High affinity ligands for nociceptin receptor ORL-1

Abstract

Novel compounds of the formula 1

Description

BACKGROUND

[0001] 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.

[0002] In late 1995, nociceptin 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 axiolytic 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.

[0003] 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 contraction, indicating that nociceptin receptor agonists could be useful in the treatment of asthma. Also, it has been reported (Ciccocioppo et al, Physchpharmacology. 141 (1999), p. 220-224) hociceptin 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 OF (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.

[0004] 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 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.

[0005] 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.

SUMMARY OF THE INVENTION

[0006] Compounds of the present invention are represented by formula I 2

[0007] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0008] the dotted line represents an optional double bond;

[0009] X1 is R5-(C1-C12)alkyl, R6-(C3-C12)cycloalkyl, R7-aryl, R8-heteroaryl or R10-(C3-C7)heterocycloalkyl;

[0010] 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;

[0011] or X1 is 3

[0012] and X2 is hydrogen;

[0013] or X1 and X2 together form a spiro group of the formula 4

[0014] m is 1 or 2;

[0015] n is 1, 2 or 3, provided that when n is 1, one of R16 and R17 is —C(O)R28;

[0016] p is 0 or 1;

[0017] Q is —CH2—, —O—, —S—, —SO—, —SO2— or —NR17—;

[0018] 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;

[0019] 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;

[0020] R6 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, R7-aryl, —NR19R20, —OR13 and —SR13;

[0021] R7 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R25-aryl, (C3-C12)cycloalkyl, —CN, —CF3, —OR19, —(C1-C6)alkyl-OR19, —OCF3, —NR19R20, —(C1-C6)alkyl-NR19R20, —NHSO2R19, —SO2N(R26)2, —SO2R19, —SOR19, —SR19, —NO2, —CONR19R20, —NR20 COR19, —COR19, —COCF3, —OCOR19, —OCO2R19, —COOR19, —(C1-C6)alkyl-NHCOOC(CH3)3, —(C1-C6)alkyl-NHCOCF3, —(C1-C6)alkyl-NHSO2-(C1-C6)alkyl, —(C1-C6)alkyl-NHCONH-(C1-C6)-alkyl or 5

[0022] wherein f is 0 to 6; or R7 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;

[0023] 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;

[0024] R9 is hydrogen, (C1-C6)alkyl, halo, —OR19, —NR19R20, —NHCN, —SR19 or —(C1-C6)alkyl-NR19R20;

[0025] R10 is H, (C1-C6)alkyl, —OR19, —(C1-C6)alkyl-OR19, —NR19R20 or —(C1-C6)alkyl-NR19R20;

[0026] 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

[0027] wherein q and a are as defined above;

[0028] R12 is H, (C1-C6)alkyl, halo, —NO2, —CF3, —OCF3, —OR19, —(C1-C6)alkyl-OR19, —NR19R20 or —(C1-C6)alkyl-NR19R20;

[0029] 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;

[0030] R14 and R15 are independently selected from the group consisting of H, R5-(C1-C6)alkyl, R7-aryl and 7

[0031] wherein q and a are as defined above;

[0032] 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;

[0033] R19 and R20 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C3-C12)cycloalkyl, aryl and aryl(C1-C6)alkyl;

[0034] 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;

[0035] R18 is hydrogen or (C1-C6)alkyl;

[0036] Z1 is R5-(C1-C12)alkyl, R7-aryl, R8-heteroaryl, R6-(C3-C12)cycloalkyl, 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

[0037] 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;

[0038] 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;

[0039] 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;

[0040] R25 is 1-3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy and halo;

[0041] R26 is independently selected from the group consisting of H, (C1-C6)alkyl and R25-C6H4—CH2—;

[0042] R27 is H, (C1-C6)alkyl, R7-aryl(C1-C6)alkyl, or (C3-C12)cycloalkyl;

[0043] 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;

[0044] provided that when X1 is 9

[0045] or X1 and X2 together are 10

[0046] and Z1 is R7-phenyl, Z2 is not hydrogen or (C1-C3)alkyl;

[0047] provided that when Z1, Z2 and Z3, together with the carbon to which they are attached, form 11

[0048] and X1 and X2 together are 12

[0049] R11 is not H, (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)hydroxyalkyl;

[0050] 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

[0051] provided that when X1 is 14

[0052] and Z1 is R6-(C3-C12)-cycloalkyl, Z2 is not H.

[0053] 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.

[0054] 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.

[0055] 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

[0056] 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

[0057] wherein m is 1, R17 is phenyl and R11 is —(C1-C6)alkyl-OR19 or —(C1-C6)alkyl-NR19R2, or 17

[0058] In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.

[0059] 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, cough, asthma, alcohol abuse or depression, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I.

[0060] 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 a second agent 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, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists.

[0061] In still another aspect, the invention relates to a pharmaceutical composition comprising a nociceptin receptor ORL-1 agonist and a second agent selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists.

[0062] In yet another aspect, the present invention relates to a novel compound not included in the structure of formula I, said compound being: 18

BRIEF DESCRIPTION OF THE DRAWINGS

[0063] FIG. 1 illustrates the effect in guinea pigs of Compounds A and B (see Example 12) compared to baclofen on capsaicin-induced cough.

[0064] 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

[0065] As used herein, the following terms are used as defined below unless otherwise indicated:

[0066] 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;

[0067] Bu is butyl; Et is ethyl; Me is methyl; and Ph is phenyl;

[0068] 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;

[0069] 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;

[0070] alkynyl represents an alkyl chain of 2 to 6 carbon atoms comprising one triple bond in the chain, e.g., ethynyl or propynyl;

[0071] 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;

[0072] 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;

[0073] 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;

[0074] 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;

[0075] 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;

[0076] 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;

[0077] halo represents fluoro, chloro, bromo and iodo;

[0078] 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: 19

[0079] 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;

[0080] 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-piperizinyl, 2- or 4-dioxanyl, morpholinyl, 20

[0081] wherein R17 is as defined above and t is 0, 1 or 2.

[0082] When the optional double bond in the piperidinyl ring of formula I is present, one of X1 and X2 forms the bond with the 3-position carbon and the remaining X1 or X2 is not hydrogen.

[0083] 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 to the 4-position carbon of the piperidinyl ring, e.g., compounds of the following formulas are formed: 21

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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 purpopses of the invention.

[0088] Compounds of the invention 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.

