Bioavailable prodrugs of androgenic steroids and related method

Abstract

A compound is provided for increasing the concentration of a parent androgen in a subject in vivo. The parent androgen has a skeletal structure including a 1 position and a 17 position, a 17β-hydroxy group comprising a 17β-hydroxy oxygen appended to the 17 position, and a 17β-hydroxy hydrogen appended to the 17β-hydroxy oxygen. The compound includes a substrate having the skeletal structure of the parent androgen. It includes a 1 position and a 17 position corresponding to the 1 and 17 positions respectively of the parent androgen. The substrate has a carbon-carbon double bond at the 1 position. The compound also has a promoiety appended to the 17β-hydroxy oxygen of the substrate as a substitute for the 17β-hydroxy hydrogen of the parent androgen. The promoiety includes, and preferably consists of, an alkylcarbonate ester. A related method also is provided.

1 . A composition for increasing the concentration of a parent androgen in a subject in vivo, the parent androgen having a skeletal structure including a 1 position and a 17 position and the parent androgen further having a 17β-hydroxy group comprising a 17β-hydroxy oxygen appended to the 17 position and a 17β-hydroxy hydrogen appended to the 17β-hydroxy oxygen, the composition comprising: 
 a substrate having the skeletal structure of the parent androgen comprising a 1 position and a 17 position corresponding to the 1 and 17 positions respectively of the parent androgen, the substrate comprising a carbon-carbon double bond at the 1 position; and    a promoiety appended to the 17β-hydroxy oxygen of the substrate as a substitute for the 17β-hydroxy hydrogen of the parent androgen, the promoiety comprising an alkylcarbonate ester.    
     
     
         2 . (canceled)  
     
     
         3 . A composition as set forth in  claim 1 , wherein the substrate has the skeletal structure of the parent androgen and wherein the parent androgen is selected from the group consisting of 5α-estr-1-ene-3α,17β-diol and 5α-estr-1-ene-3β,17β-diol.  
     
     
         4 . A composition as set forth in  claim 1 , wherein the substrate has the skeletal structure of the parent androgen and wherein the parent androgen comprises 17β-hydroxy-5α-androst-1-ene-3-one.  
     
     
         5 . A composition as set forth in  claim 1 , wherein the substrate has the skeletal structure of the parent androgen and wherein the parent androgen is selected from the group consisting of 17β-hydroxyandrost-1,4-diene-3-one, 17β-hydroxy-5α-estr-1,4-diene-3-one, and 17β-hydroxy-5α-estr-1-ene-3-one.  
     
     
         6 . A composition as set forth in  claim 1 , wherein the alkylcarbonate ester has an alkyl chain length of less than 12.  
     
     
         7 . A composition as set forth in  claim 1 , wherein the alkylcarbonate ester is selected from the group consisting of methyl carbonate, ethyl carbonate, propyl carbonate, isopropyl carbonate, butyl carbonate, isobutyl carbonate, t-butyl carbonate, valeryl carbonate, hexyl carbonate, heptyl carbonate, octyl carbonate, nonyl carbonate, decyl carbonate, dodecyl carbonate, undecyl carbonate, dodecyl carbonate, cyclopentyl methyl carbonate, cyclopentylpropyl carbonate, cyclohexyl methyl carbonate, cyclohexylpropyl carbonates and mixtures thereof.  
     
     
         8 . A composition as set forth in  claim 1 , wherein the composition comprises 17β-hydroxy-5α-androst-1-ene-3-one 17β-alkylcarbonate.  
     
     
         9 . (canceled)  
     
     
         10 . A composition as set forth in  claim 1 , wherein the composition comprises 17β-hydroxyandrost-1,4-diene-3-one 17β-alkycarbonate.  
     
     
         11 . A composition as set forth in  claim 1 , wherein the composition comprises 17β-hydroxyandrost-1,4-diene-3-one 17β-ethylcarbonate.  
     
     
         12 . A as set forth in  claim 1 , wherein the composition comprises 17β-hydroxy-5α-estr-1-ene-3-one 17β-alkylcarbonate.  
     
