High affinity ligands for nociceptin receptor ORL-1

Abstract

The present invention relates to the method of treating cough with ORL-1 agonists, alone or in combination with additional agents for treating symptoms of cough, allergy or asthma, pharmaceutical compositions comprising the combinations, and to compounds of the formula 1

Description

BACKGROUND

[0002] The nociceptin receptor ORL-1 has been shown to be involved with modulation of pain in animal models. ORL-1 (the nociceptin receptor) was discovered as an “orphan opioid-like receptor” i.e. a receptor whose ligand was unknown. The nociceptin receptor is a G protein coupled receptor. While highly related in structure to the three classical opioid receptors, i.e. the targets for traditional opioid analgesics, it is not activated by endogenous opioids. Similarly, endogenous opioids fail to activate the nociceptin receptor. Like the classical opioid receptors, the nociceptin receptor has a broad distribution in the central nervous system.

[0003] In late 1995, nociceptin, also known as Orphanin FQ (OFQ), was discovered and shown to be an endogenous peptide ligand that activates the nociceptin receptor. Data included in the initial publications suggested that nociceptin and its receptor are part of a newly discovered pathway involved in the perception of painful stimuli. Subsequent work from a number of laboratories has shown that nociceptin, when administered intraspinally to rodents, is an analgesic. The efficacy of nociceptin is similar to that of endogenous opioid peptides. Recent data has shown that nociceptin acts as an anxiolytic when administered directly into the brain of rodents. When tested in standard animals models of anxiety, the efficacy of nociceptin is similar to that seen with classical benzodiazapine anxiolytics. These data suggest that a small molecule agonist of the nociceptin receptor could have significant analgesic or anxiolytic activity.

[0004] Additional recent data (Rizzi, et al, Life Sci., 64, (1999), p. 157-163) has shown that the activation of nociceptin receptors in isolated guinea pig bronchus inhibits tachykinergic, non-adrenergic, non-cholinergic contractions, indicating that nociceptin receptor agonists could be useful in the treatment of asthma. Also, it has been reported (Ciccocioppo et al, Physchopharmacology, 141 (1999), p. 220-224) nociceptin reduces the rewarding properties of ethanol in msP alcohol preferring rats, suggesting that intervention of nociceptin could be useful in the treatment of alcohol abuse. In EP 856,514, 8-substituted 1,3,8-triazaspiro[4,5]decan-4-on derivatives were disclosed as agonists and/or antagonists of orphanin FQ (i.e., nociceptin) useful in the treatment of various disorders, including depression; 2-oxoimidazole derivatives disclosed in WO98/54168 were described as having similar utility. Earlier, benzimidazolyl piperidines were disclosed in U.S. Pat. No. 3,318,900 as having analgesic activity.

[0005] Potent analgesic agents such as traditional opioids, e.g. morphine, carry with them significant side-effects. Clinically relevant side-effects include tolerance, physical dependence, respiratory depression, sedation and a decrease in gastrointestinal motility. For many patients, particularly those subjected to chronic opioid therapy, i.e. cancer patients, these side effects limit the dose of opioid that can be administered. Clinical data suggests that more than one-third of cancer patients have pain which is poorly controlled by present agents. Data obtained with nociceptin suggest the potential for advantages over opioids. When administered chronically to rodents, nociceptin, in contrast to morphine, showed no addiction liability. Additionally, chronic morphine treatment did not lead to a “cross-tolerance” to nociceptin, suggesting that these agents act via distinct pathways.

[0006] In view of the current interest in pain relief, a welcome contribution to the art would be additional compounds useful for modifying the effect of nociceptin, a natural ligand to ORL-1 and therefore useful in the management of pain and anxiety. Such a contribution is provided by this invention. We have also unexpectedly found that ORL-1 receptor agonists are useful in treating cough.

SUMMARY OF THE INVENTION

[0007] Compounds of the present invention are represented by formula I 2

[0008] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0009] the dotted line represents an optional double bond;

[0010] X1 is R5—(C1-C12)alkyl, R6—(C3-C12)cycloalkyl, R7-aryl, R8-heteroaryl or R10—(C3-C7)heterocycloalkyl;

[0011] 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;

[0012] or X1 is 3

[0013] and X2 is hydrogen;

[0014] or X1 and X2 together form a spiro group of the formula 4

[0015] is 1 or2;

[0016] n is 1, 2 or 3, provided that when n is 1, one of R16 and R17 is —C(O)R28;

[0017] p is 0 or 1;

[0018] Q is —CH2—, —O—, —S—, —SO—, —SO2— or —NR17—;

[0019] R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen and (C1-C6)alkyl, or (R1 and R4) or (R2 and R3) or (R1 and R3) or (R2 and R4) together can form an alkylene bridge of 1 to 3 carbon atoms;

[0020] 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;

[0021] R6 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, R7-aryl, —NR19R20, —OR13 and —SR13;

[0022] 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, —NR20COR19, —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 5

[0023] wherein f is 0 to 6; or R7 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;

[0024] 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;

[0025] R9 is hydrogen, (C1-C6)alkyl, halo, —OR19, —NR19R20, —NHCN, —SR19 or —(C1-C6)alkyl-NR19R20;

[0026] R10 is H, (C1-C6)alkyl, —OR19, —(C1-C6)alkyl-OR19, —NR19R20 or —(C1-C6)alkyl-NR19R20;

[0027] R11 is independently selected from the group consisting of H, R5—(C1-C6)alkyl, R6—(C3-C12)cycloalkyl, —(C1-C6)alkyl(C3-C12)cycloalkyl, —(C1-C6)alkyl-OR19, —(C1-C6)alkyl-NR19R20 and 6

[0028] wherein q and a are as defined above;

[0029] R12 is H, (C1-C6)alkyl, halo, —NO2, —CF3, —OCF3, —OR19, —(C1-C6)alkyl-OR19, —NR19R20 or —(C1-C6)alkyl-NR19R20;

[0030] R13 is H, (C1-C6)alkyl, R7-aryl, —(C1-C6)alkyl-OR19, —(C1-C6)alkyl-NR19R20; —(C1-C6)alkyl-SR19; or aryl (C1-C6) alkyl;

[0031] R14 and R15 are independently selected from the group consisting of H, R5—(C1-C6)alkyl, R7-aryl and 7

[0032] wherein q and a are as defined above;

[0033] R16 and R17 are independently selected from the group consisting of hydrogen, R5—(C1-C6)alkyl, R7-aryl, (C3-C12)cycloalkyl, R8-heteroaryl, R8-heteroaryl (C1-C6)alkyl, —C(O)R28, —(C1-C6)alkyl(C3-C7)-heterocycloalkyl, —(C1-C6)alkyl-OR19 and —(C1-C6)alkyl-SR19;

[0034] R19 and R20 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C3-C12)cycloalkyl, aryl and aryl(C1-C6)alkyl;

[0035] 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-NR18—(C1-C6)alkyl-NR18—(C1-C6)alkyl;

[0036] R18 is hydrogen or (C1-C6)alkyl;

[0037] Z1 is R5—(C1-C12)alkyl, R7-aryl, R8-heteroaryl, R6—(C3-C12)cyclo-alkyl, R10—(C3-C7)heterocycloalkyl, —CO2(C1-C6)alkyl, CN or —C(O)NR19R20; Z2 is hydrogen or Z1; Z3 is hydrogen or (C1-C6)alkyl; or Z1, Z2 and Z3, together with the carbon to which they are attached, form the group 8

[0038] wherein r is 0 to 3; w and u are each 0-3, provided that the sum of w and u is 1-3; c and d are independently 1 or 2; s is 1 to 5; and ring A is a fused R7-phenyl or R8-heteroaryl ring;

[0039] R23 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, —OR19, —(C1-C6)alkyl-OR19, —NR19R20 and —(C1-C6)alkyl-NR19R20;

[0040] R24 is 1 to 3 substituents independently selected from the group consisting of R23, —CF3, —OCF3, NO2 or halo, or R24 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;

[0041] R25 is 1-3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy and halo;

[0042] R26 is independently selected from the group consisting of H, (C1-C6)alkyl and R25—C6H4—CH2—;

[0043] R27 is H, (C1-C6)alkyl, R7-aryl(C1-C6)alkyl, or (C3-C12)cycloalkyl;

[0044] R28 is (C1-C6)alkyl, —(C1-C6)alkyl(C3-C12)cycloalkyl, R7-aryl, R7-aryl-(C1-C6)alkyl, R8-heteroaryl, —(C1-C6)alkyl-NR19R20, —(C1-C6)alkyl-OR19 or —(C1-C6)alkyl-SR19;

[0045] provided that when X1 is 9

[0046] or X1 and X2 together are 10

[0047] and Z1 is R7-phenyl, Z2 is not hydrogen or (C1-C3)alkyl;

[0048] provided that when Z1, Z2 and Z3, together with the carbon to which they are attached, form 11

[0049] and X1 and X2 together are 12

[0050] R11 is not H, (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)hydroxyalkyl;

[0051] provided that when R2 and R4 form an alkylene bridge, Z1, Z2 and Z3, together with the carbon to which they are attached, are not 13

[0052] provided that when X1 is 14

[0053] and Z1 is R6—(C3-C12)-cycloalkyl, Z2 is not H.

[0054] Preferred compounds of the invention are those wherein Z1 and Z2 are each R7-aryl, particularly R7-phenyl. Preferred R7 substituents are (C1-C6)alkyl and halo, with ortho-substitution being more preferred.

[0055] Compounds wherein R1, R2, R3 and R4 are each hydrogen are preferred, as well as compounds wherein R1 and R3 are each hydrogen and R2 and R4 are an alkylene bridge of 2 or 3 carbons.

[0056] Preferred are compounds wherein X1 is R7-aryl, for example R7-phenyl, and X2 is OH (i.e., X2 is —(CH2)vOR13, wherein v is 0 and R13 is H) or —NC(O)R28, compounds wherein X1 is 15

[0057] wherein R12 is hydrogen and R11 is (C1-C6)alkyl, —(C1-C6) alkyl(C3-C12)cycloalkyl, —(C1-C6)alkyl-OR19 or —(C1-C6)alkyl-NR19R20; and compounds wherein X1 and X2 together form the spirocyclic group 16

[0058] wherein m is 1, R17 is phenyl and R11 is —(C1-C6)alkyl-OR19 or —(C1-C6)alkyl-NR19R2, or 17

[0059] Also preferred are compounds of formula I wherein X1 and X2 form a spiro group, Z1 is R7-aryl, preferably R7-phenyl, and Z2 is C4-12 alkyl.

[0060] In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. The compounds of the present invention are agonists and/or antagonists of the ORL-1 receptor, and therefore, in another aspect, the invention relates to a method of treating pain, anxiety, asthma, alcohol abuse or depression, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I.

[0061] In another aspect, the invention relates to a method of treating cough comprising administering an ORL-1 agonist to a mammal in need of such treatment. The use of any compound having ORL-1 agonist activity is claimed, but the following non-limiting list of compounds exemplifies ORL-1 agonists:

[0062] a) a compound represented by the structural formula IA: 18

[0063] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0064] the dotted line represents an optional double bond;

[0065] X1 is R5—(C1-C12)alkyl, R6—(C3-C12)cycloalkyl, R7-aryl, R8-heteroaryl or R10—(C3-C7)heterocycloalkyl;

[0066] 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;

[0067] or X1 is 19

[0068] and X2 is hydrogen;

[0069] or X1 and X2 together form a spiro group of the formula 20

[0070] is 1 or 2;

[0071] n is 1, 2 or 3, provided that when n is 1, one of R16 and R17 is —C(O)R28;

[0072] p is 0 or 1;

[0073] Q is —CH2—, —O—, —S—, —SO—, —SO2—or —NR17—;

[0074] R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen and (C1-C6)alkyl, or (R1 and R4) or (R2 and R3) or (R1 and R3) or (R2 and R4) together can form an alkylene bridge of 1 to 3 carbon atoms;

[0075] R5 is 1 to 3 substituents independently selected from the group consisting of H, R7-aryl, R6—(C3-C12)cycloalkyl, R8-heteroaryl, R1—(C3-C7)heterocycloalkyl, —NR19R20, —OR13 and —S(O)0-2R13;

[0076] R6 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, R7-aryl, —NR19R20, —OR13 and —SR13;

[0077] 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, —NR20COR19, —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 21

[0078] wherein f is 0 to 6; or R7 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;

[0079] 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;

[0080] R9 is hydrogen, (C1-C6)alkyl, halo, —OR19, —NR19R20, —NHCN, —SR19 or —(C1-C6)alkyl-NR19R20;

[0081] R10 is H, (C1-C6)alkyl, —OR19, —(C1-C6)alkyl-OR19, —NR19R20 or —(C1-C6)alkyl-NR19R20;

[0082] R11 is independently selected from the group consisting of H, R5—(C1-C6)alkyl, R6—(C3-C12)cycloalkyl, —(C1-C6)alkyl(C3-C12)cycloalkyl, —(C1-C6)alkyl-OR19, —(C1-C6)alkyl-NR19R20 and 22

[0083] wherein q and a are as defined above;

[0084] R12 is H, (C1-C6)alkyl, halo, —NO2, —CF3, —OCF3, —OR19, —(C1-C6)alkyl-OR19, —NR19R20 or —(C1-C6)alkyl-NR19R20;

[0085] R13 is H, (C1-C6)alkyl, R7-aryl, —(C1-C6)alkyl-OR19, —(C1-C6)alkyl-NR19R20; —(C1-C6)alkyl-SR19; or aryl (C1-C6) alkyl;

[0086] R14 and R15 are independently selected from the group consisting of H, R5—(C1-C6)alkyl, R7-aryl and 23

[0087] wherein q and a are as defined above;

[0088] R16 and R17 are independently selected from the group consisting of hydrogen, R5—(C1-C6)alkyl, R7-aryl, (C3-C12)cycloalkyl, R8-heteroaryl, R8-heteroaryl(C1-C6)alkyl, —C(O)R28, —(C1-C6)alkyl(C3-C7)-heterocycloalkyl, —(C1-C6)alkyl-OR19 and —(C1-C6)alkyl-SR19;

[0089] R19 and R20 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C3-C12)cycloalkyl, aryl and aryl(C1-C6)alkyl;

[0090] 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;

[0091] R18 is hydrogen or (C1-C6)alkyl;

[0092] Z1 is R5—(C1-C12)alkyl, R7-aryl, R8-heteroaryl, R6—(C3-C12)cyclo-alkyl, R10—(C3-C7)heterocycloalkyl, —CO2(C1-C6)alkyl, CN or —C(O)NR19R20; Z2 is hydrogen or Z1; Z3 is hydrogen or (C1-C6)alkyl; or Z1, Z2 and Z3, together with the carbon to which they are attached, form the group 24

[0093] wherein r is 0 to 3; w and u are each 0-3, provided that the sum of w and u is 1-3; c and d are independently 1 or 2; s is 1 to 5; and ring A is a fused R7-phenyl or R8-heteroaryl ring;

[0094] R23 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, —OR19, —(C1-C6)alkyl-OR19, —NR19R20 and —(C1-C6)alkyl-NR19R20;

[0095] R24 is 1 to 3 substituents independently selected from the group consisting of R23, —CF3, —OCF3, NO2 or halo, or R24 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;

[0096] R25 is 1-3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy and halo;

[0097] R26 is independently selected from the group consisting of H, (C1-C6)alkyl and R25—C6H4—CH2—;

[0098] R27 is H, (C1-C6)alkyl, R7-aryl(C1-C6)alkyl, or (C3-C12)cycloalkyl; and

[0099] R28 is (C1-C6)alkyl, —(C1-C6)alkyl(C3-C12)cycloalkyl, R7-aryl, R7-aryl-(C1-C6)alkyl, R8-heteroaryl, —(C1-C6)alkyl-NR19R20, —(C1-C6)alkyl-OR19 or —(C1-C6)alkyl-SR19.

