High affinity ligands for nociceptin receptor ORL-1

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) 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.

[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

[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

[0012] and X2 is hydrogen;

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

[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, R10-(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, —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

[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

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

[0028] R12 is H, (C1-C6)alkyl, halo, —NO2, —CF3, —OCF3, —OR19, —(C1-C 6)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

[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)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

[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 P25-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

[0045] or X1 and X2 together are

[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

[0048] and X1 and X2 together are

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

[0049] 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

[0050] provided that when X1 is

[0051] and Z1 is R6-(C3-C12)-cycloalkyl, Z2 is not H.

[0052] 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.

[0053] 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.

[0054] 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

[0055] 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

[0056] wherein m is 1, R17 is phenyl and R11 is —(C1-C6)alkyl-OR19 or —(C1-C6)alkyl-NR19R20, or

[0057] In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.

[0058] 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.

[0059] 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.

[0060] 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 ireceptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAA agonists.

[0061] In yet another aspect, the present invention relates to a novel compound not included in the structure of formula I, said compound being:

BRIEF DESCRIPTION OF THE DRAWINGS

[0062]
FIG. 1 illustrates the effect in guinea pigs of Compounds A and B (see Example 12) compared to baclofen on capsaicin-induced cough.

[0063]
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

[0064] As used herein, the following terms are used as defined below unless otherwise indicated:

[0065] 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;

[0066] Bu is butyl; Et is ethyl; Me is methyl; and Ph is phenyl;

[0067] 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;

[0068] 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;

[0069] alkynyl represents an alkyl chain of 2 to 6 carbon atoms comprising one triple bond in the chain, e.g., ethynyl or propynyl;

[0070] 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;

[0071] 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;

[0072] 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;

[0073] 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;

[0074] 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;

[0075] 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;

[0076] halo represents fluoro, chloro, bromo and iodo;

[0077] 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:

[0078] 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;

[0079] 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,

[0080] wherein R17 is as defined above and t is 0, 1 or 2.

[0081] 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.

[0082] 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:

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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:

[0090] 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.

[0091] 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.

[0092] 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 I, and n-butyl-lithium.

[0093] 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:

[0094] 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 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:

[0095] Compounds of formula I 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).

[0096] 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.

[0097] 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:

[0098] wherein Pr is a N-protecting group, Ph is phenyl and z is 1-2.

[0099] 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:

[0100] Similar procedures, or others known in the art, can be used to prepare compounds wherein the Z substituents are other than phenyl.

[0101] 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.

[0102] 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

[0103]

[0104] 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): 61.80 (m, 2 H), 2.25 (m, 2 H), 2.42 (m, 2 H), 2.90 (m, 2 H), 4.40 (s,1 H), 7.2-7.6 (m, 15 H).

EXAMPLE 2

[0105]

[0106] 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.

[0107] 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, 6 H, ArH), 7.3 (t, 4 H, ArH), 7.2 (t, 4 H, ArH), 4.35 (s,1 H), 2.8 (d, 2 H), 2.4 (m, 5 H), 2.2 (td, 2 H), 1.75 (d, 2 H); 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

[0108]

[0109] 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, 2 H), 7.35 (bt, 4 H), 7.25 (m, 3 H), 7.2 (m, 2 H), 4.4 (s,1 H), 2.8 (d, 2 H), 2.5 (t, 2 H), 2.3 (dt, 2 H), 2.0 (d, 2 H); 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

[0110]

[0111] 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, 4 H), 2.50 (m, 2 H), 2.85 (m, 2 H), 4.25 (s, 1 H), 7.20-7.50 (m, 15H), 9.42 (s,1 H).

[0112] 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 1 N 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, 2 H), 2.25 (m, 4 H), 2.65 (m, 2 H), 3.65 (d, 2 H), 4.20 (s, 1 H), 4.25 (d,1 H), 7.2-7.6 (m, 15 H).