     
         13 . A composition as set forth in  claim 1 , wherein the composition comprises 17β-hydroxyestr-1-ene-3-one 17β-ethylcarbonate.  
     
     
         14 . A composition as set forth in  claim 1 , wherein the composition comprises 17β-hydroxyestr-1,4-diene-3-one 17β-alkycarbonate.  
     
     
         15 . A as set forth in  claim 1 , wherein the composition comprises 17β-hydroxyestr-1,4-diene-3-one 17β-ethylcarbonate.  
     
     
         16 . A composition as set forth in  claim 1 , wherein the composition comprises 5α-androst-1-ene-3,17β-diol 17β-alkylcarbonate.  
     
     
         17 . A composition as set forth in  claim 1 , wherein the composition comprises 5α-androst-1-ene-3,17β-diol 17β-ethylcarbonate.  
     
     
         18 . (canceled)  
     
     
         19 . (canceled)  
     
     
         20 . A composition as set forth in  claim 1 , further including a carrier.  
     
     
         21 . A composition as set forth in  claim 1 , wherein the carrier comprises a solid carrier.  
     
     
         22 . A composition as set forth in  claim 1 , wherein the carrier comprises a liquid carrier.  
     
     
         23 . A composition as set forth in  claim 1 , wherein the carrier comprises a semi-solid carrier.  
     
     
         24 . A method for increasing the concentration of a parent androgen in a subject in vivo, the parent androgen having a skeletal structure including a 1 position and a 17 position and the parent androgen further having a 17β-hydroxy group comprising a 17β-hydroxy oxygen appended to the 17 position and a 17β-hydroxy hydrogen appended to the 17β-hydroxy oxygen, the method comprising: 
 administering to the subject a composition comprising a substrate and a promoiety, the substrate having the skeletal structure of the parent androgen comprising a 1 position and a 17 position corresponding to the 1 and 17 positions respectively of the parent androgen, and the substrate comprising a carbon-carbon double bond at the 1 position, the promoiety being appended to the 17β-hydroxy oxygen of the substrate as a substitute for the 17β-hydroxy hydrogen of the parent androgen, the promoiety comprising an alkylcarbonate ester; and    converting the composition in vivo into the parent androgen.    
     
     
         25 . A method as set forth in  claim 24 , wherein the subject is a human being and the in vivo conversion comprises converting the composition into the parent androgen in vivo within the human being.  
     
     
         26 . A method as set forth in  claim 24 , wherein the substrate has the skeletal structure of the parent androgen and wherein the parent androgen is selected from the group consisting of 5α-androst-1-ene-3α,17β-diol and 5α-androst-1-ene-3β,17β-diol.  
     
     
         27 . A method as set forth in  claim 24 , wherein the substrate has the skeletal structure of the parent androgen and wherein the parent androgen is selected from the group consisting of 5α-estr-1-ene-3α,17β-diol and 5α-estr-1-ene-3β,17β-diol.  
     
     
         28 . A method as set forth in  claim 24 , wherein the substrate has the skeletal structure of the parent androgen and wherein the parent androgen comprises 17β-hydroxy-5α-androst-1-ene-3-one.  
     
     
         29 . A method as set forth in  claim 24 , wherein the substrate has the skeletal structure of the parent androgen and wherein the parent androgen is selected from the group consisting of 17β-hydroxyandrost-1,4-diene-3-one, 17β-hydroxyestr-1,4-diene-3-one, and 17β-hydroxy-5α-estr-1-ene-3-one.  
     
     
         30 . A method as set forth in  claim 24 , wherein the alkylcarbonate ester has an alkyl chain length of less than 12.  
     
     
         31 . A method as set forth in  claim 24 , wherein the alkylcarbonate ester is selected from the group consisting of methyl carbonate, ethyl carbonate, propyl carbonate, isopropyl carbonate, butyl carbonate, isobutyl carbonate, t-butyl carbonate, valeryl carbonate, hexyl carbonate, heptyl carbonate, octyl carbonate, nonyl carbonate, decyl carbonate, undecyl carbonate, dodecyl carbonate, cyclopentyl methyl carbonate, cyclopentylpropyl carbonate, cyclohexyl methyl carbonate, cyclohexylpropyl carbonate, and mixtures thereof.  
     
