METHOD OF MAKING AND USING 7alpha,11beta-DIMETHYL-17beta-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.

1 - 38 . (canceled) 
   
   
       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 
     
       
         
         
             
             
         
       
     
   
   
       42 . A compound of formula 7 
     
       
         
         
             
             
         
       
     
   
   
       43 . A compound of formula 9 
     
       
         
         
             
             
         
       
     
   
   
       44 - 45 . (canceled) 
   
   
       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-17β-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 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate and a pharmaceutically-acceptable carrier. 
   
   
       76 . The oral dosage formulation of  claim 75 , 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 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) reducing the carbonyl group at C17 and ketalizing the carbonyl group at C3 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 11α- and 11β-methyl isomers, Compounds 6a and 6b, respectively) by use of a Grignard reagent; 
     
     
       
         
         
             
             
         
       
       (e) deketalizing and dehydrating Compound 6 to provide Compound 7; 
     
     
       
         
         
             
             
         
       
       (f) converting Compound 7a to Compound 9; 
     
     
       
         
         
             
             
         
       
       (g) converting Compound 9 to Compound 10; and 
     
     
       
         
         
             
             
         
       
       (h) esterifying Compound 10 to provide Compound II 
     
     
       
         
         
             
             
         
       
     
   
   
       82 . 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate (Compound II) in crystalline form. 
   
   
       83 . The compound of  claim 82 , having a m.p. of 62-64° C. 
   
   
       84 . The compound of  claim 82 , wherein the purity of the crystalline 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate is at least 99%. 
   
   
       85 . The oral dosage form of  claim 75 , wherein the formulation comprises up to about 75 mg of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate. 
   
   
       86 . The aqueous formulation of  claim 79 , wherein the formulation comprises up to about 600 mg of 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate.