Vanilloid Receptor Ligands, Pharmaceutical Compositions Containing Them, Process for Making Them, and Use Thereof for Treating Pain and Other Conditions

A compound corresponding to formula I:

• wherein
• n is 0, 1, 2, 3 or 4;
• R1 and R2 together denote a residue selected from the group consisting of —CH═N—NH—;
• —CH═N—NR71—;
• —S—C(═S)—NH—;
• —O—C(═S)—NH—;
• —S—C(═O)—NH—;
• —O—C(═O)—NH—;
• —S—C(═S)—NR63—;
• —O—C(═S)—NR63—;
• —S—C(═O)—NR63—;
• —O—C(═O)—NR63—;
• —S—CH═N—;
• —S—CR29═N—;
• —N═CH—O—;
• —N═CR30—O—;
• —NH—C(═O)—NH—;
• —NH—C(═S)—NH—;
• —NR66—C(═O)—NR65—;
• —NR66—C(═S)—NR65—;
• —O—CH2—C(═O)—NH—;
• —O—CH2—O—;
• —O—CH2—CH2—O—;
• —O—CH2—CH2—CH2—O—;
• —O—CH2—CH2—NH—, and —CH═CH—N═CH—, which is attached in any desired direction to the parent structure;
• or
• R2 and R3 together denote a residue selected from the group consisting of —CH═N—NH—;
• —CR28═N—NH—;
• —CH═N—NR62—;
• —CR28═N—NR62—;
• —S—C(═S)—NH—;
• —O—C(═S)—NH—;
• —S—C(═O)—NH—;
• —O—C(═O)—NH—;
• —S—C(═S)—NR63—;
• —O—C(═S)—NR63—;
• —S—C(═O)—NR63—;
• —O—C(═O)—NR63—;
• —S—CH═N—;
• —S—CR29═N—;
• —N═CH—O—;
• —N═CR30—O—;
• —N═CH—NH—;
• —N═CH—NR64—;
• —NH—C(═O)—NH—;
• —NH—C(═S)—NH—;
• —NR66—C(═O)—NR65—;
• —NR66—C(═S)—NR65—;
• —N═N—NH—;
• —N═N—NR67—;
• —O—CH2—C(═O)—NH—;
• —O—CH2—O—;
• —CH2—CH2—NH—;
• —CH2—CH2—CH2—NH;
• —CH2—(C═O)—NH;
• —CH2—CH2—C(═O)—NH—;
• —O—CH2—CH2—O—;
• —O—CH2—CH2—CH2—O—;
• —N═N—CH═CH—;
• —N═CH—N═CH;
• —N═CH—CH═N—;
• —CH═CH—CH═N—;
• —CH═CH—N═CH—;
• —CH═N—N═CH—, —N═N—CR68═CR69—;
• —N═CR68—N═CR69;
• —N═CR68—CR69═N—;
• —CR68═CR69—CH═N—;
• —CR68═CR69—N═CR70—;
• —CR68═N—N═CR69— and —O—CH2—CH2—NH—, which is attached in any desired direction to the parent structure;
• or
• R3 and R4 together denote a residue selected from the group consisting of —CH═N—NH—;
• —CR28═N—NH—;
• —CH═N—NR62—;
• —CR28═N—NR62—;
• —S—C(═S)—NH—;
• —O—C(═S)—NH—;
• —S—C(═O)—NH—;
• —O—C(═O)—NH—;
• —S—C(═S)—NR63—;
• —O—C(═S)—NR63—;
• —S—C(═O)—NR63—;
• —O—C(═O)—NR63—;
• —S—CH═N—;
• —S—CR29═N—;
• —N═CH—O—;
• —N═CR30—O—;
• —N═CH—NH—;
• —N═CH—NR64—;
• —NH—C(═O)—NH—;
• —NH—C(═S)—NH—;
• —NR66—C(═O)—NR65—;
• —NR66—C(═S)—NR65—;
• —N═N—NH—;
• —N═N—NR67—;
• —O—CH2—C(═O)—NH—;
• —O—CH2—O—;
• —CH2—CH2—NH—;
• —CH2—CH2—CH2—NH;
• —CH2—(C═O)—NH;
• —CH2—CH2—C(═O)—NH—;
• —O—CH2—CH2—O—;
• —O—CH2—CH2—CH2—O—;
• —N═N—CH═CH—;
• —N═CH—N═CH;
• —N═CH—CH═N—;
• —CH═CH—CH═N—;
• —CH═CH—N═CH—;
• —CH═N—N═CH—, —N═N—CR61═CR69—;
• —N═CR68—N═CR69;
• —N═CR68—CR69═N—;
• —CR68═CR69—CH═N—;
• —CR68═CR69—N═CR70—;
• —CR68═N—N═CR69— and —O—CH2—CH2—NH—, which is attached in any desired direction to the parent structure;
• or
• R4 and R5 together denote a residue selected from the group consisting of —CH═N—NH—;
• —CH═N—NR71—;
• —S—C(═S)—NH—;
• —O—C(═S)—NH—;
• —S—C(═O)—NH—;
• —O—C(═O)—NH—;
• —S—C(═S)—NR63—;
• —O—C(═S)—NR63—;
• —S—C(═O)—NR63—;
• —O—C(═O)—NR63—;
• —S—CH═N—;
• —S—CR29═N—;
• —N═CH—O—;
• —N═CR30—O—;
• —NH—C(═O)—NH—;
• —NH—C(═S)—NH—;
• —NR66—C(═O)—NR65—;
• —NR66—C(═S)—NR65—;
• —O—CH2—C(═O)—NH—;
• —O—CH2—O—;
• —O—CH2—CH2—O—, —O—CH2—CH2—CH2—O—;
• —O—CH2—CH2—NH—, and —CH═CH—N═CH—, which is attached in any desired direction to the parent structure;
• and
