Inhibiting the transient receptor potential a1 ion channel

Abstract

The present invention relates to compounds of the Formula (I), or a pharmaceutically acceptable salt, pharmaceutical preparation, or pharmaceutical composition thereof, and their use for the treatment of pain, inflammatory disease, neuropathy, dermatological disorders, pulmonary conditions, and cough, as well as inhibiting the Transient Receptor Potential A1 ion channel (TRPA1).

1 . A compound of the Formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 2  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, optionally substituted with one or more R 5  groups; 
 R 3  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 4  is halo, hydroxy, alkoxy, thiol, alkylthio, amino, alkylamino, dialkylamino, cyano, nitro, amido, alkylamido, dialkylamido, thioyl, sulfonyl, cyclyl, heterocyclyl, aryl, or heteroaryl, optionally substituted at one or more positions with 1-4 R 6  groups; 
 R 5  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, hydroxy, amino, amido, phosphonate, carboxyl, ether, alkylthio, haloalkyl, and cyano; and 
 R 6  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, alkehyde, ester, heterocycle, an aromatic or heteroaromatic ring, haloalkyl, and cyano. 
 
     
     
         2 . The compound according to the preceding claim, wherein R 1  is C 1 -C 6  alkyl. 
     
     
         3 . The compound of  claim 2 , wherein R 1  is —CH 3 . 
     
     
         4 . The compound of  claim 1 , wherein R 1  is H. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is H. 
     
     
         6 . The compound of  claim 1 , wherein R 2  is C 1 -C 6  alkyl. 
     
     
         7 . The compound of  claim 6 , wherein R 2  is —CH 3 , —CD 3 , or —CHF 2 . 
     
     
         8 . The compound of  claim 1 , wherein each of R 1  and R 2  is independently C 1 -C 6  alkyl. 
     
     
         9 . The compound of  claim 8 , wherein each of R 1  and R 2  is independently —CH 3 . 
     
     
         10 . The compound of  claim 1 , wherein each of R 1  and R 2  is independently —CH 3  and R 3  is H. 
     
     
         11 . The compound of  claim 1 , wherein R 3  is H. 
     
     
         12 . The compound of  claim 1 , wherein R 3  is C 1 -C 6  alkyl. 
     
     
         13 . The compound of  claim 12 , wherein R 3  is —CH 3 . 
     
     
         14 . The compound of  claim 1 , wherein each of R 1 , R 2 , and R 3  is independently C 1 -C 6  alkyl. 
     
     
         15 . The compound of  claim 14 , wherein each of R 1 , R 2  and R 3  is independently —CH 3 . 
     
     
         16 . The compound of  claim 1 , wherein the compound is of the Formula (Ia): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The compound of  claim 1 , wherein the compound is of the Formula (Ib): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The compound of  claim 1 , wherein R 4  is heterocyclyl. 
     
     
         19 . The compound of  claim 18 , wherein the heterocyclyl is a 4 to 8-membered ring. 
     
     
         20 . The compound of  claim 18 , wherein the heterocyclyl is linked through a nitrogen atom. 
     
     
         21 . The compound of  claim 18 , wherein R 4  is substituted heterocyclyl. 
     
     
         22 . The compound of  claim 21 , wherein R 4  is selected from the group: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 22 , wherein R 4  is selected from the group: 
       
         
           
           
               
               
           
         
       
       and m is 1. 
     
     
         24 . The compound of  claim 23 , wherein R 4  is selected from the group: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 22 , wherein R 4  is selected from the group: 
       
         
           
           
               
               
           
         
       
       and m is 1. 
     
     
         26 . The compound of  claim 25 , wherein R 4  is selected from the group: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The compound of  claim 1 , wherein m is 1. 
     
     
         28 . The compound of  claim 1 , wherein m is 0. 
     
     
         29 . The compound of  claim 1 , wherein R 6  is alkyl, haloalkyl, or cyano. 
     
     
         30 . The compound of  claim 29 , wherein R 6  is alkyl or haloalkyl. 
     
     
         31 . The compound of  claim 30 , wherein R 6  is —CF 3 . 
     
     
         32 . The compound of  claim 20 , wherein R 4  is selected from the group: 
       
         
           
           
               
               
           
         
       
     
     
         33 . The compound of  claim 1 , wherein the compound of Formula (I) is of the Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 n is an integer from 0 to 4; and 
 m is selected from an integer from 0 to 4. 
 
     
     
         34 . The compound of  claim 1 , wherein the compound of Formula (I) is of the Formula (ha): 
       
         
           
           
               
               
           
         
       
       wherein:
 n is an integer from 0 to 4; and 
 m is selected from an integer from 0 to 4. 
 
     
     
         35 . The compound of  claim 1 , wherein the compound of Formula (I) is of the Formula (IIb): 
       
         
           
           
               
               
           
         
       
       wherein:
 n is an integer from 0 to 4; and 
 m is selected from an integer from 0 to 4. 
 
