Low molecular weight modulators of the cold menthol receptor trpm8 and use thereof

Abstract

The invention relates to new types of modulators of the cold menthol receptor TRPM8, to methods of modulating the TRPM8 receptor using these modulators; and in particular the use of the modulators for inducing a sensation of coldness; and also the articles and compositions produced using these modulators.

1 .- 23 . (canceled) 
     
     
         24 . A method for the in-vitro or in-vivo modulation of the cold menthol receptor TRMP8, where the receptor is brought into contact with at least one modulator which is selected from compounds of the following structure type 
       
         
           
           
               
               
           
         
         in which 
         the bonds a and b, independently of one another, are a C—C single bond or a C—C double bond, or a and b are simultaneously in each case a C—C double bond or simultaneously in each case a C—C single bond; 
         U is —CH 2 —, —O— or a chemical single bond; 
         V is —CH 2 — or carbonyl; 
         W is N or CH; 
         X and Z, independently of one another, are selected from
 —O—, —S—, —S(═O)—, or —S(═O) 2 — groups; 
 
         Y is selected from
 straight-chain or branched C 1 -C 8 -alkylene groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH 2 , OH, SH, halogen or straight-chain or branched C 1 -C 6 -alkoxy groups; or 
 
         X—Y—Z, together with the carbon atom to which they are bonded, form a keto group: 
         R 11  to R 18 , independently of one another, are selected from:
 H; aryl; 
 straight-chain or branched, optionally mono- or polyunsaturated C 1 -C 6 -alkyl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from oxo groups (═O), NH 2 , OH, SH, halogen or straight-chain or branched C 1 -C 6 -alkoxy groups; and 
 straight-chain or branched C 1 -C 6 -alkyloxy groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH 2 , OH, SH, halogen or straight-chain or branched C 1 -C 6 -alkoxy groups; or 
 R 11  and R 12 , together with the carbon atoms to which they are bonded, form a 4-, 5-, 6- or 7-membered, saturated or mono- or polyunsaturated, carbo- or heterocyclic ring which optionally carries 1, 2, 3, 4 or 5 identical or different substituents which are selected from straight-chain or branched C 1 -C 6 -alkyl groups, and oxo groups (═O), and the ring heteroatoms are identical or different and are selected from O, N and S; 
 
         and also salts of these compounds, in particular acid addition salts with inorganic or in particular organic, mono- or in particular polybasic carboxylic acids; 
         and optionally in stereoisomerically pure form or as a mixture of stereoisomers. 
       
     
     
         25 . The method according to  claim 25 , in which the compound is selected from:
 a) compounds of the general formula IA:   
       
         
           
           
               
               
           
         
         in which: 
         a, W, X, Y, Z and R 11  to R 18  have the meanings given in  claim 25 ; 
         or 
         b) compounds of the general formula IB; 
       
       
         
           
           
               
               
           
         
         in which: 
         b, V, W, X, Y, Z and R 11  to R 18  have the meanings given in  claim 25 ; 
         U is —CH 2 — or —O—; and 
         where U and V are not simultaneously —CH 2 —, 
         or 
         c) of the general formula IC: 
       
       
         
           
           
               
               
           
         
         a, X, Y, Z and R 11  to R 18  have the meanings given in  claim 25 ; 
         U is —CH 2 — or a chemical bond; and 
         V is —CH 2 — or carbonyl; 
         where U and V are optionally not simultaneously —CH 2 —. 
       