[0089] 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.

[0090] 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: 22

[0091] Commercially availble 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.

[0092] 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 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.

[0093] An alternative method for preparing compounds of formula I 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 1, and n-butyl-lithium.

[0094] X1,X2-substituted compounds of formula I can be converted into other compounds of formula I 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: 23

[0095] A cyano-substituted piperidine (i.e., X2 is —CN) can be converted to a substituted piperidine wherein X2 is R21 R22N—CH2— or X2 is R28C(O)NH—CH2—, as shown in the following procedure for a compound of formula I 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: 24

[0096] Compounds of formula I wherein X1 is a benzofused nitrogen-containing heterocycle having an R1 1 substituent other than hydrogen are prepared by reacting the corresponding compounds wherein R11 is hydrogen with a compound of the formula R11 L (R11 is not H, and L is as defined above).

[0097] 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.

[0098] For compounds of formula I 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: 25

[0099] wherein Pr is a N-protecting group, Ph is phenyl and z is 1-2.

[0100] 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: 26

[0101] Similar procedures, or others known in the art, can be used to prepare compounds wherein the Z substituents are other than phenyl.

[0102] 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.

[0103] 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

[0104] 27

[0105] 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): δ 1.80 (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

[0106] 28

[0107] 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.

[0108] 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) δ 7.5 (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); 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

[0109] 29

[0110] 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) δ 7.5 (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

[0111] 30

[0112] 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): δ 2.40 (m, 4H), 2.50 (m, 2H), 2.85 (m, 2H), 4.25 (s,1H), 7.20-7.50 (m, 15H), 9.42 (s,1H). 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): δ 2.00 (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).

[0113] Step 3: The product of Step 2 was treated with NaH in DMF at 0° C. for 0.5 h. CH3l 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): δ 2.10 (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

[0114] 31

[0115] 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): δ 2.21 (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).

[0116] Step 2: A solution of the product (6.0 g, 17 mM) of Step 1 in Et2O (40 ml) was cooled to 0C and treated with a 1 M 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): δ 1.84 (m, 2H), 2.16 (m, 4H), 2.56 (m, 2H), 2.68 (m, 2H), 4.07 (s, 1H), 7.25 (m, 15H).

[0117] 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): δ 2.13 (m, 6H), 2.66 (m, 4H), 3.50 (s, 2H), 4.07 (s, 1H), 7.11-7.65 (m, 20H).

[0118] 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): δ 1.90 (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

[0119] 32

[0120] 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): δ 1.87 (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

[0121] 33

[0122] 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.

[0123] 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): δ 2.10 (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).

[0124] 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: δ 2.59 (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).

[0125] 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): δ 1.09 (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).

[0126] 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): δ 1.10 (bs, 2H), 1.39 (s, 7H), 1.90 (m, 2H), 2.26 (m, 4H), 2.92 (m, 4H), 7.17-7.41 (m, 5H).

[0127] 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): δ 1.07 (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).

[0128] 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: δ 2.91(m, 8H), 5.34 (s, 1H), 7.37-7.77 (m, 15H).

[0129] 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): δ 1.96 (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

[0130] 34

[0131] 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.

[0132] 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) δ 7.55 (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

[0133] 35

[0134] 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) δ 7.91 (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: 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

[0135] 36

[0136] 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).

[0137] 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) δ 7.76 (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

[0138] 37

[0139] 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.

[0140] 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 CH3l using the procedure described in Step 2 of Example 1 to produce the title compound (0.25 g). 1H NMR (CDCl3) δ 1.70 (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).

[0141] Using the procedures of Examples 1 to 11, employing the appropriate starting material, compounds shown in the following tables are prepared.

TABLE 1
             wherein X1is as defined below:
38
X1           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)
39           C27H31NO ESI 386.1 (79), 167 (100)
40           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)
41           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)
42           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)
43           C32H32N2O FAB 462.1 (15), 461.1 (41), 393 (8)
44           C32H34N2:HCl ESI 447.1 (100), 281.1 (29)
45           C33H32N2F3:HCl ESI 515 (100), 349.10 (33), 167 (49)
CH2NHCH2CH3  C27H32N2:HCl
             ESI 385.1 (100), 219.10 (26), 167 (76)
46           C29H36N2O:HCl Cl 429 (53), 351 (100) 327 (13), 167 (34)
47           C28H32N2O2 Cl 429 (100), 351 (9), 261 (11), 167 (81)
48           C28H34N2O:HCl Cl 415 (100), 327 (33), 167 (65)
49           C31H39N3O:HCl ESI 470 (100), 304 (51), 259 (16), 167 (46)
50           C31H41N3:HCl ESI 456 (100), 290 (11), 167 (11)
51           C30H30N2O2 ESI 451 (100), 283 (8), 167 (94)
52           C34H43N3O: HCl ESI 510 (88), 344 (73), 167 (100)
53           C32H41N3:HCl ESI 468 (98), 302 (22), 167 (100)
54           C31H31N3O:HCl Cl 462 (100), 384 (4), 167 (45)
55           C30H32N2O:Cl ESI 437 (100), 271 (11), 167 (41)
56           C30H32N2O:HCl ESI 437 (87), 271 (7), 167 (100)
57           C30H32N2S:HCl ESI 453 (92), 167 (100)
58           C30H32N2S:HCl ESI 453 (100), 287 (6), 167 (78)
59           C32H36N2S:HCl ESI 481 (69), 340 (5), 167 (100)
60           C29H36N2S:HCl ESI 445 (100), 399 (3), 279 (11), 167 (84)
61           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)
62           C29H30N2O:HCl Cl 423 (60), 326 (100), 167 (74)
63           C31H39N3:HCl ESI 454 (76), 326 (60), 167 (100)
64           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)

[0142]