     
     
         36 . The compound of  claim 1 , wherein the compound is selected from the following group: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         38 . The compound of  claim 37 , wherein a solid crystalline form of the compound has an X-ray powder diffraction pattern comprising characteristic peaks, expressed in terms of 2θ, at about 7.67°, about 12.52°, about 13.49°, and about 19.31°. 
     
     
         39 . The compound of  claim 37 , wherein a solid crystalline form of the compound has an X-ray powder diffraction pattern comprising characteristic peaks, expressed in terms of 2θ, at about 9.78°, about 12.98°, about 19.20°, and about 19.67°. 
     
     
         40 . The compound of  claim 1 , wherein a solid crystalline form of the compound has a melting point of greater than or equal to about 150° C. 
     
     
         41 . The compound of  claim 1 , wherein a solid crystalline form of the compound has a melting point in the range of about 180° C. to about 205° C. 
     
     
         42 . The compound of  claim 1 , wherein a solid crystalline form of the compound has a melting point in the range of about 190° C. to about 200° C. 
     
     
         43 . A purified pharmaceutical preparation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 2  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl optionally substituted with one or more R 5  groups; 
 R 3  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 4  is halo, hydroxy, alkoxy, thiol, alkylthio, amino, alkylamino, dialkylamino, cyano, nitro, amido, alkylamido, dialkylamido, thioyl, sulfonyl, cyclyl, heterocyclyl, aryl, or heteroaryl, optionally substituted at one or more positions with 1-4 R 6  groups; 
 R 5  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, hydroxy, amino, amido, phosphonate, carboxyl, ether, alkylthio, haloalkyl, and cyano; and 
 R 6  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, alkehyde, ester, heterocycle, an aromatic or heteroaromatic ring, haloalkyl, and cyano. 
 
     
     
         44 . The preparation of the preceding claim, wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         45 . The preparation of  claim 44 , wherein the preparation comprises a diastereomeric excess of greater than or equal to about 99%. 
     
     
         46 . The preparation of  claim 44 , wherein the preparation has a moisture content of less than or equal to about 0.1%. 
     
     
         47 . A pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 2  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl optionally substituted with one or more R 5  groups; 
 R 3  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 4  is halo, hydroxy, alkoxy, thiol, alkylthio, amino, alkylamino, dialkylamino, cyano, nitro, amido, alkylamido, dialkylamido, thioyl, sulfonyl, cyclyl, heterocyclyl, aryl, or heteroaryl, optionally substituted at one or more positions with 1-4 R 6  groups; 
 R 5  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, hydroxy, amino, amido, phosphonate, carboxyl, ether, alkylthio, haloalkyl, and cyano; and 
 R 6  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, alkehyde, ester, heterocycle, an aromatic or heteroaromatic ring, haloalkyl, and cyano. 
 
     
     
         48 . A method for treating a TRPA1 mediated disorder in a subject, the method comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 2  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl optionally substituted with one or more R 5  groups; 
 R 3  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 4  is halo, hydroxy, alkoxy, thiol, alkylthio, amino, alkylamino, dialkylamino, cyano, nitro, amido, alkylamido, dialkylamido, thioyl, sulfonyl, cyclyl, heterocyclyl, aryl, or heteroaryl, optionally substituted at one or more positions with 1-4 R 6  groups; 
 R 5  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, hydroxy, amino, amido, phosphonate, carboxyl, ether, alkylthio, haloalkyl, and cyano; and 
 R 6  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, alkehyde, ester, heterocycle, an aromatic or heteroaromatic ring, haloalkyl, and cyano, 
 to thereby treat the subject. 
 
     
     
         49 . A method for treating pain in a subject, the method comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 2  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl optionally substituted with one or more R 5  groups; 
 R 3  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 4  is halo, hydroxy, alkoxy, thiol, alkylthio, amino, alkylamino, dialkylamino, cyano, nitro, amido, alkylamido, dialkylamido, thioyl, sulfonyl, cyclyl, heterocyclyl, aryl, or heteroaryl, optionally substituted at one or more positions with 1-4 R 6  groups; 
 R 5  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, hydroxy, amino, amido, phosphonate, carboxyl, ether, alkylthio, haloalkyl, and cyano; and 
 R 6  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, alkehyde, ester, heterocycle, an aromatic or heteroaromatic ring, haloalkyl, and cyano, 
 to thereby treat the subject. 
 
     
     
         50 . The method of  claim 49 , wherein the pain is neuropathic pain. 
     
     
         51 . The method of  claim 49 , wherein the pain is inflammatory pain. 
     
     
         52 . The method of  claim 49 , wherein the pain is PDN or CIPN. 
     
     
         53 . The method of  claim 49 , wherein the pain is visceral pain. 
     
