Compounds for modulating trpv3 function

Abstract

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

1 . 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 that inhibits TRPV3-mediated current with an IC 50  of 1 micromolar or less. 
     
     
         2 . The method of  claim 1 , wherein said compound inhibits at least 95% of TRPV3-mediated current at 5 micromolar or less. 
     
     
         3 . The method of  claim 1 , wherein said compound inhibits TRPV3 with an IC 50  at least one order of magnitude lower than its IC 50  for inhibition of one or more of TRPV5, TRPV6, NaV 1.2, mitochondrial uniporter and hERG channel activities. 
     
     
         4 . The method of  claim 1 , wherein said compound inhibits TRPV3 with an IC 50  at least one order of magnitude lower than its IC 50  for inhibition of TRPV1. 
     
     
         5 . The method of  claim 1 , wherein said compound inhibits TRPV3 with an IC 50  of 100 nanomolar or less. 
     
     
         6 . The method of  claim 1 , wherein the agent is an organic molecule having a molecular weight of 2000 amu or less. 
     
     
         7 . The method of  claim 1 , wherein the agent is administered topically. 
     
     
         8 . The method of  claim 1 , wherein the agent is administered orally. 
     
     
         9 . The method of  claim 1 , used to prevent, treat or alleviate symptoms of acute pain, chronic pain, touch sensitivity, itching sensitivity, or as part of treating a burn. 
     
     
         10 - 12 . (canceled) 
     
     
         13 . The method of  claim 1 , used to prevent, treat or alleviate symptoms of a disorder or condition selected from the group consisting of diabetic neuropathy, inflammation, Irritable Bowel Syndrome, Crohn's Disease, psoriasis, eczema, dermatitis, post-herpetic neuralgia (shingles), incontinence, bladder incontinence, bladder cystitis, fever, hot flashes, and cough. 
     
     
         14 . The method of  claim 1 , used to prevent, treat or alleviate symptoms of osteoarthritis or rheumatoid arthritis. 
     
     
         15 - 17 . (canceled) 
     
     
         18 . A pharmaceutical preparation comprising
 an agent that inhibits inward TRPV3-mediated current with an IC 50  of 1 micromolar or less; and   a pharmaceutically acceptable excipient or solvent,   
       wherein the agent is provided in a dosage form providing an amount effective to prevent, treat or alleviate symptoms of a disease, disorder or condition involving activation of TRPV3, or for which reduced TRPV3 activity can reduce the severity, in a patient, but which agent does not cause QT interval elongation in the patient. 
     
     
         19 - 21 . (canceled) 
     
     
         22 . 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 represents an aryl or heteroaryl group; 
 Y represents Ph, OArl, SArl, or N(U)(Arl), 
 R represents H or a lower alkyl; 
 X represents CH 2 , O, S, NR 10 , CF 2 , or C(CN) 2 ; 
 W represents O, S, or NR′; 
 n is 1, or when X is CH 2 , n is 1 or 2; 
 Arl represents an aralkyl, heteroaralkyl, aryl, or heteroaryl group, which may be monocyclic or bicyclic; 
 Ph represents a substituted or unsubstituted phenyl ring, optionally fused to a substituted or unsubstituted 5- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; 
 R′, independently for each occurrence, represents H or a lower alkyl; 
 U represents hydrogen or lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl, 
 or, U, N and R′ taken together form a 5- to 7-membered heterocyclic ring, 
 or, U, Arl and N taken together form a ring fused to the aryl or heteroaryl ring of Arl, thereby forming a bicyclic structure; 
 R 10  represents H, lower alkyl, or cyano; and 
 
       
       wherein said compound inhibits TRPV3 with an with an IC 50  of 10 micromolar or less. 
     
     
         23 . The method of  claim 22 , wherein said compound inhibits a TRPV3-mediated current with an IC 50  of 10 micromolar or less. 
     