[0100] Preferred compounds of formula IA are the same as those for compounds of formula I.

[0101] b) a compound disclosed in EP 856,514 represented by the structural formula II: 25

[0102] wherein

[0103] R1a and R2a are, independently from each other, hydrogen, lower alkyl, lower alkoxy or halogen;

[0104] R3a is phenyl, optionally substituted by lower alkyl, CF3, lower alkoxy or halogen; and

[0105] R4a is hydrogen, lower alkyl, lower alkenyl, —C(O)-lower alkyl, —C(O)-phenyl, lower alkyl-C(O)-phenyl, lower alkylen-C(O)-lower alkyl, lower alkantriyl-di-C(O)O-lower alkyl, hydroxy-lower alkyl, lower alkyl-O-lower alkyl, lower alkyl-CH(OH)CF3, phenyl or benzyl;

[0106] R5a and R6a are, independently from each other, hydrogen, phenyl, lower alkyl or di-lower alkyl or may form together a phenyl ring, and

[0107] R5a and one of R1a or R2a may form together a saturated or unsaturated 6 membered ring,

[0108] Aa is a 4-7 membered saturated ring which may contain a heteroatom such as O or S,

[0109] or a pharmaceutically acceptable acid addition salt thereof.

[0110] Preferred compounds of formula II include:

[0111] (−)-8-(5,8-dichloro-1,2,3,4-tetrahydro-naphthyl-2)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0112] 8-(8-chloro-1,2,3,4-tetrahydro-naphthyl-2)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0113] 1-phenyl-8-(1,2,3,4-tetrahydro-naphthyl-1)-1,3,8-triaza-spiro[4.5]decan-4-one;

[0114] 8-indan-2-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0115] (RS)-8-(acenaphthen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0116] (RS)-8-(acenaphthen-1-yl)-3-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0117] (RS)-8-(2,3-dihydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0118] (R)-8-(acenaphthen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0119] 8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one; and

[0120] (RS)-8-(5-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1,3,8-triaza-spiro[4.5]decan-4-one.

[0121] c) a compound disclosed in EP 921,125 represented by the structural formula III 26

[0122] wherein

[0123] R1b is hydrogen, lower alkyl, halogen, lower alkoxy, CF3, lower alkyl-phenyl or (C5-7)-cycloalkyl;

[0124] R2b is hydrogen, lower alkyl, phenyl or lower alkyl-phenyl;

[0125] R3b is hydrogen, lower alkyl, benzyl, lower alkyl-phenyl, lower alkyl-diphenyl, triazinyl, cyanomethyl, lower alkyl-piperidinyl, lower alkyl-naphthyl, (C5-7)-cycloalkyl, lower alkyl-(C5-7)-cycloalkyl, lower alkyl-pyridyl, lower alkyl-morpholinyl, lower alkyl dioxolanyl, lower alkyl, oxazolyl, or lower alkyl-2-oxo-oxazolidinyl and wherein the ring systems may be substituted by additional lower alkyl, lower alkoxy, CF3 or phenyl, or —(CH2)nC(O)O-lower alkyl, —(CH2)nC(O)NH2, —(CH2)nC(O)N(lower alkyl)2, —(CH2)nOH or —(CH2)nC(O)NHCH2C6H6;

[0126] R4b is hydrogen, lower alkyl or nitrilo;

[0127] Ab is a ring system, consisting of

[0128] (a) (C5-15)-cycloalkyl, which may be in addition to R4b optionally substituted by lower alkyl, CF3, phenyl, (C5-7)-cycloalkyl, spiro-undecan-alkyl or by 2-norbornyl, or is one of the following groups 27

[0129] dodecahydro-acenaphthylen-1yl (e), bicyclo[6.2.0]dec-9-yl (f) and bicyclononan-9-yl (g); and wherein

[0130] R5b and R6b are hydrogen, lower alkyl, or taken together and with the carbon atoms to which they are attached form a phenyl ring;

[0131] R7b is hydrogen or lower alkyl;

[0132] the dotted line represents an optional double bond and n is 1 to 4;

[0133] or a pharmaceutically acceptable acid addition salt thereof.

[0134] Preferred compounds of formula III include:

[0135] 8-(decahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0136] 8-(decahydro-naphthalen-2-yl)-3-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0137] a mixture of (2RS,4aRS,8aSR)- and (2RS,4aRS,8aSR)-8-(decahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0138] (2RS,4aSR,8aRS)-8-(decahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0139] cis-8-(4-methyl-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0140] 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0141] 8-cyclononyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0142] cis-8-(4-isopropyl-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0143] (R,S)-8-cyclodecyl-1-(3-methyl-phenyl)-2-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

[0144] 8-cyclodecyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl)-acetonitrile;

[0145] 8-(cis-octahydro-inden-2-yl)l-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one; and

[0146] 8-(cis-bicyclo[6.2.0]dec-9-yl)l-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one.

[0147] d) a compound disclosed in WO 99/36421 represented by the structural formula IV: 28

[0148] or a pharmaceutically acceptable salt thereof, wherein

[0149] R1c and R2c are independently C1-C4 alkyl; or

[0150] R1c and R2c, taken together with the carbon to which they are attached, form a mono-, bi-, tri- or spiro-cyclic group having 6 to 13 carbon atoms, wherein the cyclic group is optionally substituted by 1 to 5 substituents independently selected from C1-C4 alkyl, C2-C4 alkylene, C1-C4 alkoxy, hydroxy, oxo, ═CH2 and ═CH—C1-C4 alkyl;

[0151] R3c is C1-C7 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, phenyl-C1-C5 alkyl, phenyl optionally substituted by 1 to 3 substituents independently selected from fluorine, C1-C3 alkyl and C1-C3 alkoxy, or a heteroaryl group selected from furyl, theinyl, pyrrolyl and pyridyl, wherein said heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from halo, C1-C3 alkyl and C1-C3 alkoxy, with the proviso that when both R1c and R2c are C1-C4 alkyl, then R3c is other than C1-C7 alkyl, C2-C5 alkenyl and C2-C5 alkynyl;

[0152] R4c is selected from

[0153] 1) hydrogen;

[0154] 2) optionally substituted mono- or di-substituted C1-C8 alkyl, C3-C7 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1C6 alkyl-Zc-, C1C6 alkyl-Zc-(C1C6)alkyl, C3-C7 cycloalkyl-Zc-(C1C6)alkyl, C2-C6 alkenyl-Zc-(C1C6)alkyl or C2-C6 alkynyl-Zc-(C1C6)alkyl, wherein Zc is selected from O, S, SO, SO2, CO, CO2, OCO, NRC, CONRC and NRcCO, wherein Rc is hydrogen or C1-C6 alkyl, and the substituents to be attached to the alkyl, alkenyl, alkynyl or cycloalkyl moiety are independently selected from halo, hydroxy, carboxy, amino, mono- or di-(C1-C4 alkyl)amino, hydrazino, azido, ureido, amidino and guanidino; or

[0155] 3) optionally mono- or di-substituted aryl, heterocyclic, aryl(C1-C5)alkyl, heterocyclic(C1-C5)alkyl, heterocyclic-heterocyclic(C1-C5)alkyl, aryl-heterocyclic(C1-C5)alkyl, heterocyclic-Zc-(C1-C5)alkyl, aryl-Zc-(C1-C5)alkyl, aryl(C1-C5)alkyl-Zc-(C1-C5)alkyl, or heterocyclic(C1-C5)alkyl-Zc-(C1-C5)alkyl, wherein Zc is selected from O, S, SO, SO2, CO, CO2, OCO, NRC, CONRC and NRCCO, wherein Rc is hydrogen or C1-C6 alkyl, and the substituents to be attached to the aryl or heterocyclic moiety are independently selected from halo, hydroxy, carboxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl-CO—, amino(C1-C4)alkyl-CO—, phenyl, benzyl, amino, mono- or di-(C1-C4 alkyl)amino, hydrazino, azido, ureido, amidino and guanidino;

[0156] R5c is independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylsulfonyl, CF3, carboxy, hydroxy, amino, alkylamino, acylamino, arylcarbonyl, alkylcarbonyl and hydroxyalkyl; and

[0157] n is 0, 1, 2, 3 or 4.

[0158] Preferred compounds of formula IV include:

[0159] 1-{1-[1-methyl-1-(2-thienyl)ethyl]-4-piperidinyl}1,3-dihydro-2H-1,3-benzimidazol-2-one;

[0160] 1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one;

[0161] 1-[4-piperidinyl-1-(1-propylcyclononyl)]-1,3-dihydro-2H-1,3-benzimidazol-2-one;

[0162] 1-[1-(1-phenylcyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-1 ,3-benzimidazol-2-one;

[0163] 1-[1-(1-phenylcyclononyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one;

[0164] 1-{1-[1-(4-fluorophenyl)cyclohepyl]-4-piperidinyl}-1,3-d ihydro-2H-1,3-benzimidazol-2-one;

[0165] 1-[1-(1-methylcyclononyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one;

[0166] 1-[1-(1-ethylcyclononyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one;

[0167] 1-[1-(1-methylcyclooctyl)-4-piperid inyl]-1,3-dihydro-2H- 1,3-benzimidazol-2-one;

[0168] 1-[1-(1-phenylcyclohept-4-enyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one;

[0169] 1-(6-aminohexyl)-3-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one;

[0170] 1-(2-aminoethyl)-3-[1-(1-phenylcyclohept-4-enyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one; and

[0171] 1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-3-(2-piperidinoethyl)-1,3-dihydro-2H-1,3-benzimidazol-2-one.

[0172] e) a compound disclosed in WO 98/54168 represented by the structural formula V 29

[0173] or a salt or ester thereof, wherein

[0174] Ar1d is an optionally substituted aromatic carbon ring or heterocycle, wherein the optional substituents are independently selected from halo, alkyl, amino, alkylamino, dialkylamino, hydroxy, alkoxy and carboxyl; 30

[0175] is an optionally substituted mono- or di-cyclic C3-14 aliphatic nitrogenous heterocycle;

[0176] Cyd is an optionally substituted mono-, di- or tri-cyclic C3-20 aliphatic carbon ring;

[0177] R1d is hydrogen, lower alkenyl, lower alkynyl, lower cycloalkyl, amino, lower alkylamino, di(lower alkyl)amino, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl or optionally substituted lower alkyl; and

[0178] R2d is hydrogen or lower alkyl.

[0179] f) a compound disclosed in WO 99/48492 represented by the structural formula VI 31

[0180] or a pharmaceutically acceptable salt thereof, wherein

[0181] Ae is an aryl or heterocyclyl ring;

[0182] Be is phenyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl or cyclohexenyl;

[0183] R1e and R2e are independently hydrogen, alkyl, hydroxyalkyl, amino, alkylamino or di-alkylamino;

[0184] R3e and R4e are independently hydrogen, halo or alkyl;

[0185] Xe is hydrogen, halo, alkyl, alkoxyalkyl, alkenyl, amino, CN, or —(CH2)me-Ee-(CH2)ne-Ge;

[0186] Ee is a bond, —CH═CR6e, O, S, NR7e, CO, SO2 or NHCO;

[0187] Ge is aryl, heterocyclyl, cycloalkyl or fused aryl, all optionally substituted by 1-5 R5e groups;

[0188] R5e is independently selected from halo, OH, alkyl, alkyl optionally substituted by alkoxy, alkoxyalkoxy, halo, OH or alkanoyloxy, alkoxy, alkoxyalkoxy, amino, alkylamino, di-alkylamino, NO2, CN, alkanoyl, alkanoyloxy, carboxy, alkoxycarbonyl, alkylsulfonyl and phenyl;

[0189] R6e is hydrogen or aryl;

[0190] R7e is hydrogen, alkyl or alkoxycarbonyl;

[0191] me is 0-8; and

[0192] ne is 1-4.

[0193] A preferred compound of formula VI is:

[0194] N-(4-amino-2-methyl-6-quinolyl)-2-[(4-ethylphenoxy)methyl]benzamide.

[0195] The disclosures of EP 856,514, EP921,125, WO 99/36421, WO 98/54168 and WO 99/48492 are incorporated herein by reference.

[0196] In another aspect, the invention relates to a method of treating cough, comprising administering to a mammal in need of such treatment: (a) an effective amount of a nociceptin receptor ORL-1 agonist; and (b) an effective amount of one or more agents for treating cough, allergy or asthma symptoms 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, decongestants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists.

[0197] In still another aspect, the invention relates to a pharmaceutical composition comprising a nociceptin receptor ORL-1 agonist and one or more agents 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, decongestants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists.

[0198] Preferred ORL-1 agonists for use in the combination and in the combined pharmaceutical composition are those represented in formulas IA to VI. In yet another aspect, the present invention relates to a novel compound not included in the structure of formula I, said compound being: 32

BRIEF DESCRIPTION OF THE DRAWINGS

[0199] FIG. 1 illustrates the effect in guinea pigs of Compounds A and B (see Example 12) compared to baclofen on capsaicin-induced cough.

[0200] FIGS. 2A and 2B show changes in Tidal Volume after administration of Compound A or baclofen, and FIG. 2C shows changes in frequency of breaths after administration of Compound A or baclofen.