     
     
         26 . A method for the in-vitro or in-vivo modulation of the cold menthol receptor TRMP8, where the receptor is brought into contact with at least one modulator which is selected from compounds of the following structure type II: 
       
         
           
           
               
               
           
         
         in which 
         R 21 , R 22 , R 23 , R 24  and R 25  are identical or different and are selected from
 H; 
 halogen; 
 straight-chain or branched C 1 -C 6 -alkyl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH 2 , OH, SH, halogen or straight-chain or branched C 1 -C 6 -alkoxy groups; 
 straight-chain or branched C 1 -C 6 -alkoxy groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH 2 , OH, SH, halogen or C 1 -C 6 -alkoxy groups; 
 mono- or polynuclear aryl, arylalkyl and heteroaryl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH 2 , OH, SH, halogen, straight-chain or branched C 1 -C 6 -alkyl groups and straight-chain or branched C 1 -C 6 -alkyloxy groups; where the heteroaryl groups have 1, 2, 3 or 4 ring heteroatoms which are identical or different and are selected from O, N and S; or 
 
         two adjacent radicals R 21 , R 22 , R 23 , R 24  and R 25 , together with the carbon atoms to which they are bonded, form a 4-, 5-, 6- or 7-membered, mono- or polyunsaturated heterocyclic ring which optionally carries 1, 2, 3, 4 or 5 identical or different substituents which are selected from straight-chain or branched C 1 -C 6 -alkyl groups, and which has 1, 2 or 3 ring heteroatoms which are identical or different and are selected from O, N and S; 
         R 26  and R 27  are identical or different and is selected from:
 straight-chain or branched C 1 -C 6 -alkyl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH 2 , OH, SH, halogen or straight-chain or branched C 1 -C 6 -alkoxy groups; 
 mono- or polynuclear aryl, arylalkyl, aryloxy, heteroaryl and heteroaryloxy groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH 2 , OH, SH, halogen, straight-chain or branched C 1 -C 6 -alkyl groups and straight-chain or branched C 1 -C 6 -alkoxy groups; where the heteroaryl groups have 1, 2, 3 or 4 ring heteroatoms which are identical or different and are selected from O, N and S; 
 and C 3 -C 7 -cycloalkyl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH 2 , OH, SH, halogen, straight-chain or branched C 1 -C 6 -alkyl groups, or straight-chain or branched C 1 -C 6 -alkoxy groups; where the cycloalkyl group is optionally bonded via a C 1 -C 4 -alkylene group; and where optionally 1, 2 or 3 ring carbon atoms may be replaced by identical or different heteroatoms selected from O, N and S; 
 
         X is selected from 
         a) C1-carbon bridges comprising up to 4 carbon atoms and of the general formula 
       
       
         
           
           
               
               
           
         
         in which 
         the radicals R a , independently of one another, are H, straight-chain or branched C 1 -C 3 -alkyl, straight-chain or branched C 2 -C 3 -alkenyl or C 2 -C 3 -alkynyl or both R a  radicals together a group of the formula 
       
       
         
           
           
               
               
           
         
         in which R x  and R y , independently of one another, are H, methyl or ethyl; 
         or 
         b) C2-carbon bridges comprising up to 4 carbon atoms and of the general formulae 
       
       
         
           
           
               
               
           
         
         in which 
         the radicals R a1 , R a2 , R b1  and R b2 , independently of one another, are H, methyl, ethyl, ethenyl, or ethynyl, or one or two geminal radical pairs R a1 /R a2  or R b1 /R b2 , independently of one another, are a group of the formula ═CH 2 ; 
         or 
         c) C3 carbon bridges comprising up to 4 carbon atoms and selected from 1,3-propylene, 1,3-propenylene or 1,3-propynylene bridges which optionally carry a side group selected from —CH 3  or ═CH 2 ; 
         or 
         d) linear 1,4-linked C4 carbon bridges which optionally has a C—C double bond or two conjugated C—C double bonds or one two C—C triple bonds; 
         and also salts of these compounds, in particular acid addition salts with inorganic or in particular organic, mono- or in particular polybasic carboxylic acids; 
         and optionally in stereoisomerically pure form or as a mixture of stereoisomers. 
       
     
     
         27 . The method according to  claim 27 , where, in the compound of the formula (II), X is not a methylene or linear 1,4-butylene bridge. 
     