TABLE 2
          wherein X1is as defined below
65
X1        Physical Data
66        C24H25NO FAB 343.1 (13), 342.1 (26)
67        C24H24BrNO ESI 424 (20) 422 (18) 167-2 (92)
68        C24H24NOCl Cl 363 (43), 362 (22), 167.20 (100)
69        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)
70        C25H23NOF3Cl El 369 (3), 368 (14), 167 (100)
71        C25H24F3NO FAB 413 (31), 412 (57), 167 (100)
72        C25H27NO2Cl 374.45 (M + 1), 266.30 (39%), 167.25 (100%)
73        C26H30N2O FAB 387 (86%), 369 (22%)
74        C25H26NOF FAB 376.2 (68%), 375.2 (32%). 358.20 (6)
75        C25H27NO2Cl 374.45 (58%), 375.45 (27), 356.35 (29)
76        C24H24ClNO Cl 378.35 (31%), 377.35 (18%), 360.30 (22)
77        C25H27NO Cl 358.35 (68), 357.35 (38), 340.35 (47), 167.25 (100)
78        C24H23F2NO Cl 380.35 (28%), 379.35 (22), 362.35 (23), 167.25 (100)
79        C25H27NO Cl 358.35 (63), 357.35 (43), 340.35 (53), 167.25 (100)
80        C25H27NO Cl 358.35 (49), 357.35 (41), 340.35 (35), 167.25 (100)
81        C24H24FNO Cl 362.35 (41), 361.35 (218), 344.35 (39), 167.25 (100)
82        C26H25NO FAB 368 (37), 367 (38), 366 (100), 290 (41)
83        C25H27NSO FAB 375 (10), 374.20 (40), 306.7 (13)
84        C25H27NSO FAB 390 (22), 389(27), 388 (100), 312 (48)
85        C24H23NOF2 380.2 (11), 379.2 (16), 378.2 (31)
86        C26H29NO Cl 373.45 (22), 372.40 (82), 354.35 (60), 167.25 (100)
87        C24H31NO FAB 350.3 (4), 349.3 (7), 348 917)
88        C24H33NO FAB 352 (85), 274 (189)
n propyl  C27H31NO
          ESI 386 (70), 167 (100)
n butyl   C28H33NO
          ESI 400.1 (68), 167 (100)
89        C21H25NO:HCl ESI 308.1 (32), 167.0 (100)
90        C22H23NO2:HCl Cl 334.25 (34), 333.25 (26), 316.25 (41), 167.25 (100)
91        C22H23NOS:HCl Cl 350.25 (32), 349.35 (24), 332.25 (41), 167.25 (100)
92        C22H23NOS:HCl Cl 350.25 (27), 349.35 (18), 332.25 (20), 167.25 (100)
93        C23H24N2O:HCl ESI 345.1 (68), 167 (100)
94        C22H23NO2Cl 334.25 (37), 333.25 (24), 316.25 (31), 167.25 (100)
95        C25H24N2O:HCl FAB 369.3 (3), 368.3 (6), 367.3 (13)
96        C21H27NO:HCl Cl 310.40 (38), 309.40 (25), 292.40 (33), 167.25 (100)
97        C24H24NOF:HCl FAB 362.1 (100), 232.1 (11)
98        C22H29NO:HCl FAB 324.30 (100)
99        C21H25NO:HCl Cl 308.2 (64), 307.2 (30), 290.2 (57), 167.25 (100)
100       C23H25NOS:HCl Cl 364.15 (69), 346.15 (71), 167.25 (100)
101       C21H22N2SO:HCl Cl 351.1 (52), 350.1 (8), 266.15 (12), 167.2 (100)
102       C27H28N2O:HCl FAB 397.2 (80), 167.2 (100)
103       C25H28N2O:HCl ESI 373.1 (28), 167 (100)
104       C25H27NO2:HCl ESI 374.1 (43), 167 (100)

[0143]

TABLE 3
	wherein Z1 and Z2are as defined below:
105
Z1	Z2	Physical Data
106	107	C24H24NOCl Cl 380 (30), 378.1 (100), 201 (100)
108	109	C24H23NOF2Cl 380.15 (79), 379.15 (47), 362.05 (100)
110	111	C23H24N2O:HCl ESI 345.1 (69), 327.1 (49), 168 (100)
112	113	C25H24N2O:HCl ESI 345.1 (58), 168 (100)
114	115	C25H27NO:HCl Cl 358.20 (60), 340.20 (51), 181.25 (100)
116	117	C24H24NOBr:HCl ESI 424.1 (17), 422 (17), 247.1 (100), 245.1 (99)
118	119	C25H27NO:HCl ESI 358.1 (32.70), 181 (100)
120	121	C24H24NOCl:HCl Cl 380.10 (30), 378.15 (100)
122	123	C26H29NO:HCl ESI 372,1 (24), 195.1 (100)
124	125	C25H27NO:HCl ESI 358.1 (48%), 181.1 (100)
126	127	C25H24ONF3:HCl ESI 412.1 (56), 235 (100)
128	129	C25H24ONF3:HCl ESI 412.1 (73), 235.1 (100)
130	131	C26H29NO:HCl ESI 372.1 (39), 195.1 (100)
132	133	C24H24NOBr:HCl ESI 424.10 (48), 422.1(47), 245.1 (100)
134	135	C22H23NOS:HCl ESI 350.1 (31), 173 (100)
136	137	C25H24ONF3:HCl ESI 412.1 (54), 235.10 (100)
138	139	C24H24NOF:HCl ESI 362.1 (23), 185.1 (100)
140	141	C24H23NOF:HCl Cl 380.15 (100), 362.15 (89), 203.25 (99)
142	143	C24H23NOCl2:HCl ESI 416.1 (7), 414 (32), 412 (45), 235.1 (100)
144	145	C25H24N2O2F2:HCl FAB 423.2 (100), 218.0 (18)
146	147	C24H23NOF2:HCl Cl 380.15 (79), 379.15 (45), 362.05 (100)
148	149	C26H29NO2:HCl FAB 388.3 (100), 266.1 (15)
150	151	C25H27NO2:HCl FAB 374.1 (100), 197 (73)
152	153	C24H24NOCl:HCl FAB 380.1 (27), 378.2 (80), 201.0 (100)
154	155	C25H27NO:HCl ESI 358.1 (15), 181.1 (100)
Methyl	156	C19H23NO:HCl ESI 282.1 (100), 160.0 (84.5)
Ethyl	157	C20H25NO:HCl ESI 296.1 (100), 160.0 (84)
158	159	C21H27NO:HCl ESI 310.1 (100), 160.1 (52)
160	161	C22H29NO:HCl ESI 324.1(100), 160.1 (52)
162	163	C23H31NO:HCl Cl 338.3 (100), 266.20 (77), 160.35 (17)
164	165	C24H33NO:HCl ESI 352.1 (100), 160.0 (41.83)
166	167	C23H29NO:HCl ESI 336.1 (66.39), 160.0 (63), 159 (100)
168	169	C23H30N2O2:HCl ESI 367.1 (35), 190 (100)
170	171	C23H31NO:HCl ESI 338.1 (100), 161.0 (36), 160 (70)

