11,11-dimethyl-substituted steroids
O Umted States Patent 1191 1111 3,876,670  
 Coombs Apr. 8, 1975 [54] 11,1l-DIMETHYL-SUBSTITUTED [56] References Cited STEROIDS UNITED STATES PATENTS Inventor: Robert Coombs, Chatham. J 3,116,288 l2/l963 Fried e181. 260/239.55 3299.108 1 1967 B 260 397.5 [73] Asmgnee: 3.325.520 61967 260/3 9145 [22] Filed: Sept. 4, 1973 Primary E.\&#39;aminerHenry A. French [21] Appl&#39; 393890 Attorney, Agent, or FirmGerald D. Sharkin; Richard Related U.S. Application Data E. Vila; Frederick H. Weinfeldt [63] Continuation of Ser. No. 329.735, Feb. 5, I973,  
  57 ABSTRACT [521 [LS 260/39145; 73; 2 0 3975; ll,ll-dimethyl-substituted steroids of the gonane- 42 2 3 type, e.g. l l ,l l-dimethyl-17a-ethynylestra-4-en-l7B- 1511 1111. c1 c071; 169/08; C07c l69/22 are useful as pharmaceuticals and are [58] Field of Search /Maehine Searched Steroids mined y m p Process 22 Claims, N0 Drawings 11,ll-DIMETHYL-SUBSTITUTED STEROIDS This is a continuation of application Ser. No. 329,735, filed Feb. 5, 1973, now abandoned.  
  This invention relates to steroidal compounds, and more particularly to 11,1 l-dimethyl-substituted- I gonanes, to the preparation of such compounds and to intermediates in the preparation of such compounds, as well as to compositions containing such compounds and to the use of such compositions.  
  The compounds of the invention may be conveniently represented by the structural Formula I:  
  R K t a b wherein R is oxo, or  
  01 l o O=LJ|\ n 0 (a) wherein \llll l R ---CaCH lb OIR &#34;C i CH (CHa)2f R l alrf Compounds la may be obtained by hydrolysisrearrangement of a corresponding Compound of formula ll:  
 wherein R and R&#34; are as defined above, and R is the same as R when it is other than a hydrogen atom or alkanoyl, i.e. Step A, under relatively mild acid conditions, e.g. in acid media with pH value above about 3 and preferably between 3 and 5 for a prolonged period, e.g. for a period of 3 or more hours. An organic acid, such as oxalic acid or acetic acid may be used to provide the acidic conditions. Alternatively, the conversion of a Compound II to a Compound la may be carried out under vigorous aqueous acidic conditions,  
 (Step B) i.e. at about pH value of 3 or lower, e.g. between 1 and 2; the acidic condtions being provided by, e.g. oxalic acid, p-toluene sulfonic acid or a mineral acid, such as hydrochloric acid. The conversion is accomplished under such vigorous conditions in a relatively short time, e.g. less than 3 hours.  
  Treatment of a Compound II with the mild acidic conditions of Step A for a relatively short period of time (Step C) yields the corresponding Compound lb. A Compound lb can be converted to its corresponding Compound Ia by rearrangement, (Step D). Step D may suitably be carried out by subjecting a Compound lb to acidic or basic conditions. The process may be carried out under either aqueous or nonaqueous conditions. Steps A, B and C may be carried out at temperatures of, e.g. from about 0 to 100C., preferably from about 15 to C. An inert water-miscible solvent may be employed, such as a lower alkanol, e.g. methanol.  
  Where the acid reactant is liquid it may be employed times vary, for example from A hr. to 6 hrs. Aqueous basic conditions may conveniently be obtained by using, for example, aqueous sodium or potassium hydroxide, preferably at a concentration of from 0.01N to 2N. Where non-aqueous conditions are employed, the basic conditions are conveniently provided by using an alkali metal lower alkoxide, e.g. sodium methoxide.  
  Acidic rearrangement may suitably be carried out under the conditions described above in connection with Step B. However, the aqueous nature of the conditions, essential in Step B, are not essential in the rearrangement and, accordingly, the solvent need not be water-miscible. The preparation of Compounds lc wherein R is x0 and R is as defined above, i.e. Compounds lcl, as well as intermediates for Compounds ll, i.e. Compounds J, is conveniently represented by Reaction Scheme A below, wherein kt is a ketal group which is suitable for masking an oxo group, such as wherein each R is methyl, or they may be joined to form a short alkylene chain, e.g. having two or three carbon atoms, such as ethylene or propylene or isopropylene; and R and R are as defined above:  
 REACTION SCHEME A (Part I) A kt  Step b) i Hydrolysis Step 0) Rearrangement In the preparation of Compounds lcl, the starting materials, i.e. Compounds A, are known and their preparation is described in the literature, e.g. Belgian Pat. No. 753,779, or where not known, they may be prepared in a manner analogous to that for preparing the known compounds.  