[0113] 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, 4 H), 2.40 (m, 2 H), 2.78 (m, 2 H), 2.90 (m, 2 H), 3.00(s, 3 H), 4.38 (s, 1 H), 7.21-7.52 (m, 15 H).

EXAMPLE 5

[0114]

[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 (CDCI3): δ2.21 (m, 4 H), 2.49 (t, J=12.3 Hz, 2 H), 3.11 (d, J=12.5 Hz, 2 H), 4.46 (s, 1H), 7.45 (m, 15 H).

[0116] 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 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): δ1.84 (m, 2 H), 2.16 (m, 4 H), 2.56 (m, 2 H), 2.68 (m, 2 H), 4.07 (s,1 H), 7.25 (m, 15 H).

[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): δ2.13 (m, 6 H), 2.66 (m, 4 H), 3.50 (s, 2 H), 4.07 (s, 1 H), 7.11-7.65 (m, 20 H).

[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 18h. 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, 2 H), 2.15 (m, 4 H), 2.48 (m, 2 H), 2.68 (s, 2 H), 3.53 (s, 2 H), 4.05 (s,1 H), 7.01-7.38 (m, 20 H).

EXAMPLE 6

[0119]

[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. H NMR (CD3OD): δ1.87 (m, 5 H), 2.16 (m, 4 H), 2.61 (m, 2 H), 3.31 (s, 2 H), 4.07 (s, 1 H), 7.12-7.40 (m, 20 H).

EXAMPLE 7

[0121]

[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): δ2.10 (m, 2 H), 2.40 (m, 4 H), 2.82 (d, J=11.50 Hz, 2 H), 3.57 (s, 2 H), 7.20-7.43 (m, 10 H), 8.05 (s,1 H).

[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: δ2.59 (t, J=13.3 Hz, 2 H), 2.93 (t, J= 13.3 Hz, 2 H), 3.07 (d, J=13.50 Hz, 2 H), 3.58 (d, J=13 Hz, 2 H), 4.26 (s, 2 H), 7.56 (m, 10 H).

[0125] Step 4: The product of Step 3 (24.10 g, 71 mM), CH2Cl2 (300 ml), 25 (tBoc)20 (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, 2 H), 1.39 (s, 1 H), 2.05 (m, 2 H), 2.34 (m, 4H), 2.65 (d, J=11.8 Hz, 2 H), 3.56 (s, 2 H), 7.18-7.40 (m, 10 H).

[0126] Step 5: The product of Step 4 (5.22 g, 14.2 mM), CH3O H (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. 1 H NMR (CD3OD): δ 1.10 (bs, 2 H), 1.39 (s, 7 H), 1.90 (m, 2 H), 2.26 (m, 4 H), 2.92 (m, 4 H), 7.17-7.41 (m, 5 H).

[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): δ1.07 (bs, 2 H), 1.37 (s, 7 H), 2.23 (m, 2 H), 2.24 (m, 4 H), 2.74 (d, J=12.1 Hz, 2 H), 4.27 (s,1 H), 7.10-7.47 (m,15 H).

[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: δ2.91(m, 8 H), 5.34 (s, 1 H), 7.37-7.77 (m, 15 H).

[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): δ1.96 (m, 2 H), 2.17 (m, 2 H), 2.52 (m, 4 H), 3.45 (s, 2 H), 4.24 (s,1 H), 6.76 (d. J=3.5 Hz,1 H), 6.85 (dd, J=3.6 Hz, 1 H), 7.13-7.50 (m, 16 H).

