://www.fda.gov/opacom/morechoices/fdaforms/FDA-3542.pdf). Inquiries regarding this communication should be directed to the undersigned by telephone at (571) 272-7755, or by e-mail at mary.tillGuspto.gov.

ary C. Ti Legal Advisor Office of Patent Legal Administration Office of the Deputy Commissioner for Patent Examination Policy

CC Office of Regulatory Policy RE: INSPRA& (eplerenone) 5600HFD-7 Fishers Lane (Rockwall II Rm 1101) FDA Docket No.: 2003E-0254 Rockville, MD 20857 Attention: Beverly Friedman UNITED STATES PATENT AND TRADEMARK OFFICE (12) . CERTIFICATE EXTENDING PATENT TERM UNDER 35 U.S.C. S 156

(68) PATENT NO. . 4,559,332 (45) ISSUED : December 17, 1985 (75) INVENTOR : Jirgen Grob, et al. (73) PATENT OWNER Novartis Corporation (95) PRODUCT : INSPRAGR (eplerenone)

This is to certify that an application under 35 U.S.C.S 156 has been filed in the United States Patent and Trademark Office, requesting extension of the term of U.S. Patent No. 4,559,332 based upon the regulatory review of the product INSPRACE) (eplerenone) by the Food and Drug Administration. Since it appears that the requirements of the law have been met, this certificate extends the term of the patent for the period of

(94) 1,219 days from April 9, 2004, the original expiration date of the patent, subject to the payment of maintenance fees as provided by law, with all rights pertaining thereto as provided by 35 U.S.C.s 156(b).

I have caused the seal of the United States Patent and Trademark Office to be affixed this 7th day of March 2007.

Director of the United States Patent and Trademark Office