Anti-Radical Agents

Abstract

Compounds of the formulae (1), (2) and selected hindered nitroxyl, hydroxylamine and hydroxylamine salt compounds such as the compound of formula (3), wherein Gi is hydrogen; C 1 -C 22 alkyl; C 1 -C 22 alkylthio; C 2 -C 22 alkylthioalkyl; C 5 -C 7 cycloalkyl; phenyl; C 7 -C 9 phenylalkyl; or SO 3 M; G 2 is C 1 -C 22 alkyl; C 5 -C 7 cycloalkyl; phenyl; or C 7 -C 9 phenylalkyl; E is oxyl or hydroxyl; V is —O—; or —NH—; a is 0 or 1 or 2; b, c and d and g are each independently of one another 0 or 1; e is an integer from 1 to 4; f, m, n and p are each independently of one another an integer from 1 to 3; q is 0 or an integer from 1 to 3; Q, T and G 3 are as defined in claim 1 ; G 4 and G 5 are each independently of the other hydrogen; or C 1 -C 22 alkyl; exhibit marked antiinflammatory action.

1 . A pharmaceutical composition comprising at least one of the following compounds 
     
       
         
         
             
             
         
       
       (3) hindered nitroxyl compounds, hindered hydroxylamine compounds, hindered hydroxylamine salt compounds of the formulae 
     
     
       
         
         
             
             
         
       
     
     where in the above formulae
 G 1  is hydrogen; C 1 -C 22 alkyl; C 1 -C 22 alkylthio; C 2 -C 22 alkylthioalkyl; C 5 -C 7 cycloalkyl; phenyl; C 7 -C 9 phenylalkyl; or SO 3 M; 
 G 2  is C 1 -C 22 alkyl; C 5 -C 7 cycloalkyl; phenyl; or C 7 -C 9 phenylalkyl; 
 Q is —C m H 2m —, 
 
     
       
         
         
             
             
         
       
     
     —C m H 2m —NH; a radical of formula 
     
       
         
         
             
             
         
       
       T is —C n H 2n —; —(CH 2 ) n —O—CH 2 —; phenylene; 
     
     
       
         
         
             
             
         
       
     
     or a radical of formula 
     
       
         
         
             
             
         
       
       V is —O—; or —NH—; 
       a is 0; 1; or 2; 
       d and g are each independently of one another 0; or 1; 
       e is an integer from 1 to 4; 
       f is an integer from 1 to 3; and 
       m, n and p are each independently of one another an integer from 1 to 3; 
       q is 0 or an integer from 1 to 3; 
       if e=1, each of b and c is 1; 
       G 3  is hydrogen; C 1 -C 22 alkyl; C 5 -C 7 cycloalkyl; C 1 -C 22 alkylthio; C 2 -C 22 alkylthioalkyl; C 2 -C 18 alkenyl; C 1 -C 18 phenylalkyl; M; SO 3 M; a radical of formula 
     
     
       
         
         
             
             
         
       
       
         or G 3  is propyl substituted by OH and/or by C 2 -C 22 alkanoyloxy; 
       
       M is alkali; ammonium; H; 
       if e=2, then each of b and c independently is selected from 0 and 1; 
       G 3  is a direct bond; —CH 2 —; 
     
     
       
         
         
             
             
         
       
     
     or —S—; or G 3  is propyl substituted by OH or C 2 -C 22 alkanoyloxy; 
     if
 e=3, then each of b and c independently is selected from 0 and 1; 
 G 3  is the radical of formula 
 
     
       
         
         
             
             
         
       
     
     if
 e=4, then each of b and c independently is selected from 0 and 1; 
 G 3  is 
 
     
       
         
         
             
             
         
       
       G 4  and G 5  are each independently of the other hydrogen; or C 1 -C 22 alkyl; 
       A 1  and A 2  are independently alkyl of 1 to 4 carbon atoms or are together pentamethylene, Z 1  and Z 2  are each methyl, or Z 1  and Z 2  together form a linking moiety which may additionally be substituted by an ester, ether, hydroxy, oxo, cyanohydrin, amide, amino, carboxy or urethane group, 
       h is the number of positive charges and j is the number of negative charges,
 X is an inorganic or organic anion, and 
 
       where the total charge of cations h is equal to the total charge of anions j, or a compound of the formulae (16), (18), (20), (21), (22), (23) 
     
     
       
         
         
             
             
         
       
       together with a pharmaceutically acceptable carrier or adjuvant. 
     
   
   
       2 . Pharmaceutical composition of  claim 1  comprising at least one compound of formulae (1), (2) and/or (3) 
     
       
         
         
             
             
         
       
     
     or an acid addition salt thereof, 
     wherein in formulae (1), (2) and (3)
 G 1  is hydrogen; C 1 -C 22 alkyl; C 1 -C 22 alkylthio; C 2 -C 22 alkylthioalkyl; C 5 -C 7 cycloalkyl; phenyl; C 7 -C 9 phenylalkyl; or SO 3 M; 
 G 2  is C 1 -C 22 alkyl; C 5 -C 7 cycloalkyl; phenyl; or C 7 -C 9 phenylalkyl; 
 E is oxyl or hydroxyl; 
 Q is —C m H 2m —; 
 
     
       
         
         
             
             
         
       
     
     —C m H 2m —NH; a radical of formula 
     
       
         
         
             
             
         
       
       T is —C n H 2n —; —(CH 2 ) n —O—CH 2 —; phenylene; 
     
     
       
         
         
             
             
         
       
     
     or a radical of formula 
     
       
         
         
             
             
         