[0144]

TABLE 4
172
wherein X1, X2, Z1 and Z2 are as defined below
X1	X2	Z1	Z2	Physical Data
173	NH2	174	175	C22H30N2:HCl ESI 323 (71), 306 (100), 160 (31)
176	177	178	179	C27H34N2S:HCl ESI 419 (23), 306 (100)
180	CH2NH2	181	182	C23H32N2:HCl ESI 337 (96), 174 (100), 160 (19)
183	184	185	186	C28H36N2S:HCl ESI 433 (100), 320 (65), 174 (58)
187	NH2	188	189	C25H28N2:HCl Cl 357 (47), 340 (24), 279 (8), 181 (100)
190	191	192	193	C28H36N2S:HCl ESI 433 (100), 320 (42), 174 (77)
194	195	196	197	C30H32N2S:HCl ESI 453 (24), 340 (27), 181 (100)
198	NH2	199	200	C26H30N2:HCl ESI 371 (16) 195 (100)
201	202	203	204	C31H34N2S:HCl ESI 467 (25), 354 (30), 195 (100)
205	NH2	206	207	C24H24N2Cl2:HCl ESI 413 (18), 411 (26), 396 (39), 394 (51), 237 (69), 235 (100)
208	OH	209	210	C26H28BrNO:HCl 450 (12), 195.1 (100)
211	OH	212	213	C26H28FNO:HCl ESI 390.1 (9.6), 195.1 (100)
214	OH	215	216	C26H28ClN0:HCl 407.1 (5), 195.1 (100) 406.1 (16)
217	218	219	220	C31H32N2OS ESI 481 (25), 195 (100)
221	222	223	224	C28H32N2O Cl 413 (31), 354 (8), 195 (100)
225	226	227	228	C29H28Cl2N2S:HCl ESI 509 (10), 507 (14), 396 (56), 394 (77), 237 (68), 235 (100)
229	OH	230	231	C25H26N2OCl2:HCl ESI 443 (42), 441 (56), 425 (31), 235 (100)
232	233	234	235	C30H36N2OS ESI 473 (39), 195 (100)
236	237	238	239	C33H34N2O ESI 475 (41), 195 (100)
240	241	242	243	C29H34N2O2ESI 443 (31), 195 (100)
244	245	246	247	C30H34N2O:HCl ESI 439 (17), 195 (100)
248	249	250	251	C34H42N2O:HCl ESI 495 (30), 195 (100)
252	253	254	255	C33H36N2:HCl ESI 461 (17), 354 (28), 195 (100)
256	257	258	259	C26H26N2OCl2ESI 455 (57), 453 (75), 396 (7), 394 (10), 237 (73), 235 (100)
260	OH	261	262	C29H31N2O3F3:HCl FAB 497.2 (507), 195.1 (100)
263	264	265	266	C24H32N2O:HCl ESI 365 (100), 219 (31), 160 (23)
267	268	269	270	C27H30N2O:HCl ESI 399 (60), 181 (100)
271	272	273	274	C29H34N2O:HCl ESI 427 (41), 195 (100)
275	276	277	278	C30H36N2O:HCl ESI 441 (47), 195 (100)
279	280	281	282	C28H32N3O:HCl ESI 428 (41), 195 (100)
283	OH	284	285	C27H30Cl2N2O FAB 469.2 (30), 235.1 (100)
286	OH	287	288	C28H32Cl2N2O3S Cl 549.15 (69), 548.15 (37), 547.15 (100)
289	OH	290	291	C28H32Cl2N2O3S FAB 549 (60), 547.1 (87)
292	OH	293	294	C27H30Cl2N2O3S FAB FAB 535 (78), 533 (100)
295	OH	296	297	C26H28Cl2N2O3S FAB 523 (25)
298	OH	299	300	C30H35Cl2N3O FAB 524.40 (20), 330.3 (100)
301	OH	302	303	C36H39Cl2N3O FAB 600.5 (50), 330.4 (70)
304	OH	305	306	C25H27BrN2O FAB 453.2 (100), 245 (100)
307	OH	308	309	C25H26N2F2O FAB 410.2 (25), 409.2 (100), 203.2 (50)
310	OH	311	312	C27H32N2O FAB 401.2 (95), 195 (100)
313	OH	314	315	C25H26Cl2N2O 441.1 (40), 235 (42), 157 (100)
316	OH	317	318	C25H27NO2Cl 374.25 (52), 356.2 (100), 178.25 (40), 160.25 (57)
319	OH	320	321	C25H25NO3FAB 388.23 (100), 210.8 (21), 168.28 (20)
322	OH	323	—CH2)4CH3	C24H34N2O FAB 368.3 (30), 367.3 (100)
324	OH	325	—CH2)3CH3	C23H32N2O GAB 353.3 (100)
326	OH	327	328	C25H26N2F2O FAB 410.6 (35), 409.4 (98), 203.1 (65)
329	OH	330	331	C26H28Cl2N2O FAB 457.3 (70), 455.3 (100), 237 (30), 235.1 (52)
332	OH	H	333	C19H23N2OCl FAB 331.2 (100),
334	OH	335	336	C27H32N2O FAB 402.1 (20.46), 401.1 (44.89), 195.1 (100)
337	OH	338	339	C25H27ClN2O ES 409.2 (55), 408.2 (45), 407.2 (95)
340	OH	341	342	C26H30N20 ES 387 (100)
343	OH	344	345	C25H25NO2 Cl 372.15 (100), 354.15 (38), 195.15 (37)
346	OH	347	348	C26H29NO3 FAB 404.3 (100), 227.1 (70)
349	OH	H	350	C21H34N2O FAB 331.4 (100), 266.2 (20)
351	OH	CH3(CH2)3—	C24H32N2O FAB 367.2 (100)
352	OH	353	354	C27H32N2O ES 401.1 (46), 195.1 (100)
355	OH	356	357	C31H38N2O3ES 487 (100)
358	359	360	361	C27H29Cl2N3O ESI 484.2 (72), 482.2 (100), 237 (60), 235.0 (65)
362	363	364	365	C26H27Cl2N3O ESI 470.1 (80), 468.1 (100), 235 (78)
366	367	368	369	C26H27Cl2N3O ESI 470.2 (78), 468.2 (90), 237.0 (65), 235 (100)
370	371	372	373	C29H35N3O ESI 442.3 (100)
374	OH	375	376	C25H26N2OBr2ESI 533 (55), 531 (100) 324.8 (30)