DETAILED DESCRIPTION OF THE INVENTION

[0201] As used herein in formula I and IA, the following terms are used as defined below unless otherwise indicated:

[0202] M+ represents the molecular ion of the molecule in the mass spectrum and MH+ represents the molecular ion plus hydrogen of the molecule in the mass spectrum;

[0203] Bu is butyl; Et is ethyl; Me is methyl; and Ph is phenyl;

[0204] alkyl (including the alkyl portions of alkoxy, alkylamino and dialkylamino) represents straight and branched carbon chains containing from 1 to 12 carbon atoms or 1 to 6 carbon atoms; for example methyl, ethyl, propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like;

[0205] alkenyl represents an alkyl chain of 2 to 6 carbon atoms comprising one or two double bonds in the chain, e.g., vinyl, propenyl or butenyl;

[0206] alkynyl represents an alkyl chain of 2 to 6 carbon atoms comprising one triple bond in the chain, e.g., ethynyl or propynyl;

[0207] alkoxy represents an alkyl moiety covalently bonded to an adjacent structural element through an oxygen atom, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like;

[0208] aryl (including the aryl portion of arylalkyl) represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is phenyl), wherein said aryl group optionally can be fused with aryl, (C3-C7)cycloalkyl, heteroaryl or hetero(C3-C7)cycloalkyl rings; and wherein R7-aryl means that any of the available substitutable carbon and nitrogen atoms in said aryl group and/or said fused ring(s) is optionally and independently substituted, and wherein the aryl ring is substituted with 1-3 R7 groups. Examples of aryl groups are phenyl, naphthyl and anthryl;

[0209] arylalkyl represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl moiety have been substituted with one to three aryl groups; wherein aryl is as defined above;

[0210] aryloxy represents an aryl group, as defined above, wherein said aryl group is covalently bonded to an adjacent structural element through an oxygen atom, for example, phenoxy;

[0211] cycloalkyl represents saturated carbocyclic rings of from 3 to 12 carbon atoms, preferably 3 to 7 carbon atoms; wherein R6-cycloalkyl means that any of the available substitutable carbon atoms in said cycloalkyl group is optionally and independently substituted, and wherein the cycloalkyl ring is substituted with 1-3 R6 groups;

[0212] cycloalkylalkyl represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl moiety have been substituted with one to three cycloalkyl groups, wherein cycloalkyl is as defined above;

[0213] halo represents fluoro, chloro, bromo and iodo;

[0214] heteroaryl represents cyclic groups having one to three heteroatoms selected from O, S and N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups containing from 5 to 14 carbon atoms, wherein said heteroaryl group optionally can be fused with one or more aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings; and wherein any of the available substitutable carbon or nitrogen atoms in said heteroaryl group and/or said fused ring(s) may be optionally and independently substituted, and wherein the heteroaryl ring can be substituted with 1-3 R8 groups; representative heteroaryl groups can include, for example, furanyl, thienyl, imidazoyl, pyrimidinyl, triazolyl, 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl N-oxide wherein pyridyl N-oxide can be represented as: 33

[0215] heteroarylalkyl represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced by one or more heteroaryl groups, as defined above;

[0216] heterocycloalkyl represents a saturated ring containing from 3 to 7 carbon atoms, preferably from 4 to 6 carbon atoms, interrupted by 1 to 3 heteroatoms selected from —O—, —S— and —NR21—, wherein R21 is as defined above, and wherein optionally, said ring may contain one or two unsaturated bonds which do not impart aromatic character to the ring; and wherein any of the available substitutable carbon atoms in the ring may substituted, and wherein the heterocycloalkyl ring can be substituted with 1-3 R10 groups; representative heterocycloalkyl groups include 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, 1-, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 1-, 2- or 3-piperazinyl, 2- or 4-dioxanyl, morpholinyl, 34

[0217] or 35

[0218] wherein R17 is as defined above and t is 0, 1 or 2.

[0219] When the optional double bond in the piperidinyl ring of formula I or IA is present, one of X1 and X2 forms the bond with the 3-position carbon and the remaining X1 or X2 is not hydrogen.

[0220] When X1 and X2 form a spiro group as defined above, the wavy lines in the structures shown in the definition indicate the points of attachment to the 4-position carbon of the piperidinyl ring, e.g., compounds of the following formulas are formed: 36

[0221] Certain compounds of the invention may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers). The invention contemplates all such stereoisomers both in pure form and in mixture, including racemic mixtures.

[0222] Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.

[0223] Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.

[0224] All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

[0225] Compounds of formulas I and IA can be prepared by known methods from starting materials either known in the art or prepared by methods known in the art. Examples of general procedures and specific preparative examples are given below.

[0226] Typically, X1, X2-substituted piperidines are alkylated with Z1, Z2, Z3-substituted halomethanes in the presence of excess bases such as K2CO3 and Et3N, in solvents such as DMF, THF or CH3CN, at room temperature or at elevated temperatures.

[0227] X1, X2-substituted piperidines are either commercially available or made by known procedures. For example, 4-hydroxy-4-phenyl-piperidine can be converted to a 4-tBoc-amino-4-phenylpiperidine according to the following reaction scheme, wherein Bn is benzyl, Ph is phenyl and tBoc is t-butoxycarbonyl: 37

[0228] Commercially available 4-phenyl-4-piperidinol is protected with a benzyl group and the resulting intermediate is then treated with Me3SiCN. The resultant amide is hydrolyzed with aqueous HCl in CH3OH to produce the 4-amino compound. The amino group is protected with tBoc and the N-benzyl group is removed by hydrogenolysis to produce the desired 4-amino-piperidine derivative.

[0229] The 4-(protected)amino-piperidine then can be reacted with a Z1, Z2, Z3-halomethane and the protecting group removed. The amine (i.e., X2 is —NH2) can undergo various standard conversions to obtain amine derivatives. For example, the amine of formula I or IA can be reacted with a R22-carboxaldehyde in the presence of a mild reducing agent such as Na(OAc)3BH or with a compound of the formula R22-L, wherein L is a leaving group such as Cl or Br, in the presence of a base such as Et3N.

[0230] An alternative method for preparing compounds of formula I or IA wherein X1 is R7-aryl and X2 is OH involves alkylating a 4-piperidone hydrochloride with a Z1, Z2, Z3-halomethane, then reacting the ketone with an appropriately substituted R7-phenylmagnesium bromide or with a compound of the formula X1-L1, wherein L1 is Br or I, and n-butyl-lithium.

[0231] X1, X2-substituted compounds of formula I or IA can be converted into other compounds of formula I or IA by performing reactions well known in the art on the X1 and/or X2 substituents. For example, a carboxaldehyde-substituted piperidine (i.e., X2 is —CHO) can be converted to a substituted piperidine wherein X2 is R13—O—CH2—, as shown in the following procedure for a compound of formula I wherein X1 is phenyl, Z1 and Z2 are each phenyl, and R1, R2, R3 and R4, and Z3 are H: 38

[0232] A cyano-substituted piperidine (i.e., X2 is —CN) can be converted to a substituted piperidine wherein X2 is R21R22N—CH2— or X2 is R28C(O)NH—CH2—, as shown in the following procedure for a compound of formula I or IA wherein X1 is phenyl, R21, R1, R2, R3 and R4, and Z3 are H, and L is a leaving group such as Cl or Br: 39

[0233] Compounds of formula I or IA wherein X1 is a benzofused nitrogen-containing heterocycle having an R11 substituent other than hydrogen are prepared by reacting the corresponding compounds wherein R11 is hydrogen with a compound of the formula R11L (R11 is not H, and L is as defined above).

[0234] Alternatively, X1, X2-substituted piperidine starting materials can be converted into other X1, X2-substituted piperidines by similar procedures before reacting with the Z1, Z2, Z3-substituted halomethane.

[0235] For compounds of formula I or IA wherein R1, R2, R3 and R4 variously form alkylene bridges, commercially available N-protected 4-piperidones are treated with phenyl lithium and resulting intermediate is deprotected to produce the desired compounds, for example: 40

[0236] wherein Pr is a N-protecting group, Ph is phenyl and z is 1-2.

[0237] The Z1, Z2, Z3-halomethyl derivatives wherein Z1 and Z2 are R7-phenyl are either commercially available or can be prepared using the procedure shown in the following reaction scheme: 41

[0238] Similar procedures, or others known in the art, can be used to prepare compounds wherein the Z substituents are other than phenyl.

[0239] Compounds of the present invention and preparative starting materials thereof, are exemplified by the following examples, which should not be construed as limiting the scope of the disclosure.

[0240] The following solvents and reagents are referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); and diethyl ether (Et2O). Room temperature is abbreviated as rt.

EXAMPLE 1

[0241] 42

[0242] A mixture of 4-hydroxy-4-phenyl piperidine (1.5 g, 8.47 mmol) and K2CO3 (3.0 g, 21.73 mmol) in CH3CN was stirred at rt. To this was added α-bromo-diphenylmethane (2.5 g, 10.12 mmol) and the reaction was stirred overnight. The reaction mixture was concentrated, redissolved in CH2Cl2, washed with water, dried (MgSO4) and concentrated. Chromatography (SiO2, 9:1 hexane/EtOAc) gave the title compound (2.6 g, 90%). 1H NMR (CDCl3): δ1.80 (m, 2H), 2.25 (m, 2H), 2.42 (m, 2H), 2.90 (m, 2H), 4.40 (s, 1H), 7.2-7.6 (m, 15H).

EXAMPLE 2

[0243] 43

[0244] Step 1: A solution of 4-piperidone monohydrate hydrochloride (5 g, 32.6 mmol) in CH3CN was alkylated using the procedure described in Example 1. Chromatography of the residue on silica (95:5 hexane/EtOAc) gave the desired compound.

[0245] Step 2: 4-Methylphenylmagnesium bromide (0.5 M in THF, 1.75 ml, 0.87 mmol) was added to a solution of product of Step 1 (191 mg, 0.72 mmol) in THF dropwise at 0 C. The solution was stirred at 0 for 2 h, quenched with ice-H2O, extracted with EtOAc, washed with H2O and brine, dried, and concentrated. Chromatography of the residue on silica (95:5 hexane/EtOAc, 93:7 hexane/EtOAc) gave the title compound (0.091 g, 30%). 1H NMR (CDCl3) δ7.5 (m, 6H, ArH), 7.3 (t, 4H, ArH), 7.2 (t, 4H, ArH), 4.35 (s, 1H), 2.8 (d, 2H), 2.4 (m, 5H), 2.2 (td, 2H), 1.75 (d, 2H);

[0246] MS (Cl) 358 (M+1); Elemental analysis for C25H27NO.1.2 H2O: calcd: C 79.2, H 7.82, N 3.69; observed: C 78.90, H 8.02, N 3.85.

EXAMPLE 3

[0247] 44

[0248] Add n-BuLi (2.5 M, 0.38 ml. 0.95 mmol) to a solution of 3-bromo-thiophene (0.15 g, 0.95 mmol) in Et2O dropwise at −70 C. and stir for 2 h. Add a solution of the product of Step 1 of Example 2 (230 mg, 0.87 mmol) in Et2O (4 ml) to the reaction mixture, slowly warm to rt over a period of 3 h, quench with ice-cooled NH4Cl (aq), extract with Et2O, wash with H2O and brine, dry, and concentrate. Chromatograph the residue (95:5 hexane/EtOAc) to give the title compound (90 mg). 1H NMR (CDCl3) δ7.5 (d, 2H), 7.35 (bt, 4H), 7.25 (m, 3H), 7.2 (m, 2H), 4.4 (s, 1H), 2.8 (d, 2H), 2.5 (t, 2H), 2.3 (dt, 2H), 2.0 (d, 2H); MS (Cl) 350 (M+1); Elemental analysis for C22H22NOS.1.1 HCl.0.9 H2O: calcd: C 65.11, H 6.43, N 3.54, S 7.8, Cl 9.61; observed: C 65.27, H 6.54, N 3.45, S 7.30, Cl 9.43.

EXAMPLE 4

[0249] 45

[0250] Step 1: 4-Phenyl-4-piperidinecarboxaldehyde (1.0 g, 5.29 mM) was alkylated using the procedure of Example 1, Step 1, to obtain the desired product (1.69 g, 90%). 1H NMR (CDCl3): δ2.40 (m, 4H), 2.50 (m, 2H), 2.85 (m, 2H), 4.25 (s, 1H), 7.20-7.50 (m, 15H), 9.42 (s,1 H).

[0251] Step 2: A solution of the product from Step 1 (3.0 g, 8.45 mmol) was cooled to 0° C. and treated with NaBH4 (1.0 g, 26.32 mmol). After 0.5 h, reaction mixture was treated with 1N HCl and concentrated. The residue was extracted with CH2Cl2, dried (MgSO4) and evaporated. Column chromatography on the residue (4:1 hexane:EtOAc) produced desired primary alcohol. 1H NMR (CDCl3): δ2.00 (m, 2H), 2.25 (m, 4H), 2.65 (m, 2H), 3.65 (d, 2H), 4.20 (s, 1H), 4.25 (d, 1H), 7.2-7.6 (m, 15H).

[0252] Step 3: The product of Step 2 was treated with NaH in DMF at 0° C. for 0.5 h. CH3I was added and reaction was warmed up to rt. After stirring overnight, the reaction mixture was poured on ice, extracted with Et2O, dried (MgSO4) and evaporated. Column chromatography on the residue produced the title compound. 1H NMR (CDCl3): δ2.10 (m, 4H), 2.40 (m, 2H), 2.78 (m, 2H), 2.90 (m, 2H), 3.00(s, 3H), 4.38 (s, 1H), 7.21-7.52 (m, 15H).

EXAMPLE 5

[0253] 46

[0254] Step 1: A solution of 4-cyano-4-phenylpiperidine hydrochloride (5.0 g, 22.4 mM) in DMF (30 ml) was treated with Et3N (7.20 ml, 47 mM) and bromodiphenylmethane (6.38 g, 25.80 mM) and stirred at rt under N2 for 20 h. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and H2O. The organic layer was washed with twice with water, then brine, and dried (MgSO4), filtered and concentrated. Chromatography (SiO2, 19:1 hexane/EtOAc) gave 6.0 g (76%) of the desired product. 1H NMR (CDCl3): δ2.21 (m, 4H), 2.49 (t, J=12.3 Hz, 2H), 3.11 (d, J=12.5 Hz, 2H), 4.46 (s, 1H), 7.45 (m, 15H).

[0255] Step 2: A solution of the product (6.0 g, 17 mM) of Step 1 in Et2O (40 ml) was cooled to 0° C. and treated with a 1M solution of of LAH (34.10 ml, 34 mM), dropwise, under N2, over 0.5 h. The reaction mixture was allowed to warm to rt and then refluxed for 4 h. The reaction mixture was cooled to 0° C. and treated with water (8 eq.). The reaction mixture was allowed to warm to rt and was stirred for 1 h. The resultant solid was filtered off and rinsed with Et2O, and the filtrate was concentrated to yield 5.45 g (90%) of desired product. 1H NMR (CD3OD): δ1.84 (m, 2H), 2.16 (m, 4H), 2.56 (m, 2H), 2.68 (m, 2H), 4.07 (s,1H), 7.25 (m, 15H).

[0256] Step 3: A solution of the product (0.2 g, 0.56 mM) of Step 2 in CH2Cl2 (3 ml) was treated with benzoyl chloride (0.078 ml, 0.673 mM) and pyridine (0.045 g, 0.568 mM) at rt for 18 h under N2. The reaction mixture was concentrated, then partitioned between H2O and CH2Cl2. The organic layer was washed with water (2×) and brine, then dried (MgSO4), filtered and concentrated. Chromatography (SiO2, 3:1 hexane/EtOAc) gave 0.2 g (77%) of the desired product. 1H NMR (CD3OD): δ2.13 (m, 6H), 2.66 (m, 4H), 3.50 (s, 2H), 4.07 (s, 1H), 7.11-7.65 (m, 20H).

[0257] Step 4: A solution of the product (0.075 g, 0.16 mM) of Step 3 in THF (3 ml) was cooled to 0° C. with stirring. LAH (solid, 0.025 g, 0.65 mM) was added under N2 and stirring was continued for 0.25 h. The reaction mixture was then refluxed for 5 h, then stirred at rt for 18 h. The reaction mixture was cooled to 0° C. and quenched with water (8 eq). The reaction mixture was allowed to warm to rt and was stirred for 1 h. The resultant solid was filtered off and rinsed with Et2O, the filtrate was dried (MgSO4) and concentrated. Chromatography (neutral Al2O3, CH2Cl2, then 3:1 CH2Cl2:EtOAc) gave 0.014 g (20%) of the title compound. 1H NMR (CD3OD): δ1.90 (m, 2H), 2.15 (m, 4H), 2.48 (m, 2H), 2.68 (s, 2H), 3.53 (s, 2H), 4.05 (s,1H), 7.01-7.38 (m, 20H).