  Step a, the introduction of a hydroxy and a methyl group at the ll-position, is achieved by reacting a Compound A with a metallo-organic reagent bearing a methyl group, e.g. a Grignard reagent, under conditions conventionally employed in carrying out a Grignard reaction. The selection of the particular reagent and reaction conditions are not critical and are within the skill of persons skilled in the art. For example, a methyl-active metal reagent may be used, wherein the active metal is an alkali metal such as lithium, sodium or potassium or a polyvalent metal, such as aluminum, or magnesium bromide or iodide. Such reagents are well-known and many are commercially available, methyl magnesium bromide and methyl lithium being preferred.  
  Step a involves two stages, i.e. a condensation stage which results in the formation of an intermediate which is the ll-methyl-ll-O- metallic salt of the resulting Compound B, the metallic cation being contributed by the metallo-organic reagent. The intermediate is then hydrolyzed to yield the free 1 l-hydroxy compound, i.e. the Compound B. The condensation may be conveniently carried out, e.g. at a temperature of from about to ,+60 C. and preferably from about 50 to +30 C. in an anhydrous aprotic solvent or medium suitable for reactions involving a metalloorganic reagent, e.g. an ether, such as tetrahydrofuran. The hydrolysis of the reaction product may be carried out in the manner conventionally used in hydrolyzing Grignard adducts, for example, in an aqueous medium, e.g. by  
 water or a highly concentrated aqueous solution of ammonium chloride or dilute aqueous acid or alkaline solution.  
 In Step b the ketal group of Compound B is cleaved by hydrolysis under aqueous acid conditions. Step b should be carried out under relatively mild acid conditions, e.g. in acid media with pH value above about 3 and preferably between 3 and 5, for a, e.g., for a period of from about A to 3 hours. An organic acid, such as oxalic acid or acetic acid may be used to provide the acidic conditions. Step b may be carried out at temperatures of, e.g. from about 0 to 100 C., preferably from about to 50 C. An inert water-miscible solvent may be employed, such as a lower alkanol, e.g. methanol.  
 Where the acid reactant is liquid it may be employed in excess to serve as solvent, e.g. acetic acid. Cosolvents may also be used.  
  Step 0 involves conversion of a Compound C to its corresponding Compound D by treatment with strong acid, i.e. rearrangement of a 901,1 l-dimethyl-l 1- hydroxy-l,3,5( l0)-triene (a Compound C) to the corresponding 1 1,1 l-dimethyl-1,3,5(l0),8-tetraene (a Compound D). Suitable acids are aryl or alkyl sulfonic acids, e.g. p-toluenesulfonic acid, or mineral acid, e.g., hydrogen chloride, sulfuric acid or phosphoric acid, except for l-lF or hydrofluoric acid. The reaction is carried out at elevated temperatures, e.g. from 75 to 160C., preferably at 100 to 140C., in an inert solvent, e.g., benzene, toluene or xylene, and preferably at the reflux temperature of the solvent. The strong acid preferably has a pKa of less than 4.0. A by-product of the reaction is water. The water should be eliminated from the reaction zone, e.g. by carrying out the reaction at a temperature at which water is boiled out of the system, or by use of an entrainer or medium, such as benzene, which forms an azeotrope with the water-ofreaction, thus removing it from the reaction zone at a temperature below the boiling point of water.  
  In step d, the 17-oxo function of a Compound D is reduced to a l7B-hydroxy, thus yielding the corresponding Compound E. The reduction may be achieved in the conventional manner for reducing a carbonyl function to a hydroxy, e.g. by use ofa complex hydride, e.g. sodium borohydride in a lower alkanol such as methanol, or lithium aluminum hydride in an ether, such as tetrahydrofuran, at moderate temperatures, e.g. 10 to 60C., preferably at 20 to 30C.  
  Step 2 involves reducing the 8(9 )-ethylenically unsaturated position of a Compound E, to obtain its corresponding Compound F, (a triene). The reduction may be accomplished, e.g. by treating at reduced temperature with liquid ammonia, aniline and an alkali metal, sodium being preferred; the reaction being carried out at temperatures at which the ammonia refluxes, e.g. cooling with dry ice. It will be noted that Compounds F are within the scope of Compounds 1c.  
