Methods of making and using 7a,11b-dimethyl-17b-hydroxy-4-estren-3-one 17b-trans-4-n-butylcyclohexane carboxylate and 7a,11b-dimethyl-17b-hydroxyestr-4-en-3-one 17-undecanoate

Abstract

Methods of using 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate (I) and 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate (II) for various hormonal therapies, dosage forms comprising 7α, 11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate and 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate, and processes for their preparation.

We claim as our invention:  
     
         1 . A method for providing hormonal therapy to a patient comprising the oral administration of up to about 25 mg/day of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate to a patient in need thereof.  
     
     
         2 . The method of  claim 1 , wherein the hormonal therapy continues at least 3 months.  
     
     
         3 . The method of  claim 1 , wherein the hormonal therapy is the treatment of hypogonadism in a male patient.  
     
     
         4 . The method of  claim 3 , wherein up to about 20 mg/day of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is administered to the patient.  
     
     
         5 . The method of  claim 4 , wherein up to about 15 mg/day of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is administered to the patient.  
     
     
         6 . The method of  claim 1 , wherein hormonal therapy is male contraception.  
     
     
         7 . The method of  claim 6 , wherein the therapy continues for at least 3 months.  
     
     
         8 . The method of  claim 6 , wherein up to about 20 mg/day of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is administered to the patient.  
     
     
         9 . The method of  claim 6 , wherein up to about 15 mg/day of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is administered to the patient.  
     
     
         10 . The method of  claim 6 , further comprising the administration of estrogen, a progestin, or both.  
     
     
         11 . The method of  claim 1 , wherein the hormone therapy is the promotion and maintenance of muscle mass in a patient.  
     
     
         12 . The method of  claim 11 , wherein the therapy continues for at least 3 months.  
     
     
         13 . The method of  claim 1 , wherein the hormonal therapy is the pilliative treatment of breast cancer in women.  
     
     
         14 . The method of  claim 1 , wherein the 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is administered as a formulation comprising 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate and an oily carrier.  
     
     
         15 . A method for providing hormonal therapy to a patient comprising administering parenterally to the patient an average dosage of up to about 400 mg/month of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate during the treatment period.  
     
     
         16 . The method of  claim 15 , wherein 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is parenterally administered as a formulation comprising 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate as a solid and an aqueous carrier, with the amount of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate administered at each interval being selected so that the average amount of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate administered during the period of hormonal treatment averages up to about 50 mg/week.  
     
     
         17 . The method of  claim 16 , wherein the 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is crystalline and the formulation comprises a suspension of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate in the aqueous carrier.  
     
     
         18 . The method of  claim 15 , wherein 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is parenterally administered as a formulation comprising 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate and an aqueous carrier, with up to about 200 mg of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate being administered once over a period of no less than about 1 month.  
     
     
         19 . The method of  claim 15 , wherein 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is parenterally administered as a formulation comprising 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate and an aqueous carrier, and wherein up to about 400 mg of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is administered once over a period no less than about 2 months.  
     
     
         20 . The method of  claim 15 , wherein 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is parenterally administered as a formulation comprising 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate and an aqueous carrier, and wherein up to about 600 mg of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is administered once over a period of no less than about 3 months.  
     
     
         21 . The method of  claim 15 , wherein 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is parenterally administered as a formulation comprising 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate and an aqueous carrier, and wherein up to about 100 mg of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is administered once over a period of no less than about 2 weeks.  
     
     
         22 . The method of  claim 15 , wherein the hormonal treatment is the treatment of hypogonadism in male patients.  
     
     
         23 . The method of  claim 15 , wherein the 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is administered in a parenteral formulation comprising 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate and an aqueous carrier.  
     
     
         24 . The method of  claim 15 , wherein from about 150 mg to about 450 mg of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is patenterally administered once at intervals of at least about 1 month.  
     
     
         25 . The method of  claim 24 , wherein the 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is parenterally administered once at intervals of at least about 2 months.  
     
     
         26 . The method of  claim 25 , wherein the 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is parenterally administered once at intervals of at least about 3 months.  
     
     
         27 . The method of  claim 15 , wherein the hormonal treatment is male contraception.  
     
     
         28 . The method of  claim 27 , wherein 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is parenterally administered up to about 200 mg/week.  
     
     
         29 . The method of  claim 27 , further comprising the administration of contraception-effective amounts of estrogen, progestins or mixtures thereof, wherein 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is parenterally administered up to about 100 mg at intervals of at least about 2 weeks.  
     
     
         30 . The method of  claim 29 , wherein 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is parenterally administered up to about 75 mg at intervals of at least about 2 weeks.  
     