EXAMPLE 8

[0130]

[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-2 H-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 (CDCI3) δ7.55 (m, 4 H, ArH), 7.35 (m, 5 H, ArH), 7.25 (m, 2 H, ArH), 7.15 (m, 2 H, ArH), 7.1 (m, 1 H, ArH), 4.4 (m, 2 H), 3.95 (t, 2 H), 3.15 (d, 2 H), 2.6 (dq, 2 H), 2.1 (t, 2 H, 1.8, m, 4 H), 1.5 (m, 2 H), 1.0 (t, 3 H); 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]

[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) δ7.91 (d, 1 H), 7.58 (d, 2 H), 7.54 (d, 2 H), 7.42 (t, 2 H), 7.32 (m, 5 H), 7.26 (t, 3 H), 7.16 (t, 3 H), 5.0 (s, 1 H), 2.8 (dd, 2 H), 2.5 (dq, 2 H), 2.2 (dt, 2 H), 1.75 (d, 2 H). Dissolve the title compound in ether, add HCl/Et2O (1 M) to give the HCl salt. MS Cl (378 (M+1); Elemental analysis for C24H24NOCI.HCl.0.2 H2O: 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]

[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) δ7.76 (d, 1 H), 7.62 (d, 1 H), 7.55 (d, 1 H), 7.45 (t, 1 H), 7.34 (m, 3 H), 7.24 (m, 2 H), 7.03 (t,1 H), 6.90 (d, 2 H), 4.88 (s, 1 H), 3.89 (s, 3 H), 2.94 (d,1 H), 2.82 (d,1 H), 2.45 (td, 2 H), 2.26 (t, 2 H), 1.78 (d, 2 H). 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]

[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). 1 H NMR (CDCl3) δ1.70 (d, 2 H), 2.85 (m, 6 H), 3.05(s, 3 H), 4.50 (s, 1 H), 4.72 (s, 2 H), 6.95 (t,1 H), 7.05(d 2 H), 7.20-7.60 (m, 12 H).

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

1TABLE 1

wherein X1 is as defined below:X1Physical DataHC24H25NFAB 283.3 (100), 167.2 52)OMeC25H27NOFAB 358 (80), 167 (70)OEtC26N29NO:HClFAB 342 (67) 167 (100)

C27H31NO ESI 434.2 (79), 167 (100)

C31H31NO:HCl ESI 434.2 (62), 167 (100)CNC25H24N2FAB 353.2 (53), 275.10 (24).CHOC25H25NOCl 356 (28), 167 (100)CH2OHC25H27NOCl 358.1 (37), 167 (100)

C32H33NO:HCl FAB 448.1 (46), 167.2 (100)CH2OMeC25H27NOFAB 357.10 (10), 167 (100)CH2OEtC26H29NOCl 373.3 (12), 372 (42), 167 (100)

C30H34NO Cl 440.25 (33), 439.2 (100), 167.2 (89)CH2NH2C25H28N2:2HClESI 357.10 (37), 167 (100)CH2NHCOCH3C27H30N2OESI 399.1 (53), 167.0 (100)

C32H32N2O FAB 462.1 (15), 461.1 (41), 393 (8)

C32H34N2:HCl ESI 447.1 (100), 281.1 (29)

C33H32N2F3:HCl ESI 515 (100), 349.10 (33), 167 (49)CH2NHCH2CH3C27H32N2:HClESI 385.1 (100), 219.10 (26), 167 (76)

C29H36N2O:HCl Cl 429 (53), 351 (100) 327 (13), 167 (34)

C28H32N2O2Cl 429 (100), 351 (9), 261 (11), 167 (81)

C28H34N2O:HCl Cl 415 (100), 327 (33), 167 (65)

C31H39N3O:HCl ESI 470 (100), 304 (51), 259 (16), 167 (46)

C31H41N3:HCl ESI 456 (100), 290 (11), 167 (11)

C30H30N2O2ESI 451 (100), 283 (8), 167 (94)

C34H43N3O:HCl ESI 510 (88), 344 (73), 167 (100)

C32H41N3:HCl ESI 468 (98), 302 (22), 167 (100)

C31H31N3O:HCl Cl 462 (100), 384 (4), 167 (45)

C30H32N2O:Cl ESI 437 (100), 271 (11), 167 (41)

