Autoimmune disorder treatment using rxr agonists

Abstract

The present specification provides RXR agonist compounds, compositions comprising such RXR agonists, and methods using such compounds and compositions to treat an autoimmune disorder, inflammation associated with an autoimmune disorder and/or a transplant rejection as well as use of such RXR agonists to manufacture a medicament and use of such compounds and compositions to treat an autoimmune disorder, inflammation associated with an autoimmune disorder and/or a transplant rejection.

1 - 72 . (canceled) 
     
     
         73 . A method of treating an autoimmune disorder, the method comprising the step of administering to an individual in need thereof a therapeutically effective amount of a RXR agonist, wherein administration of the RXR agonist reduces a symptom associated with the autoimmune disorder, thereby treating the individual. 
     
     
         74 . The method according to  claim 73 , wherein the RXR agonist is a compound having the structure of formula I: 
       
         
           
           
               
               
           
         
         wherein Z is a radical shown in Formula II: 
       
       
         
           
           
               
               
           
         
         Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally substituted with one or two R 4  groups, or Y is selected from phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups being optionally substituted with one or two R 4  groups, the divalent Y radical being substituted by the Z and —(CR 1 ═CR 1 ═CR 1 ═CR 1 )— groups on adjacent carbons; R 1  and R 2  independently are H, lower alkyl or fluoroalkyl; R 3  is hydrogen, lower alkyl, Cl or Br; R 4  is lower alkyl, fluoroalkyl or halogen, and B is hydrogen, —COOH or a pharmaceutically acceptable salt thereof, —COOR 8 , —CONR 9 R 10 , —CH 2 OH, —CH 2 OR 11 , —CH 2 OCOR 11 , —CHO, —CH(OR 12 ) 2 , —CHOR 13 O, —OCOR 7 , —CR 7 (OR 12 ) 2 , —CR 7 OR 13 O, or tri-lower alkylsilyl, where R 7  is an alkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons, R 8  is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R 8  is phenyl or lower alkylphenyl, R 9  and R 10  independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11  is lower alkyl, phenyl or lower alkylphenyl, R 12  is lower alkyl, and R 13  is divalent alkyl radical of 2-5 carbons; and n is 1 or 2. 
       
     
     
         75 . The method according to  claim 74 , wherein the RXR agonist is a compound having the structure of formula V: 
       
         
           
           
               
               
           
         
         where R 4  is lower alkyl of 1 to 6 carbons; B is —COOH or —COOR 8  where R 8  is lower alkyl of 1 to 6 carbons, and the configuration about the cyclopropane ring is cis, and the configuration about the double bonds in the pentadienoic acid or ester chain attached to the cyclopropane ring is trans in each of the double bonds, or a pharmaceutically acceptable salt of the compound. 
       
     
     
         76 . The method according to  claim 75 , wherein the RXR agonist is a compound having the structure of formula XII: 
       
         
           
           
               
               
           
         
       
       wherein R is H, lower alkyl or 1 to 6 carbons, or a pharmaceutically acceptable salt of the compound. 
     
     
         77 . The method according to  claim 76 , wherein the RXR agonist is 3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid, and has the structure of formula XXIX: 
       
         
           
           
               
               
           
         
       
     
     
         78 . The method according to  claim 73 , wherein the autoimmune disorder is systemic autoimmune disorder or organ-specific autoimmune disorder. 
     
     
         79 . The method according to  claim 73 , wherein the therapeutically effective amount is about 0.01 mg/kg/day to about 100 mg/kg/day. 
     
     
         80 . The method according to  claim 73 , wherein the therapeutically effective amount is about 0.1 mg/m 2 /day to about 100 mg/m 2 /day. 
     
     
         81 . The method according to  claim 73 , wherein the symptom reduced is inflammation, fatigue, dizziness, malaise, elevated fever and high body temperature, extreme sensitivity to cold in the hands and feet, weakness and stiffness in muscles and joints, weight changes, digestive or gastrointestinal problems, low or high blood pressure, irritability, anxiety, or depression, infertility or reduced sex drive (low libido), blood sugar changes, and depending on the type of autoimmune disorder, an increase in the size of an organ or tissue, or the destruction of an organ or tissue. 
     