EXAMPLE 6

[0258] 47

[0259] The product of Example 5, Step 2 (0.2 g, 0.561 mM), acetic anhydride (3 ml) and Et3N (0.096 ml, 0.67 mM) were combined and stirred at rt for 18 h. The reaction mixture was concentrated and partitioned between H2O and CH2Cl2. The organic layer was washed with water (2×), brine, then dried (MgSO4), filtered and concentrated to give 0.214 g (95%) of the title compound. 1H NMR (CD3OD): δ1.87 (m, 5H), 2.16 (m, 4H), 2.61 (m, 2H), 3.31 (s, 2H), 4.07 (s, 1H), 7.12-7.40 (m, 20H).

EXAMPLE 7

[0260] 48

[0261] Step 1: A solution of 4-phenyl-4-hydroxy piperidine (10.0 g, 56.4 mM) in DMF (60 ml) was treated with Et3N (8.28 ml, 59.2 mM) and benzyl bromide (7.37 ml, 62.10 mM) and stirred at rt under N2 for 20 h. The reaction mixture was concentrated in vacuo, basified to pH 8 with saturated NaHCO3 and partitioned between EtOAc and H2O. The organic layer was washed twice with water, then brine, and dried (MgSO4), filtered and concentrated. Chromatography (neutral Al2O3, hexane, then 1:1 hexane:EtOAc) gave 11.95 g (80%) of the desired product.

[0262] Step 2: To a mixture of the product (30.0 g, 0.112 mol) of Step 1 and (CH3)3SiCN (59.94 ml, 0.448 mol), cooled to −15° C. in an ethylene glycol/CO2 bath, under N2, is added glacial AcOH (47 ml) dropwise, while maintaining an internal temperature of −15° C. Concentrated H2SO4 (47 ml, 0.34 M) is added dropwise, with vigorous stirring, while maintaining an internal temperature of −15° C. The cooling bath was then removed and reaction mixture was stirred at rt for 18 h. The reaction mixture was poured on ice and adjusted to pH 7 with a 50% NaOH solution while maintaining a temperature of 25° C. The reaction mixture was then extracted with CH2Cl2, and the organic layer was washed with water (2×), then brine, and dried (MgSO4), filtered and concentrated. Recrystalization with EtOAc/hexane (1:10) gave 22.35 g (68%) of desired compound. 1H NMR (CD3OD): δ2.10 (m, 2H), 2.40 (m, 4H), 2.82 (d, J=11.50 Hz, 2H), 3.57 (s, 2H), 7.20-7.43 (m, 10H), 8.05 (s, 1H).

[0263] Step 3: The product of Step 2 (20 g, 67.9 mM) and 5% (w/w) concentrated HCl (aq)/CH3OH (350 ml) were stirred under N2 for 48 h. The mixture was concentrated to yield a foam which was suspended in Et2O and concentrated to remove excess HCl. The resultant solid was resuspended in Et2O, collected by vacuum filtration, washed with Et2O and dried under vacuum to give (23 g, 100%) of desired product. 1H NMR (CD3OD) of di-HCl salt: δ2.59 (t, J=13.3 Hz, 2H), 2.93 (t, J=13.3 Hz, 2H), 3.07 (d, J=13.50 Hz, 2H), 3.58 (d, J=13 Hz, 2H), 4.26 (s, 2H), 7.56 (m, 10H).

[0264] Step 4: The product of Step 3 (24.10 g, 71 mM), CH2Cl2 (300 ml), (tBoc)2O (17.0 g, 78.1 mM) and Et3N (14.37 g, 0.142 M) were combined and stirred under N2, at rt, for 18 hrs. The reaction mixture was partitioned between CH2Cl2 and H2O, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water (2×), then brine, and dried (MgSO4), filtered and concentrated. The resulting solid was suspended in Et2O and sonicated, filtered and dried to produce the desired compound (21.98 g, 90%). 1H NMR (CD3OD): δ1.09 (bs, 2H), 1.39 (s, 1H), 2.05 (m, 2H), 2.34 (m, 4H), 2.65 (d, J=11.8 Hz, 2H), 3.56 (s, 2H), 7.18-7.40 (m, 10H).

[0265] Step 5: The product of Step 4 (5.22 g, 14.2 mM), CH3OH (430 ml). Pd(OH)2/C (3.0 g) and NH4COOH (18.86 g, 0.298 M) were combined and refluxed under N2 for 8 h. The reaction mixture was filtered using celite, washing with CH3OH. The combined filtrates were concentrated to produce (3.90 g, 97%) of the desired product. 1H NMR (CD3OD): δ1.10 (bs, 2H), 1.39 (s, 7H), 1.90 (m, 2H), 2.26 (m, 4H), 2.92 (m, 4H), 7.17-7.41 (m, 5H).

[0266] Step 6: The product of Step 5 (2.74 g, 9.91 mM), CH3CN (85 ml), Et3N (1.75 ml, 12.40 mM) and bromodiphenylmethane (2.70 g, 10.9 mM) were combined and stirred at rt under N2 for 18 hrs. The mixture was concentrated and the resultant residue was partitioned between H2O and EtOAc. The EtOAc layer was washed with water (2×), brine, then dried (MgSO4), filtered and concentrated. Chromatography (neutral Al2O3, hexane, then 4:1 hexane:EtOAc) gave 2.85 g (65%) of the desired product. 1H NMR (CD3OD): δ1.07 (bs, 2H), 1.37 (s, 7H), 2.23 (m, 2H), 2.24 (m, 4H), 2.74 (d, J=12.1 Hz, 2H), 4.27 (s, 1H), 7.10-7.47 (m, 15H).

[0267] Step 7: The product of Step 6 (4.6 g, 10 mM), 1,4-dioxane (38 ml) and 4 M HCl in 1,4-dioxane (25 ml, 101 mM) were combined and stirred at rt under N2 for 4 h. The mixture was concentrated and the residue was suspended in Et2O and re-concentrated. The resultant solid was resuspended in Et2O, sonicated and the product was collected by vacuum filtration and dried to give 3.27 g (80% of the desired product. 1H NMR (CD3OD) of di-HCl salt: δ2.91(m, 8H), 5.34 (s, 1H), 7.37-7.77 (m, 15H).

[0268] Step 8: To a suspension of the product of Step 7 (0.3 g, 0.722 mM) in CH2Cl2 (3 ml), under N2 at rt, was added 2-thiophenecarboxaldehyde (0.133 ml, 1.44 mM). The pH of the reaction was adjusted to 6 with Et3N and the mixture was stirred for 0.5 h. Na(OAc)3BH (0.230 g, 1.08 mM) was then added and the reaction mixture was stirred at rt under N2 for 3 h. The reaction was quenched with saturated NaHCO3(aq) and partitioned between Et2O and H2O. The organic layer was washed with H2O (2×), brine, dried (MgSO4), filtered and concentrated. Chromatography (SiO2, toluene, then 1:19 EtOAc:toluene) gave 0.158 g (50%) of the desired product. 1H NMR (CD3OD): δ1.96 (m, 2H), 2.17 (m, 2H), 2.52 (m, 4H), 3.45 (s, 2H), 4.24 (s, 1H), 6.76 (d. J=3.5 Hz, 1H), 6.85 (dd, J=3.6 Hz, 1H), 7.13-7.50 (m, 16H).

EXAMPLE 8

[0269] 49

[0270] Step 1: Alkylate a solution of 4-(2-oxo-1-benzimidazolyl)-piperidine in CH3CN using the procedure described in Step 1 of Example 1 to produce the desired compound.

[0271] Step 2: Add NaH to a solution of 3-[1-(diphenylmethyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazo-1-one (2.5 g, 6.6 mmol) in DMF (25 ml) and stir at rt for 1 h. Add n-butyl iodide to the mixture at rt and stir overnight. Quench with ice-H2O, extract with EtOAc, wash with H2O and brine, dry (MgSO4) and concentrate. Chromatograph the residue on silica (1:9 EtOAc/hexane) to give the title compound (2.35 g). Dissolve the title compound in Et2O, add HCl in Et2O (8 ml, 1 M), stir for 1 h and filter to give the HCl salt. 1H NMR (CDCl3) δ7.55 (m, 4H, ArH), 7.35 (m, 5H, ArH), 7.25 (m, 2H, ArH), 7.15 (m, 2H, ArH), 7.1 (m, 1H, ArH), 4.4 (m, 2H), 3.95 (t, 2H), 3.15 (d, 2H), 2.6 (dq, 2H), 2.1 (t, 2H, 1.8, m, 4H), 1.5 (m, 2H), 1.0 (t, 3H); ESI-MS 440 (M+1); Elemental analysis for C29H33N3O.HCl.H2O: calcd: C 70.5, H 7.3, N 8.5, Cl 7.18; observed: C 70.48, H 7.28, N 8.49, Cl 7.49).

EXAMPLE 9

[0272] 50

[0273] Add SOCl2 (247 mg, 2.07 mmol) to a solution of 2-(chloro-phenyl)phenylmethanol (300 mg, 1.38 mmol) in CH2Cl2 at rt, stir at rt for 5 h and concentrate. Dissolve the residue in CH3CN, add K2CO3, 4-hydroxy-4-phenylpiperidine and Nal. Stir the solution at reflux overnight, filter and concentrate. Chromatograph the residue on silica (9:1 hexane/EtOAc) to give the title compound. 1H NMR (CDCl3) δ7.91 (d, 1H), 7.58 (d, 2H), 7.54 (d, 2H), 7.42 (t, 2H), 7.32 (m, 5H), 7.26 (t, 3H), 7.16 (t, 3H), 5.0 (s, 1H), 2.8 (dd, 2H), 2.5 (dq, 2H), 2.2 (dt, 2H), 1.75 (d, 2H). Dissolve the title compound in ether, add HCl/Et2O (1 M) to give the HCl salt. MS Cl (378 (M+1); Elemental analysis for C24H24NOCl.HCl.0.2H2O:l calcd: C 68.97, H 6.13, N 3.35, Cl 16.96; observed: C 68.87, H 6.04, N 3.35, Cl 17.00.

EXAMPLE 10

[0274] 51

[0275] Step 1: Alkylate a solution of 4-piperidone monohydrate hydrochloride (880 mg, 5 mmol) in CH3CN with mandelonitrile (1 g, 7.51 mmol) using the procedure described in Example 9. Chromatography of the residue on silica followed by recrystallization (EtOAc) gives the desired compound (630 mg).

[0276] Step 2: Add a solution of 2-methoxyphenylmagnesium bromide in THF (24 ml, 0.5 M, 11.85 mmol) to a solution of the product of Step 1 (330 mg, 1.185 mmol) in THF at 0 C. Remove the ice-bath and stir the reaction mixture at reflux for 6 h. Quench the reaction with NH4Cl (aq), extract with EtOAc, wash with brine, dry and concentrate. Chromatograph the residue (95:5, 9:1 hexane/EtOAc) to give the title compound (330 mg). 1H NMR (CDCl3) δ7.76 (d, 1H), 7.62 (d, 1H), 7.55 (d, 1H), 7.45 (t, 1H), 7.34 (m, 3H), 7.24 (m, 2H), 7.03 (t, 1H), 6.90 (d, 2H), 4.88 (s, 1H), 3.89 (s, 3H), 2.94 (d, 1H), 2.82 (d, 1H), 2.45 (td, 2H), 2.26 (t, 2H), 1.78 (d, 2H). Dissolve the title compound in Et2O, add HCl in Et2O, stir for 1 h and filter to give the HCl salt. MS FAB 374.1 (M+1); elemental analysis for C25H27NO2.HCl.0.15H2O: calcd: C 72.77, H 6.91, N 3.39, Cl 8.59; obserbed: C 72.76, H 7.02, N 3.59, Cl 8.83.

EXAMPLE 11

[0277] 52

[0278] Step 1 Alkylate a solution of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (0.5 g) in CH3CN using the procedure described in Step 1 of Example 1 to produce desired compound.

[0279] Step 2 Alkylate the product from Step 1, 1-phenyl-8-(diphenylmethyl)-1,3,8-triazaspiro[4,5]decan-4-one (0.4 g) with CH3I using the procedure described in Step 2 of Example 1 to produce the title compound (0.25 g). 1H NMR (CDCl3) δ1.70 (d, 2H), 2.85 (m, 6H), 3.05(s, 3H), 4.50 (s, 1H), 4.72 (s, 2H), 6.95 (t, 1H), 7.05(d 2H), 7.20-7.60 (m, 12H).

[0280] Using the procedures of Examples 1 to 11, employing the appropriate starting material, compounds shown in the following tables are prepared.

TABLE 1
53
wherein X2 is as defined below:
X2           Physical Data
H            C24H25N
             FAB 283.3 (100), 167.2 52)
OMe          C25H27NO
             FAB 358 (80), 167 (70)
OEt          C26N29NO:HCl
             FAB 342 (67) 167 (100)
54           C27H31NO ESI 386.1 (79), 167 (100)
55           C31H31NO:HCl ESI 434.2 (62), 167 (100)
CN           C25H24N2
             FAB 353.2 (53), 275.10 (24).
CHO          C25H25NO
             Cl 356 (28), 167 (100)
CH2OH        C25H27NO
             Cl 358.1 (37), 167 (100)
56           C32H33NO:HCl FAB 448.1 (46), 167.2 (100)
CH2OMe       C25H27NO
             FAB 357.10 (10), 167 (100)
CH2OEt       C26H29NO
             Cl 373.3 (12), 372(42), 167 (100)
57           C30H34NO Cl 440.25 (33), 439.2 (100), 167.2 (89)
CH2NH2       C25H28N2:2HCl
             ESI 357.10 (37), 167 (100)
CH2NHCOCH3   C27H30N2O
             ESI 399.1 (53), 167.0 (100)
58           C32H32N2O FAB 462.1(15), 461.1(41), 393 (8)
59           C32H34N2:HCl ESI 447.1 (100), 281.1 (29)
60           C33H32N2F3:HCl ESI 515(100), 349.10 (33), 167 (49)
CH2NHCH2CH3  C27H32N2:HCl
             ESI 385.1(100), 219.10 (26), 167 (76)
61           C29H36N2O:HCl Cl 429 (53), 351 (100) 327 (13), 167 (34)
62           C28H32N2O2Cl 429 (100), 351 (9), 261 (11), 167 (81)
63           C28H34N2O:HCl Cl 415(100), 327 (33), 167 (65)
64           C31H39N3O:HCl ESI 470 (100), 304 (51), 259 (16), 167 (46)
65           C31H41N3:HCl ESI 456 (100), 290 (11), 167 (11)
66           C30H30N2O2ESI 451(100), 283 (8), 167 (94)
67           C34H43N3O:HCl ESI 510 (88), 344 (73), 167 (100)
68           C32H41N3:HCl ESI 468 (98), 302 (22), 167 (100)
69           C31H31N3O:HCl Cl 462(100), 384 (4), 167 (45)
70           C30H32N2O:Cl ESI 437 (100), 271 (11), 167 (41)
71           C30H32N2O:HCl ESI 437 (87), 271 (7), 167 (100)
72           C30H32N2S:HCl ESI 453 (92), 167 (100)
73           C30H32N2S:HCl ESI 453 (100), 287 (6), 167 (78)
74           C32H36N2S:HCl ESI 481 (69), 340 (5), 167 (100)
75           C29H36N2S:HCl ESI 445 (100), 399 (3), 279 (11), 167 (84)
76           C29H33N2F3:HCl ESI 467 (69), 167 (100)
CH2NMe2      C27H32N2:HCl
             FAB 385.3 (100), 219.2 (6), 162.2 (77)
NH2          C24H26N2:HCl
             ESI 343 (48), 326 (70), 167 (100)
NH(CH2)3NEt2 C31H41N3:HCl
             ESI 456 (72), 326 (74), 167 (100)
77           C29H30N2O:HCl Cl 423 (60), 326 (100), 167 (74)
78           C31H39N3:HCl ESI 454(76), 326 (60), 167 (100)
79           C29H30N2S:HCl FAB 439 (90), 326 (25), 167 (100)
NHMe         C25H28N2:HCl
             ESI 357 (20), 326 (87), 167 (100)
NMe2         C26H30N2:HCl
             ESI 371 (11), 326 (81), 167 (100)