     
         24 . The method of  claim 23 , wherein said compound inhibits a TRPV3 mediated current with an IC 50  at least one order of magnitude lower than its IC 50  for inhibition of TRPV1. 
     
     
         25 . The method of  claim 23 , wherein said compound inhibits a TRPV3 mediated current with an IC 50  at least one order of magnitude lower than its IC 50  for inhibition of one or more of TRPV5, TRPV6, NaV 1.2, mitochondrial uniporter and hERG channel activities. 
     
     
         26 . The method of  claim 23 , wherein said compound is represented in Formula Ia, or is a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt: 
       
         
           
           
               
               
           
         
         wherein
 Ar represents an aryl or heteroaryl group; 
 Y represents Ph, OArl, SArl, or N(U)(Arl), 
 R represents H or a lower alkyl; 
 X represents O, S, NR 10 , CF 2 , or C(CN) 2 ; 
 W represents O, S, or NR′; 
 Arl represents an aralkyl, heteroaralkyl, aryl, or heteroaryl group, which may be monocyclic or bicyclic; 
 Ph represents a substituted or unsubstituted phenyl ring, optionally fused to a substituted or unsubstituted 5- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; 
 R′, independently for each occurrence, represents H or a lower alkyl; 
 U represents hydrogen or lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl, 
 or, U, N and R′ taken together form a 5- to 7-membered heterocyclic ring, 
 or, U, Arl and N taken together form a ring fused to the aryl or heteroaryl ring of Arl, thereby forming a bicyclic structure; 
 R 10  represents H, lower alkyl, or cyano; and 
 
       
       wherein said compound inhibits TRPV3 with an with an IC 50  of 10 micromolar or less. 
     
     
         27 . The method of  claim 26 , wherein Y is N(U)(Arl). 
     
     
         28 . The method of  claim 27 , wherein Y represents 
       
         
           
           
               
               
           
         
         wherein
 R 1  and R 2 , each independently, is absent or represents one or more substituents on the ring to which it is attached; 
 Ar′ represents an aryl or heteroaryl group; 
 R 5  represents CH 2 , O, NR 6 ; 
 R 6  represents H or lower alkyl; and 
 n represents 1, 2, or 3. 
 
       
     
     
         29 . The method of  claim 28 , wherein Ar′ represents phenyl, thiophene, imidazole, thiazole, furan, oxazole, tetrazole, thiadiazole, pyridine, pyrimadine, or triazole. 
     
     
         30 . The method of  claim 28 , wherein each R 1  is independently selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R 1  taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and each R 2  is independently selected from H, lower alkyl, alkoxy, carboxyl, ester amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF 3 , or cyano. 
     
     
         31 . The method of  claim 28 , wherein Y represents 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  each, independently, are absent or represent one or more substituents on the ring to which they are attached. 
       
     
     
         32 . The method of  claim 31 , wherein, independently for each occurrence, R 1  is selected from H, lower alkyl, alkoxy, carboxyl, ester, arnido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R 1  taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and independently for each occurrence, R 2  is selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF 3 , or cyano. 
     
     
         33 . The method of  claim 31 , wherein Y represents 
       
         
           
           
               
               
           
         
         wherein
 R 1  represents H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R 1  taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and 
 R 2  represents H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamide, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF 3 , or cyano. 
 
       
     
     
         34 . The method of  claim 33 , wherein R 1  represents H, lower alkyl, alkoxy, or R 1  taken together with the carbon to which it is attached forms a carbonyl, and R 2  represents H, lower alkyl, alkoxy or halogen. 
     
     
         35 . The method of  claim 26 , wherein Ar represents 
       
         
           
           
               
               
           
         
         wherein
 Cy represents an aryl or heteroaryl ring; 
 Z represents O, S, NR 11 , CF 2 , or C(CN) 2 ; 
 R 3  is absent or represents one or more substituents on the ring to which it is attached; 
 R 11  represents H, lower alkyl, or cyano; 
 A represents N or C(R 2a ); and 
 R 2a  represents H, lower alkyl, alkoxy, or halogen. 
 