  Step f involves oxidation of the 17 hydroxy function of 21 Compound F to an oxo function thus yielding a compound Icl. The oxidation may be carried out in the conventional manner for oxidizing a secondary hydroxyfunction to a carbonyl function, e.g. using the well-known Oppenauer reaction or the Jones reagent. For example, the Jones reagent may be used at, e.g.  
 r from 0 to 35C. preferably at 0 to 15C. in a suitable solvent, e.g. acetone.  
  Various Compounds 10 are suitable as intermediates in the preparation of Compounds 11, which are in turn intermediates for Compounds la and 1b, as noted above. Thus, a compound F may be reduced (Step g] to yield a Compound G, as shown in Reaction Scheme A, part II, by employing the well-known Birch reduction method which broadly involves use of a light metal, e.g. lithium, and tert.-butanol, in liquid ammonia at reduced temperatures (sufficient to maintain the ammonia in a liquid state). As the ammonia can serve as the reaction medium, no solvent is required, but can be used, e.g. benzene or tetrahydrofuran. Alternatively, a Compound Icl may be converted to its corresponding Compound G by reducing the aromatic unsaturation, i.e. the l,3,5(l0)-double bond system of ring A, to a 2,5(10)-dien system, and also reducing the l7-oxo function (Step g). If desired, the tetraene intermediates, Compounds D and E can likewise be convertec directly to a Compound G by employing the Birch reduction method (Steps g and g, respectively).  
  1n Step h, the l7-hydroxy function of a Compound G is oxidized to an oxo function, yielding the corresponding Compound J. The oxidation may be accomplished by those means conventionally used for oxidizing a secondary aliphatic hydroxy to a carbonyl, which do not involve aqueous acidic conditions, for example, by employing the so-called Oppenauer oxidation, which broadly involves oxidizing a hydroxy function in the presence of a metallic alkoxide and a ketone, e.g. aluminum isopropoxide and Z-butanone, e.g. at temperatures of about 60 to C., in an inert organic solvent, such as benzene, toluene and the like.  
  Alternatively, treatment of a Compound B by step c yields the l7-ketal form of the corresponding Compound D, which can then be hydrolyzed by step b to obtain the desired Compound D. During recovery of the product of step c from the resulting acidic reaction mixture, if a small amount of water is encountered, the resulting aqueous acidic conditions can provide the conditions of step b to achieve hydrolysis of the l7-ketal.  
  As will be appreciated, Compounds lcl or F may be converted to other Compounds lc by conventional means. R i.e. the 3-alkoxy function of a Compound 10] or F, may be cleaved by conventional means for cleaving an ether linkage to obtain the corresponding Compound 1c wherein R is H. For example, the cleavage may be carried out by heating a 3-alkoxycompound with pyridine .HCl at from about 100 to 200C, preferably at about 180C. The resulting Compound lc may then be acylated by conventional means to obtain, e.g. a corresponding Compound 1c wherein R is an alkanoyl group.  
  As noted above, Compounds 101 or J may serve as intermediates for Compounds la or 112, as may be conveniently represented by Reaction Scheme B, which follow. In Reaction Scheme B, R and R are asdefined above, and A is the same as R, but is other than a hydrogen atom, i.e. it is an alkanoyl group; Compounds la] and lbl being the same as Compounds Ia and lb, wherein R is a hydrogen atom and Compounds [a2 and 5 1b2 being the same as Compounds la and lb wherein R&#34; is alkanoyl, as defined above; while Compounds 11a and REA CTION SCHEME B O R I 2): I J  
 Step j lEthynylation&#34; OH R -\-oz CH 3) (c alzf Ha I I I p k I I kw (acylation) Rzlow Hydrolysis- Hydrolysis Rearrangementl (mild) Steps A or B \Step R CECH (CH3) Y (CI-Ia) H I /\I/ Rearrangement I I Step D A I 12&#39; I sat IDA T)A R ---o= CH ---e=on (CH3) r (CHa) EL /\I/ I I I 0.. I82 Step D o Ib2 I Steps A or B [Step 0 pH R 05011 Ibl The reduction may be accomplished in the conventional manner, e.g. under the conditions of Step d.  
  in Step j, a l7-oxo intermediate (a Compound J) is converted to its corresponding l7a-hydroxy-17B-ethynyl-substituted analog. i.e. a Compound Ila. Stepj may be accomplished by conventional methods, e.g. using a Grignard technique in which a metallo-organic reagent bearing the ethynyl group is employed. A particularly convenient method of preparing a Compound lla is to use as the metallo-organic reagent lithium acetylide/ethylenediamine complex in dimethyl sulfoxide or dimethylacetamide, under the reaction conditions of Step a.  
