Small molecule modulators of the cold and menthol receptor trpm8

Abstract

The present invention relates to the use of compounds which are capable of producing a cooling sensation when they are brought into contact with the human body. In particular, the present invention relates to the use of compounds modulating TRPM8, and optionally to the use of compounds selectively exhibiting agonist activity at the TRPM8 channel. Such compounds have applications in many fields, particularly in oral and personal hygiene products and foodstuffs, but also in pharmaceutical composition products, cosmetics, textile products and packaging products. The present invention further relates to products containing such compounds and to the medical use of such compounds.

1 . A product comprising a Compound I.2 having the following general formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable derivative thereof; 
         wherein:
 R 1  is selected from —H; —OT 3 , —ST 3 , or —(C 1 -C 3 )alkyl, wherein T 3  is selected from —H or —(C 1 -C 2 )alkyl; 
 R 3  is selected from -phenyl or -heteroaryl selected from the group consisting of pyridine, pyrazine, pyridazine and pyrimidine, each of which is unsubstituted or substituted with 1 or 2 independently selected R 6  groups; 
 R 4  is selected from —(C 1 -C 3 )alkyl, —(C 2 -C 3 )alkenyl, —(C 2 -C 3 )alkynyl, or —(C 1 -C 3 )alkoxy; and 
 R 6  is selected from —H, —(C 1 -C 2 )alkyl, —(C 2 )alkenyl, —(C 2 )alkynyl, —OR 7 , —SR 7 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —N(R 7 )OH, —C(═O)R 7 , —C(═O)OR 7 , —S(═O)R 7 , or —S(═O) 2 R 7 ; 
 each R 7  is independently selected from —H, or —CH 3 ; and 
 each halo is independently selected from —F, —Cl, —Br, or —I; 
 
         and wherein the product is selected from the group consisting of a cosmetic product composition, a food product composition, a textile product, a pharmaceutical product composition and a packaging product. 
       
     
     
         2 . The product of  claim 1 , wherein the compound exhibits selective agonist activity at TRPM8. 
     
     
         3 . The product of  claim 1 , wherein the compound exhibits activity at TRPM8, which activity is at least three times, or even at least four times, greater than the activity of the compound at TRPA1. 
     
     
         4 . The product of  claim 3 , wherein in a functional cell based assay the compound modulates the intracellular calcium level of human cells recombinantly expressing human TRPM8 at least four times more efficient than that of human cells recombinantly expressing human TRPA1. 
     
     
         5 . (canceled) 
     
     
         6 . The product of  claim 1 , wherein the compound is Compound I.3 having the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         7 . (canceled) 
     
     
         8 . The product of  claim 1 , wherein the cosmetic product composition is selected from the group consisting of an insect repellent composition, an oral hygiene composition, a skin care composition, and a hair care composition or the food product composition is selected from the group consisting of ice cream, mousse, crème, beverages and confectionery or the textile product is selected from the group consisting of shirts, trousers, socks, towels, headgear, underwear and shoes or the pharmaceutical product composition is selected from the group consisting of anticancer medicaments, bladder disease medicaments and medicaments for the treatment of pain. 
     
     
         9 - 11 . (canceled) 
     
     
         12 . A method of treating a patient comprising administering a compound as defined in  claim 1  to a patient in need thereof. 
     
     
         13 . A method of treating pain comprising administering a compound as defined in  claim 1  to a patient in need thereof. 
     
     
         14 . A method of producing a cooling sensation, the method comprising contacting skin and/or a mucosal membrane of a human or animal with an effective amount of a compound as defined in  claim 1  to produce the cooling sensation. 
     
     
         15 . In vitro method of modulating the cold and menthol receptor TRPM8, wherein TRPM8 is contacted with a compound as defined in  claim 1 . 
     
     
         16 . The product of  claim 5 , wherein the cosmetic product composition is selected from the group consisting of an insect repellent composition, an oral hygiene composition, a skin care composition, and a hair care composition or the food product composition is selected from the group consisting of ice cream, mousse, crème, beverages and confectionery or the textile product is selected from the group consisting of shirts, trousers, socks, towels, headgear, underwear and shoes or the pharmaceutical product composition is selected from the group consisting of anticancer medicaments, bladder disease medicaments and medicaments for the treatment of pain. 
     
     
         17 . A method of treating a patient comprising administering a compound as defined in  claim 5  to a patient in need thereof. 
     
     
         18 . A method of treating pain comprising administering a compound as defined in  claim 5  to a patient in need thereof. 
     
     
         19 . A method of producing a cooling sensation, the method comprising contacting skin and/or a mucosal membrane of a human or animal with an effective amount of a compound as defined in  claim 5  to produce the cooling sensation. 
     
     
         20 . In vitro method of modulating the cold and menthol receptor TRPM8, wherein TRPM8 is contacted with a compound as defined in  claim 5 .