       
     
     
         36 . The method of  claim 35 , wherein Cy represents a phenyl, thiophene, imidazole, thiazole, furan, oxazole, tetrazole, thiadiazole, pyridine, pyrimadine, or triazole. 
     
     
         37 . The method of  claim 35 , wherein R 3  is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF 3 , or cyano. 
     
     
         38 - 42 . (canceled) 
     
     
         43 . 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 V or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt: 
       
         
           
           
               
               
           
         
         wherein
 X represents O, S, NR 10 , CF 2 , or C(CN) 2 ; 
 Z represents O, S, NR 11 , CF 2 , or C(CN) 2 ; 
 R 10  represents H, lower alkyl, or cyano; 
 R 11  represents H, lower alkyl, or cyano; 
 A represents N or C(R 2 ); 
 G represents N or C(R 3 ); 
 R 1  is absent or represents one or more substituents on the ring to which it is attached; 
 R 2  represents, independently for each occurrence, H or a substituent; 
 R 3  represents, independently for each occurrence, H or a substituent; 
 D represents O or N; and 
 
       
       wherein said compound inhibits TRPV3 with an with an IC 50  of 10 micromolar or less. 
     
     
         44 . The method of  claim 43 , wherein said compound inhibits a TRPV3-mediated current with an IC 50  of 10 micromolar or less. 
     
     
         45 . The method of  claim 44 , wherein said compound inhibits a TRPV3 mediated current with an IC 50  at least one order of magnitude lower than its IC 50  for inhibition of TRPV1. 
     
     
         46 . The method of  claim 44 , wherein said compound inhibits a TRPV3 mediated current with an IC 50  at least one order of magnitude lower than its IC 50  for inhibition of one or more of TRPV5, TRPV6, NaV 1.2, mitochondrial uniporter and hERG channel activities. 
     
     
         47 . The method of  claim 43 , 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, pancreatitis, incontinence, fever, chronic regional pain syndrome, 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. 
     
     
         48 - 49 . (canceled) 
     
     
         50 . 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 VI or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt: 
       
         
           
           
               
               
           
         
         wherein
 X represents O, S, NR 10 , CF 2 , or C(CN) 2 ; 
 R 10  represents H, lower alkyl, or cyano; 
 A represents N or C(R 2 ); 
 G represents N or C(R 3 ); 
 R 1  is absent or represents one or more substituents on the ring to which it is attached; 
 R 2  represents, independently for each occurrence, H or a substituent; 
 R 3  represents, independently for each occurrence, H or a substituent; 
 R 4  represents H or a substituent; 
 D represents O or N; and 
 
       
       wherein said compound inhibits TRPV3 with an with an IC 50  of 10 micromolar or less. 
     
     
         51 . The method of  claim 50 , wherein said compound inhibits a TRPV3-mediated current with an IC 50  of 10 micromolar or less. 
     
     
         52 . The method of  claim 51 , wherein said compound inhibits a TRPV3 mediated current with an IC 50  at least one order of magnitude lower than its IC 50  for inhibition of TRPV1. 
     
     
         53 . The method of  claim 52 , wherein said compound inhibits a TRPV3 mediated current with an IC 50  at least one order of magnitude lower than its IC 50  for inhibition of one or more of TRPV5, TRPV6, NaV 1.2, mitochondrial uniporter and hERG channel activities. 
     
     
         54 . The method of  claim 51 , 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, pancreatitis, incontinence, fever, chronic regional pain syndrome, 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. 
     
     
         55 . 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 II or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt: 
       
         
           
           
               
               
           
         
         wherein
 W represents O or S; 
 X′ represents NR 12 ; 
 R 12  represents H or lower alkyl; 
 Ar and Ar′ independently represent substituted or unsubstituted aryl or heteroaryl rings; and 
 
       
       wherein said compound inhibits TRPV3 with an with an IC 50  of 10 micromolar or less. 
     
