Isolated Isomers of Norelgestromin and Methods of Making and Using the Same

Abstract

The invention is directed to a process of preparing substantially pure d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-3E- and -3Z-oxime isomers, as well as a process for the synthesis of the mixture of isomers and the pure isomers. The invention also relates to substantially pure d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene20-yn-3-one-3E-oxime and substantially pure d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-3Z-oxime isomer. Further aspects of the invention include a composition comprising substantially pure d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene20-yn-3-one-3E-oxime or substantially pure d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-3Z-oxime isomer, and methods of treatment using said compositions.

1 - 20 . (canceled) 
   
   
       21 . A process for preparing norelgestromin, comprising hydrolyzing the acetate group at position 17 of the 3E- or 3Z-isomer of norgestimate in alcoholic solvent with an equivalent of alkali metal hydroxide. 
   
   
       22 . The process according to  claim 21 , further comprising recrystallizing the norelgestromin. 
   
   
       23 . The process according to  claim 21 , wherein the norgestimate is substantially pure 3Z-norgestimate. 
   
   
       24 . The process according to  claim 21 , wherein the norgestimate is substantially pure 3E-norgestimate. 
   
   
       25 . The process according to  claim 21 , wherein the hydrolysis is carried out at a temperature of about 5° C. to about 30° C.; the alkali metal is lithium hydroxide monohydrate; and the solvent is methanol. 
   
   
       26 . Isolated, substantially pure d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-(3E)-oxime suitable for use in a pharmaceutical composition. 
   
   
       27 . Isolated, substantially pure d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-(3Z)-oxime suitable for use in a pharmaceutical composition. 
   
   
       28 . A pharmaceutical composition comprising the substantially pure d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-(3E)-oxime of  claim 26 , and a pharmaceutically acceptable carrier. 
   
   
       29 . The pharmaceutical composition according to  claim 28 , wherein said composition contains less than 5% of d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-(3Z)-oxime. 
   
   
       30 . The pharmaceutical composition according to  claim 28 , wherein said composition contains less than 2% of d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-(3Z)-oxime. 
   
   
       31 . The pharmaceutical composition according to  claim 28 , wherein said composition contains less than 1% of d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-(3Z)-oxime. 
   
   
       32 . The pharmaceutical composition according to  claim 28 , wherein said carrier is selected from the group consisting of excipients, diluents, stabilizers, flavoring additives, aromatizing additives, formulation-promoting additives, formulation-providing additives, and combinations thereof. 
   
   
       33 . The composition according to  claim 28 , wherein said composition is a patch. 
   
   
       34 . The composition according to  claim 28 , wherein said composition is an oral dosage form. 
   
   
       35 . A pharmaceutical composition comprising the substantially pure d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-)3Z)-oxime of  claim 27 , and a pharmaceutically acceptable carrier. 
   
   
       36 . The pharmaceutical composition according to  claim 35 , wherein said composition contains less than 5% of d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-(3E)-oxime. 
   
   
       37 . The pharmaceutical composition according to  claim 35 , wherein said composition contains less than 2% of d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-(3E)-oxime. 
   
   
       38 . The pharmaceutical composition according to  claim 35 , wherein said composition contains less than 1% of d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-(3E)-oxime. 
   
   
       39 . The pharmaceutical composition according to  claim 35 , wherein said carrier is selected from the group consisting of excipients, diluents, stabilizers, flavoring additives, aromatizing additives, formulation-promoting additives, formulation-providing additives, and combinations thereof. 
   
   
       40 . The composition according to  claim 35 , wherein said composition is a patch. 
   
   
       41 . The composition according to  claim 35 , wherein said composition is an oral dosage form. 
   
   
       42 . A method of effecting contraception in a female, comprising administering a pharmaceutical composition comprising a substantially pure oxime isomer of norelgestromin selected from: d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-(3E)-oxime and d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-(3Z)-oxime; and a pharmaceutically acceptable excipient or carrier, wherein said oxime isomer is administered in an amount effective to effect contraception.