Use of catecholamines and related compounds as anti-angiogenic agents

Abstract

The present invention provides a method for inhibiting angiogenesis in a human subject in need of such inhibition. The method comprises administering to the human subject an anti-angiogenic effective amount of a physiologically tolerated salt thereof, or any mixture of the compounds of formula (I) a physiologically tolerated salt thereof, a prodrug thereof, a physiologically functional derivative thereof or any mixture thereof as an anti-angiogenic agent. The anti-angiogenic agent should have greater lipophilicity than (S)-noradrenaline.

1 . A method for inhibiting angiogenesis in a human subject in need of such inhibition, comprising administering to the human subject an anti-angiogenic effective amount of a physiologically tolerated salt thereof, or any mixture of the compounds of formula (I) 
       
         
           
           
               
               
           
         
         a physiologically tolerated salt thereof, a prodrug thereof, a physiologically functional derivative thereof or any mixture thereof as an anti-angiogenic agent, and wherein the anti-angiogenic agent has greater lipophilicity than (S)-noradrenaline, and wherein 
         R 1  and R 7  each independently are H, a C 2-10  alkyl group, a C 3-10  cycloalkyl group or a C 1-10  acyl group derived from an aliphatic acid or aromatic acid, or R 1  and R 7  are bonded together to form a C 3-7  nitrogen-containing heterocycle; 
         R 2  and R′ 2  each independently are a H, a C 1-10  alkyl group, a C 3-10  cycloalkyl group, or COON, or one of R 2  or R′ 2  is bonded together with R 1  to form C 3-7  nitrogen containing heterocycle; 
         R 3  represents OR 8 , SR 8 , NR 8 R 9 , wherein R 8  and R 9  each independently are H, a C 1-10  alkyl group, a C 3-10  cycloalkyl group or a C 1-10  acyl group derived from an aliphatic acid or aromatic acid, provided that that R 8  and R 9  are not both acyl groups; 
         R 4  and R 5  each independently are OY, NHY or SY, wherein Y represents H, 
       
       
         
           
           
               
               
           
         
         wherein R 11  and R 12  each independently are H, a C 1-10  alkyl group or a C 3-10  cycloalkyl group; 
         R 6a , R 6b , and R 6c  each independently are H, F, Cl, Br, I, OR 10 , or SR 10 , wherein R 10  is a C 1-10  acyl group derived from an aliphatic acid or aromatic acid; 
         (S) is a chiral centre defining an (S)-configuration of the compound; 
         each C 1-10  alkyl group, C 3-10  cycloalkyl group, C 1-10  acyl group, C 3-8  nitrogen-containing heterocyclic group independently includes or does not include one or more heteroatoms N, O or S, and is independently unsubstituted or substituted with one or more C 6-10  aryl groups, C 6-18  alkaryl groups or C 6-18  aralkyl groups; and 
         provided that R 1  and R 7  are not both H when R 2  and R′ 2  are both H. 
       
     
     
         2 . The method according to  claim 1 , wherein
 R 1  represents a C 2-10  alkyl group;   R 2  represents a H or a C 2-10  alkyl group;   R′ 2  represents H;   R 3  represents OR 8 , wherein R 8  represents H or a C 1-10  alkyl group;   R 4  and R 5  each independently represents O—Y, wherein Y represents   
       
         
           
           
               
               
           
         
         wherein R 9  represents C 1-10  alkyl group, aryl group or a C 3-10  cycloalkyl group; 
         R 6a , R 6b , and R 6c  represent H; and 
         R 7  represents H. 
       
     
     
         3 . The method according to  claim 2 , wherein R 2  and R′ 2  both represent H. 
     
     
         4 . The method according to  claim 2 , wherein R 2  represent CH 2 CH 3 , and R′ 2  represents H. 
     
     
         5 . The method according to  claim 1 , wherein R 4  and R 6  each independently represents OY, and each Y independently represents H, pivaloyl, acetyl, propionyl, butanoyl, isobutanoyl, pentanoyl, 2-butenoyl, cyclopropanoyl, cyclohexanoyl, benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, phenacetyl, 4-methylphenacetyl, methoxyaceryl, or N,N-dimethylamido. 
     
     
         6 . The method according to  claim 1 , wherein R 4  and R 5  each represent OY, and each Y represents pivaloyl. 
     
     
         7 . The method use according to  claim 1 , wherein R 4  and R 5  each represent OY, and each Y represents H. 
     
     
         8 . The method use according to  claim 1 , wherein the compound is (S)-isoproterenol, (S)-N-ethylnoradrenaline, (S)-N-tert-butylnoradrenaline, (S)-N-n-butylnoradrenaline, (S)-N-n-propylnoradrenaline, 1-(3,4-dihydroxyphenyI)-2-(isopropylamino)-1(S)-butanol, erythro-(D,L)dopaserine, dextronordefrin, (S)-dioxifedrine, (S)dioxethedrin or (S)-norbudrine. 
     
     
         9 . The method use according to  claim 1 , wherein the compound is (S)-4-(hydroxy-2-piperidinyl-methyl)-1,2-benzenediol, (S)-pipratecol, (S)-arbutamine, (S)-protokylol, (S)-theodrenalinel, (S,S)-hexoprenaline, or (S)-PTFMA. 
     
     
         10 . The method use according to  claim 1 , wherein the compound is (S)-isoproterenol or (S)-isoproterenol dipivalate. 
     
     
         11 . The method according to  claim 1 , wherein the compound is (S)-N-ethyladrenaline dipivalate, (S)-N-propylnoradrenaline dipivalate, (S)-N-n-butyl noradrenaline dipivalate, (S)-isoproterenol dipivalate, (S)-isoproterenol diisobutyrate, (S)-isoproterenol dibenzoylate, (S)-isoproterenol ditoluoylate or isoetharine dipivalate.