  In Reaction Scheme B, Stepj is shown to be applied to a Compound J. However, a Compound lc wherein R is l7B-hydroxy, l7oz-ethynyl and R is a hydrogen atom or alkyl, may be obtained by treating in a manner analogous to Step j, a Compound lc wherein R is 0x0 and R is a hydrogen atom or alkyl. A compound lc wherein each of R&#34; and R&#34; is a hydrogen atom may be obtained by reducing the l7-oxo function of a Compound lcl.  
  in Reaction Scheme B, acylation of Compounds Ia] and lbl is shown to yield the corresponding compounds wherein R is alkanoyl, as defined above. However, Compounds 10 wherein R is a hydrogen atom, as well as Compounds la, lb or lc wherein R is a hydrogen atom, i.e. Compounds I bearing a hydroxy group at any of positions 3- and 17- may be acylated to obtain those Compounds 1 wherein any of R and R is alkanoyl as defined above (Step k).  
  The Step k may be effected by processes known per se for the acylation of steroid alcohols. With respect to compounds of Class lc having two hydroxy groups, it will be noted that, a hydroxy group at the 3-position is phenolic and a hydroxy group at the l7B-position is secondary or tertiary. As one skilled in the art wilk be aware, the ease of acylation is phenolic seqondary x be chosen depending on the degree of acylation re quired employing conventional techniques. Suitable acylating agents for phenolic and/or secondary hydroxy functions include acids, acyl halides and acid anhydrides of formulae acyl-OH, acyl-Hal and (acyl)-,O, respectively, wherein acyl is alkanoyl as defined above, Hal signifies bromine or chlorine, and mixtures thereof. Where the desired acyl moiety is acetyl, a preferred acylating agent is acetic anhydride. ln carrying out the acylation, inert solvent may be employed or excess acylating agent may serve as solvent, An acid-binding agent, e.g. pyridine, is preferably used. Preferred temperatures vary between 10 and 50 C. For acylation of a tertiary hydroxy, more stringent conditions may be used, characterized by the presence of a strongly acidic catalyst, e.g. p-toluenesulphonic acid, perchloric acid and the like. If such catalysts are used, in addition to the above-listed acylating agents, enol acylates, preferably esters of isopropenyl alcohol, e.g. isopropenyl acetate, may also be employed as is recognized in the art, such acylation reactions exhibit some degree of se lectivity. Hence to obtain the 3-mono-acylated product of a 3,17B-diol, the acylation should be halted before appreciable acylation of the l7B-hydroxy function occurs. The considerations involved are well within the scope of one skilled in the art.  
  Furthermore, the diester form of Compounds 10 may be selectively saponified employing conventional means, e.g. by treatment with methanolic potassium bicarbonate, to obtain the corresponding 3-hydroxyl 7,8- acyloxy-substituted Compound 10. Hence, one skilled in the art can use such knowledge to obtain the desired combination of free hydroxy and acylated positions.  
  It will be noted that Step D, (rearrangement of a Compound lb to its corresponding Compound Ia), may be carried out under basic conditions, as well as acid conditions. As will be appreciated, subjection of a Compound 1192 to basic conditions in carrying out Step D, could result in saponification of the 178- alkanoyloxy group. Accordingly, where a Compound [a2 is desired, it is preferred to carry out Step D under acidic conditions, or to first obtain a Compound lal, which is then acylated to its corresponding Compound 1112. If desired a Compound llb may be formed and hydrolyzed via Step C to the corresponding Compound Ib2, or via Steps A or B to the corresponding Compound la2.  
  Compounds 1 are useful because they possess pharmacological properties in animals. In particular, they possess estrogenic activity and are useful in replacement therapy for estrogen deficiencies, fertility control in birds and mammals and regulation of estrus or the menstrual cycle in mammals. The estrogenic activity is indicated by conventional techniques, e.g. observing increase in white mouse uterine weight, e.g. as described in Endocrinology 65, 265 (1959) or by observing for cornification of vaginal epithelium of adult female ovariecomized White rats scored according to the method of Biggers and Claringbold, when said animals are given from 0.01 to 10 milligrams of active agent.  
  Compounds I may be combined with a solid or liquid pharmaceutically acceptable carrier or adjuvant in the conventional manner. They maybe administered orally or parenterally. For the above-mentioned uses, the dosage will vary depending upon the mode of administration utilized and the particular compound employed.  