       
       V is —O—; or —NH—; 
       ; 
       a is 0; 1; or 2; 
       b, c and d and g are as defined in  claim 1 ; 
       e is an integer from 1 to 4; 
       f is an integer from 1 to 3; and 
       m, n and p are each independently of one another an integer from 1 to 3; 
       q is 0 or an integer from 1 to 3; 
       if e=1, or in formula (3), then 
       G 3  is hydrogen; C 1 -C 22 alkyl; C 5 -C 7 cycloalkyl; C 1 -C 22 alkylthio; C 2 -C 22 alkylthioalkyl; C 2 -C 18 alkenyl; C 1 -C 18 phenylalkyl; M; SO 3 M; a radical of formula (1d) 
     
     
       
         
         
             
             
         
       
     
     or G 3  is propyl substituted by OH and/or by C 2 -C 22 alkanoyloxy;
 M is alkali; ammonium; H; 
 
     if e=2, then
 G 3  is a direct bond; —CH 2 —; 
 
     
       
         
         
             
             
         
       
     
     or —S—; or G 3  is propyl substituted by OH or C 2 -C 22 alkanoyloxy; 
     if
 e=3, then 
 G 3  is the radical of formula (1g) 
 
     
       
         
         
             
             
         
       
     
     if
 e=4, then 
 G 3  is 
 
     
       
         
         
             
             
         
       
       G 4  and G 5  are each independently of the other hydrogen; or C 1 -C 22 alkyl; 
     
     together with a pharmaceutically acceptable carrier or adjuvant. 
   
   
       3 . A pharmaceutical composition according to  claim 2 , where in the compounds a is 1;
 Q, where present, is —C m H 2m — and, preferably, a methylene or ethylene radical,   T, where present, is —C n H 2m — or phenylene;   G 3  is hydrogen; C 1 -C 22 alkyl; SO 3 M; propyl substituted by OH and/or by C 2 -C 22 alkanoyloxy;   or G 3  is a direct bond; —CH 2 —;   
     
       
         
         
             
             
         
       
     
     or propylene substituted by OH or C 2 -C 22 alkanoyloxy; 
     or G 3  is 
     
       
         
         
             
             
         
       
     
   
   
       4 . A pharmaceutical composition according to  claim 2 , where in the compound of the formula (1) or (2)
 G 1  and G 2  are, independently of each other, C 1 -C 5 alkyl, especially tert.-butyl, and G 1  is located in meta-position relative to G 2 ; and   G 4  and G 5  independently are H or C 1 -C 4 alkyl, especially methyl.   
   
   
       5 . A pharmaceutical composition according to  claim 2 , where in the compound of the formula (1), e is 1 or 2 or 4 and G 3  is SO 3 M or propyl substituted by OH and/or by C 12 -C 22 alkanoyloxy; or G 3  is a direct bond; —CH 2 —; 
     
       
         
         
             
             
         
       
     
     or propylene
 substituted by OH or C 12 -C 22 alkanoyloxy; or G is 
 
     
       
         
         
             
             
         
       
     
     where M is alkali and q is 0 or 1;
 Q, where present, is ethylene, 
 T, where present, is p-phenylene; 
 and where the compound of the formula (3) conforms to the formula 
 
     
       
         
         
             
             
         
       
     
     where E is oxyl or hydroxyl; 
     or a pharmaceutically acceptable acid addition salt thereof. 
   
   
       6 . A pharmaceutical composition according to  claim 1 , wherein the compound (1), (2), (3) is selected from the group consisting of compounds of formulae (7) to (35) 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     the reaction product of glycerine, coconut oil and a compound of the formula 
     
       
         
         
             
             
         
       
     
     citrate. 
   
   
       7 . A pharmaceutical composition according to  claim 1 , wherein the compounds (1), (2) and/or (3) are present in a total amount of 0.001 to 10% by weight of the total composition. 
   
   
       8 . A pharmaceutical composition according to  claim 1  for the treatment of radical-induced skin damage or inflammatory or allergic conditions. 
   
   
       9 . (canceled) 
   
   
       10 . A medicament or formulation for the treatment or prevention of radical-induced skin damage or inflammatory or allergic conditions comprising an effective amount of compound (1), (2) and/or (3) as defined in  claim 1 . 
   
   
       11 . A pharmaceutical composition according to  claim 1 , which additionally comprises at least one substance selected from the group consisting of antiphlogistic agents, antiinflammatory agents, vitamins, antipsoriatic agents, further skin actives, cell proliferation regulators, antiallergic, UV protecting, moisturizing, antiageing agents, and DNA-protectants. 
   
   
       12 . A pharmaceutical composition according to  claim 1 , which contains the compounds (1), (2) and/or (3), and optionally a further active ingredient, in nanodispersed or encapsulated form. 
   
   
       13 . A process for the preparation of a pharmaceutical composition, which process comprises addition of an effective amount of the pharmaceutically active compound (1), (2) and/or (3) as defined in  claim 1  to a pharmaceutically acceptable carrier. 
   
   
       14 . A method for the local treatment or prevention of radical induced body impairments comprising administering to a patient in need of such treatment an effective amount of the pharmaceutical composition according to  claim 1 . 
   
   
       15 . A method according to  claim 14  for the local treatment or prevention of inflammatory conditions comprising administering to a patient in need of such treatment an effective amount of said pharmaceutical composition. 
   
   
       16 . A method according to  claim 14  for the local treatment or prevention of allergic conditions comprising administering to a patient in need of such treatment an effective amount of said pharmaceutical composition. 
   
   
       17 . A method according to  claim 14  for the local treatment or prevention of skin impairments comprising administering to a patient in need of such treatment an effective amount of said pharmaceutical composition.