     
         54 . The method of  claim 49 , wherein the pain is selected from the group: cancer pain, burn pain, oral pain, crush and injury-induced pain, incisional pain, bone pain, sickle cell disease pain, fibromyalgia and musculoskeletal pain. 
     
     
         55 . The method of  claim 49 , wherein the pain is from hyperalgesia or allodynia. 
     
     
         56 . A method for treating inflammatory disease in a subject, the method comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 2  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl optionally substituted with one or more R 5  groups; 
 R 3  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 4  is halo, hydroxy, alkoxy, thiol, alkylthio, amino, alkylamino, dialkylamino, cyano, nitro, amido, alkylamido, dialkylamido, thioyl, sulfonyl, cyclyl, heterocyclyl, aryl, or heteroaryl, optionally substituted at one or more positions with 1-4 R 6  groups; 
 R 5  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, hydroxy, amino, amido, phosphonate, carboxyl, ether, alkylthio, haloalkyl, and cyano; and 
 R 6  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, alkehyde, ester, heterocycle, an aromatic or heteroaromatic ring, haloalkyl, and cyano. 
 
     
     
         57 . A method for treating neuropathy in a subject, the method comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 2  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl optionally substituted with one or more R 5  groups; 
 R 3  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 4  is halo, hydroxy, alkoxy, thiol, alkylthio, amino, alkylamino, dialkylamino, cyano, nitro, amido, alkylamido, dialkylamido, thioyl, sulfonyl, cyclyl, heterocyclyl, aryl, or heteroaryl, optionally substituted at one or more positions with 1-4 R 6  groups; 
 R 5  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, hydroxy, amino, amido, phosphonate, carboxyl, ether, alkylthio, haloalkyl, and cyano; and 
 R 6  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, alkehyde, ester, heterocycle, an aromatic or heteroaromatic ring, haloalkyl, and cyano, 
 to thereby treat the subject. 
 
     
     
         58 . The method of  claim 57 , wherein the neuropathy is from diabetes, chemical injury, chemotherapy, and or trauma. 
     
     
         59 . A method for treating a dermatological disorder in a subject, the method comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 2  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl optionally substituted with one or more R 5  groups; 
 R 3  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 4  is halo, hydroxy, alkoxy, thiol, alkylthio, amino, alkylamino, dialkylamino, cyano, nitro, amido, alkylamido, dialkylamido, thioyl, sulfonyl, cyclyl, heterocyclyl, aryl, or heteroaryl, optionally substituted at one or more positions with 1-4 R 6  groups; 
 R 5  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, hydroxy, amino, amido, phosphonate, carboxyl, ether, alkylthio, haloalkyl, and cyano; and 
 R 6  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, alkehyde, ester, heterocycle, an aromatic or heteroaromatic ring, haloalkyl, and cyano, 
 to thereby treat the subject. 
 
     
     
         60 . The method of  claim 59 , wherein the dermatological disorder is selected from atopic dermatitis, acute pruritus, psoriasis, hives, eczema, dyshidrotic eczema, mouth ulcers, and diaper rash. 
     
     
         61 . A method for treating a pulmonary disease in a subject, the method comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 2  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl optionally substituted with one or more R 5  groups; 
 R 3  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 4  is halo, hydroxy, alkoxy, thiol, alkylthio, amino, alkylamino, dialkylamino, cyano, nitro, amido, alkylamido, dialkylamido, thioyl, sulfonyl, cyclyl, heterocyclyl, aryl, or heteroaryl, optionally substituted at one or more positions with 1-4 R 6  groups; 
 R 5  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, hydroxy, amino, amido, phosphonate, carboxyl, ether, alkylthio, haloalkyl, and cyano; and 
 R 6  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, alkehyde, ester, heterocycle, an aromatic or heteroaromatic ring, haloalkyl, and cyano, 
 to thereby treat the subject. 
 
     
     
         62 . The method of  claim 61 , wherein the pulmonary disease is an obstructive disease. 
     
     
         63 . The method of  claim 61 , wherein the pulmonary disease is chronic obstructive pulmonary disease or asthma. 
     
     
         64 . A method for treating cough in a subject, the method comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 2  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl optionally substituted with one or more R 5  groups; 
 R 3  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 4  is halo, hydroxy, alkoxy, thiol, alkylthio, amino, alkylamino, dialkylamino, cyano, nitro, amido, alkylamido, dialkylamido, thioyl, sulfonyl, cyclyl, heterocyclyl, aryl, or heteroaryl, optionally substituted at one or more positions with 1-4 R 6  groups; 
 R 5  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, hydroxy, amino, amido, phosphonate, carboxyl, ether, alkylthio, haloalkyl, and cyano; and 
 R 6  is independently H, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, alkehyde, ester, heterocycle, an aromatic or heteroaromatic ring, haloalkyl, and cyano, 
 to thereby treat the subject. 
 
     
     
         65 . The method of  claim 64 , wherein the cough is allergy-induced cough.