[0281]

TABLE 2
80
wherein X1 is as defined below
X1        Physical Data
81        C24H25NO FAB 343.1 (13), 342.1 (26)
82        C24H24BrNO ESI 424 (20) 422 (18) 167-2 (92)
83        C24H24NOCl Cl 363 (43), 362 (22), 167.20 (100)
84        C24H24FNO 361 (22), 167.2 (75)
Benzyl    C25H27NO
          Cl 358.1 (62), 167 (78)
n-Propyl- C27H31NO:HCl
phenyl    FAB 386.1 (46), 167 (100)
85        C25H23NOF3Cl El 369 (3), 368 (14), 167 (100)
86        C25H24F3NO FAB 413(31), 412 (57), 167 (100)
87        C25H27NO2Cl 374.45(M + 1), 266.30 (39%), 167.25 (100%)
88        C26H30N2O FAB 387 (86%), 369 (22%)
89        C25H26NOF FAB 376.2 (68%), 375.2 (32%). 358.20 (6)
90        C25H27NO2Cl 374.45 (58%), 375.45 (27), 356.35 (29)
91        C24H24ClNO Cl 378.35 (31%), 377.35 (18%), 360.30 (22)
92        C25H27NO Cl 358.35 (68), 357.35 (38), 340.35 (47), 167.25 (100)
93        C24H23F2NO Cl 380.35(28%), 379.35 (22), 362.35 (23), 167.25 (100)
94        C25H27NO Cl 358.35 (63), 357.35 (43), 340.35 (53), 167.25 (100)
95        C25H27NO Cl 358.35 (49), 357.35 (41), 340.35 (35), 167.25 (100)
96        C24H24FNO Cl 362.35 (41), 361.35 (218), 344.35 (39), 167.25 (100)
97        C26H25NO FAB 368(37), 367 (38), 366(100), 290 (41)
98        C25H27NSO FAB 375 (10), 374.20 (40), 306.7 (13)
99        C25H27NSO FAB 390 (22), 389(27), 388 (100), 312 (48)
100       C24H23NOF2380.2 (11), 379.2 (16), 378.2 (31)
101       C26H29NO Cl 373.45 (22), 372.40 (82), 354.35 (60), 167.25 (100)
102       C24H31NO FAB 350.3 (4), 349.3 (7), 348 917)
n Hexyl   C24H33NO
          FAB 352 (85), 274 (189)
n propyl  C27H31NO
          ESI 386 (70), 167 (100)
n butyl   C28H33NO
          ESI 400.1 (68), 167 (100)
103       C21H25NO:HCl ESI 308.1 (32), 167.0 (100)
104       C22H23NO2:HCl Cl 334.25 (34), 333.25 (26), 316.25 (41), 167.25 (100)
105       C22H23NOS:HCl Cl 350.25 (32), 349.35 (24), 332.25 (41), 167.25 (100)
106       C22H23NOS:HCl Cl 350.25 (27), 349.35 (18), 332.25 (20), 167.25 (100)
107       C23H24N2O:HCl ESI 345.1(68), 167 (100)
108       C22H23NO2Cl 334.25(37), 333.25 (24), 316.25 (31), 167.25 (100)
109       C25H24N2O:HCl FAB 369.3 (3), 368.3 (6), 367.3 (13)
110       C21H27NO:HCl Cl 310.40 (38), 309.40 (25), 292.40 (33), 167.25 (100)
111       C24H24NOF:HCl FAB 362.1 (100), 232.1 (11)
112       C22H29NO:HCl FAB 324.30(100)
113       C21H25NO:HCl Cl 308.2 (64), 307.2 (30), 290.2 (57), 167.25 (100)
114       C23H25NOS:HCl Cl 364.15 (69), 346.15 (71), 167.25 (100)
115       C21H22N2SO:HCl Cl 351.1 (52), 350.1 (8), 266.15 (12), 167.2 (100)
116       C27H28N2O:HCl FAB 397.2 (80), 167.2 (100)
117       C25H28N2O:HCl ESI 373.1 (28), 167 (100)
118       C25H27NO2:HCl ESI 374.1 (43), 167 (100)

[0282]

TABLE 3
119
wherein Z1 and Z2 are as defined below:
Z1	Z2	Physical Data
120	121	C24H24NOCl Cl 380 (30), 378.1 (100), 201 (100)
122	123	C24H23NOF2Cl 380.15 (79), 379.15 (47), 362.05 (100)
124	125	C23H24N2O:HCl ESI 345.1(69), 327.1 (49), 168 (100)
126	127	C23H24N2O:HCl ESI 345.1 (58), 168 (100)
128	129	C25H27NO:HCl Cl 358.20 (60), 340.20 (51), 181.25 (100)
130	131	C24H24NOBr:HCl ESI 424.1 (17), 422 (17), 247.1 (100), 245.1 (99)
132	133	C25H27NO:HCl ESI 358.1(32.70), 181 (100)
134	135	C24H24NOCl:HCl Cl 380.10 (30), 378.15 (100)
136	137	C26H29NO:HCl ESI 372.1 (24), 195.1 (100)
138	139	C25H27NO:HCl ESI 358.1 (48%), 181.1 (100)
140	141	C25H24ONF3:HCl ESI 412.1 (56), 235 (100)
142	143	C25H24ONF3:HCl ESI 412.1 (73), 235.1 (100)
144	145	C26H29NO:HCl ESI 372.1 (39), 195.1 (100)
146	147	C24H24NOBr:HCl ESI 424.10 (48), 422.1(47), 245.1 (100)
148	149	C22H23NOS:HCl ESI 350.1 (31), 173 (100)
150	151	C25H24ONF3:HCl ESI 412.1 (54), 235.10 (100)
152	153	C24H24NOF:HCl ESI 362.1 (23), 185.1 (100)
154	155	C24H23NOF2:HCl Cl 380.15 (100), 362.15 (89), 203.25 (99)
156	157	C24H23NOCl2:HCl ESI 416.1 (7), 414 (32), 412 (45), 235.1 (100)
158	159	C25H24N2O2F2:HCl FAB 423.2 (100), 218.0 (18)
160	161	C24H23NOF2:HCl Cl 380.15 (79), 379.15 (45), 362.05 (100)
162	163	C26H29NO2:HCl FAB 388.3 (100), 266.1 (15)
164	165	C25H27NO2:HCl FAB 374.1 (100), 197 (73)
166	167	C24H24NOCl:HCl FAB 380.1(27), 378.2 (80), 201.0 (100)
168	169	C25H27NO:HCl ESI 358.1 (15), 181.1 (100)
Methyl	170	C19H23NO:HCl ESI 282.1 (100), 160.0 (84.5)
Ethyl	171	C20H25NO:HCl ESI 296.1 (100), 160.0 (84)
172	173	C21H27NO:HCl ESI 310.1 (100), 160.1 (52)
174	175	C22H29NO:HCl ESI 324.1(100), 160.1 (52)
176	177	C23H31NO:HCl Cl 338.3 (100), 266.20 (77), 160.35 (17)
178	179	C24H33NO:HCl ESI 352.1 (100), 160.0 (41.83)
180	181	C23H29NO:HCl ESI 336.1 (66.39), 160.0 (63), 159 (100)
182	183	C23H30N2O2:HCl ESI 367.1 (35), 190 (100)
184	185	C23H31NO:HCl ESI 338.1 (100), 161.0 (36), 160 (70)

[0283]

TABLE 4
186
wherein X1, X2, Z1 and Z2 are as defined below
X1	X2	Z1	Z2	Physical Data
187	NH2	188	189	C22H30N2:HCl ESI 323(71), 306(100), 160(31)
190	191	192	193	C27H34N2S:HCl ESI 419 (23), 306 (100)
194	CH2NH2	195	196	C23H32N2:HCl ESI 337 (96), 174 (100), 160 (19)
197	198	199	200	C28H36N2S:HCl ESI 433 (100), 320 (65), 174 (58)
201	NH2	202	203	C25H28N2:HCl Cl 357 (47), 340 (24), 279 (8), 181(100)
204	205	206	207	C28H36N2S:HCl ESI 433 (100), 320 (42), 174 (77)
208	209	210	211	C30H32N2S:HCl ESI 453 (24), 340(27), 181 (100)
212	NH2	213	214	C26H30N2:HCl ESI 371 (16) 195 (100)
215	216	217	218	C31H34N2S:HCl ESI 467 (25), 354 (30), 195 (100)
219	NH2	220	221	C24H24N2Cl2:HCl ESI 413 (18), 411 (26), 396 (39), 394 (51), 237 (69), 235 (100)
222	OH	223	224	C26H28BrNO:HCl 450 (12), 195.1 (100)
225	OH	226	227	C26H28FNO:HCl ESI 390.1 (9.6), 195.1 (100)
228	OH	229	230	C26H28ClNO:HCl 407.1 (5), 195.1 (100) 406.1 (16)
231	232	233	234	C31H32N2OS ESI 481 (25), 195 (100)
235	236	237	238	C28H32N2O Cl 413(31), 354 (8), 195 (100)
239	240	241	242	C29H28Cl2N2S:HCl ESI 509 (10), 507 (14), 396 (56), 394 (77), 237 (68), 235 (100)
243	OH	244	245	C25H26N2OCl2:HCl ESI 443(42), 441 (56), 425 (31), 235 (100)
246	247	248	249	C30H36N2OS ESI 473 (39), 195 (100)
250	251	252	253	C33H34N2O ESI 475 (41), 195 (100)
254	255	256	257	C29H34N2O2ESI 443(31), 195 (100)
258	259	260	261	C30H34N2O:HCl ESI 439 (17), 195 (100)
262	263	264	265	C34H42N2O:HCl ESI 495 (30), 195 (100)
266	267	268	269	C33H36N2:HCl ESI 461 (17), 354 (28), 195 (100)
270	271	272	273	C26H26N2OCl2ESI 455 (57), 453 (75), 396 (7), 394 (10), 237 (73), 235 (100)
274	OH	275	276	C29H31N2O3F3:HCl FAB 497.2 (507), 195.1 (100)
277	278	279	280	C24H32N2O:HCl ESI 365 (100), 219 (31), 160 (23)
281	282	283	284	C27H30N2O:HCl ESI 399 (60), 181 (100)
285	286	287	288	C29H34N2O:HCl ESI 427 (41), 195 (100)
289	290	291	292	C30H36N2O:HCl ESI 441 (47), 195 (100)
293	294	295	296	C28H32N3O:HCl ESI 428 (41), 195 (100)
297	OH	298	299	C27H30Cl2N2O FAB 469.2 (30), 235.1 (100)
300	OH	301	302	C28H32Cl2N2O3S Cl 549.15 (69), 548.15 (37), 547.15 (100)
303	OH	304	305	C28H32Cl2N2O3S FAB 549 (60), 547.1 (87)
306	OH	307	308	C27H30Cl2N2O3S FAB FAB 535 (78), 533 (100)
309	OH	310	311	C26H28Cl2N2O3S FAB 523 (25)
312	OH	313	314	C30H35Cl2N3O FAB 524.40(20), 330.3 (100)
315	OH	316	317	C36H39Cl2N3O FAB 600.5 (50), 330.4 (70)
318	OH	319	320	C25H27BrN2O FAB 453.2 (100), 245 (100)
321	OH	322	323	C25H26N2F2O FAB 410.2 (25), 409.2 (100), 203.2 (50)
324	OH	325	326	C27H32N2O FAB 401.2 (95), 195 (100)
327	OH	328	329	C25H26Cl2N2O 441.1 (40), 235 (42), 157 (100)
330	OH	331	332	C25H27NO2Cl 374.25 (52), 356.2 (100), 178.25 (40), 160.25 (57)
333	OH	334	335	C25H25NO3FAB 388.23 (100), 210.8 (21), 168.28 (20)
336	OH	337	—(CH2)4CH3	C24H34N2O FAB 368.3 (30), 367.3 (100)
338	OH	339	—(CH2)3CH3	C23H32N2O GAB 353.3 (100)
340	OH	341	342	C25H26N2F2O FAB 410.6 (35), 409.4 (98), 203.1 (65)
343	OH	344	345	C26H28Cl2N2O FAB 457.3 (70), 455.3 (100), 237 (30), 235.1 (52)
346	OH	H	347	C19H23N2OCl FAB 331.2 (100),
348	OH	349	350	C27H32N2O FAB 402.1 (20.46), 401.1 (44.89), 195.1 (100)
351	OH	352	353	C25H27ClN2O ES 409.2 (55), 408.2 (45), 407.2 (95)
354	OH	355	356	C26H30N2O ES 387 (100)
357	OH	358	359	C25H25NO2Cl 372.15 (100), 354.15 (38), 195.15 (37)
360	OH	361	362	C26H29NO3FAB 404.3 (100), 227.1 (70)
363	OH	H	364	C21H34N2O FAB 331.4 (100), 266.2 (20)
365	OH	CH3(CH2)3—	366	C24H34N2O FAB 367.2 (100)
367	OH	368	369	C27H32N2O ES 401.1 (46), 195.1 (100)
370	OH	371	372	C31H38N2O3ES 487 (100)
373	374	375	376	C27H29Cl2N3O ESI 484.2 (72), 482.2 (100), 237 (60), 235.0 (65)
377	378	379	380	C26H27Cl2N3O ESI 470.1 (80), 468.1 (100), 235 (78)
381	382	383	384	C26H27Cl2N3O ESI 470.2 (78), 468.2 (90), 237.0 (65), 235 (100)
385	386	387	388	C29H35N3O ESI 442.3 (100)
389	OH	390	391	C25H26N2OBr2ESI 533 (55), 531 (100), 324.8 (30)

[0284]