     
         28 . The method according to  claim 27 , in which, in the compounds of the formula II, R 21 , R 24  and R 25  are H and
 R 22  and R 23 , together with the carbon atoms to which they are bonded, form a methylenedioxy group.   
     
     
         29 . The method according to  claim 27 , in which, in the compounds of the formula II, the radicals R 26  and R 27 , independently of one another, are an in each case mononuclear aryl or heteroaryl radical or a C 3 -C 7 -cycloalkyl radical. 
     
     
         30 . A method for the in-vitro or in-vivo modulation of the cold menthol receptor TRMP8, where the receptor is brought into contact with at least one modulator which is selected from compounds of the following structure type III: 
       
         
           
           
               
               
           
         
         in which 
         the bond a represents a C—C single bond or a C—C double bond; 
         R 21 , R 22 , R 23 , R 24  and R 25  are identical or different and are selected from
 H; 
 halogen; 
 straight-chain or branched C 1 -C 6 -alkyl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH 2 , OH, SH, halogen or straight-chain or branched C 1 -C 6 -alkoxy groups; 
 straight-chain or branched C 1 -C 6 -alkoxy groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH 2 , OH, SH, halogen or C 1 -C 6 -alkoxy groups; 
 mono- or polynuclear aryl, arylalkyl and heteroaryl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH 2 , OH, SH, halogen, straight-chain or branched C 1 -C 6 -alkyl groups and straight-chain or branched C 1 -C 6 -alkyloxy groups; where the heteroaryl groups have 1, 2, 3 or 4 ring heteroatoms which are identical or different and are selected from O, N and S; or 
 
         two adjacent radicals R 21 , R 22 , R 23 , R 24  and R 25 , together with the carbon atoms to which they are bonded, form a 4-, 5-, 6- or 7-membered, mono- or polyunsaturated heterocyclic ring which optionally carries 1, 2, 3, 4 or 5 identical or different substituents which are selected from straight-chain or branched C 1 -C 6 -alkyl groups, and which has 1, 2 or 3 ring heteroatoms which are identical or different and are selected from O, N and S; 
         R 26  and R 27  are identical or different and is selected from:
 straight-chain or branched C 1 -C 6 -alkyl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH 2 , OH, SH, halogen or straight-chain or branched C 1 -C 6 -alkoxy groups; 
 mono- or polynuclear aryl, arylalkyl, aryloxy, heteroaryl and heteroaryloxy groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH 2 , OH, SH, halogen, straight-chain or branched C 1 -C 6 -alkyl groups and straight-chain or branched C 1 -C 6 -alkoxy groups; where the heteroaryl groups have 1, 2, 3 or 4 ring heteroatoms which are identical or different and are selected from O, N and S; 
 
         and C 3 -C 7 -cycloalkyl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH 2 , OH, SH, halogen, straight-chain or branched C 1 -C 6 -alkyl groups, or straight-chain or branched C 1 -C 6 -alkoxy groups; where the cycloalkyl group is optionally bonded via a C 1 -C 4 -alkylene group; and where optionally 1, 2 or 3 ring carbon atoms may be replaced by identical or different heteroatoms selected from O, N and S; and 
         R 28  and R 29  are identical or different and are selected from H and straight-chain or branched alkyl, such as C 1 -C 8 -alkyl, straight-chain or branched alkenyl, such as C 2 -C 8 -alkenyl, straight-chain or branched alkynyl, such as C 2 -C 8 -alkynyl, cycloalkyl, such as C 3 -C 12 -cycloalkyl or cycloalkenyl, such as C 5 -C 8 -cycloalkenyl, where the carbon chain, or the carbon ring of these radicals is optionally interrupted by one or more, such as e.g. 1, 2, 3 or 4, in particular 1 or 2, heteroatoms (in the chain or in the ring), selected from O, S and N (or —NH—), in particular O, or carries one or more, such as, in particular, 1, 2 or 3, heteroatom-containing substituents, such as e.g. —COOH, —COO-alkyl, —OH, —SH, —CN, amino, nitro, as defined herein, where the sum of the carbon atoms in the radicals R 28  and R 29  together is at least 3; 
         and also salts of these compounds, in particular acid addition salts with inorganic or in particular organic, mono- or in particular polybasic carboxylic acids; 
         and optionally in stereoisomerically pure form or as a mixture of stereoisomers. 
       
