New aporphine esters and their use in therapy

Abstract

New aporphine derivatives are disclosed which have formula (I) and the physiologically acceptable salts thereof. Said derivatives may be used for the treatment of Parkinson's disease, hemicrania, restless legs syndrome (RLS), sexual dysfunction in men and women, hyperprolactemia and psychotic disorders, and/or evaluation of Parkinson's disease. Processes for the preparation of such derivates are also disclosed.

1 . A method of treating sexual dysfunction in a subject in need thereof comprising administering a composition comprising a pharmaceutically acceptable carrier, diluent or excipient and an effective amount of an aporphine derivative of formula (I)  
       
         
           
           
               
               
           
         
         wherein  
         one of R 1  and R 2  is hydrogen or acetyl and the other one is selected from the group consisting of (C 3 -C 20 )alkenoyl; halo-(C 3 -C 20 )alkanoyl; (C 3 -C 20 )alkanoyl; (C 4 -C 7 )cycloalkanoyl; (C 3 -C 6 )-cycloalkyl(C 2 -C 16 )alkanoyl; aroyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulphonyloxy, (C 1 -C 3 )alkyl and (C 1 -C 3 )alkoxy, which latter may in turn be substituted by 1 to 3 halogen atoms; aryl(C 2 -C 16 )alkanoyl which is unsubstituted or substituted in the aryl moiety by 1 to 3 substituents selected from the group consisting of halogen, (C 1 -C 3 )alkyl and (C 1 -C 3 )alkoxy, which latter may in turn be substituted by 1 to 3 halogen atoms; and hetero-arylalkanoyl having one to three heteroatoms selected from O, S and N in the heteroaryl moiety, said heteroaryl moiety being a five or six membered ring, and 2 to 10 carbon atoms in the alkanoyl moiety and which is unsubstituted or substituted in the heteroaryl moiety by 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethane sulphonyloxy, (C 1 -C 3 )alkyl, and (C 1 -C 3 )alkoxy, which latter may in turn be substituted by 1 to 3 halogen atoms; and  
         R 3  is selected from the group consisting of hydrogen; (C 1 -C 4 )-alkyl, which is unsubstituted or substituted by 1 to 3 halogen atoms; cyclopropyl and cyclopropylmethyl, or a physiologically acceptable salt thereof.  
       
     
     
         2 . The method according to  claim 1 , wherein one of R 1  and R 2  is hydrogen or acetyl and the other one is selected from the group consisting of (C 3 -C 20 )alkanoyl, (C 4 -C 7 )cycloalkanoyl, benzoyl which is unsubstituted or substituted by a chlorine atom or 1 to 3 methoxy groups, phenylacetyl which may be substituted with a chlorine atom, and heteroarylacetyl, and R 3  is (C 1 -C 3 )alkyl or cyclopropyl.  
     
     
         3 . The method according to  claim 2 , wherein one of R 1  and R 2  is hydrogen and the other one is selected from the group consisting of propanoyl, propenoyl, butanoyl, isobutanoyl, pivaloyl, decanoyl, hexadecanoyl, cyclopropanoyl and benzoyl and R 3  is methyl or propyl.  
     
     
         4 . The method according to  claim 2 , wherein one of R 1  and R 2  is acetyl and the other one is selected from the group consisting of butanoyl, isobutanoyl, cyclopropanoyl, cyclohexanoyl, pivaloyl, decanoyl and hexadecanoyl and R 3  is methyl.  
     
     
         5 . The method according to  claim 1 , wherein said composition is in the form of a patch or ointment for transdermal administration.  
     
     
         6 . The method according to  claim 5 , wherein said composition further comprises one or more stabilizers, solubilizers and permeation activators to facilitate the passage of the active principle through the skin.  
     
     
         7 . The method according to  claim 1 , wherein said composition is in the form of a depot preparation for subcutaneous or intramuscular administration comprising said aporphine derivative of formula I or the physiologically acceptable salt thereof dissolved or suspended in an oil.  
     
     
         8 . The method according to  claim 7 , wherein said composition further comprises a local anesthetic.  
     
     
         9 . The method according to  claim 1 , wherein said composition is in a form suited for oral, sublingual, pulmonary, rectal, vaginal or intraduodenal administration.  
     
     
         10 . The method according to  claim 1 , wherein said composition further comprises an effective amount of an anti-emetic agent.  
     
     
         11 . A method of treating sexual dysfunction in a subject in need thereof comprising administering a composition comprising a pharmaceutically acceptable carrier, diluent or excipient and an effective amount of an aporphine derivative of formula (I)  
       
         
           
           
               
               
           
         
         wherein  
         one of R 1  and R 2  is hydrogen or acetyl and the other one is a (C 3 -C 20 )alkanoyl, a (C 3 -C 20 )alkenoyl, a (C 4 -C 7 )cycloalkanoyl, or benzoyl; and  
         R 3  is selected from the group consisting of hydrogen; (C 1 -C 4 )-alkyl, which is unsubstituted or substituted by 1 to 3 halogen atoms; cyclopropyl and cyclopropylmethyl, or a physiologically acceptable salt thereof.  
       
     
     
         12 . The method according to  claim 11 , wherein R 3  is (C 1 -C 3 )alkyl or cyclopropyl.  
     
     
         13 . The method according to  claim 12 , wherein one of R 1  and R 2  is hydrogen and the other one is selected from the group consisting of propanoyl, propenoyl, butanoyl, isobutanoyl, pivaloyl, decanoyl, hexadecanoyl, cyclopropanoyl and benzoyl and R 3  is methyl or propyl.  
     
     
         14 . The method according to  claim 12 , wherein one of R 1  and R 2  is hydrogen and the other one is selected from the group consisting of butanoyl, isobutanoyl, cyclopropanoyl, cyclohexanoyl, pivaloyl, decanoyl and hexadecanoyl and R 3  is methyl.  
     
     
         15 . The method according to  claim 12 , wherein one of one of R 1  and R 2  is hydrogen and the other one is pivaloyl and R 3  is methyl.  
     
     
         16 . The method according to  claim 11 , wherein said composition is in the form of a patch or ointment for transdermal administration.  
     
     
         17 . The method according to  claim 16 , wherein said composition further comprises one or more stabilizers, solubilizers and permeation activators to facilitate the passage of the active principle through the skin.  
     
     
         18 . The method according to  claim 11 , wherein said composition is in the form of a depot preparation for subcutaneous or intramuscular administration comprising said aporphine derivative of formula I or the physiologically acceptable salt thereof dissolved or suspended in an oil.  
     
     
         19 . The method according to  claim 18 , wherein said composition further comprises a local anesthetic.  
     
     
         20 . The method according to  claim 11 , wherein said composition is in a form suited for oral, sublingual, pulmonary, rectal, vaginal or intraduodenal administration.  
     
     
         21 . The method according to  claim 11 , wherein said composition further comprises an effective amount of an anti-emetic agent.