TABLE 5
392
wherein R11, Z1 and Z2 are as defined in the following table,
wherein Ac is acetyl, Me is methyl and Et is ethyl::
R11	CH(Z1)(Z2)	Physical Data
H	Benzhydryl
393	Benzhydryl	C32H37N3O:HCl Cl 480 (100), 167.25 (22)
394	Benzhydryl	C29H31N3O3:HCl Cl 470.15 (100), 167.25 (25)
395	Benzhydryl	C29H31N3O:HCl Cl 438.20 (100), 167.25 (29)
396	Benzhydryl	C30H33N3O:HCl FAB 452.3 (100), 167.0 (92)
397	Benzhydryl	C29H33N3O:HCl Cl 440.20 (100), 167.25 (22)
Me	Benzhydryl	C26H27N3O:HCl
		Cl 398.15 (100), 167.25 (39)
Ethyl	Benzhydryl	C27H29N3O:HCl
		Cl 412.15 (100), 167.25 (32)
n propyl	Benzhydryl	C28H31N3O:HCl
		ESI 426.1(14), 167 (100)
n butyl	Benzhydryl	C29H33N3O:HCl
		ESI 440.10 (100), 167.10 (33)
isopropyl	Benzhydryl	C28H31N3O:HCl
		ESI 446.10 (28), 167. (100)
398	Benzhydryl	C28H31N3O2:HCl ESI 442.10 (15), 167. (100)
399	Benzhydryl	C27H29N3O2:HCl FAB 428.3 (65), 232.1 (57)
H	400	C23H29N3O:HCl ESI 364.1 (58), 218.1 (100)
401	402	C25H33N3O2:HCl ESI 408.1 (93), 262.1 (100)
n pentyl	Benzhydryl	C30H35N3O:Hcl
		ESI 454.1 (46), 167.1 (100)
n-hexyl	Benzhydryl	C31H37N3O:HCl
		ESI 468.1 (26), 167 (100)
403	Benzhydryl	C28H31N3O2:HCl ESI 442.10 (15), 167 (100)
404	405	C31H35N3O:HCl ESI 466.1 (44), 181.1 (100)
406	407	C29H33N3O2:HCl ESI 456.1 (48), 181.10(100)
H	408	C24H31N3O:HCl Cl 378.25 (100), 306.20 (22), 218.20 (24)
H	409	C26H27N3O:HCl ESI 398.10 (44), 181.1 (100)
410	411	C27H33N3O:HCl ESI 416.10(36), 286.1 (39)
412	413	C30H31N3OCl2:HCl ESI 522.1 (79), 521.1 (48), 520 (100)
414	Benzhydryl	C30H34N2O:HCl Cl 439.25 (100), 168.30 (20)
H	415	C27H29N3O:HCl Cl 412.20(32), 218.20 (42), 195.35 (100)
416	Benzhydryl	C29H31N3O3:HCl ESI 470.1 (100), 167.1 (77.40)
H	417	C25H23N3Cl2O:HCl ESI 452.1 (100), 235 (85)
418	419	C30H33N3O2Cl2:HCl ESI 525.1 (39), 524.1 (82), 522 (100)
420	421	C28H29N3OCl2:HCl ESI 511.1 (46), 510 (100), 514 (20), 513.1 (33.50)
422	423	C32H39N3O:HCl ESI 482.1 (48), 195.1 (100)
424	425	C30H35N3O2:HCl ESI 471.1 (13), 470.1 (30), 195.1 (100)
H	426	C25H24N3OCl:HCl FAB 420.2 (35), 418.2 (100), 201.0 (75)
H	427	C25H24N3OF:HCl Elemental Analysis C: 68.12; H: 5.83; N: 9.48; Cl: 8.21; F;: 4.59
428	Benzhydryl	C28H32N4O:HCl ESI 442.1 (39), 441.1 (92), 167 (100)
429	Benzhydryl	C29H34N4O:HCl ESI 455.1 (100), 290.1 (14), 289.1 (57.88), 167 (94)
430	Benzhydryl	C27H30N4O:HCl ESI 428.1 (42), 427.1(97), 167 (100)
431	Benzhydryl	C30H36N4O.HCl ESI 470.1 (48), 469 (100), 303 (93), 167 (82.75)
432	Benzhydryl	C29H34N4O:HCl ESI 457.1(13), 456 (57), 455.1 (100), 167 (72)
433	Benzhydryl	C28H29N3O3FAB 456.2 (78), 167.0 (100)
434	435	C22H23Cl2N3O3FAB 450.1 (27), 448.0 (100)
H	436	C24H31N3O FAB 378.4 (100), 218.2 (30)
437	Benzhydryl	C31H35N3O3498.2 (100), 167.1 (90)
438	Benzhydryl	C29H31N3O3ESI 470.1 (100), 167.1 (55)
439	440	C23H27Cl2N3O ESI 434.1 (80), 432.1 (100)
441	442	C22H25Cl2N3O2ESI 436.1 (58), 434.1 (100)
443	444	C23H27Cl2N3O ESI 434.1 (35), 432.1 (100)
445	446	C24H27Cl2N3O ESI 446.1 (77)), 444.1 (100)
447	448	C21H22Cl2N4O2FAB 435.1 (78), 433.1 (100)

[0285]

TABLE 6
449
wherein R11, Z1 and Z2 are as defined in the following table:
R11	CH(Z1)(Z2)	Physical Data
H	Benzhydryl
450	Benzhydryl	C29H33N3O ESI: 440 (100) 167 (80)
451	Benzhydryl	C29H31N3O ESI: 438 (100) 167 (99)
452	Benzhydryl	C30H35N3O ESI: 454 (100) 167 (94)
453	Benzhydryl	C29H29N3O ESI: 436 (99) 167 (100)
CH3	Benzhydryl	C27H29N3O
		FAB: 412 (100)
454	Benzhydryl	C28H31N3O FAB: 426 (100)
455	Benzhydryl	C30H33N3O3FAB: 484 (7) 261 (14) 167 (100)
456	Benzhydryl	C30H33N3O ESI: 452 (100) 167 (60)
457	Benzhydryl	C33H39N3O ESI: 494 (100) 167 (30)
458	Benzhydryl	C31H35N3O.HCl FAB: 466 (100)
459	Benzhydryl	C30H33N3O3.HCl FAB: 484 (100) 167 (41)
460	Benzhydryl	C33H38N4O2.HCl FAB: 523 (100)
H	461	C26H25N3F2O.HCl ESI: 434 (29) 203 (100)
H	462	C26H25N3F2O.HCl Cl: 434 (100)
H	463	C26H26N3ClO.HCl ESI: 432 (60) 201 (100)
464	Benzhydryl	C29H33N3O.HCl ESI: 440 (100) 167 (89)
465	Benzhydryl	C33H37N3O2.HCl ESI: 508 (100) 167 (35)
H	466	C24H30N3ClO.HCl ESI: 412 (100) 232 (92)
H	467	C24H31N3O.HCl ESI: 378 (100) 232 (82)
H	468	C21H24N3ClO.HCl ESI: 370 (86) 265 (100)
H	469	C24H30N3FO.HCl ESI: 396 (31) 232 (100)
H	470	C24H30N3BrO.HCl ESI: 456 (39) 232 (100)
H	471	C25H33N3O.HCl ESI: 392 (73) 232 (100)
H	472	C25H31N3O.HCl FAB: 390 (100)
473	474	C28H39N3O.HCl ESI: 434 (68) 288 (100)
475	476	C31H43N3O.HCl ESI: 474 (90) 328 (100)
477	478	C27H37N3O.HCl ESI: 420 (81) 274 (100)
H	479	C27H29N3O.HCl FAB: 412 (25) 181 (100)
480	481	C29H41N3O.HCl ESI: 448 (97) 288 (100)
482	483	C27H37N3O.HCl ESI: 420 (62) 274 (100)
484	485	C28H39N3O.HCl ESI: 434 (66) 274 (100)
H	486	C25H33N3O.HCl ESI: 392 (59) 232 (100)
487	488	C31H37N3O.HCl ESI: 468 (100) 322 (92)
489	490	C28H39N3O.HCl ESI: 434 (100) 274 (86)
H	491	C22H25N3O3.HCl Cl: 380 (100)
492	493	C32H39N3O.HCl ESI: 482 (100) 322 (78)
H	494	C21H25N3O2.HCl FAB: 352 (100)
495	496	C33H41N3O.HCl FAB: 496 (100)
H	497	C28H31N3O.HCl ESI: 426 (19) 195 (100)
H	498	C26H26N3Cl2O.HCl ESI: 466 (79) 235 (100)
H	499	C25H32N4O2.HCl ESI: 421 (40) 190 (100)
H	500	C26H26N3FO.HCl FAB: 416 (100)
H	501	C26H25N3Cl2O.HCl ESI: 466 (100) 235 (60)
H	502	C26H26N3ClO.HCl ESI: 432 (48) 201 (100)
H	503	C26H26N3F2O.HCl ESI: 434 (69) 203 (100)
504	505	C29H37N3O.HCl ESI: 444 (52) 326 (100)
506	507	C27H33N3O.HCl ESI: 416 (33) 300 (100)
508	509	C28H29N3Cl2O2.HCl ESI: 510 (100)
510	511	C31H33N3Cl2O2.HCl ESI: 550 (100)
512	513	C30H33N3Cl2O.HCl ESI: 522 (100)
514	515	C31H35N3Cl2O.HCl ESI: 536 (100)
516	517	C29H29N3Cl2O3.HCl FAB: 538 (100)
518	519	C29H31N3Cl2O2.HCl ESI: 524 (100)
520	521	C32H36N4Cl2O.HCl FAB: 563 (100) 235 (55)
522	523	C27H37N3O2.HCl FAB: 436 (100)
524	525	C24H31N3O3.HCl FAB: 410 (100)
526	527	C25H33N3O2.HCl FAB: 408 (100)
528	529	C26H35N3O2.HCl FAB: 422 (100)
530	531	C29H32N4Cl2O.2HCl FAB: 523 (100)
532	533	C31H36N4Cl2O.2HCl FAB: 551 (100)
534	535	C30H34N4Cl2O.2HCl FAB: 537 (100)
536	537	C30H34N4Cl2O.2HCl FAB: 537 (100)
538	539	C29H38N4O.2HCl FAB: 459 (100)
540	541	C33H38N4Cl2O.2HCl ESI: 577 (56) 343 (100)
542	543	C33H38Cl2N4O ESI 577 (100), 343 (45)
544	545	C33H38Cl2N4O ESI 577 (100), 343 (45)
546	547	C34H40Cl2N4O ESI 591 (100), 357 (81)
548	549	C31H44N4O ESI 487 (100), 327 (51)
550	551	C33H39Cl2N5O ESI 592 (100), 358 (71), 235 (64)
552	553	C31H34Cl2N4O ESI 549 (100), 315 (52)
554	555	C31H42N4O ESI 487 (100), 329 (85)
556	557	C31H44N4O ESI 489 (100), 331 (99)
558	559	C33H38Cl2N4O2ESI 593 (100), 359 (45), 297 (45)
560	561	C34H40Cl2N4O ESI 591 (100), 357 (82), 235 (99)
562	563	C34H39Cl2N5O2ESI 620 (100), 386 (12), 235 (28)
564	565	C32H38Cl2N4O ESI 565 (100), 331 (56), 235 (52)
566	567	C32H36Cl2N4O2ESI 579 (100), 345 (51), 235 (76)
568	569	C33H38Cl2N4O2ESI 593 (100), 359 (63), 235 (90)
570	571	C35H42Cl2N4O ESI 605 (100), 371 (83)
572	573	C37H44Cl2N4O3FAB 663 (100), 234 (42)
574	575	C25H32Cl2N4O2ESI 491 (100), 333 (29)
576	577	C26H32Cl2N4O ESI 487 (100), 319 (31)
578	579	C26H34Cl2N4O ESI 489 (100), 331 (18)
580	581	C32H46N4O2ESI 519 (91), 361 (100)
582	583	C25H32N4Cl2O ESI 475 (100), 317 (24), 159 (69)
584	585	C28H38N4O FAB 447.3 (100), 289.2 (25), 242.2 (36)
586	587	C29H40N4O FAB 461.2 (100), 303.2 (20)
588	589	C31H42N4O2ESI 503.1 (100), 345.1 (95)
590	591	C30H42N4O ESI 475.1 (99), 317.1 (100)
592	593	C30H42N4O ESI 4 75.1 (89), 317.1 (100)
594	595	C33H48N4O2ESI 519.1 (95), 361.1 (100)256.1 (12)
596	597	C29H40N4O2ESI 477.1 (100), 319.1 (100)
598	599	C31H42N4O ESI 487.10 (100), 329.1 (88)
600	601	C28H38N4O FAB 447 (100), 391 (30), 317 (20)
602	603	C29H41N5O FAB 476 (100), 346 (40)
604	605	C29H40N4O FAB 461 (100), 391 (40), 167 (22)
606	607	C28H38N4O FAB 447 (100), 391 (60)
608	609	C31H42N4O ESI 487.1 (100), 329.1 (86)
610	611	C30H42N4O2ESI 491.1 (63), 333.10 (100)
612	613	C34H48N4O ESI 529.1 (79), 371.1 (100)
614	615	C31H45N5O ESI 504.1 (99), 358.1 (100)
616	617	C32H45N5O ESI 516.1 (92), 358.1 (100), 251.1 (28)
618	619	C25H32Cl2N4O ESI 475 (100), 317 (16)
620	621	C24H30Cl2N4O ESI 461 (100), 303 (25)
622	623	C23H28Cl2N4O ESI 447 (100), 224 (64)
624	625	C26H34Cl2N4O ESI 489 (100), 331 (33)
626	627	C27H25F4N3O ESI 484 (100)
628	629	C26H32Cl2N4O ESI 487 (100), 433 (39)
630	631	C26H32Cl2N4O ESI 487 (100), 433 (46)
632	633	C31H44N4O ESI 489.1 (100), 331.1 (68)
634	635	C30H40N4O ESI 473.1 (100), 315.1 (55)
636	637	C32H46N4O ESI 503.1 (100), 345.1 (834)
638	639	C33H46N4O ESI 515.1 (73), 357.1 (100), 258.1 (9)
640	641	C32H40N4OS ESI 433.1 (22), 371.1 (83)
642	643	C32H44N4O ESI 501.1 (80), 343.1 (100), 251.1 (7), 159.1 (69)
644	645	C32H40N4O2ESI 513.1 (87), 433.1 (32), 355.1 (100), 275.1 (12)
646	647	C34H42N4O ESI 523.1 (91), 365.1 (100)
648	649	C32H38Cl2N4O ESI 565 (100), 331 (56), 235 (52)
H	650	C26H27N3O ESI 398 (100), 397 (4)
651	652	C26H34FN4O ESI 457 (92), 229 (100)
653	654	C29H40N4O ESI 461 (99), 231 (100)
655	656	C30H42N4O2ESI 491.1 (90), 331.1 (65), 61 (100)
657	658	C31H43ClN4O ESI 525.1 (42), 524.1 (53), 523.1 (65), 331.1 (60), 193.1 (100)
659	660	C28H38N4O2ESI 463 (100), 331 (38)
661	662	C29H40N4O3ESI 494 (100), 247 (95)
663	664	C26H34Cl2N4O ESI 491(86) 489 (100), 245 (72)
665	666	C28H38N4O ESI 447 (88), 224 (100)
667	668	C26H35ClN4O ESI 455 (100), 228 (85)
669	670	C26H35ClN4O ESI 455 (100), 228 (60)
671	672	C24H31ClN4O ESI 427 (100), 303 (10), 214 (48)
673	674	C23H29BrN4O ESI 459 (99), 457 (100), 230 (45)
675	676	C26H35BrN4O FAB 501 (99), 499 (100), 235 (40)
677	678	C26H35BrN4O FAB 501 (99), 499 (100), 171 (28)
679	680	C26H35BrN4O FAB 499(99), 497 (100), 171 (20)
681	682	C26H33FN4O FAB 439 (100), 220 (7)
683	684	C26H35FN4O FAB 439 (100), 220 (40)
H	685	C21H25N3O FAB 336 (100), 171 (100)
686	687	C23H29FN4O FAB 397 (100), 242 (100)
688	689	C24H31FN4O FAB 411 (100), 242 (90)
H	690	C19H27N3O FAB 314 (100), 247 (7)
691	692	C29H39FN4O ESI 479.1(100), 424.1 (31), 331.1 (43), 203.1 (61)
693	694	C29H39FN4O ESI 479.1(100), 424.1 (11), 331.1 (39), 203.1 (38)
695	696	C29H39ClN4O ESI 495.1 (70), 345.1 (37), 65.0 (100)
H	697	C24H25N3O ESI 372.1 (100), 200.1 (4)
698	699	C30H38N4O ESI 471.1 (100), 331.1 (36)
H	700	C20H29N3O ESI 328 (100)
H	701	C21H31N3O ESI 342 (100)
H	702	C22H33N3O ESI 356.1 (100), 171.1 (5)
703	704	C24H37N3O ESI 370.1 (100), 247.1 (20)