     
     
         31 . The method according to  claim 25 , where the receptor is brought into contact with at least one compound which, in a cellular activity test using cells which recombinantly express the human TRPM8 receptor, modulates the permeability of these cells for Ca 2+  ions. 
     
     
         32 . The method according to  claim 25 , where the modulating compound has an agonistic or antagonistic effect on the cellular Ca 2+  ion permeability. 
     
     
         33 . The method according to  claim 25 , where the modulating compound is a TRPM8 receptor agonist. 
     
     
         34 . The use of a compound according to the definition in  claim 25  for inducing a sensation of coldness in humans and/or animals, in particular for non-therapeutic purposes. 
     
     
         35 . The use of a compound according to the definition in  claim 25  as active constituent of a pharmaceutical composition. 
     
     
         36 . The use of a compound according to the definition in  claim 25  for the treatment of prostate carcinomas, for the treatment of bladder weakness or in pain therapy. 
     
     
         37 . The use of a compound according to the definition in  claim 25  for inducing a sensation of coldness through a packaging. 
     
     
         38 . The use of a compound according to the definition in  claim 25  for inducing a sensation of coldness through a textile. 
     
     
         39 . The use according to  claim 35 , where a composition is used comprising one or more of the compounds in a concentration of from 0.1 ppm to 10% by weight, based on the total weight of the composition, for achieving a cooling effect on skin or mucosa which, compared with the cooling effect of a composition of identical composition in which merely the compound or the compounds according to the definitions from any one of claims  1  to  7  are exchanged for menthanecarboxylic acid N-ethylamide in identical concentration, is extended by at least 10 minutes. 
     
     
         40 . A substance according to the definition according to  claim 25  for use as mediator of the TRMP8 receptor. 
     
     
         41 . A composition comprising at least one compound according to  claim 25 . 
     
     
         42 . The composition according to  claim 42 , selected from
 a. pharmaceutical compositions, such as antitumor agents, agents for the treatment of diseases of the bladder, painkillers;   b. foods, such as ice cream, mousse, cream, beverages, confectionery,   c. mouthcare compositions, such as toothpaste, mouthwash, chewing gum,   d. bodycare compositions, such as skincare and haircare compositions, such as suncream, sunburn cream, lotions, shampoos, plasters,   e. foams and gels.   
     
     
         43 . The composition according to  claim 43 , comprising
 a) one or more further substances with a physiological cooling effect, where the further substance or one, several or all of the further substances (i) cause a gustatory effect or (ii) do not cause a gustatory effect,   and/or   b) one or more aroma substances without a physiological cooling effect   and/or   c) one or more trigeminally or mouth-washing effective substances without a physiological cooling effect   and/or   d) (iii) one or (iv) several compounds which, in the case of (iv), independently of one another or together, additionally cause a taste-modulating effect and/or a trigeminal and/or mouth-washing stimulus.   
     
     
         44 . A product comprising at least one compound according to the definition in  claim 25 , selected from
 a) textile products,   b) packaging materials,   c) tobacco products;   d) remedies;   e) hygiene products, or   f) freshening wipes.   
     
     
         45 . The substance according to the definition according to  claim 25 . 
     
     
         46 . The substance according to  claim 46 , selected from compounds according to tables 1 or 2 A to D. 
     
     
         47 . The composition according to  claim 41  for preventing, controlling or alleviating symptoms of coughing, sneezing, inflammation, throat pain or hoarseness.