High affinity ligands for nociceptin receptor ORL-1

A pharmaceutical composition comprising:

• a therapeutically effective amount of a nociceptin receptor ORL-1 agonist of the formula
• or a pharmaceutically acceptable salt or solvate thereof, wherein:
• the dotted line represents an optional double bond;
• X1 is R5—(C1–C12)alkyl, R6—(C3–C12)cycloalkyl, R7-aryl, R8-heteroaryl or R10—(C3–C7)heterocycloalkyl;
• X2 is —CHO, —CN, —NHC(═NR26)NHR26, —CH(═NOR26), —NHOR26, R7-aryl, R7-aryl(C1–C6)alkyl, R7-aryl(C1–C6)alkenyl, R7-aryl(C1–C6)-alkynyl, —(CH2)vOR13, —(CH2)vCOOR27, —(CH2)vCONR14R15, —(CH2)vNR21R22 or —(CH2)vNHC(O)R21,
• wherein v is zero, 1, 2 or 3 and wherein q is 1 to 3 and a is 1 or 2;
• R1 and R3 are each hydrogen;
• R2 and R4 together form an alkylene bridge of 1 to 3 carbon atoms;
• R5 is 1 to 3 substituents independently selected from the group consisting of H, R7-aryl, R6—(C3–C12)cycloalkyl, R8-heteroaryl, R10—(C3–C7)heterocycloalkyl, —NR19R20, —OR13 and —S(O)0-2R13;
• R6 is 1 to 3 substituents independently selected from the group consisting of H, (C1–C6)alkyl, R7-aryl, —NR19R20, —OR13 and —SR13;
• R7 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1–C6)alkyl, R25-aryl, (C3–C12)cycloalkyl, —CN, —CF3, —OR19, —(C1–C6)alkyl-OR19, —OCF3, —NR19R20, —(C1–C6)alkyl-NR19R20, —NHSO2R19, —SO2N(R26)2, —SO2R19, —SOR19, —SR19, —NO2, —CONR19R20, —NR20 COR19, —COR19, —COCF3, —OCOR19, —OCO2R19, —COOR19, —(C1–C6)alkyl-NHCOOC(CH3)3, —(C1–C6)alkyl-NHCOCF3, —(C1–C6)alkyl-NHSO2—(C1–C6)alkyl, —(C1–C6)alkyl-NHCONH—(C1–C6)-alkyl or
• wherein f is 0 to 6;
• or R7 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
• R8 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1–C6)alkyl, R25-aryl, (C3–C12)cycloalkyl, —CN, —CF3, —OR19, —(C1–C6)alkyl-OR19, —OCF3, —NR19R20, —(C1–C6)alkyl-NR19R20, —NHSO2R19, —SO2N(R26)2, —NO2, —CONR19R20, —NR20COR19, —COR19, —OCOR19, —OCO2R19 and —COOR19;
• R9 is hydrogen, (C1–C6)alkyl, halo, —OR19, —NR19R20, —NHCN, —SR19 or —(C1–C6)alkyl-NR19R20;
• R10 is H, (C1–C6)alkyl, —OR19, —(C1–C6)alkyl-OR19, —NR19R20 or —(C1–C6)alkyl-NR19R20;
• R13 is H, (C1–C6)alkyl, R7-aryl, —(C1–C6)alkyl-OR19, —(C1–C6)alkyl-NR19R20 or —(C1–C6)alkyl-SR19;
• R14 and R15 are independently selected from the group consisting of H, R5—(C1–C6)alkyl, R7-aryl and
• wherein q and a are as defined above;
• R19 and R20 are independently selected from the group consisting of hydrogen, (C1–C6)alkyl, (C3–C12)cycloalkyl, aryl and aryl(C1–C6)alkyl;
• R21 and R22 are independently selected from the group consisting of hydrogen, (C1–C6)alkyl, (C3–C12)cycloalkyl, (C3–C12)cycloalkyl(C1–C6)alkyl, (C3–C7)heterocycloalkyl, —(C1–C6)alkyl(C3–C7)-heterocycloalkyl, R7-aryl, R7-aryl(C1–C6)alkyl, R8-heteroaryl(C1–C12)alkyl, —(C1–C6)alkyl-OR19, —(C1–C6)alkyl-NR19R20, —(C1–C6)alkyl-SR19, —(C1–C6)alkyl-NR18—(C1–C6)alkyl-O—(C1–C6)alkyl and —(C1–C6)alkyl-NR18—(C1–C6)alkyl-NR18—(C1–C6)alkyl;
• R18 is hydrogen or (C1–C6)alkyl;
• and Z1 is R7-aryl;
• Z2 is R7-aryl;
• Z3 is hydrogen or (C1–C3)alkyl;
• R25 is 1–3 substituents independently selected from the group consisting of H, (C1–C6)alkyl, (C1–C6)alkoxy and halo;
• R26 is independently selected from the group consisting of H, (C1–C6)alkyl and R25—C6H4—CH2—;
• R27 is H, (C1–C6)alkyl, R7-aryl(C1–C6)alkyl, or (C3–C12)cycloalkyl;
• and a therapeutically effective amount of a second agent selected from the group consisting of:
• antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists;
• and a pharmaceutically acceptable carrier.