Novel 3,5,and/or 6 substituted analogues of swainsonine processes for their preparation and their use as therapeutic agents

Abstract

The invention relates to novel 3, 5, and/or 6 swainsoninc analogues, processes for their preparation and their use as therapeutic agents. The invention also relates to pharmaceutical compositions containing the compounds and their use as therapeutics.

We claim:  
     
         1 . A a compound of the formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 (1) R 1 , R 2  and R 3  are the same or different and represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, aryl, or R 1  and R 2  together or R 2  and R 3  together form a carbocyclic or heterocylic ring;  
 (2) W, W′ and W″ are the same or different and represent hydroxyl, alkoxy, thiol, thioalkyl, thioaryl, halo or amino, or one or more of W and W″ and W′ and W″ together form a carbocyclic or heterocyclic ring;  
 or one or more of R 1  and W, R 2  and W′, and R 3  and W″ form a spiro ring system;  
 (3) X, X′, Y, Y′, Z, and Z′ are the same or different and represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, aryl, alkoxy, aryloxy, hydroxyl, thiol, thioaryl, amino, ammonium, halogen, carboxylic acid or esters or thioesters thereof, ketone, aldehyde, carbonate, carbamate, amide, azide, imide, imine, imidazole, acetal, ketal, nitrile, diazo, nitro, hydrazine, hydrazide, hydrazone, hydroxamic acid, hydroxylamine, epooxide, alkoxy or aryloxy amine, sulfate, sulfonic or sulfinic acid or esters thereof, sulfonamide, phosphate or phosphonate acids or esters thereof, silyl, sulfoxide, sulfone, oxime, guanidino, phosphonate, thioamide, thiocarbamate, thiocyanate, thioketone, thiourea, thioethers, triazole, urea, xanthate, cyano, nitrile, —SR 8  wherein R 9  is alkyl, cycloalkyl, alkenyl, alkynyl, or unsatured monocyclic hydrocarbons, and —OR where R is alkyl is alkyl, cycloalkyl, alkenyl, alkynyl, or unsaturated monocyclic hydrocarbons; or 
 (i) X and Y, X′ and Y, X′ and Y, or X′ and Y′ may together form a carbocyclic, or heterocyclic ring, or Y and Z, Y and Z′, or Y′ and Z′ may together form a carbocyclic, or heterocyclic ring;  
 (ii) one or more of X and X′ together, Y and Y′ together, and Z and Z′ together may form a spiro ring; or  
 (iii) one or more of X and X′ together, Y and Y′ together, and Z and Z′ together represent ═O, ═S, or ═NR 4  wherein R 4  is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, aryl, alkoxy, hydroxyl, or ═CR 5 R 6  wherein R 5  and R 6  are the same or different and represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl;  
 with the proviso that X, X′, Y, Y′, and Z, Z′ cannot all be hydrogen,  
 and salts and optically active and racemic forms of a compound of the formula I.  
 
 
     
     
         2 . A compound of the formula I wherein when R 1 , R 2 , R 3 , X, X′, Y, Y′ are hydrogen, W, W′, W, W′, and W″ are not hydroxyl.  
     
     
         3 . A compound of the formula I wherein when R 1 , R 2 , R 3 , X, X′, Z and Z′ are hydrogen, and W, W′, and W″ are hydroxyl, Y and Y′ together cannot by —O or one of Y and Y′ cannot be alkoxy.  
     
     
         4 . A compound of the formula I as claimed in  claim 1  wherein W, W′ and W″ are the same and represent hydroxyl.  
     
     
         5 . A compound of the formula I as claimed in  claim 1  wherein R 1 , R 2 , and R 3  are the same and represent hydrogen.  
     
     
         6 . A compound of the formula I as claimed in  claim 1  wherein R 1 , R 2 , and R 3  are the same and represent hydrogen, and W, W′ and W″ are the same and represent hydroxyl.  
     
     
         7 . A compound of the formula I as claimed in  claim 1 , R 1 , R 2 , and R 3  represent hydrogen, W, W′ and W″ represent hydroxyl, and Z and Z′ represent hydrogen.  
     
     
         8 . A compound of the formula I as claimed in  claim 1  wherein R 1 , R 2 , and R 3  represent hydrogen, W, W′ and W″ represent hydroxyl, and X and X′ represent hydrogen.  
     
     
         9 . A compound of the formula I as claimed in  claim 1  wherein R 1 , R 2 , and R 3  represent hydrogen, W, W′ and W″ represent hydroxyl, and X, X′, Z and Z′ represent hydrogen.  
     