• the remaining residues of R1, R2, R3, R4 and R5 each independently represent H;
• F;
• Cl;
• Br;
• I;
• —SF5;
• —NO2;
• —CN;
• —NH2;
• —OH;
• —SH;
• —C(═O)—NH2;
• —S(═O)2—NH2;
• —C(═O)—NH—OH;
• —C(═O)—OH;
• —C(═O)—H;
• —S(═O)2—OH;
• —C(═NH)—NH2;
• —C(═NH)—NH—R9;
• —N═C(NH2)2;
• —N═C(NHR10)(NHR11);
• —O—P(═O)2—O—R12;
• —NHR13;
• —NR14R15;
• —NH—C(═O)—R13;
• —OR16;
• —SR17;
• —C(═O)—NHR18;
• —C(═O)—NR19R20;
• —S(═O)2—NHR21;
• —S(═O)2—NR22R23;
• —C(═O)—OR24;
• —C(═O)—R25;
• —S(═O)—R26;
• —S(═O)2—R27 or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C1-10 residue;
• R6 denotes H or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C1-10 residue;
• R7 denotes hydrogen or —OH;
• or
• R6 and R7 together with the carbon atom to which they are attached form a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3-, 4-, 5-, 6- or 7-membered cycloaliphatic residue;
• R8 denotes —SF5;
• —O—CF3;
• —CF3;
• —O—CFH2;
• —O—CF2H;
• —CFH2;
• —CF2H;
• or an unsubstituted, monosubstituted or polysubstituted tert.-butyl residue;
• T denotes C—R35;
• U denotes C—R36;
• V denotes N, and W denotes C—R38;
• or
• T denotes C—R35;
• U denotes N;
• V denotes C—R37, and W denotes C—R38;
• or
• T denotes N;
• U denotes C—R36;
• V denotes C—R37, and W denotes C—R38;
• or
• T denotes N;
• U denotes N;
• V denotes C—R37, and W denotes C—R38;
• or
• T denotes N;
• U denotes C—R36;
• V denotes N, and W denotes C—R38;
• or
• T denotes C—R35;
• U denotes N;
• V denotes N, and W denotes C—R38;
• or
• T denotes C—R35;
• U denotes C—R36;
• V denotes C—R37, and W denotes C—R38;
• R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 each independently denote a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C1-10 residue;
• or
• an unsaturated or saturated, unsubstituted, monosubstituted or polysubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered cycloaliphatic residue optionally comprising at least one heteroatom as a ring member, wherein said cycloaliphatic residue optionally may be fused with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted mono- or polycyclic ring system, or optionally may be attached via a linear or branched, unsubstituted, monosubstituted or polysubstituted C1-6 alkylene group or 2- to 6-membered heteroalkylene group, or both;
• or
• an unsubstituted, monosubstituted or polysubstituted 5- to 14-membered aryl or heteroaryl residue, which optionally may be fused with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted mono- or polycyclic ring system, or optionally may be attached via a linear or branched, unsubstituted, monosubstituted or polysubstituted C1-6 alkylene group or 2- to 6-membered heteroalkylene group, or both;
• R28 denotes F;
• Cl;
• Br;
• I;
• —SF5;
• —NO2;
• —CF3;
• —CN;
• —NH2 or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C1-10 residue;
• R29 and R30 each independently denote —NH—C(═O)—R31;
• —NH2;
• —NH—S(—O)2—R32;
• —NH—C(═O)—O—R33;
• —S—R34 or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C1-10 residue;
• R31, R32, R33 and R34 each independently denote a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C1-10 residue;
• R35, R36 and R37 each independently denote H;
