Organic compounds as TRPM8 activators

A method of modulating of transient receptor potential channel melastatin member 8 (TRPM8) comprising bringing the receptor into contact with a compound of formula (I), a salt or solvate thereof

• wherein one of X1, X2, and X3 is >N—C (O) R and the other two are independently selected from C, N, and O, with the proviso that not both of them are C, and wherein R is selected from C1-C15 hydrocarbon residue optionally comprising one heteroatom selected from O and S;
• and
• a) R1 is H;
• and B represents a monovalent residue (a)
• or
• b) R1 is selected from
• i) halogen,
• ii) C6-C10 aryl optionally substituted with up to four substituents independently selected from the group consisting of:
• halogen;
• OH (hydroxyl);
• C≡N (cyano);
• NO2 (nitro);
• C1-C6 alky optionally comprising up to 5 halogen atoms;
• C1-C3 alkyl comprising up to 3 OH groups;
• C2-C6 alkenyl;
• C1-C6 alkoxy optionally comprising up to 3 halogen atoms;
• C1-C3 alkoxy C1-C3 alkyl;
• C3-C7 cycloalkyl;
• —C(O) R10 wherein R10 is selected from C1-C3 alkyl;
• —OC(O) R11 wherein R11 is selected from H, and C1-C3 alkyl;
• —C(O) O—R12 wherein R12 is selected from hydrogen and C1-C3 alkyl;
• —(CH2)mN (R13)R14 wherein m is 0 or 1, R13 is selected from hydrogen, C1-C3 alkyl, and —SO2R15 wherein R15 is C1-C3 alkyl, and R14 is selected from hydrogen, C1-C3 alkyl, and —SO2R16 wherein R16 is C1-C3 alkyl, or wherein R13 and R14 form together with the N atom to which they are attached morpholine, thiomorpholine, or 1,1-dioxothiomorpholine;
• —SR17 wherein R17 is selected from hydrogen and C1-C3 alkyl;
• and
• —S(O)2R18 wherein R18 is selected from hydrogen and C1-C3 alkyl;
• with the proviso that when the aryl ring is substituted with two or more substituents, two substituents may form a cyclic ring together with the carbon atoms to which they are attached, and
• iii) C5-C10 mono- or bicyclic heteroaryl wherein up to 2 C-atoms are replaced by a hetero atoms independently selected from sulfur, nitrogen, and oxygen, optionally substituted with up to four substituents selected from the group consisting of halogen;
• OH;
• C≡N;
• NO2;
• C1-C6 alky optionally comprising up to 5 halogen atoms;
• C2-C6 alkenyl;
• C1-C6 alkoxy optionally comprising up to 3 halogen atoms;
• C1-C3 alkoxy C1-C3 alkyl;
• C3-C7 cycloalkyl;
• —C(O)R20 wherein R20 is selected from C1-C3 alkyl;
• —OC(O)R21 wherein R21 is selected from H, and C1-C3 alkyl;
• —C(O)O-R22 wherein R22 is selected from hydrogen and C1-C3 alkyl;
• —(CH2)mN(R23)R24 wherein m is 0 or 1, R23 is selected from hydrogen, C1-C3 alkyl, and —SO2R25 wherein R25 is C1-C3 alkyl, and R24 is selected from hydrogen, C1-C3 alkyl, and —SO2R26 wherein R26 is C1-C3 alkyl, or wherein R23 and R24 form together with the N atom to which they are attached morpholine, thiomorpholine, or 1,1-dioxothiomorpholine;
• —SR27 wherein R27 is selected from hydrogen and C1-C3 alkyl;
• and
• —S(O)2R28 wherein R28 is selected from hydrogen and C1-C3 alkyl;
• and
• B represents a monovalent residue (b)
• wherein
• R4, R5 and R6 form together with the carbon atom to which they are attached a hydrocarbon group optionally comprising up to five hetero atoms selected from O, N, S, and F;
• and
• Z is either C, S or S(O).