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

A substance, wherein the substance is a modulator for use as a mediator of the TRMP8 receptor and is a compound selected from the group consisting of:

• a) compounds of the general formula IA:
• in which:
• a is a C—C single bond or a C—C double bond,
• W is N or CH,
• X and Z, independently of one another, are —O—, —S—, —NR18—, —S(═O)—, or —S(═O)2—,
• Y is selected from straight-chain or branched C1-C8-alkylene groups which optionally carry 1, 2, 3, or 4 identical or different substituents which are selected from NH2, OH, SH, halogen or straight-chain or branched C1-C6-alkoxy groups, or
• X—Y—Z, together with the carbon atom to which they are bonded, form a keto group;
• R11 to R18, independently of one another, are selected from:
• H;
• aryl;
• straight-chain or branched, optionally mono- or polyunsaturated C1-C6-alkyl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from oxo groups (═O), NH2, OH, SH, halogen or straight-chain or branched C1-C6-alkoxy groups;
• and
• straight-chain or branched C1-C6-alkyloxy groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH2, OH, SH, halogen or straight-chain or branched C1-C6-alkoxy groups;
• or
• R11 and R12, together with the carbon atoms to which they are bonded, form a 4-, 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 C1-C6-alkyl groups, and oxo groups (═O), and the ring heteroatoms are identical or different and are selected from O, N and S;
• or
• b) compounds of the general formula IB;
• in which:
• b is a C—C single bond or a C—C double bond,
• V is —CH2— or carbonyl;
• W, X, Y, Z and R11 to R18 have the meanings given above;
• U is —CH2— or —O—;
• and
• where U and V are not simultaneously —CH2—;
• or
• c) of the general formula IC:
• a, X, Y, Z and R11 to R18 have the meanings given above;
• U is —CH2— or a chemical bond;
• and
• V is —CH2— or carbonyl;
• where U and V are optionally not simultaneously —CH2—;
• wherein the modulator is not

The composition according to claim 41, wherein the composition is selected from the group consisting of

• a. pharmaceutical compositions;
• b. foods,
• c. mouthcare compositions,
• d. bodycare compositions, and
• e. foams and gels.

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
• R21, R22, R23, R24 and R25 are identical or different and are selected from
• H;
• halogen;
• straight-chain or branched C1-C6-alkyl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH2, OH, SH, halogen or straight-chain or branched C1-C6-alkoxy groups;
• straight-chain or branched C1-C6-alkoxy groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH2, OH, SH, halogen or C1-C6-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 NH2, OH, SH, halogen, straight-chain or branched C1-C6-alkyl groups and straight-chain or branched C1-C6-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 R21, R22, R23, R24 and R25, 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 C1-C6-alkyl groups, and which has 1, 2 or 3 ring heteroatoms which are identical or different and are selected from O, N and S;
• R26 and R27 are identical or different and is selected from:
• straight-chain or branched C1-C6-alkyl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH2, OH, SH, halogen or straight-chain or branched C1-C6-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 NH2, OH, SH, halogen, straight-chain or branched C1-C6-alkyl groups and straight-chain or branched C1-C6-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 C3-C7-cycloalkyl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH2, OH, SH, halogen, straight-chain or branched C1-C6-alkyl groups, or straight-chain or branched C1-C6-alkoxy groups;
• where the cycloalkyl group is optionally bonded via a C1-C4-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 Ra, independently of one another, are H, straight-chain or branched C1-C3-alkyl, straight-chain or branched C2-C3-alkenyl or C2-C3-alkynyl or both Ra radicals together a group of the formula
• in which Rx and Ry, 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 Ra1, Ra2, Rb1 and Rb2, independently of one another, are H, methyl, ethyl, ethenyl, or ethynyl, or one or two geminal radical pairs Ra1/Ra2 or Rb1/Rb2, independently of one another, are a group of the formula ═CH2;
• 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 —CH3 or ═CH2;
• 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.

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;
• R21, R22, R23, R24 and R25 are identical or different and are selected from
• H;
• halogen;
• straight-chain or branched C1-C6-alkyl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH2, OH, SH, halogen or straight-chain or branched C1-C6-alkoxy groups;
• straight-chain or branched C1-C6-alkoxy groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH2, OH, SH, halogen or C1-C6-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 NH2, OH, SH, halogen, straight-chain or branched C1-C6-alkyl groups and straight-chain or branched C1-C6-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 R21, R22, R23, R24 and R25, 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 C1-C6-alkyl groups, and which has 1, 2 or 3 ring heteroatoms which are identical or different and are selected from O, N and S;
• R26 and R27 are identical or different and is selected from:
• straight-chain or branched C1-C6-alkyl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH2, OH, SH, halogen or straight-chain or branched C1-C6-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 NH2, OH, SH, halogen, straight-chain or branched C1-C6-alkyl groups and straight-chain or branched C1-C6-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 C3-C7-cycloalkyl groups which optionally carry 1, 2, 3 or 4 identical or different substituents which are selected from NH2, OH, SH, halogen, straight-chain or branched C1-C6-alkyl groups, or straight-chain or branched C1-C6-alkoxy groups;
• where the cycloalkyl group is optionally bonded via a C1-C4-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
• R28 and R29 are identical or different and are selected from H and straight-chain or branched alkyl, such as C1-C8-alkyl, straight-chain or branched alkenyl, such as C2-C8-alkenyl, straight-chain or branched alkynyl, such as C2-C8-alkynyl, cycloalkyl, such as C3-C12-cycloalkyl or cycloalkenyl, such as C5-C8-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 R28 and R29 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.