• F;
• Cl;
• Br;
• I;
• —SF5;
• —NO2;
• —CF3;
• —CN;
• —NH2;
• —OH;
• —SH;
• —C(═O)—NH2;
• —S(═O)2—NH2;
• —C(═O)—NH—OH;
• —C(═O)—OH;
• —C(═O)—H;
• —S(═O)2—OH;
• —NHR13;
• —NR14R15;
• —NH—C(═O)—R13;
• —OR16;
• —SR17;
• —C(═O)—NHR18;
• —C(═O)—NR19R20;
• —S(═O)2—NHR21;
• —S(═O)2—NR22R23;
• —C(═O)—OR24;
• —C(═O)—R25;
• —S(═O)—R26;
• —S(═O)2—R27;
• or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C1-10 residue;
• or
• an unsubstituted, monosubstituted or polysubstituted 5- to 14-membered aryl or heteroaryl residue, which optionally may be fused with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted mono- or polycyclic ring system, or optionally may be attached via a linear or branched, unsubstituted, monosubstituted or polysubstituted C1-6 alkylene group or C2-6 alkenylene group or C2-6 alkynylene group, or both;
• R38 denotes H;
• F;
• Cl;
• Br;
• I;
• —SF5;
• —NO2;
• —CF3;
• —CF2Cl;
• —CN;
• —NH2;
• —OH;
• —SH;
• —C(═O)—NH2;
• —S(═O)2—NH2;
• —C(═O)—NH—OH;
• —C(═O)—OH;
• —C(═O)—H;
• —S(═O)2—OH;
• —NHR39;
• —NR4OR41;
• —OR42;
• —SR43;
• —C(═O)—NHR44;
• —C(═O)—NR45R46;
• —S(═O)2—NHR47;
• —S(═O)2—NR43R49;
• —C(═O)—OR50;
• —C(═O)—R51;
• —S(═O)—R52;
• —S(═O)2—R53;
• —C(═NH)—NH2;
• —C(═NH)—NH—R54;
• —N═C(NH2)2;
• —N═C(NHR55)(NHR56);
• or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C1-10 residue;
• or
• an unsaturated or saturated, unsubstituted, monosubstituted or polysubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered cycloaliphatic residue optionally comprising one or more heteroatoms as ring member(s), wherein said cycloaliphatic residue is attached to the parent structure via a carbon atom in the ring of the cycloaliphatic residue, and wherein said cycloaliphatic residue optionally may be fused with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted mono- or polycyclic ring system, or optionally may be attached via a linear or branched, unsubstituted, monosubstituted or polysubstituted C1-6 alkylene group or C2-6 alkenylene group or C2-6 alkynylene group, or both;
• or
• an unsubstituted, monosubstituted or polysubstituted 5- to 14-membered aryl or heteroaryl residue, which optionally may be fused with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted mono- or polycyclic ring system, or optionally may be attached via a linear or branched, unsubstituted, monosubstituted or polysubstituted C1-6 alkylene group or C2-6 alkenylene group or C2-6 alkynylene group, or both;
• R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55 and R56 each independently denote a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C1-10 residue;
• or
• an unsaturated or saturated, unsubstituted, monosubstituted or polysubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered cycloaliphatic residue optionally comprising one or more heteroatom(s) as ring member(s), wherein said cycloaliphatic residue optionally be fused with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted mono- or polycyclic ring system, or optionally may be attached via a linear or branched, unsubstituted, monosubstituted or polysubstituted C1-6 alkylene group or 2- to 6-membered heteroalkylene group, or both;
