Compounds for modulating trpv3 function

Abstract

The present application relates to compounds and methods for treating pain and other conditions related to TRPV3.

We claim: 
     
         1 . A pharmaceutical preparation suitable for use in a human patient for treating or preventing a condition involving activation of TRPV3 or for which reduced TRPV3 activity can reduce the severity, comprising an effective amount of a compound of Formula I or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt, and one or more pharmaceutically acceptable excipients: 
       
         
           
           
               
               
           
         
       
       wherein
 Ar and Ar′ each independently represent an aryl or heteroaryl group; 
 G 1  and G 2  each independently represent lower alkyl, or together with the carbons to which they are attached, G 1  and G 2  form an aryl or heteroaryl group fused to the pyrimidinone ring; 
 L represents a linker having 1-3 atoms; and 
 
       wherein said compound inhibits TRPV3 with an IC 50  of 10 micromolar or less. 
     
     
         2 . A compound of Formula IV or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt: 
       
         
           
           
               
               
           
         
       
       wherein
 R represents H, a pharmaceutically acceptable counterion, or a physiologically labile moiety; 
 R′ represents lower alkyl; 
 L represents a linker selected from cis- or trans-ethene; and 
 Ph represents a 2,3-, 2,4-, 2,5- or 2,6-disubstituted phenyl ring, wherein each substituent of the 2,3-, 2,4-, 2,5- or 2,6-disubstituted phenyl ring is independently selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, lower cycloalkyl, halogen, carbonyl, thiocarbonyl, ketone, aldehyde, hydroxy, alkoxy, acyloxy, amino, acylamino, amido, alkylsulfonyl, sulfamoyl, alkylsulfonamido, cyano, nitro, alkylthio, or azido, or Ph represents a monosubstituted 2-substituted phenyl ring, wherein the substituent of the monosubstituted 2-substituted phenyl ring is an electron withdrawing group, or Ph represents a 3,4-disubstituted phenyl ring, wherein each substituent of the 3,4-disubstituted phenyl ring is independently selected from substituted or unsubstituted alkyl or halogen, or Ph represents a monosubstituted 3-substituted phenyl ring, wherein the substituent of the monosubstituted 3-substituted phenyl ring is a substituted alkyl group or a lower alkyl group of two or more carbon atoms, or Ph represents a monosubstituted 4-substituted phenyl ring, wherein the substituent of the monosubstituted 4-substituted phenyl ring is a halogen. 
 
     
     
         3 . A compound of Formula V or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt: 
       
         
           
           
               
               
           
         
       
       wherein
 R represents H, a pharmaceutically acceptable counterion, or a physiologically labile moiety; 
 R′ represents lower alkyl; and 
 Ph represents a substituted or unsubstituted phenyl ring. 
 
     
     
         4 . A method for treating or preventing a condition involving activation of TRPV3 or for which reduced TRPV3 activity can reduce the severity, comprising administering an effective amount of a compound of Formula I or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt: 
       
         
           
           
               
               
           
         
       
       wherein
 Ar and Ar′ each independently represent an aryl or heteroaryl group; 
 G 1  and G 2  each independently represent lower alkyl, or together with the carbons to which they are attached, G 1  and G 2  form an aryl or heteroaryl group fused to the pyrimidinone ring; 
 L represents a linker having from 1-3 atoms; and 
 
       wherein said compound inhibits TRPV3 with an IC 50  of 10 micromolar or less. 
     
     
         5 . The method of  claim 4 , wherein Ar′ represents a substituted or unsubstituted phenyl ring. 
     
     
         6 . The method of  claim 5 , wherein Ar′ is optionally substituted with one or more of the following: substituted or unsubstituted alkyl, alkenyl, alkynyl, lower cycloalkyl, halogen, carbonyl, thiocarbonyl, ketone, aldehyde, hydroxy, alkoxy, acyloxy, amino, acylamino, amido, alkylsulfonyl, sulfamoyl, alkylsulfonamido, cyano, nitro, alkylthio, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or two adjacent substituents together represent —NHSO 2 NH— or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, or azido; and R 7  is lower alkyl. 
     