 However, in general, satisfactory results are obtained when the compounds are given at a daily dosage of from about 0.01 milligram. to 30 milligrams for the abovedescribed pertinent uses. As is appreciated by those skilled in the art, the dosages are independent of body weight. Dosage forms suitable for internal administration comprise from about 0.01 milligram to about 30 milligrams of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent, preferably in solid orally administrable form, e.g. as tablets or capsules.  
  When Compounds I are used as menstrual function regulating agents, they may be administered alone in the manner and dosage described above, or in combination with a suitable progestational agent. Alternatively, a Compound I may be administered alone in the first part of the menstrual cycle, and in admixture with a progestational agent in the latter days of the cycle of the host, i.e. a higher primate.  
  The following examples are presented as illustrative of the invention. In the examples, all temperatures are centigrade, and room temperature is 20 to 30C., unless indicated otherwise.  
 EXAMPLE 1 11,1 1-dimethyl-3-methoxyestra-1,3,5(10)-trien-I7B- 01 Step A 901,1 la-Dimethyl-17,17-ethylenedioxy- 1 1B-hydroxy-3-methoxyestra-1,3,5( l0)-triene.  
  To a refluxing solution of 3.6 g. of 17,17- ethylenedioxy- 3-methoxy-9a-methylestra-1,3,5(10)-trien-1 l-one in 145 ml. of anhydrous tetrahydrofuran (THF), stirred under nitrogen, is added dropwise 57.5 ml. ofa 2 M solution of methyl magnesium bromide in THF over a period of 15 min. After the addition is complete, refluxing is continued for a further 2 hr. at which time the mixture is cooled in ice and saturated sodium chloride solution is added dropwise until a filterable precipitate forms. The precipitate is filtered off and washed with 250 ml. of ether. The combined ether washings and filtrate are washed with water, dried over anhydrous sodium sulfate and evaporated to give a residue which is crystallized from methanol to obtain 901,1 la-dimethyl- 17,17-ethylenedioxy-l 1,8-hydroxy-3-methoxyestra- 1,3,5(10)-triene, m.p. 107l09.  
  Step B 9a,1 la-Dimethyl-l lB-hydroxy-B-methoxyestra- 1,3,5(10)-trien-17-one A solution of 4.0 g. of the product of Step A in ml. of glacial acetic acid and 16 ml. of water is allowed to stir at room temperature for 2 hours. It is then concentrated under reduced pressure and ice is added to the residue followed by 200 ml. of ether. The ether layer is washed with 5% sodium bicarbonate solution and water, then dried and evaporated to obtain a residue which is then crystallized from ether to give 90:,1 la-dimethyl-l ll3-hydroxy-3-methoxyestra 1,3,5( 10)-trien-l7-one, m.p. 170-172.  
 Step C 1 1,1 1-dimethyl-3-methoxyestra-l,3,5( l), 8( 9 )-tetraenl 7-one A solution of 3.3 g. of 901,1 la-dimethyl-l 1B- hydroxy-3-methoxyestra-l ,3,5( 10)-trien-17-one in 225 ml. of toluene containing 585 mg. of p-toluenesulfonic acid is refluxed for 4 hours. It is then cooled and washed with 5% sodium bicarbonate solution and water, then being dried and evaporated to obtain a residue. The residue is crystallized from ether to give 1 1,1- 1-dimethyl-3-methoxyestra-1,3,5(l0), 8(9)-tetraen- 17-one., m.p. l87-190.  
 Step D 1 1,1l-dimethyl-3-methoxyestra-1,3,5(l0), 8(9)-tetraen-l7B-ol dimethyl-3-methoxyestra-1 ,3,5( 8(9)-tetraen-17B- 01. mp 96-100; (U.V. max. 278 nm, e 13,000).  
  StepE 1 1,1 1-dimethyl-3-methoxyestra-l,3,5(10)-trien-l7,B-  
 A solution of 6.3 g. of 11,11-dimethy1-3- methoxyestra-l,3,8( l0), 8(9)-tetraen-l 73-01 in 200 ml. of anhydrous THF and 100 ml. of aniline is added to 360 ml. of liquid ammonia under reflux with a dryice condenser. To this stirred mixture is added 6.3 g. of sodium in several portions over minutes and the resulting blue solution is stirred under reflux for a further 2 hours. The ammonia is then allowed to evaporate over several hours. To the residue is cautiously added 100 ml. of methanol and 250 ml. of water. The mixture is then extracted thrice with 250 ml. portions of ether and the combined ether extracts washed with 2N hydrochloric acid and then water. After drying and removal of the solvent there is obtained a residue of crude title product, characterized by its U.V. absorption maxima at 277 and 286 nm (e=1,500).  