[0145]

TABLE 5
377
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
378	Benzhydryl	C32H37N3O:HCl Cl 480 (100), 167.25 (22)
379	Benzhydryl	C29H31N3O3:HCl Cl 470.15 (100), 167.25 (25)
380	Benzhydryl	C29H31N3O:HCl Cl 438.20 (100), 167.25 (29)
381	Benzhydryl	C30H33N3O:HCl FAB 452.3 (100), 167.0 (92)
382	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)
383	Benzhydryl	C28H31N3O2:HCl ESI 442.10 (15), 167. (100)
384	Benzhydryl	C27H29N3O2:HCl FAB 428.3 (65), 232.1 (57)
H	385	C23H29N3O:HCl ESI 364.1 (58), 218.1 (100)
386	387	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)
388	Benzhydryl	C28H31N3O2:HCl ESI 442.10 (15), 167 (100)
389	390	C31H35N3O: HCl ESI 466.1 (44), 181.1 (100)
391	392	C29H33N3O2:HCl ESI 456.1 (48), 181.10 (100)
H	393	C24H31N3O:HCl Cl 378.25 (100), 306.20 (22), 218.20 (24)
H	394	C26H27N3O:HCl ESI 398.10 (44), 181.1 (100)
395	396	C27H33N3O:HCl ESI 416.10 (36), 286.1 (39)
397	398	C30H31N3OCl2:HCl ESI 522.1 (79), 521.1 (48), 520 (100)
399	Benzhydryl	C30H34N2O:HCI Cl 439.25 (100), 168.30 (20)
H	400	C27H29N3O:HCl Cl 412.20 (32), 218.20 (42), 195.35 (100)
401	Benzhydryl	C29H31N3O3:HCl ESI 470.1 (100), 167.1 (77.40)
H	402	C25H23N3Cl2O:HCl ESI 452.1 (100), 235 (85)
403	404	C30H33N3O2Cl2:HCl ESI 525.1 (39), 524.1 (82), 522 (100)
405	406	C28H29N3OCl2:HCl ESI 511.1 (46), 510 (100), 514 (20), 513.1 (33.50)
407	408	C32H39N3O:HCl ESI 482.1 (48), 195.1 (100)
409	410	C30H35N3O2:HCl ESI 471.1 (13), 470.1 (30), 195.1 (100)
H	411	C25H24N3OCl:HCl FAB 420.2 (35), 418.2 (100), 201.0 (75)
H	412	C25H24N3OF:HCl Elemental Analysis C: 68.12; H: 5.83; N: 9.48; Cl: 8.21; F;: 4.59
413	Benzhydryl	C28H32N4O:HCl ESI 442.1 (39), 441.1 (92), 167 (100)
414	Benzhydryl	C29H34N4O:HCl ESI 455.1 (100), 290.1 (14), 289.1 (57.88), 167 (94)
415	Benzhydryl	C27H30N4O:HCl ESI 428.1 (42), 427.1 (97), 167 (100)
416	Benzhydryl	C30H36N4O.HCl ESI 470.1 (48), 469 (100), 303 (93), 167 (82.75)
417	Benzhydryl	C29H34N4O:HCl ESI 457.1 (13), 456 (57), 455.1 (100), 167 (72)
418	Benzhydryl	C28H29N3O3FAB 456.2 (78), 167.0 (100)
419	420	C22H23Cl2N3O3FAB 450.1 (27), 448.0 (100)
H	421	C24H31N3O FAB 378.4 (100), 218.2 (30)
422	Benzhydryl	C31H35N3O3498.2 (100), 167.1 (90)
423	Benzhydryl	C29H31N3O3ESI 470.1 (100), 167.1 (55)
424	425	C23H27Cl2N3O ESI 434.1 (80), 432.1 (100)
426	427	C22H25Cl2N3O2ESI 436.1 (58), 434.1 (100)
428	429	C23H27Cl2N3O ESI 434.1 (35), 432.1 (100)
430	431	C24H27Cl2N3O ESI 446.1 (77)), 444.1 (100)
432	433	C21H22Cl2N4O2FAB 435.1 (78), 433.1 (100)

[0146]