• or
• an unsubstituted, monosubstituted or polysubstituted 5- to 14-membered aryl or heteroaryl residue, which optionally may be fused with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted mono- or polycyclic ring system, or optionally may be attached via a linear or branched, unsubstituted, monosubstituted or polysubstituted C1-6 alkylene group or 2- to 6-membered heteroalkylene group, or both;
• or
• R40 and R41 together with the nitrogen atom to which they are attached form a saturated or unsaturated or unsubstituted heterocycloaliphatic residue or a 4-, 5-, 6-, 7-, 8- or 9-membered heterocycloaliphatic residue substituted with 1, 2, 3, 4 or 5 residues R57 and optionally comprising one or more further heteroatom(s) as ring member(s), wherein said heterocycloaliphatic residue optionally may be fused with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted mono- or polycyclic ring system;
• R57 denotes —NHR58, —NR59R60;
• or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C1-10 residue;
• R58, R59 and R60 each independently denote —C(═O)—R61;
• or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C1-10 residue;
• or
• an unsubstituted, monosubstituted or polysubstituted 5- to 14-membered aryl or heteroaryl residue, which optionally may be fused with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted mono- or polycyclic ring system, or optionally may be attached via a linear or branched, unsubstituted, monosubstituted or polysubstituted C1-6 alkylene group or C2-6 alkenylene group or C2-6 alkynylene group, or both;
• R61 denotes a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C1-10 residue;
• R62, R63, R64, R65, R66 and R67 each independently denote a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C1-10 residue;
• R63, R69 and R70 each independently denote F, Cl, Br, I, or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C1-10 residue;
• and
• R71 denotes an unsubstituted, monosubstituted or polysubstituted 5- to 14-membered aryl or heteroaryl residue, which optionally may be fused with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted mono- or polycyclic ring system, or optionally may be attached via a linear or branched, unsubstituted, monosubstituted or polysubstituted C1-6 alkylene group or C2-6 alkenylene group or C2-6 alkynylene group, or both;
• or a salt thereof;
• wherein:
• said aliphatic C1-10 residues and tert.-butyl residues each optionally may be substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —NH2, —SH, —O(C1-5-alkyl), —S(C1-5-alkyl), —NH(C1-5-alkyl), —N(C1-5-alkyl)(C1-5-alkyl), —C(═O)—O—C1-5-alkyl, —O—C(═O)—C1-5-alkyl, —O-phenyl, phenyl, —OCF3 and —SCF3;
• said 2- to 6-membered heteroalkylene groups, C1-6 alkylene groups, C2-6 alkenylene groups and C2-6 alkynylene groups each optionally may be substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —NH2, —SH, —O(C1-5-alkyl), —S(C1-5-alkyl), —NH(C1-5-alkyl), —N(C1-5-alkyl)(C1-5-alkyl), —OCF3 and —SCF3;
• said heteroalkylene groups each optionally may comprise 1, 2 or 3 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen as NH, and sulfur as chain link(s);