  Repeating the procedure of this example but employing in place of the l7,17-ethylenedioxy-3-methoxy-9a methylestra-1,3,5(10)-trien-1l-one used in Step A, an equivalent amount of either a) 17,17-ethylenedioxy-3- ethoxy-9a-methylestra-l,3,5(10)-trien-1 l-one, b) 3- methoxy-17,17-propylenedioxy-9a-methylestra- 1,3,5(l0)-trien-l1-one or c) 17,17-ethylenedioxy-l3- ethyl-3-methoxy-9a-methylgona-1,3,5( 10 )-trienl l-one, there is similarly obtained a) 1 1,1 l-dimethyl-3- ethoxyestra-1,3,5(10)-trien-17[3-ol, b) 11,1 l-dimethyl- 3-methoxyestra-l,3,5(10)-trien-17B-ol and c) 11,1 1- dimethyl- 13-ethyl-3-methoxygona-l,3,5( l0)-trien- 1 713-01, spectively.  
 EXAMPLE 2 1 1,1 l-Dimethyl-3-methoxyestra-1,3,5( l0)-trienl7-one CH3 a)|( CHaO OS To an ice cold solution of 900 mg. of l 1,1 l-dimethyl- 3-methoxy-estra-1 ,3,5( l0)-trien-l7B-ol in 20 ml. of acetone is added dropwise 2 ml. of Jones reagent by which time the orange color of the reagent just persists in the reaction mixture. After standing at room temperature for 10 minutes, sufficient 5% sodium bicarbonate solution is then added to the mixture to achieve neutrality and the resulting mixture is filtered through diatomatious earth (celite). The solvents are removed under reduced pressure and the residue is dissolved in ether. The organic solution is washed with water, dried and evaported. The residue so obtained is crystallized from ether to give the title product, m.p. 7.  
  Repeating the procedure of this example, but replacing the 1 1,1l-dimethyl-3-methoxyestra-1,3,5(l0)- trien-l7B-ol with an equivalent amount of a) 11,11- dimethyl-3-ethoxyestra-1 ,3,5( 10)-trien-l 73-01 or b) 1 1,1 l-dimethyl-l 3-ethyl- 3-methoxygona-l,3,5( l0)-trien-l7/3-ol, there is similarly obtained a) 1 1,1 l-dimethyl-3-ethoxyestral,3,5( l0)-trien-l7-one and b) 11,1l-dimethyl-13- ethyl-3-methoxygona-1,3,5( 10)-triene-17-one, respectively.  
 EXAMPLE 3 1 1,1 l-Dimethyll 7a-ethynyll 7B-hydroxyestra-4-en- 3-one Step A l 1,1 l-dimethyl-3-methoxyestra-2,5( 10)-dien-1 73-01 A solution of 500 mg. of 11,11-dimethyl-3- methoxyestra-l ,3,5( l0)-trien-l7-one, obtainable by Example 2 above, in 20 ml. of THF and 6.0 ml. of ten.- butanol is added to 25 ml. of liquid ammonia maintained under reflux. To this stirred solution is added 250 mg. of lithium in several portions over 10 mins. and the resulting blue solution is allowed to reflux for 5 hours. The ammonia is then allowed to evaporate and 5.0 m1. of methanol is added to the residue, followed by 50 ml. of saturated sodium chloride solution. The mixture is extracted with ether three times and the combined organic extracts are washed with water, dried and evaporated to obtain a residue, crude 11,11- dimethyl-3-methoxyestra-2,5( l0)-dien-l 7B-ol characterized by its lack of significant U.V. absorption above 240 n.m. The crude product is used in Step B below.  
  1 3 Step B 1 1,1 1Dimethyl-3-methoxyestra-2,5(10)-dien-l7-one A mixture of 500 mg. of 11,1 1-dimethyl-3- methoxyestra-2,5( )-dien-17B-ol and 500 mg. of aluminum isopropoxide in 5.0 ml. of 2-butanone and 17 ml. of benzene is stirred and refluxed for 18 hours. At this time a further 250 mg. of aluminum isopropoxide is added along with 2.5 ml. of 2-butanone and the refluxing is continued for 5 further hours. It is then cooled, and 25 m1. of a 5% solution of sodium hydroxide is added. After stirring at room temperature for minutes, the organic layer is separated, washed with water and dried. Removal of the solvents gives a resi- I due which is crystallized from ether/hexane, 1/l, yielding 1 1,1 l-dimethyl-3-methoxyestra-2,5( 10)-dien- 17-one, m.p. 1857.  