TABLE 6
434
wherein R11, Z1 and Z2 are as defined in the following table:
R11	CH(Z1)(Z2)	Physical Data
H	Benzhydryl
435	Benzhydryl	C29H33N3O ESI: 440 (100) 167 (80)
436	Benzhydryl	C29H31N3O ESI: 438 (100) 167 (99)
437	Benzhydryl	C30H35N3O ESI: 454 (100) 167 (94)
438	Benzhydryl	C29H29N3O ESI: 436 (99) 167 (100)
CH3	Benzhydryl	C27H29N3O FAB: 412 (100)
439	Benzhydryl	C28H31N3O FAB: 426 (100)
440	Benzhydryl	C30H33N3O3FAB: 484 (7) 261 (14) 167 (100)
441	Benzhydryl	C30H33N3O ESI: 452 (100) 167 (60)
442	Benzhydryl	C33H39N3O ESI: 494 (100) 167 (30)
443	Benzhydryl	C31H35N3O .HCl FAB: 466 (100)
444	Benzhydryl	C30H33N3O3 . HCl FAB: 484 (100 167 41
445	Benzhydryl	C33H38N4O2 . HCl FAB: 523 (100)
H	446	C26H25N3F2 . HCl ESI: 434 (29) 203 (100)
H	447	C26H25N3F2O . HCl Cl: 434 (100)
H	448	C26H26N3ClO . HCl ESI: 432 (60) 201 (100)
449	Benzhydryl	C29H33N3O .HCl ESI: 440 (100) 167 (89)
450	Benzhydryl	C33H37N3O2 . HCl ESI: 508 (100) 167 (35)
H	451	C24H30N3ClO. HCl ESI: 412 (100) 232 (92)
H	452	C24H31N3O. HCl ESI: 378 (100) 232 (82)
H	453	C21H24N3ClO. HCl ESI: 370 (86) 265 (100)
H	454	C24H30N3FO. HCl ESI: 396 (31) 232 (100)
H	455	C24H30N3BrO . HCl ESI: 456 (39) 232 (100)
H	456	C25H33N3O. HCl ESI: 392 (73) 232 (100)
H	457	C25H31N3O. HCl FAB: 390 (100)
458	459	C28H39N3O. HCl ESI: 434 (68) 288 (100)
460	461	C31H43N3O. HCl ESI: 474 (90) 328 (100)
462	463	C27H37N3O. HCl ESI: 420 (81) 274 (100)
H	464	C27H29N3O. HCl FAB: 412 (25) 181 (100)
465	466	C29H41N3O . HCl ESI: 448 (97) 288 (100)
467	468	C27H37N3O. HCl ESI: 420 (62) 274 (100)
469	470	C28H39N3O. HCl ESI: 434 (66) 274 (100)
H	471	C25H33N3O. HCl ESI: 392 (59) 232 (100)
472	473	C31H37N3O. HCl ESI: 468 (100) 322 (92)
474	475	C28H39N3O. HCl ESI: 434 (100) 274 (86)
H	476	C22H25N3O3 . HCl Cl: 380 (100)
477	478	C32H39N3O . HCl ESI: 482 (100) 322 (78)
H	479	C21H25N3O2 . HCl FAB: 352 (100)
480	481	C33H41N3O . HCl FAB: 496 (100)
H	482	C28H31N3O . HCl ESI: 426 (19) 195 (100)
H	483	C26H26N3Cl2O. HCl ESI: 466 (79) 235 (100)
H	484	C25H32N4O2 . HCl ESI: 421 (40) 190 (100)
H	485	C26H26N3FO . HCl FAB: 416 (100)
H	486	C26H25N3Cl2O . HCl ESI: 466 (100) 235 (60)
H	487	C26H26N3ClO. HCl ESI: 432 (48) 201 (100)
H	488	C26H26N3F2O . HCl ESI: 434 (69) 203 (100)
489	490	C29H37N3O . HCl ESI: 444 (52) 326 (100)
491	492	C27H33N3O . HCl ESI: 416 (33) 300 (100)
493	494	C28H29N3Cl2O2 . HCl ESI: 510 (100)
495	496	C31H33N3Cl2O2 . HCl ESI: 550 (100)
497	498	C30H33N3Cl2O . HCl ESI: 522 (100)
499	500	C31H35N3Cl2O . HCl ESI: 536 (100)
501	502	C29H29N3Cl2O3 . HCl FAB: 538 (100)
503	504	C29H31N3Cl2O2 . HCl ESI: 524 (100)
505	506	C32H36N4Cl2O. HCl FAB: 563 (100) 235 (55)
507	508	C27H37N3O2 . HCl FAB: 436 (100)
509	510	C24H31N3O3 . HCl FAB: 410 (100)
511	512	C25H33N3O2 . HCl FAB: 408 (100)
513	514	C26H35N3O2 . HCl FAB: 422 (100)
515	516	C29H32N4Cl2O . 2HCl FAB: 523 (100)
517	518	C31H36N4Cl2O . 2HCl FAB: 551 (100)
519	520	C30H34N4Cl2O . 2HCl FAB: 537 (100)
521	522	C30H34N4Cl2O . 2HCl FAB: 537 (100)
523	524	C29H38N4O . 2HCl FAB: 459 (100)
525	526	C33H38N4Cl2O . 2HCl ESI: 577 (56) 343 (100)
527	528	C33H38Cl2N4O ESI 577 (100), 343 (45)
529	530	C33H38Cl2N4O ESI 577 (100), 343 (45)
531	532	C34H40Cl2N4O ESI 487 (100), 327 (51)
533	534	C31H44N4O ESI 487 (100), 327 (51)
535	536	C33H39Cl2N5O ESI 592 (100), 358 (71), 235 (64)
537	538	C31H34Cl2N4O ESI 549 (100), 315 (52)
539	540	C31H42N4O ESI 487 (100), 329 (85)
541	542	C31H44N4O ESI 487 (100), 331 (99)
543	544	C33H38Cl2N4O2ESI 593 (100), 359 (45), 297 (45)
545	546	C34H40Cl2N4O ESI 591 (100), 357 (82), 235 (99)
547	548	C34H39Cl2N5O2ESI 620 (100), 386 (12), 235 (28)
549	550	C32H38 Cl2N4O ESI 565 (100), 331 (56), 235 (52)
551	552	C32H36Cl2N4O2ESI 579 (100), 345 (51), 235 (76)
553	554	C33H38Cl2N4O2ESI 593 (100), 359 (63), 235 (90)
555	556	C35H42Cl2N4O ESI 605 (100), 371 (83)
557	558	C37H44Cl2N4O3FAB 663 (100), 234 (42)
559	560	C25H32Cl2N4O2ESI 491 (100), 333 (29)
561	562	C26H32Cl2N4O ESI 487 (100), 319 (31)
563	564	C26H34Cl2N4O ESI 489 (100), 331 (18)
565	566	C32H46N4O2ESI 519 (91), 361 (100)
567	568	C25H32N4Cl2O ESI 475 (100), 317 (24), 159 (69)
569	570	C28H38N4O FAB 447.3 (100), 289.2 (25), 242.2 (36)
571	572	C29H40N4O FAB 461.2 (100), 303.2 (20)
573	574	C31H42N4O2ESI 503.1 (100), 345.1 (95)
575	576	C30H42N4O ESI 475.1 (99), 317.1 (100)
577	578	C30H42N4O ESI 475.1 (89), 317.1 (100)
579	580	C33H48N4O2ESI 519.1 (95), 361.1 (100) 256.1 (12)
581	582	C29H40N4O2ESI 477.1 (100), 319.1 (100)
583	584	C31H42N4O ESI 487.10 (100), 329.1 (88)
585	586	C28H38N4O FAB 447 (100), 391 (30), 317 (20)
587	588	C29H41N5O FAB 476 (100), 346 (40)
589	590	C29H40N4O FAB 461 (100), 391 (40), 167 (22)
591	592	C28H38N4O FAB 447 (100), 391 (60)
593	594	C31H42N4O ESI 487.1 (100), 329.1 (86)
595	596	C30H42N4O2ESI 491.1 (63), 333.10 (100)
597	598	C34H48N4O ESI 529.1 (79), 371.1 (100)
599	600	C31H45N5O ESI 504.1 (99), 358.1 (100)
601	602	C32H45N5O ESI 516.1 (92), 358.1 (100), 251.1 (28)
603	604	C25H32Cl2N4O ESI 475 (100), 317 (16)
605	606	C24H30Cl2N4O ESI 461 (100), 303 (25)
607	608	C23H28Cl2N4O ESI 447 (100), 224 (64)
609	610	C26H34Cl2N4O ESI 489 (100), 331 (33)
611	612	C27H25F4N3O ESI 484 (100)
613	614	C26H32Cl2N4O ESI 487 (100), 433 (39)
615	616	C26H32Cl2N4O ESI 487 (100), 433 (46)
617	618	C31H44N4O ESI 489.1 (100), 331.1 (68)
619	620	C30H40N4O ESI 473.1 (100), 315.1 (55)
621	622	C32H46N4O ESI 503.1 (100), 345.1 (834)
623	624	C33H46N4O ESI 515.1 (73), 357.1 (100), 258.1 (9)
625	626	C32H40N4OS ESI 433.1 (22), 371.1 (83)
627	628	C32H44N4O ESI 501.1 (80), 343.1 (100), 251.1 (7), 159.1 (69)
629	630	C32H40N4O2ESI 513.1 (87), 433.1 (32), 355.1 (100), 275.1 (12)
631	632	C34H42N4O ESI 523.1 (91), 365.1 (100)
633	634	C32H38Cl2N4O ESI 565 (100), 331 (56), 235 (52)
H	635	C26H27N3O ESI 398 (100), 397 (4)
636	637	C26H34FN4O ESI 457 (92), 229 (100)
638	639	C29H40N4O ESI 461 (99), 231 (100)
640	641	C30H42O2ESI 491.1 (90), 331.1 (65), 61 (100)
642	643	C31H43ClN4O ESI 525.1 (42), 524.1 (53), 523.1 (65), 331.1 (60), 193.1 (100)
644	645	C28H38N4O2ESI 463 (100), 331 (38)
646	647	C29H40N4O3ESI 494 (100), 247 (95)
648	649	C26H34Cl2N4O ESI 491 (86) 489 (100), 245 (72)
650	651	C28H38N4O ESI 447 (88), 224 (100)
652	653	C26H35ClN4O ESI 455 (100), 228 (85)
654	655	C26H35ClN4O ESI 455 (100), 228 (60)
656	657	C24H31ClN4O ESI 427 (100), 303 (10), 214 (48)
658	659	C23H29BrN4O ESI 459 (99), 457 (100), 230 (45)
660	661	C26H35BrN4O FAB 501 (99), 499 (100), 235 (40)
662	663	C26H35BrN4O FAB 501 (99), 499 (100), 171 (28)
664	665	C26H35BrN4O FAB 499 (99), 497 (100), 171 (20)
666	667	C26H33FN4O FAB 439 (100), 220 (7)
668	669	C26H35FN4O FAB 439 (100), 220 (40)
H	670	C21H25N3O FAB 336 (100), 171 (100)
671	672	C23H29FN4O FAB 397 (100), 242 (100)
673	674	C24H31FN4O FAB 411 (100), 242 (90)
H	675	C19H27N3O FAB 314 (100), 247 (7)
676	677	C29H39FN4O ESI 479.1(100), 424.1 (31), 331.1 (43), 203.1 (61)
678	679	C29H39FN4O ESI 479.1 (100), 424.1 (11), 331.1 (39), 203.1 (38)
680	681	C29H39ClN4O ESI 495.1 (70), 345.1 (37), 65.0 (100)
H	682	C24H25N3O ESI 372.1 (100), 200.1 (4)
683	684	C30H38N4O ESI 471.1 (100), 331.1 (36)
H	685	C20H29N3O ESI 328 (100)
H	686	C21H31N3O ESI 342 (100)
H	687	C22H33N3O ESI 356.1 (100), 171.1 (5)
688	689	C24H37N3O ESI 370.1 (100), 247.1 (20)