     
         31 . An oral dosage formulation comprising up to about 25 mg of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate and a pharmaceutically-acceptable carrier.  
     
     
         32 . The oral dosage formulation of  claim 31 , wherein the pharmaceutically-acceptable carrier comprises an oil.  
     
     
         33 . The oral dosage formulation of  claim 32 , wherein the formulation comprises up to about 20 mg of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate.  
     
     
         34 . The oral dosage formulation of  claim 33 , wherein the formulation comprises up to about 15 mg of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate.  
     
     
         35 . An aqueous formulation for parenteral administration comprising up to about 300 mg of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate and water.  
     
     
         36 . The aqueous formulation of  claim 35 , wherein the 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate is in crystalline form.  
     
     
         37 . A method for preparing 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate comprising the steps of: 
 (a) converting the ether group of Compound 1  
                     
 to a carbonyl group, providing Compound 2  
                     
 (b) ketalizing the carbonyl group of Compound 2 to provide Compound 4;  
                     
 (c) epoxidizing Compound 4 to provide the epoxide of Compound 5;  
                     
 (d) opening the epoxide ring in Compound 5 and substituting an alkyl group at C 11  to provide Compound 6 (comprising a mixture of 7α- and 7β-methyl isomers, Compounds 6a and 6b, respectively) by use of a Grignard reagent;  
                     6a: R=alpha-Me    6b: R=beta-Me    
 (e) deketalizing and dehydrating Compound 6 to provide Compound 7;  
                     7a: R=alpha-Me    7b: R=beta-Me    
 (f) converting Compound 7a to Compound 9;  
                     
 (g) converting Compound 9 to Compound 10; and  
                     
 (h) esterifying Compound 10 to provide Compound I (7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate).  
                     
 
     
     
         38 . The process of  claim 37 , further comprising, prior to step (f), ketalizing the isomers of Compound 7 to provide Compound 8  
       
         
           
           
               
               
           
         
         and subsequently deketalizing Compound 8 followed by epimerization, wherein the ratio of the 11β-methyl isomer (Compound 7b) to the 11α-methyl isomer (Compound 7a) is increased.  
       
     
     
         39 . A crystalline compound of formula 10  
       
         
           
           
               
               
           
         
         having a melting point of 155-157° C.  
       
     
     
         40 . A compound of formula 5  
       
         
           
           
               
               
           
         
       
     
     
         41 . A compound of formula 6  
       
         
           
           
               
               
           
         
         6a: R=alpha-Me  
         6b: R=beta-Me.  
       
     
     
         42 . A compound of formula 7  
       
         
           
           
               
               
           
         
         7a: R=alpha-Me  
         7b: R=beta-Me.  
       
     
     
         43 . A compound of formula 9  
       
         
           
           
               
               
           
         
       
     
     
         44 . A crystalline compound of formula I  
       
         
           
           
               
               
           
         
         having a melting point of 130-132° C.  
       
     
     
         45 . The compound of  claim 42 , wherein the purity of crystalline Compound I is at least 99%.  
     
     
         46 . A method for providing hormonal therapy to a patient comprising the oral administration of up to about 75 mg/day of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate to a patient in need thereof.  
     
     
         47 . The method of  claim 46 , wherein the hormonal therapy continues at least 3 months.  
     
     
         48 . The method of  claim 46 , wherein the hormonal therapy is the treatment of hypogonadism in a male patient.  
     
     
         49 . The method of  claim 48 , wherein up to about 50 mg/day of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3 -one 17-undecanoate is administered to the patient.  
     
     
         50 . The method of  claim 49 , wherein up to about 25 mg/day of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is administered to the patient.  
     
     
         51 . The method of  claim 46 , wherein hormonal therapy is male contraception.  
     
     
         52 . The method of  claim 51 , wherein the therapy continues for at least 3 months.  
     
     
         53 . The method of  claim 51 , wherein up to about 50 mg/day 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is administered to the patient.  
     
     
         54 . The method of  claim 51 , wherein up to about 30 mg/day of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is administered to the patient.  
     
     
         55 . The method of  claim 51 , further comprising the administration of estrogen, a progestin, or both.  
     
     
         56 . The method of  claim 46 , wherein the hormone therapy is the promotion and maintenance of muscle mass in a patient.  
     
     
         57 . The method of  claim 56 , wherein the therapy continues for at least 3 months.  
     
     
         58 . The method of  claim 46 , wherein the hormonal therapy is the pilliative treatment of breast cancer in women.  
     