[0286]

TABLE 7
compounds of the formulas shown, wherein Ph is phenyl
Compound Physical Data
705      C25H27NO.HCl ESI 358.1 (44.50), 167.0 (100)
706      C25H27NO.HCl FAB 358.2 (100), 232.1 (23.70)
707      C27H29NO.HCl Cl 348.20 (58), 366.25 (48)
708      C26H27NO.HCl FAB 370.1 (100), 167.0 (100)
709      C28H31NO.HCl FAB 398.1 (100), 195.1 (98)
710      C26H25NOCl2.HCl FAB 440.1 (65), 438.0 (100), 236.9 (38), 234.9 (60)
711      C25H23NO2.HCl FAB 370.2 (100), 292.2 (18)
712      C25H25NO.HCl ESI 356.1 (14.77), 168 (20.98), 167 (100)
713      C26H27N.HCl ESI 354.1 (55.06), 167.1 (100),
714      C26H25N.HCl ESI 352.1 (41.94), 167.1 (100)
715      C25H25NO2.HCl ESI 372.1 (15.42), 167 (100)
716      C26H27NO2.HCl Cl 386.10 (73), 354.05 (88), 167.25 (100),
717      C25H24N3Cl.HCl Cl 402 (55), 366.20 (77), 250.15 (34), 167.25 (100),
718      C24H27N3O.HCl Cl 398.05 (100), 232.10 (19), 167.25 (74),
719      C25H26N2Cl 356.2 (26) 355.2 (100), 167(28)
720      C26H25N3O2:HCl ESI 412 (20), 167.1 (100)
721      C26H25F2NO ESI 406.1 (100), 203.1 (89.11)
722      C26H26ClNO ESI 406.1 (34.35), 404.10 (81.42), 201.10 (100)
723      C27H29NO ESI 384.1 (54.52), 181 (100)
724      C27H28Cl2N2O ESI 399.1 (13.87), 398.1 (56.98), 397.1 (100)
725      C26H26FNO ESI 388.2 (90), 185.0 (100)
726      C29H34N2O ESI 429.1 (8.33), 428.10 (36.55), 427.1 (74.28)
727      C24H31NO FAB 350.4 (100), 204.3 (18)
728      C25H33NO FAB 364.40 (100), 204.3 (20)
729      C27H28F2N2O FAB 435.2 (100), 203.1 (55)
730      C26H26BrNO FAB 448.1 (100), 247.0 (58), 166.1 (38)
731      C26H25Br2NO ESI 528 (100), 325.1 (54.35)
732      C27H28Br2N2O FAB 560 (20), 557 (100), 324.8 (60)
733      C27H27NO3Cl 414.20 (100), 396.20 (34), 211.15 (47), 186.15 (30)
734      C19H19N3O ESI 306.1 (100)
735      C21H29N3O ESI 341.1 (30.27), 340.1 (100)
736      C23H33N3O ESI 369.1 (39.66), 368.1 (100)
737      C28H31NO3ESI 430.1 (100), 204.1 (52.46)
738      C28H27NO3FAB 426.3 (100), 225.0 (18), 195 (18)
739      C30H35NO ESI 426.1 (100), 408 (11), 223.0 (43)
740      C28H31NO3ESI 430.1 (100), 412.1 (11.0), 227.0 (24.2)
741      C25H33NO ESI 364.10 (100), 346 (7)
742      C21H23NO3FAB 338.1 (100)
743      C21H21F4NO2ESI 396.1 (100)
744      C22H27NO3CI 354 (100), 336 (78)
745      C21H21F4NO ESI 380.1 (100)

[0287]

TABLE 8
746
wherein Z1 and Z2 are as defined in the following table:
Z1	Z2	Physical Data
747	748	C25H24N2O.HCl FAB 369.2 (75), 167.1 (100)
749	750	C27H28N2O.HCl FAB 397.2 (40), 195.1 (100)
751	752	C26H26N2O.HCl ESI 383.1 (11.64), 181.1 (100)
753	754	C25H24N2Cl2O.HCl ESI 441.1 (11.05), 440.1 (15.61), 439.1 (48.02), 438.1 (23.94), 437.1 (64.05), 235.1 (100)
755	756	C25H22N2OF2.HCl FAB 405.2 (100), 203.1 (76)
757	758	C25H23ClN2O:HCl FAB 403.1 (100) 201(70)

[0288] Compounds of formulas II to VI can be prepared according to the procedures disclosed in the cited patent specifications.

[0289] Assays

[0290] Nociceptin Binding Assay

[0291] CHO cell membrane preparation expressing the ORL-1 receptor (2 mg) was incubated with varying concentrations of [125I][Tyr14]nociceptin (3-500 pM) in a buffer containing 50 mM HEPES (pH7.4), 10 mM NaCl, 1 mM MgCl2, 2.5 mM CaCl2, 1 mg/ml bovine serum albumin and 0.025% bacitracin. In a number of studies, assays were carried out in buffer 50 mM tris-HCl (pH 7.4), 1 mg/ml bovine serum alumbin and 0.025% bacitracin. Samples were incubated for 1 h at room temperature (22° C.). Radiolabelled ligand bound to the membrane was harvested over GF/B filters presoaked in 0.1% polyethyleneimine using a Brandell cell harvester and washed five times with 5 ml cold distilled water. Nonspecific binding was determined in parallel by similar assays performed in the presence of 1 μM nociceptin. All assay points were performed in duplicates of total and non-specific binding.

[0292] Calculations of Ki were made using methods well known in the art.

[0293] For compounds of this invention, Ki values were determined to be in the range of 0.6 to 3000 nM, with compounds having a Ki value less than 10 nM being preferred. Ki values for representative compounds of the invention are as follows:

Compounds Ki (nM)
759       13
760       200
761       60
762       0.6
763       2.3
764       77
765       18
766       3,000

[0294] Using the procedures described in the European Journal of Pharmacology, 336 (1997), p. 233-242, the agonist activity of compounds of the invention was determined:

         % Stimulation of
         [35S]-GTPγS
         binding to human
         ORL-1 receptor
Compound @ 100 nM
767      77
768      43
769      59
770      102
771      71
772      43
773      15
774      95
775      107
776      120
777      70
778      101

EXAMPLE 12

[0295] Cough Studies

[0296] The effects of nociceptin agonist Compound A (0.3-10 mg/kg, p.o.) and Compound B (10 mg/kg, p.o.) 779

[0297] were evaluated in capsaicin-induced cough in the guinea pig according to the methods of Bolser et al. British Journal of Pharmacology (1995) 114, 735-738. This model is a widely used method to evaluate the activity of potential antitussive drugs. Overnight fasted male Hartley guinea pigs (350-450 g, Charles River, Bloomington, Mass., USA) were placed in a 12″×14″transparent chamber. The animals were exposed to aerosolized capsaicin (300 μM, for 4 min) produced by a jet nebulizer (Puritan Bennett, Lenexa, Kans., USA) to elicit the cough reflex. Each guinea pig was exposed only once to capsaicin. The number of coughs were detected by a microphone placed in the chamber and verified by a trained observer. The signal from the microphone was relayed to a polygraph which provided a record of the number of coughs. Either vehicle (methylcellulose 1 ml/kg, p.o.) or Compound A or Compound B were given 2 hours before aerosolized capsaicin. The antitussive activity of baclofen (3 mg/kg, p.o.) was also tested as a positive control. The results are summarized in the bar graph in FIG. 1.

EXAMPLE 13

[0298] Respiratory Measurements

[0299] Studies were performed on male Hartley guinea pigs ranging in weight from 450 to 550 g. The animals were fasted overnight but given water and libitum. The guinea pigs were placed in a whole-body, head-out plethysmograph and a rubber collar was placed over the animal's head to provide an airtight seal between the guinea pig and the plethysmograph. Airflow was measured as a differential pressure across a wire mesh screen which covered a 1-in hole in the wall of the plethysmograph. The airflow signal was integrated to a signal proportional to volume using a preamplifier circuit and a pulmonary function computer (Buxco Electronics, Sharon, Conn., model XA). A head chamber was attached to the plethysmograph and air from a compressed gas source (21% O2, balance N2) was circulated through the head chamber for the duration of study. All respiratory measurements were made while the guinea pigs breathed this circulating air.

[0300] The volume signal from each animal was fed into a data acquisition/analysis system (Buxco Electronics, model XA) that calculated tidal volume and respiratory rate on a breath-by-breath basis. These signals were visually displayed on a monitor. Tidal volume and respiratory rate were recorded as an average value every minute.

[0301] The guinea pigs were allowed to equilibrate in the plethysmograph for 30 min. Baseline measurements were obtained at the end of this 30 min period. The guinea pigs were then removed from the plethysmograph and orally dosed with Compound A from Example 12 (10 mg/kg, p.o.), baclofen (3 mg/kg, p.o.) or a methylcellulose vehicle placebo (2 ml/kg, p.o.). Immediately after dosing, the guinea pigs were placed into the plethysmograph, the head chamber and circulating air were reconnected and respiratory variables were measured at 30, 60, 90 and 120 min post treatment. This study was performed under ACUC protocol #960103.

[0302] Data Analysis

[0303] The data for tidal volume (VT), respiratory rate (f) and minute volume (MV=VT×f) were made for the baseline condition and at each time point after the drug or vehicle. The results are expressed as the mean ±SEM. The results are shown in FIGS. 2A, 2B and 2C. FIG. 2A shows the change in Tidal Volume, FIG. 2B shows the change in Tidal Volume and FIG. 2C shows the change in frequency of breaths.

[0304] We have surprisingly discovered that nociceptin receptor ORL-1 agonists exhibit anti-tussive activity, making them useful for suppressing coughing in mammals. The ORL-1 agonists decrease the severity and frequency of coughing. The coughing can be chronic, intractable or caused by transient medical or environmental conditions. Non-limiting examples of the causes for coughing are irritants, inflammatory diseases, influenza, asthma and upper respiratory diseases. Non-limitative examples of nociceptin receptor ORL-1 agonists include the nociceptin receptor ORL-1 agonist compounds described herein.

[0305] For mammals treated for coughing, the nociceptin receptor ORL-1 agonists may be administered along with one or more additional agents for treating cough, allergy or asthma symptoms selected from antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, decongestants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists. For example, the ORL-1 agonist can be administered in combination with an expectorant or an antihistamine, or with both an expectorant and an antihistamine. The combination preferably comprises 2 to 4 active agents.

[0306] Non limitative examples of antihistamines include: astemizole, azatadine, azelastine, acrivastine, brompheniramine, certirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine (also known as SCH-34117), doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, equitazine, mianserin, noberastine, meclizine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine.

[0307] Non-limitative examples of histamine H3 receptor antagonists include: thioperamide, impromidine, burimamide, clobenpropit, impentamine, mifetidine, S-sopromidine, R-sopromidine, SKF-91486, GR-175737, GT-2016, UCL-1199 and clozapine. Other compounds can readily be evaluated to determine activity at H3 receptors by known methods, including the guinea pig brain membrane assay and the guinea pig neuronal ileum contraction assay, both of which are described in U.S. Pat. No. 5,352,707. Another useful assay utilizes rat brain membranes and is described by West et al., “Identification of Two-H3-Histamine Receptor Subtypes,” Molecular Pharmacology, Vol. 38, pages 610-613 (1990).

[0308] The term “leukotriene inhibitor” includes any agent or compound that inhibits, restrains, retards or otherwise interacts with the action or activity of leukotrienes. Non-limitative examples of leukotriene inhibitors include montelukast [R-(E)]-1[[[1-[3-[2-(7-chloro-2-quinolinyl)-ethenyl]phenyl]-3[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclo-propaneacetic acid and its sodium salt, described in EP 0 480 717; 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio) methylcyclopropaneacetic acid, and its sodium salt, described in WO 97/28797 and U.S. Pat. No. 5,270,324; 1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl) propyl)thio) methyl)cyclopropaneacetic acid, and its sodium salt, described in WO 97/28797 and U.S. Pat. No. 5,472,964; pranlukast, N-[4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl]-p-4-phenylbutoxy) benzamide) described in WO 97/28797 and EP 173,516; zafirlukast, (cyclopentyl-3-[2-methoxy-4-[(o-tolylsulfonyl) carbamoyl]benzyl]-1-methylindole-5-carbamate) described in WO 97/28797 and EP 199,543; and [2-[[2(4-tert-butyl-2-thiazolyl)-5-benzofuranyl] oxymethyl]phenyl]acetic acid, described in U.S. Pat. No. 5,296,495 and Japanese patent JP08325265 A.

[0309] The term “5-lipoxygenase inhibitor” or “5-LO inhibitor” includes any agent or compound that inhibits, restrains, retards or otherwise interacts with the enzymatic action of 5-lipoxygenase. Non-limitative examples of 5-lipoxygenase inhibitors include zileuton, docebenone, piripost, ICI-D2318, and ABT 761.

[0310] Non-limitative examples of β-adrenergic receptor agonists include: albuterol, bitolterol, isoetharine, mataproterenol, perbuterol, salmeterol, terbutaline, isoproterenol, ephedrine and epinephrine.

[0311] A non-limitative example of a xanthine derivative is theophylline.

[0312] Non-limitative examples of x-adrenergic receptor agonists include arylalkylamines, (e.g., phenylpropanolamine and pseudephedrine), imidazoles (e.g., naphazoline, oxymetazoline, tetrahydrozoline, and xylometazoline), and cycloalkylamines (e.g., propylhexedrine).

[0313] A non-limitative example of a mast cell stabilizer is nedocromil sodium.

[0314] Non-limitative examples of anti-tussive agents include codeine, dextromethorphan, benzonatate, chlophedianol, and noscapine.

[0315] A non-limitative example of an expectorant is guaifenesin.

[0316] Non-limitative examples of decongestants are pseudoephedrine, phenylpropanolamine and phenylephrine. Non-limitative examples of NK1, NK2 and NK3 tachykinin receptor antagonists include CP-99,994 and SR 48968.

[0317] Non-limitatve examples of GABAB agonists include baclofen and 3-aminopropyl-phosphinic acid.

[0318] For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 70 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

[0319] For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0320] Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection.

[0321] Liquid form preparations may also include solutions for intranasal administration.

[0322] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.

[0323] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

[0324] The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

[0325] Preferably the compound is administered orally.