C30H32N2O:HCl ESI 437 (87), 271 (7), 167 (100)

C30H32N2S:HCl ESI 453 (92), 167 (100)

C30H32N2S:HCl ESI 453 (100), 287 (6), 167 (78)

C32H36N2S:HCl ESI 481 (69), 340 (5), 167 (100)

C29H36N2S:HCl ESI 445 (100), 399 (3), 279 (11), 167 (84)

C29H33N2F3:HCl ESI 467 (69), 167 (100)CH2NMe2C27H32N:HClFAB 385.3 (100), 219.2 (6), 162.2 (77)NH2C24H26N2:HClESI 343 (48), 326 (70), 167 (100)NH(CH2)3NEt2C31H41N3:HClESI 456 (72), 326 (74), 167 (100)

C29H30N2O:HCl Cl 423 (60), 326 (100), 167 (74)

C31H39N3:HCl ESI 454 (76), 326 (60), 167 (100)

C29H30N2S:HCl FAB 439 (90), 326 (25), 167 (100)NHMeC25H28N2:HClESI 357 (20), 326 (87), 167 (100)NMe2C26H30N2:HClESI 371 (11), 326 (81), 167 (100)

[0142]

2

TABLE 2

wherein X1 is as defined below

X1
Physical Data

C24H25NO FAB 343.1 (13), 342.1 (26)

C24H24BrNO ESI 424 (20) 422 (18) 167-2 (92)

C24H24NOCl Cl 363 (43), 362 (22), 167.20 (100)

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)

C25H23NOF3Cl EI 369 (3), 368 (14), 167 (100)

C25H24F3NO FAB 413 (31), 412 (57), 167 (100)

C25H27NO2Cl 374.45 (M + 1), 266.30 (39%), 167.25 (100%)

C26H30N2O FAB 387 (86%), 369 (22%)

C25H26NOF FAB 376.2 (68%), 375.2 (32%), 358.20 (6)

C25H27NO2Cl 374.45 (58%), 375.45 (27), 356.35 (29)

C24H24ClNO Cl 378.35 (31%), 377.35 (18%), 360.30 (22)

C25H27NO Cl 358.35 (68), 357.35 (38), 340.35 (47), 167.25 (100)

C24H23F2NO Cl 380.35 (28%), 379.35 (22), 362.35 (23), 167.25 (100)

C25H27NO Cl 358.35 (63), 357.35 (43), 340.35 (53), 167.25 (100)

C25H27NO Cl 358.35 (49), 357.35 (41), 340.35 (35), 167.25 (100)

C24H24FNO Cl 362.35 (41), 361.35 (218), 344.35 (39), 167.25 (100)

C26H25NO FAB 368 (37), 367 (38), 366 (100), 290 (41)

C25H27NSO FAB 375 (10), 374.20 (40), 306.7 (13)

C25H27NSO FAB 390 (22), 389 (27), 388 (100), 312 (48)

C24H23NOF2380.2 (11), 379.2 (16), 378.2 (31)

C26H29NO Cl 373.45 (22), 372.40 (82), 354.35 (60), 167.25 (100)

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)

C21H25NO:HCl ESI 308.1 (32), 167.0 (100)

C22H23NO2:HCl Cl 334.25 (34), 333.25 (26), 316.25 (41), 167.25 (100)

C22H23NOS:HCl Cl 350.25 (32), 349.35 (24), 332.25 (41), 167.25 (100)

C22H23NOS:HCl Cl 350.25 (27), 349.35 (18), 332.25 (20), 167.25 (100)

C23H24N2O:HCl ESI 345.1 (68), 167 (100)

C22H23NO2Cl 334.25 (37), 333.25 (24), 316.25 (31), 167.25 (100)

C25H24N2O:HCl FAB 369.3 (3), 368.3 (6), 367.3 (13)

C21H27NO:HCl Cl 310.40 (38), 309.40 (25), 292.40 (33), 167.25 (100)