  Step C 1 1,1 1-dimethyl-17oz-ethynyl-3-methoxyestra-2,5( l0)- dien-l7B-ol To a solution of 1.0 g. of lithium acetylide/ethylene diamine complex in 10 mg of dimethylsulfoxide is added in one portion 630 mg. of 11,1l-dimethyl-3- methoxyestra-2,5( l0)-dien-17-one. The resulting redbrown solution is stirred at room temperature for 6 hours and then poured onto ice yielding a gummy solid which is extracted with ether and the ether extract is washed with water before being dried and evaporated. The residue is crystallized from hexane/ether, 2/1, to  
 give 1 1 ,1 l-dimethyl- 1 7a-ethynyl-3-methoxyestra- 2,5(10) -dien-17a-ol, m.p. 102l06.  
  Step D l 1,1 l-dimethyl-l7a-ethynyl-17B-hydroxyestra-4-en- 3-one To a solution of 250 mg. of 11,11-dimethyl-l7aethyny1-3-methoxyestra-2,5(10)-dien-17B-ol in 10 ml. of methanol at 60 is added 3 drops of concentrated hydrochloric acid. After standing at 60 for 30 minutes the solution is poured on to ice, and the resulting precipitate is filtered off. The thus-recovered, solids are dissolved in ether and the solution is dried. Removal of the solvent gives a residue which is crystallized from ether yielding the title product, 183186.  
  Carrying out Steps A, B, C and D of this Example, but employing in place of the 11,1 1-dimethyl-3- methoxyestra-l,3,5(10)-trien-l7 one used in Step A and equivalent amount of a) 11,1 1-dimethy1-13-ethyl- 3-methoxygona-l,3,5(10)-trien-17-one or b) 11,11- dimethy1-3-methoxy- 1 3-n-propy1gonal ,3,5( 10)-trienl7-one, there is similarly obtained a) 11,11-dimethyl- 13-ethyll 7a-ethynyll 7B-hydroxygona-4-en-3-one, and b) 1 1,1 1-dimethyl-17a-ethynyl-17/3-hydroxy-l3-npropylgona-4-en-3-one, respectively.  
 EXAMPLE 4 1 1, l-dimethyl-l7a-ethynyl-17B-hydroxyestra-5( 10)- en-3-one on em ogen Carrying out the procedure of Step B of Example 1 but employing in place of the 9,1 la-dimethyl-l7,l7- ethylenedioxy-l 1,B-hydroxy-3-methoxyestral,3,5(10)-triene used therein, an equivalent amount of 1 1,1 l-dimethyl-l7a-ethynyl-3-methoxyestra-2,5( 10)- dien-l7B-ol (obtainable by Step C of Example 3) there is obtained the title product.  
 EXAMPLE 5 3-Acetoxy-l 1,1 1-dimethylestra-1,3,5( 10)-trien- 17-One CH l JO Step A l 1,1 1-dimethyl-3-hydroxyestra-1 ,3,5( 10)-trien-l7-one An intimate mixture of 2 g. pyridine hydrochloride and 300 mg. of 1 1,1 1-dimethyl-3-methoxyestral,3,5(lO)-trien-17-one is kept at for 15 minutes. After cooling, 20 m1. of water is added and the product extracted with methylene chloride. The extract is then dried over anhydrous sodium sulfate, and solvent evaporated off under vacuum to obtain 11,1l-dimethyl-3- hydroxyestra-1,3,5( l0)-trien-17-one as residue.  
  Step B 3-Acetoxy-1 1,1 1-dimethylestra-l,3,5( l0)-trien-17-one A solution of 350 mg. of the product of Step A, and of 1.2 g. of acetic anhydride in 10 ml. of pyridine is kept at 0 for 18 hours and then poured on ice-water whereupon the title product separates and is recovered.  
  Repeating the procedure of Step A, this Example but replacing the 1 1,1 1-dimethyl-3-methoxyestral,3,5(10)-trien-l7-one used in Step A with an equivalent amount of 1 1,11-dimethyl-3-methoxyestra- 1,3,5(10)-trien-l7B-ol there is obtained 11,1 1- dimethylestra-1,3,5(10)-trien-3,17B-diol.  