     
         7 . The method of  claim 5 , wherein Ar′ represents 
       
         
           
           
               
               
           
         
       
       wherein
 R 5  is selected from hydrogen, substituted or unsubstituted alkyl, nitro, amino, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or —OR, wherein R represents hydrogen, a pharmaceutically acceptable counterion, or a physiologically labile moiety; 
 R 8  is selected from hydrogen, halogen, lower alkyl, lower alkoxy, amino, or —NHSO 2 NH 2 , or R 5  and R 8  together represent —NHSO 2 NH— or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached; 
 R 7  represents lower alkyl; and 
 R 6  represents hydrogen, halogen, lower alkyl, lower alkoxy, amino, or —NHSO 2 NH 2 . 
 
     
     
         8 . The method of  claim 7 , wherein R 5  is —OR, wherein R represents hydrogen, a pharmaceutically acceptable counterion, or a physiologically labile moiety; R 8  is lower alkoxy; and R 6  is hydrogen. 
     
     
         9 . The method of  claim 4 , wherein Ar represents a substituted or unsubstituted phenyl ring. 
     
     
         10 . The method of  claim 9 , wherein Ar is optionally substituted with one or more of the following: substituted or unsubstituted alkyl, alkenyl, alkynyl, lower cycloalkyl, halogen, carbonyl, thiocarbonyl, ketone, aldehyde, hydroxy, alkoxy, acyloxy, amino, acylamino, amido, alkylsulfonyl, sulfamoyl, alkylsulfonamido, cyano, nitro, alkylthio, azido, —NHSO 2 NH 2 , or —NHS0 2 CH 3 . 
     
     
         11 . The method of  claim 9 , wherein Ar represents 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  are each independently selected from hydrogen, substituted or unsubstituted alkyl, hydroxyl, lower alkoxy, cyano, nitro, amino, halogen, thioether, or lower cycloalkyl; 
 R 3  is selected from hydrogen, substituted or unsubstituted alkyl, lower alkoxy, cyano, amino, —NHSO 2 NH 2 , or —NHSO 2 CH 3 ; and 
 R 4  is selected from hydrogen, substituted or unsubstituted alkyl, hydroxyl, lower alkoxy, —NHSO 2 NH 2 , or —NHSO 2 CH 3 . 
 
     
     
         12 . The method of claim  21 , wherein R 1  and R 2  are each independently selected from hydrogen, substituted or unsubstituted alkyl, or lower alkoxy; R 3  is selected from hydrogen or substituted or unsubstituted alkyl; and R 4  is selected from hydrogen or substituted or unsubstituted alkyl. 
     
     
         13 . The method of  claim 4 , wherein G 1  and G 2  are lower alkyl. 
     
     
         14 . The method of  claim 4 , wherein L represents a linker selected from ethylene, substituted or unsubstituted, cis- or trans-ethene, or cyclopropane. 
     
     
         15 . The method of  claim 4 , wherein the compound is represented by Formula II: 
       
         
           
           
               
               
           
         
       
       wherein
 Q is an aryl or heteroaryl group; 
 R is absent or represents one or more substituents; 
 Ar and Ar′ each independently represent an aryl or heteroaryl group; and 
 L represents a linker having 1-3 atoms. 
 
     
     
         16 . The method of  claim 5 , wherein the compound is represented by Formula III: 
       
         
           
           
               
               
           
         
       
       wherein
 R is absent or represents one or more substituents; 
 Ar and Ar′ each independently represent an aryl or heteroaryl group; and 
 L represents a linker having 1-3 atoms. 
 
     
     
         17 . The method of  claim 16 , wherein each R is independently selected from lower alkyl, lower alkoxy, carboxyl, ester, ketone, amido, sulfonamide, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, trifluoromethyl, cyano, acyloxy, or —NHSO 2 NH 2 . 
     
     
         18 . The method of  claim 16 , wherein R is absent. 
     
     
         19 . The method of  claim 16 , wherein L represents a linker selected from ethylene, substituted or unsubstituted, cis- or trans-ethene, or cyclopropane. 
     
     
         20 . The method of  claim 4 , used to prevent, treat or alleviate symptoms of a disorder or condition selected from the group consisting of acute or chronic pain, touch sensitivity, burns, inflammation, diabetic neuropathy, psoriasis, eczema, dermatitis, post-herpetic neuralgia (shingles), migraine, incontinence, fever, hot flashes, osteoarthritis, rheumatoid arthritis and cough, or is used as a depilatory to promote loss of or inhibit the growth of hair on a patient.