C24H24NOF:HCl FAB 362.1 (100), 232.1 (11)

C22H29NO:HCl FAB 324.30 (100)

C21H25NO:HCl Cl 308.2 (64), 307.2 (30), 290.2 (57), 167.25 (100)

C23H25NOS:HCl Cl 364.15 (69), 346.15 (71), 167.25 (100)

100

C21H22N2SO:HCl Cl 351.1 (52), 350.1 (8), 266.15 (12), 167.2 (100)

101

C27H28N2O:HCl FAB 397.2 (80), 167.2 (100)

102

C25H28N2O:HCl ESI 373.1 (28), 167 (100)

103

C25H27NO2:HCl ESI 374.1 (43), 167 (100)

[0143]

3

TABLE 3

104

wherein Z1 and Z2 are as defined below:

Z1
Z2
Physical Data

105

106

C24H24NOCl Cl 380 (30), 378.1 (100), 201 (100)

107

108

C24H23NOF2Cl 380.15 (79), 379.15 (47), 362.05 (100)

109

110

C23H24N2O:HCl ESI 345.1 (69), 327.1 (49), 168 (100)

111

112

C23H24N2O:HCl ESI 345.1 (58), 168 (100)

113

114

C25H27NO:HCl Cl 358.20 (60), 340.20 (51), 181.25 (100)

115

116

C24H24NOBr:HCl ESI 424.1 (17), 422 (17), 247.1 (100), 245.1 (99)

117

118

C25H27NO:HCl ESI 358.1 (32.70), 181 (100)

119

120

C24H24NOCl:HCl Cl 380.10 (30), 378.15 (100)

121

122

C26H29NO:HCl ESI 372,1 (24), 195.1 (100)

123

124

C25H27NO:HCl ESI 358.1 (48%), 181.1 (100)

125

126

C25H24ONF3:HCl ESI 412.1 (56), 235 (100)

127

128

C25H24ONF3:HCl ESI 412.1 (73), 235.1 (100)

129

130

C26H29NO:HCl ESI 372.1 (39), 195.1 (100)

131

132

C24H24NOBr:HCl ESI 424.10 (48), 422.1 (47), 245.1 (100)

133

134

C22H23NOS:HCl ESI 350.1 (31), 173 (100)

135

136

C25H24ONF3:HCl ESI 412.1 (54), 235.10 (100)

137

138

C24H24NOF:HCl ESI 362.1 (23), 185.1 (100)

139

140

C24H23NOF2:HCl Cl 380.15 (100), 362.15 (89), 203.25 (99)

141

142

C24H23NOCl2:HCl ESI 416.1 (7), 414 (32), 412 (45), 235.1 (100)

143

144

C25H24N2O2F2:HCl FAB 423.2 (100), 218.0 (18)

145

146

C24H23NOF2:HCl Cl 380.15 (79), 379.15 (45), 362.05 (100)

147

148

C26H29NO2:HCl FAB 388.3 (100), 266.1 (15)

149

150

C25H27NO2:HCl FAB 374.1 (100), 197 (73)

151

152

C24H24NOCl:HCl FAB 380.1 (27), 378.2 (80), 201.0 (100)

153

154

C25H27NO:HCl ESI 358.1 (15), 181.1 (100)

Methyl

155

C19H23NO:HCl ESI 282.1 (100), 160.0 (84.5)

Ethyl

156

C20H25NO:HCl ESI 296.1 (100), 160.0 (84)

157

158

C21H27NO:HCl ESI 310.1 (100), 160.1 (52)

159

160

C22H29NO:HCl ESI 324.1 (100), 160.1 (52)

161

162

C23H31NO:HCl Cl 338.3 (100), 266.20 (77), 160.35 (17)

163

164

C24H33NO:HCl ESI 352.1 (100), 160.0 (41.83)

165

166

C23H29NO:HCl ESI 336.1 (66.39), 160.0 (63), 159 (100)

