Treatment of T-helper cell type 2-mediated immune diseases by retinoid antagonists

Abstract

Retinoids with retinoid receptor antagonistic activity, pharmaceutically acceptable salts and pharmaceutically acceptable hydrolyzable esters thereof, have been found efficacious in treating T-helper cell type 2 (Th2)-mediated immune diseases, such as immunoglobulin E (IgE)-mediated allergic diseases.

1 . A method of treating a T-helper cell type 2-mediated immune disease or a disease mediated by T-helper celltype 2-related cytokines, which comprises administering to a subject having a T-helper cell type 2-mediated immune disease or a disease mediated by T-helper cell type 2-related cytokines an effective amount of a compound selected from the group consisting of retinoid antagonists, pharmaceutically acceptable salts of retinoid antagonists, and pharmaceutically acceptable hydrolyzable esters of such retinoid antagonists and their salts.  
   
   
       2 . The method of  claim 1 , wherein the T-helper cell type 2-mediated immune disease is an immunoglobulin E-mediated allergic disease.  
   
   
       3 . The method of  claim 2 , wherein the immunoglobulin E-mediated allergic disease is atopic dermatitis.  
   
   
       4 . The method of  claim 2 , wherein the immunoglobulin E-mediated allergic disease is allergic rhinitis.  
   
   
       5 . The method of  claim 2 , wherein the immunoglobulin E-mediated allergic disease is allergic bronchial asthma.  
   
   
       6 . The method of  claim 1 , wherein the disease mediated by Th2-related cytokines is mediated by IL-4 or IL-5.  
   
   
       7 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     wherein R 1  is C 5-10 -alkyl,  
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable, hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       8 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     wherein R 1  is C 5-10 -alkyl,  
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       9 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     wherein R 2  and R 3  are each independently hydrogen or fluorine,  
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       10 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     wherein R 2  and R 3  are each independently hydrogen or fluorine,  
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       11 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     wherein R 4  is diamantyl, X is O or NH,  
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       12 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     wherein either ring A or ring B is present,  
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       13 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     wherein R 5  is phenyl or benzyl,  
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       14 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     wherein R 6  and R 7  are each independently hydroxy, C 1-4 -alkoxy, C 1-5 -alkyl, branched C 1-5 -alkyl, or adamantyl,  
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       15 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       16 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
     
   
   
       17 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     wherein Y is —CH 2 — or sulfur and Z is —CH═ or nitrogen,  
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       18 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       19 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     R 8  is hydrogen or C 1-4 -alkyl;  
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       20 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       21 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     wherein  
     
       
         
         
             
             
         
       
     
     is a single bond or a double bond, when a double bond is present, R 9  is methyl and R 10  is hydrogen, and when a single bond is present, R 9  and R 10  taken together are methylene thus forming a cis-substituted cyclopropyl ring, and R 11  is C 1-4 -alkoxy,  
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       22 . The method of  claim 1 , wherein the compound is a retinoid antagonist of the formula:  
     
       
         
         
             
             
         
       
     
     wherein R 11  is C 1-4 -alkoxy,  
     or a pharmaceutically acceptable salt of such retinoid antagonist or a pharmaceutically acceptable hydrolyzable ester of such retinoid antagonist or its salt.  
   
   
       23 . The method of  claim 1 , wherein the administering comprises oral administration.  
   
   
       24 . The method of  claim 23 , wherein the oral administration is at a daily dosage of from about 0.05 mg to about 20 mg of the compound per kg of body weight of the subject.  
   
   
       25 . The method of  claim 24 , wherein the oral administration is at a daily dosage of from about 0.3 mg to about 1.5 mg of the compound per kg of body weight of the subject.  
   
   
       26 . The method of  claim 23 , wherein the oral administration comprises is administering a tablet, capsule, pill or sachet containing from about 5 mg to about 200 mg of the compound.  
   
   
       27 . The method of  claim 26 , wherein the oral administration comprises administering a tablet, capsule, pill or sachet containing from about 20 mg to about 100 mg of the compound.  
   
   
       28 . The method of  claim 1 , wherein the administering comprises topical administration.  
   
   
       29 . The method of  claim 28 , wherein the topical administration comprises administering an ointment cream, lotion, or spray containing from about 0.01 percent to about 5.0 percent by weight of the compound.  
   
   
       30 . The method of  claim 29 , wherein the topical administration comprises administering an ointment, cream, lotion, or spray containing from about 0.1 percent to about 1.0 percent by weight of the compound.  
   
   
       31 . The method of  claim 1 , wherein the administering comprises inhalation.  
   
   
       32 . The method of  claim 31 , wherein the inhalation comprises administering a nasal aerosol, aerosol for inhalation, or dry powder for inhalation containing from about 0.01 percent to about 5.0 percent by weight of the compound.  
   
   
       33 . The method of  claim 32 , wherein the inhalation comprises administering a nasal aerosol, aerosol for inhalations, or dry powder for inhalation containing from about 0.1 percent to about 1.0 percent by weight of the compound.  
   
   
       34 . The method of  claim 1 , wherein the compound is a retinoid antagonists or a alkali metal salt, alkaline earth metal salt, benzyl ester, lower alkylester, or 9-fluorenylmethyl ester thereof.