  Repeating the procedure of Step B of this example, but replacing the 11,11-dimethy1-3-hydroxyestra- 1,3,5 10)-trien-l 7-one, with 1 1,1 1-dimethy1-3- methoxyestra-l,3,5(10)-trien-17B-ol, there is obtained 17B-acetoxy-1 1,1 1-dimethyl-3-methoxyestra- 1,3,5(10)-triene, m.p. (from methanol) 127- EXAMPLE 6 3B,17/3-Diacetoxy-l 1,1 1-dimethylestra-1,3,5( l0)- triene 340 mg. of 11,1 1-dimethylestra-l,3,5(10)-trien- 3,17B-diol is dissolved in 3 ml. of acetic acid-acetic anhydride (2:1 and after addition of 300 mg. of p-toluenesulfonic acid monohydrate, kept at 25 for 24 hours. The reaction mixture is then poured on icewater, stirred until the excess acetic anhydride hydrolyzed. The product, i.e. 3B,l7B-di-acetoxy-11,1 l-dimethylestra-1,3,5(10)-triene is isolated by extraction with methylene chloride, drying the extract over anhydrous sodium sulfate, filtering, and evaporation off the solvent from the filtrate to obtain the product as residue.  
  Repeating this example but replacing the 11.11- dimethylestra-l,3,5(l)-trien-3,l7B-diol with an equivalent amount of ll,ll-dimethyl-l7a-ethynyll7/3-hydroxyestra-4-en-3-one, there is obtained 17B- acetoxy-l l,l l-dimethyl-l 7a-ethynylestra-4-en-3-one.  
 EXAMPLES 7 and 8 Tablets and Capsules Suitable for Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating estrogen deficiency at a dose of one tablet or capsule daily.  
 What is claimed is: l. A compound of the formula wherein R is alkyl having from one to three carbon atoms; and wherein R&#34; is a hydrogen atom, or ethynyl, and R&#34; is a hydrogen atom, or alkanoyl having from two to four carbon atoms; and ring A has the structure l O! O- 0- R20 wherein R is a hydrogen atom, alkyl having from one to four carbon atoms, or alkanoyl having from two to four carbon atoms; provided that when ring A is of type (a) or (b) then R is not 0x0 or llllll l 2. A compound of claim 1 wherein ring A is of type (a). 3. A compound of Claim 2 wherein R is methyl.  
  4. The compound ofclaim 3 which is l 1,1 l-dimethyll7a-ethynyll 7B-hydroxyestra-4-en-3-one.  
 5. A compound of claim 1 wherein ring A is of type (b).  
 6. A compound of claim 5 wherein R is methyl.  
 7. A compound of claim 1 wherein ring A is of type (c).  
 8. A compound of claim 7 wherein R is methyl.  
 9. A compound of claim 8 wherein R is methyl.  
  10. The compound of claim 9 which is 11,1 1- dimethyl-3-methoxyestral ,3,5( l0)-trien-17B-ol.  
  11. The compound of claim 9 which is 11,1 1- dimethyl-3-methoxyestra-l ,3,5( 10 )-trienl 7-one.  
  12. The compound of claim 9 which is l7B-acetoxyl 1,1 l-dimethyl-3-methoxyestra-l,3,5( l0)-triene.  
 13. A compound of formula Wheretn Q is 0x0 or E R is alkyl having from one to three carbon atoms; and  
 R is alkyl having from one to four carbon atoms.  
  14. The compound of claim 13 which is 1l,lldimethyl-3-methoxyestra-l,3,5(10), 8(9 )-tetraenl7-one.  
  15. The compound of claim 13 which is 11,11- dimethyl-3-methoxyestra-1,3,5( l0),8(9)-tetraen-l7B- ol.  
 16. A compound of the formula R is alkyl having from one to four carbon atoms. 17. The compound of claim 16 which is 11.11- dimethyl-3-methoxyestra-2,5( l0)-dienl 7-one.  
  18. The compound of claim 16 which is ll,1l- 5 cllilnligetlliyll 7a-ethynyl-3-methoxyestra-2,5( l0)-dienl7 18 19. A method of preparing a compound of the foratoms, with a strong acid at an elevated temperature. mula 20. A compound of the formula --H (CH3) 5 (CH3). W l R C- wherein R and R are as defined in claim 13, which f comprises treating a Compound of the formula: R s alkyl having from one to three carbon atoms; and l 5 R is alkyl having from one to four carbon atoms. K 21. The compound of claim which is l l,] l- H dimethyl-3-methoxyestra-2,5( l0)-dien- 1 713-01.  
 HO HaC\/ 22. A compound of the formula 0A s)e( W m&#39;o wherein R and R are as defined above and K is 0x0 or l a ketal function of the formula m I wherein R is alkyl having from one to three carbon atoms;  
  R is alkyl having from one to four carbon atoms; wherein each of R is methyl, or they may be joined to and form an alkylene chain having two to three carbon A is alkanoyl having from two to four carbon atoms.