发明名称 Vanilloid receptor ligands, pharmaceutical compositions containing them, process for making them, and use thereof to treat pain and other conditions
摘要 Vanilloid receptor ligand compounds corresponding to formula I:; pharmaceutical compositions containing such compounds, a process for producing such compounds, and methods of using such compounds for treating or inhibiting pain and various other disorders or conditions.
申请公布号 US8785474(B2) 申请公布日期 2014.07.22
申请号 US201113210719 申请日期 2011.08.16
申请人 Gruenenthal GmbH 发明人 Frank Robert;Bahrenberg Gregor;Christoph Thomas;Schiene Klaus;De Vry Jean;Saunders Derek;Sundermann Bernd;Lee Jeewoo
分类号 C07D401/12;C07D401/14;A61K31/4709;A61K31/4725 主分类号 C07D401/12
代理机构 Crowell & Moring LLP 代理人 Crowell & Moring LLP
主权项 1. A compound corresponding to formula I: wherein n is 0, 1, 2, 3 or 4; R1 and R2 together denote —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═CH—CH═N—; —CH═CH—N═CH—; —CR68═CR69—CH═N—; and —CR68═CR69—N═CR70—, 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═CH—CH═N—; —CH═CH—N═CH—; —CR68═CR69—CH═N—; and —CR68═CR69—N═CR70—, which is attached in any desired direction to the parent structure; or R4 and R5 together denote —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; oran 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; 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 —NR40R41; —OR42; or —SR43; R40, R41, R42, and R43 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; oran 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; and R68, 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; 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; andsaid 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).
地址 Aachen DE
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