[0326] Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

[0327] The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, more preferably from about 1 mg. to 300 mg, according to the particular application.

[0328] The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

[0329] The amount and frequency of administration of the compounds of the invention and the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended dosage regimen for compounds of formula I is oral administration of from 10 mg to 2000 mg/day preferably 10 to 1000 mg/day, in two to four divided doses to provide relief from pain, anxiety, depression, asthma or alcohol abuse. The compounds are non-toxic when administered within this dosage range.

[0330] For treating cough, the amount of nociceptin receptor ORL-1 agonist in a unit dose is preferably from about 0.1 mg to 1000 mg, more preferably, from about 1 mg to 300 mg. A typical recommended dosage regimen is oral administration of from 1 mg to 2000 mg/day, preferably 1 to 1000 mg/day, in two to four divided doses. When the nociceptin receptor ORL-1 agonist and one or more additional agents are administered together, they are preferably administered in a combined dosage form (e.g., a single tablet), although they can be administered separately. The additional agents are administered in amounts effective to provide relief from cough, allergy or asthma symptoms, preferably from about 0.1 mg to 1000 mg, more preferably from about 1 mg to 300 mg per unit dose. A typical recommended dosage regimen of the additional agent is from 1 mg to 2000 mg/day, preferably 1 to 1000 mg/day, in two to four divided doses.

[0331] The following are examples of pharmaceutical dosage forms which contain a compound of the invention. The scope of the invention in its pharmaceutical composition aspect is not to be limited by the examples provided.

[0332] Pharmaceutical Dosage Form Examples

EXAMPLE A-Tablets
No.	Ingredients	mg/tablet	mg/tablet
1.	Active compound	100	500
2.	Lactose USP	122	113
3.	Corn Starch, Food Grade, as a	30	40
	10% paste in Purified Water
4.	Corn Starch, Food Grade	45	40
5.	Magnesium Stearate	3	7
	Total	300	700

[0333] Method of Manufacture

[0334] Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., ¼″, 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weigh on a suitable tablet machine.

EXAMPLE B-Capsules
No.	Ingredient	mg/capsule	mg/capsule
1.	Active compound	100	500
2.	Lactose USP	106	123
3.	Corn Starch, Food Grade	40	70
4.	Magnesium Stearate NF	7	7
	Total	253	700

[0335] Method of Manufacture

[0336] Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine.

[0337] While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

1. A method of treating cough comprising administering to a mammal in need of such treatment an effective amount of an ORL-1 agonist, alone or in combination with an effective amount of one or more agents for treating cough, allergy or asthma symptoms.

2. The method of claim 1 wherein the ORL-1 agonist is selected from the group consisting of: a) a compound represented by the structural formula IA: 780or 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; or X1 is 781and X2 is hydrogen; or X1 and X2 together form a spiro group of the formula 782is 1 or 2; n is 1, 2 or 3, provided that when n is 1, one of R16 and R17 is —C(O)R28; p is 0 or 1; Q is —CH2—, —O—, —S—, —SO—, —SO2— or —NR17—; R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen and (C1-C6)alkyl, or (R1 and R4) or (R2 and R3) or (R1 and R3) or (R2 and R4) together can 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, —NR20COR19, —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 783wherein 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; R11 is independently selected from the group consisting of H, R5—(C1-C6)alkyl, R6—(C3-C12)cycloalkyl, —(C1-C6)alkyl(C3-C12)cycloalkyl, —(C1-C6)alkyl-OR19, —(C1-C6)alkyl-NR19R20 and 784wherein q and a are as defined above; R12 is H, (C1-C6)alkyl, halo, —NO2, —CF3, —OCF3, —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; —(C1-C6)alkyl-SR19; or aryl (C1-C6) alkyl; R14 and R15 are independently selected from the group consisting of H, R5—(C1-C6)alkyl, R7-aryl and 785wherein q and a are as defined above; R16 and R17 are independently selected from the group consisting of hydrogen, R5—(C1-C6)alkyl, R7-aryl, (C3-C12)cycloalkyl, R8-heteroaryl, R8-heteroaryl(C1-C6)alkyl, —C(O)R28, —(C1-C6)alkyl(C3-C7)-heterocycloalkyl, —(C1-C6)alkyl-OR19 and —(C1-C6)alkyl-SR19; 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-NR18—(C1-C6)alkyl-NR18—(C1-C6)alkyl; R18 is hydrogen or (C1-C6)alkyl; Z1 is R5—(C1-C12)alkyl, R7-aryl, R8-heteroaryl, R6—(C3-C12)cyclo-alkyl, R10—(C3-C7)heterocycloalkyl, —CO2(C1-C6)alkyl, CN or —C(O)NR19R20; Z2 is hydrogen or Z1; Z3 is hydrogen or (C1-C6)alkyl; or Z1, Z2 and Z3, together with the carbon to which they are attached, form the group 786wherein r is 0 to 3; w and u are each 0-3, provided that the sum of w and u is 1-3; c and d are independently 1 or 2; s is 1 to 5; and ring A is a fused R7-phenyl or R8-heteroaryl ring; R23 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, —OR19, —(C1-C6)alkyl-OR19, —NR19R20 and —(C1-C6)alkyl-NR19R20; R24 is 1 to 3 substituents independently selected from the group consisting of R23, —CF3, —OCF3, NO2 or halo, or R24 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring; 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 R28 is (C1-C6)alkyl, —(C1-C6)alkyl(C3-C12)cycloalkyl, R7-aryl, R7-aryl-(C1-C6)alkyl, R8-heteroaryl, —(C1-C6)alkyl-NR19R20, —(C1-C6)alkyl-OR19 or —(C1-C6)alkyl-SR19; b) a compound represented by the structural formula II: 787wherein R1a and R2a are, independently from each other, hydrogen, lower alkyl, lower alkoxy or halogen; R3a is phenyl, optionally substituted by lower alkyl, CF3, lower alkoxy or halogen; and R4a is hydrogen, lower alkyl, lower alkenyl, —C(O)-lower alkyl, —C(O)-phenyl, lower alkyl-C(O)-phenyl, lower alkylen-C(O)-lower alkyl, lower alkantriyl-di-C(O)O-lower alkyl, hydroxy-lower alkyl, lower alkyl-O-lower alkyl, lower alkyl-CH(OH)CF3, phenyl or benzyl; R5a and R6a are, independently from each other, hydrogen, phenyl, lower alkyl or di-lower alkyl or may form together a phenyl ring, and R5a and one of R1a or R2a may form together a saturated or unsaturated 6 membered ring, Aa is a 4-7 membered saturated ring which may contain a heteroatom such as O or S, or a pharmaceutically acceptable acid addition salt thereof; c) a compound represented by the structural formula III 788wherein R1b is hydrogen, lower alkyl, halogen, lower alkoxy, CF3, lower alkyl-phenyl or (C5-7)-cycloalkyl; R2b is hydrogen, lower alkyl, phenyl or lower alkyl-phenyl; R3b is hydrogen, lower alkyl, benzyl, lower alkyl-phenyl, lower alkyl-diphenyl, triazinyl, cyanomethyl, lower alkyl-piperidinyl, lower alkyl-naphthyl, (C5-7)-cycloalkyl, lower alkyl-(C5-7)-cycloalkyl, lower alkyl-pyridyl, lower alkyl-morpholinyl, lower alkyl dioxolanyl, lower alkyl, oxazolyl, or lower alkyl-2-oxo-oxazolidinyl and wherein the ring systems may be substituted by additional lower alkyl, lower alkoxy, CF3 or phenyl, or —(CH2)nC(O)O-lower alkyl, —(CH2)nC(O)NH2, —(CH2)nC(O)N(lower alkyl)2, —(CH2)nOH or —(CH2)nC(O)NHCH2C6H6; R4b is hydrogen, lower alkyl or nitrilo; Ab is a ring system, consisting of (a) (C5-15)-cycloalkyl, which may be in addition to R4b optionally substituted by lower alkyl, CF3, phenyl, (C5-7)-cycloalkyl, spiro-undecan-alkyl or by 2-norbornyl, or is one of the following groups 789dodecahydro-acenaphthylen-1yl (e), bicyclo[6.2.0]dec-9-yl (f) and bicyclononan-9-yl (g); and wherein R5b and R6b are hydrogen, lower alkyl, or taken together and with the carbon atoms to which they are attached form a phenyl ring; R7b is hydrogen or lower alkyl; the dotted line represents an optional double bond and n is 1 to 4; or a pharmaceutically acceptable acid addition salt thereof; d) a compound represented by the structural formula IV: 790or a pharmaceutically acceptable salt thereof, wherein R1c and R2c are independently C1-C4 alkyl; or R1c and R2c, taken together with the carbon to which they are attached, form a mono-, bi-, tri- or spiro-cyclic group having 6 to 13 carbon atoms, wherein the cyclic group is optionally substituted by 1 to 5 substituents independently selected from C1-C4 alkyl, C2-C4 alkylene, C1-C4 alkoxy, hydroxy, oxo, ═CH2 and ═CH—C1-C4 alkyl; R3c is C1-C7 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, phenyl-C1-C5 alkyl, phenyl optionally substituted by 1 to 3 substituents independently selected from fluorine, C1-C3 alkyl and C1-C3 alkoxy, or a heteroaryl group selected from furyl, theinyl, pyrrolyl and pyridyl, wherein said heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from halo, C1-C3 alkyl and C1-C3 alkoxy, with the proviso that when both R1c and R2c are C1-C4 alkyl, then R3c is other than C1-C7 alkyl, C2-C5 alkenyl and C2-C5 alkynyl; R4c is selected from 1) hydrogen; 2) optionally substituted mono- or di-substituted C1-C8 alkyl, C3-C7 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1C6 alkyl-Zc-, C1C6 alkyl-Zc-(C1C6)alkyl, C3-C7 cycloalkyl-Zc-(C1C6)alkyl, C2-C6 alkenyl-Zc-(C1C6)alkyl or C2-C6 alkynyl-Zc-C1C6)alkyl, wherein Zc is selected from O, S, SO, SO2, CO, CO2, OCO, NRc, CONRc and NRcCO, wherein Rc is hydrogen or C1-C6 alkyl, and the substituents to be attached to the alkyl, alkenyl, alkynyl or cycloalkyl moiety are independently selected from halo, hydroxy, carboxy, amino, mono- or di-(C1-C4 alkyl)amino, hydrazino, azido, ureido, amidino and guanidino; or 3) optionally mono- or di-substituted aryl, heterocyclic, aryl(C1-C5)alkyl, heterocyclic(C1-C5)alkyl, heterocyclic-heterocyclic(C1-C5)alkyl, aryl-heterocyclic(C1-C5)alkyl, heterocyclic-Zc(C1-C5)alkyl, aryl-Zc-(C1-C5)alkyl, aryl(C1-C5)alkyl-Zc-(C1-C5)alkyl, or heterocyclic(C1-C5)alkyl-Zc-(C1-C5)alkyl, wherein Zc is selected from O, S, SO, SO2, CO, CO2, OCO, NRc, CONRc and NRcCO, wherein Rc is hydrogen or C1-C6 alkyl, and the substituents to be attached to the aryl or heterocyclic moiety are independently selected from halo, hydroxy, carboxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl-CO—, amino(C1-C4)alkyl-CO—, phenyl, benzyl, amino, mono- or di-(C1-C4 alkyl)amino, hydrazino, azido, ureido, amidino and guanidino; R5c is independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylsulfonyl, CF3, carboxy, hydroxy, amino, alkylamino, acylamino, arylcarbonyl, alkylcarbonyl and hydroxyalkyl; and n is 0, 1, 2, 3 or4; e) a compound represented by the structural formula V 791or a salt or ester thereof, wherein Ar1d is an optionally substituted aromatic carbon ring or heterocycle, wherein the optional substituents are independently selected from halo, alkyl, amino, alkylamino, dialkylamino, hydroxy, alkoxy and carboxyl; 792is an optionally substituted mono- or di-cyclic C3-14 aliphatic nitrogenous heterocycle; Cyd is an optionally substituted mono-, di- or tri-cyclic C3-20 aliphatic carbon ring; R1d is hydrogen, lower alkenyl, lower alkynyl, lower cycloalkyl, amino, lower alkylamino, di(lower alkyl)amino, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl or optionally substituted lower alkyl; and R2d is hydrogen or lower alkyl; and f) a compound represented by the structural formula VI 793or a pharmaceutically acceptable salt thereof, wherein Ae is an aryl or heterocyclyl ring; Be is phenyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl or cyclohexenyl; R1e and R2e are independently hydrogen, alkyl, hydroxyalkyl, amino, alkylamino or di-alkylamino; R3e and R4e are independently hydrogen, halo or alkyl; Xe is hydrogen, halo, alkyl, alkoxyalkyl, alkenyl, amino, CN, or —(CH2)me-Ee-(CH2)ne-Ge; Ee is a bond, —CH═CR6e, O, S, NR7e, CO, SO2 or NHCO; Ge is aryl, heterocyclyl, cycloalkyl or fused aryl, all optionally substituted by 1-5 R5e groups; R5e is independently selected from halo, OH, alkyl, alkyl optionally substituted by alkoxy, alkoxyalkoxy, halo, OH or alkanoyloxy, alkoxy, alkoxyalkoxy, amino, alkylamino, di-alkylamino, NO2, CN, alkanoyl, alkanoyloxy, carboxy, alkoxycarbonyl, alkylsulfonyl and phenyl; R6e is hydrogen or aryl; R7e is hydrogen, alkyl or alkoxycarbonyl; me is 0-8; and ne is 1-4.

3. The method of claim 2 wherein the compound is represented by structural formula IA.

4. The method of claim 3 wherein, in the compound of formula IA, Z1 and Z2 are each R7-aryl.

5. The method of claim 4, wherein R7 is selected from the group consisting of (C1-C6)alkyl and halo.

6. The method of claim 3 wherein, in the compound of formula IA, X1 is R7-aryl and and X2 is OH; or X2 is hydrogen and X1 is

7. The method of claim 6 wherein X1 is

8. The method of claim 6 wherein X1 and X2 together form

9. The method of claim 1 wherein the ORL-1 agonist is selected from

10. The method of claim 1 wherein the agents for treating cough, allergy or asthma symptoms are 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, decongestants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists.

11. A pharmaceutical composition comprising: a therapeutically effective amount of a nociceptin receptor ORL-1 agonist; a therapeutically effective amount of one or more agents 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, decongestants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists; and a pharmaceutically acceptable carrier.

12. A compound represented by the formula

13. A compound of claim 12 wherein Z1 is R7-aryl, Z2 is C4-12-alkyl and X1 and X2 form a spirocyclic group.

14. A compound of claim 13 wherein Z1 is R7-phenyl, and X1 and X2 together form the spirocyclic group

15. A compound of claim 14 wherein m is 1, R17 is phenyl and R11 is —(C1-C6)alkyl-OR19 or —(C1-C6)alkyl-NR19R20.

16. A pharmaceutical composition comprising a therapeutically effective amount of compound of claim 13 in combination with a pharmaceutically acceptable carrier.

17. A method of treating pain, anxiety, asthma, depression or alcohol abuse comprising administering an effective amount of a compound of claim 13 to a mammal in need of such treatment.

18. A compound of claim 13 selected from the group consisting of compounds represented by the formula

19. A compound selected from the group consisting of compounds represented by the formula