     
         59 . The method of  claim 47 , wherein 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is administered as a formulation comprising 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate and an oily carrier.  
     
     
         60 . A method for providing hormonal therapy to a patient comprising administering parenterally to the patient an average dosage of up to about 600 mg/month of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate during the treatment period.  
     
     
         61 . The method of  claim 60 , wherein 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is parenterally administered as a formulation comprising 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate as a solid and an aqueous carrier, with the amount of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate administered at each interval being selected so that the average amount of 7α,11β-dimethyl-17α-hydroxyestr-4-en-3-one 17-undecanoate administered during the period of hormonal treatment averages up to about 50 mg/week.  
     
     
         62 . The method of  claim 61 , wherein 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is crystalline and the formulation comprises a suspension of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate in the aqueous carrier.  
     
     
         63 . The method of  claim 60 , wherein 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is parenterally administered as a formulation comprising 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate and an aqueous carrier, with up to about 600 mg of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate being administered once over a period of at least about 1 month.  
     
     
         64 . The method of  claim 60 , wherein 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is parenterally administered as a formulation comprising 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate and an aqueous carrier, with up to about 450 mg of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate being administered once over a period of at least about 2 months.  
     
     
         65 . The method of  claim 60 , wherein 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is parenterally administered as a formulation comprising 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate and an aqueous carrier, with up to about 300 mg of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate being administered once over a period of at least about 3 months.  
     
     
         66 . The method of  claim 60 , wherein the hormonal treatment is the treatment of hypogonadism in male patients.  
     
     
         67 . The method of  claim 61 , wherein 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is administered in a parenteral formulation comprising 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate and an aqueous carrier.  
     
     
         68 . The method of  claim 67 , wherein from about 150 mg to about 450 mg of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is patenterally administered once over a period of at least about 1 month.  
     
     
         69 . The method of  claim 68 , wherein 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is parenterally administered once over a period of at least about 2 months.  
     
     
         70 . The method of  claim 67 , wherein 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is parenterally administered once over a period of at least about 3 months.  
     
     
         71 . The method of  claim 60 , wherein the hormonal treatment is male contraception.  
     
     
         72 . The method of  claim 71 , wherein 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is parenterally administered at an average dosage of up to about 200 mg/week.  
     
     
         73 . The method of  claim 71 , further comprising the administration of contraception-effective amounts of estrogen, progestins or mixtures thereof, wherein 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is parenterally administered up to about 100 mg at intervals of at least about 2 weeks.  
     
     
         74 . The method of  claim 73 , wherein 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is parenterally administered up to about 75 mg at intervals of at least about 1 month.  
     
     
         75 . An oral dosage formulation comprising up to about 75 mg of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate and a pharmaceutically-acceptable carrier.  
     
     
         76 . The oral dosage formulation of  claim 50 , wherein the pharmaceutically-acceptable carrier comprises an oil.  
     
     
         77 . The oral dosage formulation of  claim 76 , wherein the formulation comprises up to about 25 mg of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate.  
     
     
         78 . The oral dosage formulation of  claim 77 , wherein the formulation comprises up to about 15 mg of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate.  
     
     
         79 . An aqueous formulation for parenteral administration comprising up to about 600 mg of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate and water.  
     
     
         80 . The aqueous formulation of  claim 79 , wherein 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is in crystalline form.  
     
     
         81 . A method for preparing 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate (Compound II) comprising the steps of: 
 (a) converting the ether group of Compound 1  
                     
 to a carbonyl group, providing Compound 2  
                     
 (b) ketalizing the carbonyl group of Compound 2 to provide Compound 4;  
                     
 (c) epoxidizing Compound 4 to provide the epoxide of Compound 5;  
                     
 (d) opening the epoxide ring in Compound 5 and substituting an alkyl group at C 11  to provide Compound 6 (comprising a mixture of 7α- and 7β-methyl isomers, Compounds 6a and 6b, respectively) by use of a Grignard reagent;  
                     
 6a: R=alpha-Me  
 6b: R=beta-Me  
 (e) deketalizing and dehydrating Compound 6 to provide Compound 7;  
                     
 7a: R=alpha-Me  
 7b: R=beta-Me  
 (f) converting Compound 7a to Compound 9;  
                     
 (g) converting Compound 9 to Compound 10; and  
                     
 (h) esterifying Compound 10 to provide Compound II  
                     
 
     
     
         83 . 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate (Compound II) in crystalline form.  
     
     
         84 . The compound of  claim 83 , having a m.p. of 62-64° C.  
     
     
         85 . The compound of  claim 83 , wherein the purity of the crystalline 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is at least 99%.