[0147]

TABLE 7
compounds of the formulas shown, wherein Ph is phenyl
Compound Physical Data
690      C25H27NO.HCl ESI 358.1 (44.50), 167.0 (100)
691      C25H27NO.HCl FAB 358.2 (100), 232.1 (23.70)
692      C27H29NO.HCl Cl 348.20 (58), 366.25 (23.70)
693      C26H27NO.HCl FAB 370.1 (100), 167.0 (100)
694      C28H31NO.HCl FAB 398.1 (100), 195.1 (98)
695      C26H25NOCl2.HCl FAB 440.1 (65), 438.0 (100), 236.9 (38), 234.9 (60)
696      C25H23NO2.HCl FAB 370.2 (100), 292.2 (18)
697      C25H25NO.HCl ESI 356.1 (14.77), 168 (20.98), 167 (100)
698      C26H27N.HCl ESI 354.1 (55.06), 167.1 (100),
699      C26H25NO2.HCl ESI 352.1 (41.94), 167.1 (100)
700      C25H25NO2.HCl ESI 372.1 (15.42), 167 (100)
701      C26H27NO2.HCl Cl 386.10 (73), 354.05 (88), 167.25 (100).
702      C25H24N3Cl.HCl Cl 402 (55), 366.20 (77), 250.15 (34), 167.25 (74).
703      C25H26N2Cl 356.2 (26) 355.2 (100), 167 (28)
704      C26H25N3O2:HCl ESI 412 (20), 167.1 (100)
705      C26H25F2NO ESI 406.1 (100), 203.1 (89.11)
706      C26H26ClNO ESI 406.1 (34.35), 404.10 (81.42), 201.10 (100)
707      C27H29NO ESI 384.1 (54.52), 181 (100)
708      C27H28Cl2N2O ESI 399.1 (13.87), 398.1 (56.98), 397.1 (100)
709      C26H26FNO ESI 388.2 (90), 185.0 (100)
710      C29H34N2O ESI 429.1 (8.33), 428.10 (36.55), 427.1 (74.28)
711      C24H31NO FAB 350.4 (100), 204.3 (18)
712      C25H33NO FAB 364.40 (100), 204.3 (20)
713      C27H28F2N2O FAB 435.2 (100), 203.1 (55)
714      C26H26BrNO FAB 448.1 (100), 247.0 (58), 166.1 (38)
715      C26H25Br2NO ESI 528 (100), 325.1 (54.35)
716      C27H28Br2N2O FAB 560 (20), 557 (100), 324.8 (60)
717      C27H27NO3Cl 414.20 (100), 396.20 (34), 211.15 (47), 186.15 (30)
718      C19H19N3O ESI 306.1 (100)
719      C21H29N3O ESI 341.1 (30.27), 340.1 (100)
720      C23H33N3O ESI 369.1 (39.66), 368.1 (100)
721      C28H31NO3ESI 430.1 (100), 204.1 (52.46)
722      C28H27NO3FAB 426.3 (100), 225.0 (18), 195 (18)
723      C30H35NO ESI 426.1 (100), 408 (11), 223.0 (43)
724      C28H31NO3ESI 430.1 (100), 412.1 (11.0), 227.0 (24.2)
725      C25H33NO ESI 364.10 (100), 346 (7)
726      C21H23NO3FAB 338.1 (100)
727      C21H21F4NO2ESI 396.1 (100)
728      C22H27NO3Cl 354 (100), 336 (78)
729      C21H21F4NO ESI 380.1 (100)