     
         10 . A compound of the formula I as claimed in  claim 1  wherein R 1 , R 2 , and R 3  represent hydrogen, W, W′ and W″ represent hydroxyl, and Y and Y′ represent hydrogen  
     
     
         11 . A compound of the formula I as claimed in  claim 1  wherein one of Y and Y′ represents methyl, ethyl, phenyl, benzyl, trifluoromethyl, hydroxymethyl, or benzyloxymethyl.  
     
     
         12 . A compound of the formula I as claimed in  claim 1  wherein one of X and X′ represents thiomethyl, fluoromethyl, or methoxy.  
     
     
         13 . A compound of the formula I as claimed in  claim 1  wherein W″ and R 3  are the same and represent halogen.  
     
     
         14 . A compound of the formula I as claimed in  claim 1  wherein Y and Y′ are the same and represent halogen.  
     
     
         15 . A compound of the formula I as claimed in  claim 1  wherein R 1 , R 2 , and R 3  represent hydrogen, W, W′ and W″ represent hydroxyl, Z and Z′ represent hydrogen, one of X and X′, which may be substituted, is alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, —CH 2 OR 52  where R 52  represents alkyl or aryl, and the other of X and X′ is hydrogen, or X and X′ together represent ═O, and, one of Y and Y′, which may be substituted, is alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, —CH 2 OR 52  where R 52  represents alkyl or aryl, benzyl, or and the other of Y and Y′ is hydrogen.  
     
     
         16 . A compound of the formula I as claimed in  claim 1  wherein R 1 , R 2 , and R 3  represent hydrogen, W, W′ and W″ represent hydroxyl, Y and Y′ represent hydrogen, X and X′, which may be substituted, are the same or different and represent hydrogen, alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, thiaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, or pyridinyl, or —CH 2 OR 52  where R 52  represents alkyl or aryl, and Z and Z′ are the same or different and represent alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, or pyridinyl, or CH 2 OR 52  where R 52  represents alkyl or aryl, with the proviso that at least one of X and X′ and at least one of Z and Z′ cannot by hydrogen.  
     
     
         17 . A compound of the formula I as claimed in  claim 1  wherein R 1 , R 2 , and R 3  represent hydrogen, and W, W′ and W″ represent hydroxyl, and X and X′ represents hydrogen, Y, Y′, Z, and Z′ are the same or different and represent hydrogen, alkyl, aryl, aldoxy, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, or —CH 2 OR 50  where R 52  represents alkyl or aryl, with the proviso that at least one of Y and Y′ and one of Z and Z′ cannot be hydrogen.  
     
     
         18 . A compound of the formula I as claimed in  claim 1  wherein R 1 , R 2  , and R 3  represent hydrogen, and W, W′ and W″ represent hydroxyl, and X, X′, Z and Z represent hydrogen, and one of Y and Y′ represent hydrogen, alkyl, aryl, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, or —CH2OR 50  where R 50  represents alkyl or aryl, and the other of Y and Y′ represents hydrogen, alkyl, aryl, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, or —CH2OR 50  where R 50  represents alkyl or aryl.  
     
     
         19 . A compound of the formula I as claimed in  claim 1  wherein R 1 , R 2 , and R 3  represent hydrogen, and W, W′ and W″ represent hydroxyl, and Y, Y′, Z and Z′ represent hydrogen, and one of X and X′ represents hydrogen, alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, or —CH 2 OR 50  where R 50  represents alkyl or aryl, and the other of X and X′ represent hydrogen, alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, or —CH2OR 52  where R 52  represents alkyl or aryl, or X and X′ together represent ═O.  
     
     
         20 . A compound of the formula I as claimed in  claim 1  wherein R 1 , R 2 , and R 3  represent hydrogen, and W, W′ and W″ represent hydroxyl, and Z and Z′ represent hydrogen, and X and Y, X′ and Y′, X′ and Y, or X and Y′ together form a 6 member heterocyclic ring containing one or two of O, S, or N.  
     
     
         21 . A compound of the formula I as claimed in  claim 1  wherein R 1 , R 2 , and R 3  represent hydrogen, W, W′ and W″ represent hydroxyl, X, X′, Z and Z′ represent hydrogen, and one of Y and Y′ represents methyl, ethyl, phenyl, or benzyl which may be substituted, preferably trifluoromethyl, hydroxymethyl, benzyloxymethyl, and the other of Y and Y′ represent hydrogen.  
     
     
         22 . A compound of the formula I as claimed in  claim 1  wherein R 1 , R 2 , and R 3  represent hydrogen, and W represents hydroxyl, and W′ and W′ represent halogen, preferably fluoro; X, X′, Z and Z′ represent hydrogen, and one of Y and Y′ represents methyl, ethyl, phenyl, benxyl, trifluormethyl, hydroxymethyl, or benzyloxymethyl, and the other of Y and Y′ represents hydrogen.  
     