167

168

C23H30N2O2:HCl ESI 367.1 (35), 190 (100)

169

170

C23H31NO:HCl ESI 338.1 (100), 161.0 (36), 160 (70)

[0144]

4

TABLE 4

171

wherein X1, X2, Z1 and Z2 are as defined below

X1
X2
Z1
Z2
Physical Data

172

NH2

173

174

C22H30N2:HCl ESI 323 (71), 306 (100), 160 (31)

175

176

177

178

C27H34N2S:HCl ESI 419 (23), 306 (100)

179

CH2NH2

180

181

C23H32N2:HCl ESI 337 (96), 174 (100), 160 (19)

182

183

184

185

C28H36N2S:HCl ESI 433 (100), 320 (65), 174 (58)

186

NH2

187

188

C25H28N2:HCl Cl 357 (47), 340 (24), 279 (8), 181 (100)

189

190

191

192

C28H36N2S:HCl ESI 433 (100), 320 (42), 174 (77)

193

194

195

196

C30H32N2S:HCl ESI 453 (24), 340 (27), 181 (100)

197

NH2

198

199

C26H30N2:HCl ESI 371 (16) 195 (100)

200

201

202

203

C31H34N2S:HCl ESI 467 (25), 354 (30), 195 (100)

204

NH2

205

206

C24H24N2Cl2:HCl ESI 413 (18), 411 (26), 396 (39), 394 (51), 237 (69), 235 (100)

207

208

209

C26H28BrNO:HCl 450 (12), 195.1 (100)

210

211

212

C26H28FNO:HCl ESI 390.1 (9.6), 195.1 (100)

213

214

215

C26H28ClNO:HCl 407.1 (5), 195.1 (100) 406.1 (16)

216

217

218

219

C31H32N2OS ESI 481 (25), 195 (100)

220

221

222

223

C28H32N2O Cl 413 (31), 354 (8), 195 (100)

224

225

226

227

C29H28Cl2N2S:HCl ESI 509 (10), 507 (14), 396 (56), 394 (77), 237 (68), 235 (100)

228

229

230

C25H26N2OCl2:HCl ESI 443 (42), 441 (56), 425 (31), 235 (100)

231

232

233

234

C30H36N2OS ESI 473 (39), 195 (100)

235

236

237

238

C33H34N2O ESI 475 (41), 195 (100)

239

240

241

242

C29H34N2O2ESI 443 (31), 195 (100)

243

244

245

246

C30H34N2O:HCl ESI 439 (17), 195 (100)

247

248

249

250

C34H42N2O:HCl ESI 495 (30), 195 (100)

251

252

253

254

C33H36N2:HCl ESI 461 (17), 354 (28), 195 (100)

255

256

257

258

C26H26N2OCl2ESI 455 (57), 453 (75), 396 (7), 394 (10), 237 (73), 235 (100)

259

260

261

C29H31N2O3F3:HCl FAB 497.2 (507), 195.1 (100)

262

263

264

265

C24H32N2O:HCl ESI 365 (100), 219 (31), 160 (23)

266

267

268

269

C27H30N2O:HCl ESI 399 (60), 181 (100)

270

271

272

273

C29H34N2O:HCl ESI 427 (41), 195 (100)

274

275

276

277

C30H36N2O:HCl ESI 441 (47), 195 (100)

278

279

280

281

C28H32N3O:HCl ESI 428 (41), 195 (100)

282

283

284

C27H30Cl2N2O FAB 469.2 (30), 235.1 (100)

285

286

287

C28H32Cl2N2O3S Cl 549.15 (69), 548.15 (37), 547.15 (100)

288

289

290

C28H32Cl2N2O3S FAB 549 (60), 547.1 (87)

291

292

293

C27H30Cl2N2O3S FAB FAB 535 (78), 533 (100)

294

295

296

C26H28Cl2N2O3S FAB 523 (25)

297

298

299

C30H35Cl2N3O FAB 524.40 (20), 330.3 (100)