[0148]

TABLE 8
730
wherein Z1 and Z2 are as defined in the following table:
Z1	Z2	Physical Data
731	732	C25H24N2O.HCl FAB 369.2 (75), 167.1 (100)
733	734	C27H28N2O.HCl FAB 397.2 (40), 195.1 (100)
735	736	C26H26N2O.HCl ESI 383.1 (11.64), 181.1 (100)
737	738	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)
739	740	C25H22N2OF2.HCl FAB 405.2 (100), 203.1 (76)
741	742	C25H23ClN2O:HCl FAB 403.1 (100) 201 (70)

Assays

[0149] Nociceptin Binding Assay

[0150] CHO cell membrane preparation expressing the ORL-1 receptor (2 mg) was incubated with varying concentrations of [125 I][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.

[0151] Calculations of Ki were made using methods well known in the art.

[0152] 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)
743       13
744       200
745       60
746       0.6
747       2.3
748       77
749       18
750       3,000

[0153] Using the procedures described 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
Compound to human ORL-1 receptor @ 100 nM
751      77
752      43
753      59
754      102
755      71
756      43
757      15
758      95
759      107
760      120
761      70
762      101

EXAMPLE 12

[0154] Cough Studies

[0155] The effects of nociceptin agonist Compound A (0.3-10 mg/kg, p.o.) and Compound B (10 mg/kg, p.o.) 763

[0156] 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

[0157] Respiratory Measurements

[0158] 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.

[0159] 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.

[0160] 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.

[0161] Data Analysis

[0162] 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.

[0163] We have surprisingly discovered that nociceptin receptor ORL-1 agonists exhibit anti-tussive activity, making them useful for suppressing coughing in mammals. Non-limitative examples of nociceptin receptor ORL-1 agonists include the nociceptin receptor ORL-1 agonist compounds described herein. 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, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists.

[0164] 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.

[0165] 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-1 199 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).

[0166] 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; praniukast, 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.

[0167] 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.

[0168] Non-limitative examples of β-adrenergic receptor agonists include: albuterol, bitolterol, isoetharine, mataproterenol, perbuterol, salmeterol, terbutaline, isoproterenol, ephedrine and epinephrine.

[0169] A non-limitative example of a xanthine derivative is theophylline.

[0170] Non-limitative examples of α-adrenergic receptor agonists include arylalkylamines, (e.g., phenylpropanolamine and pseudephedrine), imidazoles (e.g., naphazoline, oxymetazoline, tetrahydrozoline, and xylometazoline), and cycloalkylamines (e.g., propylhexedrine).

[0171] A non-limitative example of a mast cell stabilizer is nedocromil sodium.

[0172] Non-limitative examples of anti-tussive agents include codeine, dextromethorphan, benzonatate, chlophedianol, and noscapine.

[0173] A non-limitative example of an expectorant is guaifenesin.

[0174] Non-limitative examples of NK1, NK2 and NK3 tachykinin receptor antagonists include CP-99,994 and SR 48968.

[0175] Non-limitatve examples of GABAB agonists include baclofen and 3-aminopropyl-phosphinic acid.

[0176] 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.

[0177] 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.

[0178] Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection.

[0179] Liquid form preparations may also include solutions for intranasal administration.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] Preferably the compound is administered orally.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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 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.

[0188] 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 treating coughing, the nociceptin receptor ORL-1 agonist may be administered with one or more additional 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, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists. The nociceptin receptor ORL-1 agonist and the additional agents 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.

[0189] 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.

Pharmaceutical Dosage Form Examples

[0190]

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

Method of Manufacture

[0191] 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

[0192] Method of Manufacture

[0193] 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.

[0194] 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 compound represented by the formula

2. A compound of claim 1 wherein Z1 and Z2 are each R7-aryl.

3. A compound of claim 2 wherein Z1 and Z2 are each R7-phenyl.

4. A compound of claim 3 wherein R7 is selected from the group consisting of (C1-C6)alkyl and halo.

5. A compound of claim 1 wherein R1, R2, R3 and R4 are each hydrogen.

6. A compound of claim 1 wherein R1 and R3 are each hydrogen and R2 and R4 are an alkylene bridge of 2 or 3 carbons.

7. A compound of claim 1 wherein X1 is R7-aryl and and X2 is OH or —NC(O)R28.

8. A compound of claim 7 wherein X1 is R7-phenyl.

9. A compound of claim 1 wherein X1 is

10. A compound of claim 9 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.

11. A compound of claim 1 wherein X1 and X2 together form the spirocyclic group

12. A compound of claim 11 wherein m is 1, R17 is phenyl and R16 is —(C1-C6)alkyl-OR19 or —(C1-C6)alkyl-NR19R20.

13. A compound selected from the group consisting of

14. A pharmaceutical composition comprising a therapeutically effective amount of compound of claim 1 in combination with a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising: a therapeutically effective amount of a nociceptin receptor ORL-1 agonist; a therapeutically effective amount of a second agent selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, [-adrenergic receptor agonists, xanthine derivatives, a-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists; and a pharmaceutically acceptable carrier.

16. A method of treating pain, anxiety, asthma, depression or alcohol abuse comprising administering an effective amount of a compound of claim 1 to a mammal in need of such treatment.

17. A method of treating cough comprising administering an effective amount of a nociceptin receptor ORL-1 agonist to a mammal in need of such treatment.

18. The method of claim 17, wherein in addition to the nociceptin receptor ORL-1 agonist, an effective amount of a second agent 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, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists is administered.