     
         23 . A compound of the formula I as claimed in  claim 1  wherein one of Y and Y′ is hydrogen and the other of Y and Y′ is methyl, and one of Z and Z′ is hydroxymethyl, —COCH 2 CH 3 , —CN, —CH 2 NH 2 , —CH 2 NHAc, or —CH 2 NHCR 60 ═NH where R 60  is alkyl or aryl.  
     
     
         24 . A compound of the formula I as claimed in  claim 1  wherein one of Y and Y′ and one of Z and Z′ represents alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, benzyl, pyridinyl, or —CH2OR 52  where R 52  represents alkyl or aryl, which may be substituted, and the other of Y and Y′ and Z and Z′ represents hydrogen.  
     
     
         25 . A compound of the formula I as claimed in  claim 1  wherein one of Z and Z′ is —CONR 70 R 71  where R 70 and  R 71  are the same or different and represent hydrogen, alkyl, or aryl, —COOH, —COOC 2 H 5 , methyl, or CH 2 OH, or Z and Z′ together form a spiro ring.  
     
     
         26 . A compound of the formula I as claimed in  claim 1  wherein X and Y form a carbocyclic or heterocyclic ring of the formula R 75 -R 76 -R 77 -R 78 -R 79  where R 75  and R 79  are part of the swainsonine skeleton and one or more of R 74 , R 77 , and R 78  represent CH, CH 2 , O, S, or N.  
     
     
         27 . A compound of the formula I as claimed in  claim 1  which is (5R)-5-methylswainsonine, (5R)-5-methylswainsonine formate salt, (5S)-5-methylswainsonine (5R)-8-Epi-5-methylswainsonine, (5S)-5-ethylswainsonine, (5S,6S)-6-hydroxymethyl-5-methylswainsonine; (5R)-5-benzyloxymethylswainsonine, (5R,6R)-6-hydroxymethyl-5-methylswainsonine,(5R)-5-hydroxymethylswainsonine, (5S)-5-hydroxymethylswainsonine, (5R,6R)-6-hydroxymethyl-5-methyl swainsonine, (5S)-5-benzyloxymethylswainsonine, or (5S)-5-benzyloxymethylswainsonine.  
     
     
         28 . A pharmaceutical formulation comprising a compound of the formula I as claimed in any one of  claims 1  to  27  as an active agent, and a pharmaceutically acceptable carrier, excipient or diluent.  
     
     
         29 . A method for stimulating the immune system, treating proliferative disorders, or microbial infections in a patient comprising administering an effective amount of a compound of the formula I as claimed in any one of  claims 1  to  27 .  
     
     
         30 . Use of a compound of the formula I as claimed in any one of  claims 1  to  27  in the preparation of a medicament for stimulating the immune system, and/or for treating proliferative disorders, and microbial infections.  
     
     
         31 . A method for stimulating the immune system, treating proliferative disorders, or microbial infections in a patient comprising administering an effective amount of a compound of the formula I as claimed in  claim 1  wherein R 1 , R 2 , and R 3  represent hydrogen, W, W′ and W″ represent hydroxyl, Y, Y′, Z and Z′ represent hydrogen, and one of X and X′ represents methyl, phenyl, benzyl, hydroxymethyl, and the other of X and X′ represent hydrogen.  
     
     
         32 . Use of a compound of the formula I as claimed in  claim 1  wherein R 1 , R 2 , and R 3  represent hydrogen, W, W′ and W″ represent hydroxyl, Y, Y′, Z and Z′ represent hydrogen, and one of X and X′ represents methyl, phenyl, or benzyl which may be substituted, and the other of X and X′ represent hydrogen; R 1 , R 2 , and R 3  represent hydrogen, W, W′ and W″ represent hydroxyl, X, X′, Z and Z′ represent hydrogen, and one of Y and Y′ represents methyl, ethyl, phenyl, or benzyl which may be substituted, and the other of Y and Y′ represents hydrogen; R 1 , R 2 , and R 3  represent hydrogen, and W, W′ and W″ represent hydroxyl, and Y and Y′ represent hydrogen, X and X′ are the same or different and represent hydrogen, alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, or pyridinyl, or —CH 2 OR 52  where R 52  represents alkyl or aryl, which may be substituted, and one of Z and Z′ are the same or different and represent alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, or pyridinyl, or CH 2 OR 52  where R 52  represents alkyl or aryl, with the proviso that at least one of X and X′ and at least one of Z and Z′ cannot be hydrogen, in the preparation of a medicament for stimulating the immune system, and/or for treating proliferative disorders, and microbial infections.