300

301

302

C36H39Cl2N3O FAB 600.5 (50), 330.4 (70)

303

304

305

C25H27BrN2O FAB 453.2 (100), 245 (100)

306

307

308

C25H26N2F2O FAB 410.2 (25), 409.2 (100), 203.2 (50)

309

310

311

C27H32N2O FAB 401.2 (95), 195 (100)

312

313

314

C25H26Cl2N2O 441.1 (40), 235 (42), 157 (100)

315

316

317

C25H27NO2Cl 374.25 (52), 356.2 (100), 178.25 (40), 160.25 (57)

318

319

320

C25H25NO3FAB 388.23 (100), 210.8 (21), 168.28 (20)

321

322

—(CH2)4CH3
C24H34N2O FAB 368.3 (30), 367.3 (100)

323

324

—(CH2)3CH3
C23H32N2O GAB 353.3 (100)

325

326

327

C25H26N2F2O FAB 410.6 (35), 409.4 (98), 203.1 (65)

328

329

330

C26H28Cl2N2O FAB 457.3 (70), 455.3 (100), 237 (30), 235.1 (52)

331

OH
H

332

C19H23N2OCl FAB 331.2 (100),

333

334

335

C27H32N2O FAB 402.1 (20.46), 401.1 (44.89), 195.1 (100)

336

337

338

C25H27ClN2O ES 409.2 (55), 408.2 (45), 407.2 (95)

339

340

341

C26H30N2O ES 387 (100)

342

343

344

C25H25NO2Cl 372.15 (100), 354.15 (38), 195.15 (37)

345

346

347

C26H29NO3FAB 404.3 (100), 227.1 (70)

348

OH
H

349

C21H34N2O FAB 331.4 (100), 266.2 (20)

350

OH
CH3(CH2)3—

351

C24H34N2O FAB 367.2 (100)

352

353

354

C27H32N2O ES 401.1 (46), 195.1 (100)

355

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

375

376

C25H26N2OBr2ESI 533 (55), 531 (100), 324.8 (30)

[0145]

5

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
C28H31N30: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:HCl Cl 439.5 (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

C32H29N3O: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]

6

H

434

C24H31N3O FAB 378.4 (100), 218.2 (30)

435

Benzhydryl
C31H35N3O3498.2 (100), 167.1 (90)

436

Benzhydryl
C29H31N3O3ESI 470.1 (100), 167.1 (55)

437

438

C23H27Cl2N3O ESI 434.1 (80), 432.1 (100)

439

440

C22H25Cl2N3O2ESI 436.1 (58), 434.1 (100)

441

442

C23H27Cl2N3O ESI 434.1 (35), 432.1 (100)

443

444

C24H27Cl2N3O ESI 446.1 (77)), 444.1 (100)

445

446

C21H22Cl2N4O2FAB 435.1 (78), 433.1 (100)

[0147]

7

TABLE 6

447

wherein R11, Z1 and Z2 are as defined in the following table:

R11
CH(Z1)(Z2)
Physical Data

H
Benzhydryl

448

Benzhydryl
C29H33N3O ESI: 440 (100) 167 (80)

449

Benzhydryl
C29H31N3O ESI: 438 (100) 167 (99)

450

Benzhydryl
C30H35N3O ESI: 454 (100) 167 (94)

451

Benzhydryl
C29H29N3O ESI: 436 (99) 167 (100)

CH3
Benzhydryl
C27H29N3O

FAB: 412 (100)

452

Benzhydryl
C28H31N3O FAB: 426 (100)

453

Benzhydryl
C30H33N3O3FAB: 484 (7) 261 (14) 167 (100)

454

Benzhydryl
C30H33N3O ESI: 452 (100) 167 (60)

455

Benzhydryl
C33H39N3O ESI: 494 (100) 167 (30)

456

Benzhydryl
C31H35N3O.HCl FAB: 466 (100)