     
         82 . A method of treating a transplant rejection, the method comprising the step of administering to an individual in need thereof a therapeutically effective amount of a RXR agonist, wherein administration of the RXR agonist reduces a symptom associated with the transplant rejection, thereby treating the individual. 
     
     
         83 . The method according to  claim 82 , wherein the RXR agonist is a compound having the structure of formula I: 
       
         
           
           
               
               
           
         
         wherein Z is a radical shown in Formula II: 
       
       
         
           
           
               
               
           
         
         Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally substituted with one or two R 4  groups, or Y is selected from phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups being optionally substituted with one or two R 4  groups, the divalent Y radical being substituted by the Z and —(CR 1 ═CR 1 ═CR 1 ═CR 1 )— groups on adjacent carbons; R 1  and R 2  independently are H, lower alkyl or fluoroalkyl; R 3  is hydrogen, lower alkyl, Cl or Br; R 4  is lower alkyl, fluoroalkyl or halogen, and B is hydrogen, —COOH or a pharmaceutically acceptable salt thereof, —COOR 8 , —CONR 9 R 10 , —CH 2 OH, —CH 2 OR 11 , —CH 2 OCOR 11 , —CHO, —CH(OR 12 ) 2 , —CHOR 13 O, —OCOR 7 , —CR 7 (OR 12 ) 2 , —CR 7 OR 13 O, or tri-lower alkylsilyl, where R 7  is an alkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons, R 8  is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R 8  is phenyl or lower alkylphenyl, R 9  and R 10  independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11  is lower alkyl, phenyl or lower alkylphenyl, R 12  is lower alkyl, and R 13  is divalent alkyl radical of 2-5 carbons; and n is 1 or 2. 
       
     
     
         84 . The method according to  claim 83 , wherein the RXR agonist is a compound having the structure of formula V: 
       
         
           
           
               
               
           
         
         where R 4  is lower alkyl of 1 to 6 carbons; B is —COOH or —COOR 8  where R 8  is lower alkyl of 1 to 6 carbons, and the configuration about the cyclopropane ring is cis, and the configuration about the double bonds in the pentadienoic acid or ester chain attached to the cyclopropane ring is trans in each of the double bonds, or a pharmaceutically acceptable salt of the compound. 
       
     
     
         85 . The method according to  claim 84 , wherein the RXR agonist is a compound having the structure of formula XII: 
       
         
           
           
               
               
           
         
         wherein R is H, lower alkyl or 1 to 6 carbons, or a pharmaceutically acceptable salt of the compound. 
       
     
     
         86 . The method according to  claim 85 , wherein the RXR agonist is 3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid, and has the structure of formula XXIX: 
       
         
           
           
               
               
           
         
       
     
     
         87 . The method according to  claim 82 , wherein the transplant rejection is a hyperacute rejection, an acute rejection, or a chronic rejection. 
     
     
         88 . The method according to  claim 82 , wherein the transplant rejection is a graft-versus-host-disease. 
     
     
         89 . The method according to  claim 82 , wherein the therapeutically effective amount is about 0.01 mg/kg/day to about 100 mg/kg/day. 
     
     
         90 . The method according to  claim 82 , wherein the therapeutically effective amount is about 0.1 mg/m 2 /day to about 100 mg/m 2 /day. 
     
     
         91 . The method according to  claim 82 , wherein the symptom reduced is inflammation, fatigue, dizziness, malaise, elevated fever and high body temperature, extreme sensitivity to cold in the hands and feet, weakness and stiffness in muscles and joints, weight changes, digestive or gastrointestinal problems, low or high blood pressure, irritability, anxiety, or depression, infertility or reduced sex drive (low libido), blood sugar changes, and depending on the type of transplant rejection, an increase in the size of an organ or tissue, or the destruction of an organ or tissue. 
     
     
         92 . A method of treating an autoimmune disorder, the method comprising the step of administering to an individual in need thereof a therapeutically effective amount of a RXR agonist, wherein the RXR agonist is 3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid; and wherein administration of the RXR agonist reduces a symptom associated with the autoimmune disorder, thereby treating the individual.