     
         56 . The method of  claim 55 , wherein said compound inhibits a TRPV3-mediated current with an IC 50  of 10 micromolar or less. 
     
     
         57 . The method of  claim 56 , wherein said compound inhibits a TRPV3 mediated current with an IC 50  at least one order of magnitude lower than its IC 50  for inhibition of TRPV1. 
     
     
         58 . The method of  claim 56 , wherein said compound inhibits a TRPV3 mediated current with an IC 50  at least one order of magnitude lower than its IC 50  for inhibition of one or more of TRPV5, TRPV6, NaV 1.2, mitochondrial uniporter and hERG channel activities. 
     
     
         59 . The method of  claim 55 , 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, pancreatitis, incontinence, fever, chronic regional pain syndrome, 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. 
     
     
         60 . 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 III or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt: 
       
         
           
           
               
               
           
         
         wherein
 Ar represents a substituted or unsubstituted aryl or heteroaryl ring; 
 Q represents O, S, NR, or CH 2 ; 
 R, independently for each occurrence, represents H or lower alkyl; 
 R′ represents H or a substituted or unsubstituted lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl; 
 R″, independently for each occurrence, represents H or lower alkyl; 
 V is absent or represents C═O, C═S, or SO 2 ; 
 W represents a hydrogen-bond acceptor, such as ═O, ═S, amino, hydroxyl, or ether; 
 E represents H, a substituted or unsubstituted lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl, or halogen, carbonyl (e.g., ester, carboxyl, or formyl), thiocarbonyl (e.g., thioester, thiocarboxylate, or thioformate), ketone, aldehyde, amino, acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxide, sulfate, sulfonate, sulfamoyl, sulfonamide, or phosphoryl; 
 x represents 0 or 1 wherein when x is 0, the carbons bearing W and V are directly linked by a single or double bond; and 
 
       
       wherein said compound inhibits TRPV3 with an with an IC 50  of 10 micromolar or less. 
     
     
         61 . 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 IV or a salt thereof, or a solvate, hydrate, oxidative metabolite or pro drug of the compound or its salt: 
       
         
           
           
               
               
           
         
         wherein
 Ar and Ar′ independently represent substituted or unsubstituted aryl or heteroaryl rings; 
 R, independently for each occurrence, represents H or lower alkyl; 
 X, independently for each occurrence, represents O, S, NR, CF 2 , or CR 2 ; 
 M, independently for each occurrence, represents a substituted or unsubstituted methylene group; and 
 
       
       wherein said compound inhibits TRPV3 with an with an IC 50  of 10 micromolar or less. 
     
     
         62 . A pharmaceutical preparation suitable for use in a human patient, or for veterinary use, 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 represents an aryl or heteroaryl group; 
 Y represents Ph, OArl, SArl, or N(U)(Arl), 
 R represents H or a lower alkyl; 
 X represents O, S, NR 10 , CF 2 , or C(CN) 2 ; 
 W represents O, S, or NR′; 
 Arl represents an aralkyl, heteroaralkyl, aryl, or heteroaryl group, which may be monocyclic or bicyclic; 
 Ph represents a substituted or unsubstituted phenyl ring, optionally fused to a substituted or unsubstituted 5- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; 
 R′, independently for each occurrence, represents H or a lower alkyl; 
 U represents hydrogen or lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl, 
 or, U, N and R 1  taken together form a 5- to 7-membered heterocyclic ring, 
 or, U, Arl and N taken together form a ring fused to the aryl or heteroaryl ring of Arl, thereby forming a bicyclic structure; 
 R 10  represents H, lower alkyl, or cyano; and 
 
       
       wherein said compound inhibits TRPV3 with an with an IC 50  of 10 micromolar or less. 
     
     
         63 - 84 . (canceled)