     
         32 . A method as set forth in  claim 24 , wherein the composition comprises 17β-hydroxy-5α-androst-1-ene-3-one 17β-alkylcarbonate.  
     
     
         33 . A method as set forth in  claim 24 , wherein the composition comprises 17β-hydroxy-5α-androst-1-ene-3-one 17β-ethylcarbonate.  
     
     
         34 . A method as set forth in  claim 24 , wherein the composition comprises 17β-hydroxyandrost-1,4-diene-3-one 17β-alkycarbonate.  
     
     
         35 . A method as set forth in  claim 24 , wherein the composition comprises 17β-hydroxyandrost-1,4-diene-3-one 17β-ethylcarbonate.  
     
     
         36 . A method as set forth in  claim 24 , wherein the composition comprises 17β-hydroxy-5α-estr-1-ene-3-one 17β-alkylcarbonate.  
     
     
         37 . A method as set forth in  claim 24 , wherein the composition comprises 17β-hydroxy-5α-estr-1-ene-3-one 17β-ethylcarbonate.  
     
     
         38 . A method as set forth in  claim 24 , wherein the composition comprises 17β-hydroxyestr-1,4-diene-3-one 17β-alkycarbonate.  
     
     
         39 . A method as set forth in  claim 24 , wherein the composition comprises 17β-hydroxyestr-1,4-diene-3-one 17β-ethylcarbonate.  
     
     
         40 . A method as set forth in  claim 24 , wherein the composition comprises 5α-androst-1-ene-3,17β-diol 17β-alkylcarbonate.  
     
     
         41 . A method as set forth in  claim 24 , wherein the composition comprises 5α-androst-1-ene-3,17β-diol 17β-ethylcarbonate.  
     
     
         42 . A method as set forth in  claim 24 , wherein the composition comprises 5α-androst-1-ene-3,17β-diol 3,17β-di(alkylcarbonate).  
     
     
         43 . A method as set forth in  claim 24 , wherein the composition comprises 5α-androst-1-ene-3,17β-diol 3,17β-di(ethylcarbonate).  
     
     
         44 . A method as set forth in  claim 24 , wherein the composition administration comprises peroral administration.  
     
     
         45 . A method as set forth in  claim 24 , wherein the composition administration comprises pernasal administration.  
     
     
         46 . A method as set forth in  claim 24 , wherein the composition administration comprises transdermal administration.  
     
     
         47 . A method as set forth in  claim 24  wherein the composition administration comprises injecting the composition into the subject.  
     
     
         48 . A method as set forth in  claim 24 , wherein the composition administration comprises administering the composition sublingually.  
     
     
         49 . A method as set forth in  claim 24 , wherein the composition administration comprises complexing the composition with an hydroxypropyl beta cyclodextrin.  
     
     
         50 . A method as set forth in  claim 24 , wherein the composition administration comprises complexing the composition with an hydroxypropyl gamma cyclodextrin.  
     
     
         51 . A method as set forth in  claim 24 , wherein the composition administration comprises administering a dosage periodically for a maximum of two weeks, followed by at least two weeks of non-administration to permit recovery of natural parent androgen production in the subject.  
     
     
         52 . A method as set forth in  claim 24 , wherein the composition administration comprises administering the composition only in morning-time.  
     
     
         53 . A method as set forth in  claim 24 , wherein the composition administration comprises administering the composition in an amount ranging from 1.0 mg to 1000 mg per day.  
     
     
         54 . A method as set forth in  claim 24 , wherein the composition administration comprises administering the composition in an amount ranging from 50 mg to 500 mg per day.  
     
     
         55 . A method as set forth in  claim 24 , wherein the administration comprises administering the composition in an amount ranging from 100 mg to 400 mg per day.  
     
     
         56 . A method as set forth in  claim 24 , wherein the composition administration further includes applying an enteric coating to the composition prior to administering the composition.