• said (hetero)cycloaliphatic residues each optionally may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of —C1-6-alkylene-OH, ═CH2, —O—C1-5-alkylene-oxetanyl, —C1-5-alkylene-O—C1-5-alkylene-oxetanyl, —CH2—NH—C1-5-alkyl, —CH2—N(C1-5-alkyl)2, —N[—C(═O)—C1-5-alkyl]-phenyl, —CH2—O—C1-5-alkyl, oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—C1-5-alkyl, —O—C(═O)—C1-5-alkyl, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—C1-5-alkyl, —C1-5-alkyl, —C(═O)—C1-5-alkyl, —C(═O)—OH, —C(═O)—O—C1-5-alkyl, —NH—C1-5-alkyl, —N(C1-5-alkyl)2, —NH-phenyl, —N(—C1-5-alkyl)-phenyl, cyclohexyl, cyclopentyl, (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5)-thiadiazolyl, thiophenyl, phenethyl, piperidinyl, pyrrolidinyl, —(CH2)-pyridinyl, pyridinyl, —O-phenyl, —O-benzyl, phenyl and benzyl, wherein the cyclic moiety of the oxetanyl, (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5)-thiadiazolyl, thiophenyl, phenethyl, —N[—C(═O)—C1-5-alkyl]-phenyl, —NH-phenyl, —N(—C1-5-alkyl)-phenyl, —(CH2)-pyridinyl, pyridinyl, —O-phenyl, —O-benzyl, phenyl and benzyl residues optionally may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —C1-5 alkyl, —O—C1-5-alkyl, —O—CF3, —S—CF3, phenyl and —O-benzyl;
• unless otherwise stated, said (hetero)cycloaliphatic residues each optionally may comprise 1, 2 or 3 (further) heteroatom(s) independently selected from the group consisting of oxygen, nitrogen and sulfur;
• the rings of said mono- or polycyclic ring systems each optionally may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of oxo (═O), thioxo (═S),), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—C1-5-alkyl, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—C1-5-alkyl, —C1-5-alkyl, —C(═O)—C1-5-alkyl, —C(═O)—OH, —C(═O)—O—C1-5-alkyl, —NH—C1-5-alkyl, —N(C1-5-alkyl)2, —O-phenyl, —O-benzyl, phenyl and benzyl, wherein the cyclic moiety of the —O-phenyl, —O-benzyl, phenyl and benzyl residues optionally may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —C1-5 alkyl, —O—C1-5-alkyl, —O—CF3, —S—CF3, phenyl and —O-benzyl;
• the rings of said mono- or polycyclic ring systems each are 5-, 6- or 7-membered and optionally may comprise 1, 2, 3, 4 or 5 heteroatom(s) as ring member(s), which are independently selected from the group consisting of oxygen, nitrogen and sulfur;
• said aryl or heteroaryl residues each optionally may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—C1-5-alkyl, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—C1-5-alkyl, —C1-5-alkyl, —C(═O)—OH, —C(═O)—C1-5-alkyl, —NH—C1-5-alkyl, —N(C1-5-alkyl)2, —NH—S(═O)2—C1-5-alkyl, —NH—C(═O)—O—C1-5-alkyl, —C(═O)—H, —C(═O)—C1-5-alkyl, —C(═O)—NH2, —C(═O)—NH—C1-5-alkyl, —C(═O)—N—(C1-5-alkyl)2, —O-phenyl, —O-benzyl, phenyl and benzyl, wherein the cyclic moiety of the —O-phenyl, —O-benzyl, phenyl and benzyl residues optionally may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —C1-5 alkyl, —O—C1-5-alkyl, —O—CF3, —S—CF3, phenyl and —O-benzyl;
• and
• said heteroaryl residues each optionally may comprise 1, 2, 3, 4 or 5 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen and sulfur as ring member(s).