457

Benzhydryl
C30H33N3O3.HCl FAB: 484 (100) 167 (41)

458

Benzhydryl
C33H38N4O2.HCl FAB: 523 (100)

H

459

C26H25N3F2O.HCl ESI: 434 (29) 203 (100)

H

460

C26H25N3F2O.HCl Cl: 434 (100)

H

461

C26H26N3ClO.HCl ESI: 432 (60) 201 (100)

462

Benzhydryl
C29H33N3O.HCl ESI: 440 (100) 167 (89)

463

Benzhydryl
C33H37N3O2.HCl ESI: 508 (100) 167 (35)

H

464

C24H30N3ClO.HCl ESI: 412 (100) 232 (92)

H

465

C24H31N3O.HCl ESI: 378 (100) 232 (82)

H

466

C21H24N3ClO.HCl ESI: 370 (86) 265 (100)

H

467

C24H30N3FO.HCl ESI: 396 (31) 232 (100)

H

468

C24H30N3BrO.HCl ESI: 456 (39) 232 (100)

H

469

C25H33N3O.HCl ESI: 392 (73) 232 (100)

H

470

C25H31N3O.HCl FAB: 390 (100)

471

472

C28H39N3O.HCl ESI: 434 (68) 288 (100)

473

474

C31H43N3O.HCl ESI: 474 (90) 328 (100)

475

476

C27H37N3O.HCl ESI: 420 (81) 274 (100)

H

477

C27H29N3O.HCl FAB: 412 (25) 181 (100)

478

479

C29H41N3O.HCl ESI: 448 (97) 288 (100)

480

481

C27H37N3O.HCl ESI: 420 (62) 274 (100)

482

483

C28H39N3O.HCl ESI: 434 (66) 274 (100)

H

484

C25H33N3O.HCl ESI: 392 (59), 232 (100)

485

486

C31H37N3O.HCl ESI: 468 (100) 322 (92)

487

488

C28H39N3O.HCl ESI: 434 (100) 274 (86)

H

489

C22H25N3O3.HCl Cl: 380 (100)

490

491

C32H29N3O.HCl ESI: 482 (100) 322 (78)

H

492

C21H25N3O2.HCl FAB: 352 (100)

493

494

C33H41N3O.HCl FAB: 496 (100)

H

495

C28H31N3O.HCl ESI: 426 (19) 195 (100)

H

496

C26H26N3Cl2O.HCl ESI: 466 (79) 235 (100)

H

497

C25H32N4O2.HCl ESI: 421 (40) 190 (100)

H

498

C26H26N3FO.HCl FAB: 416 (100)

H

499

C26H25N3Cl2O.HCl ESI: 466 (100) 235 (60)

H

500

C26H26N3ClO.HCl ESI: 432 (48) 201 (100)

H

501

C26H26N3F2O.HCl ESI: 434 (69) 203 (100)

502

503

C29H37N3O.HCl ESI: 444 (52) 326 (100)

504

505

C27H33N3O.HCl ESI: 416 (33) 300 (100)

506

507

C28H29N3Cl2O2.HCl ESI: 510 (100)

508

509

C31H33N3Cl2O2.HCl ESI: 550 (100)

510

511

C30H33N3Cl2O.HCl ESI: 522 (100)

512

513

C31H35N3Cl2O.HCl ESI: 536 (100)

514

515

C29H29N3Cl2O3.HCl FAB: 538 (100)

516

517

C29H31N3Cl2O2.HCl ESI: 524 (100)

518

519

C32H36N4Cl2O.HCl FAB: 563 (100) 235 (55)

520

521

C27H37N3O2.HCl FAB: 436 (100)

522

523

C24H31N3O3.HCl FAB: 410 (100)

524

525

C25H33N3O2.HCl FAB: 408 (100)

526

527

C26H35N3O2.HCl FAB: 422 (100)

528

529

C29H32N4Cl2O.2HCl FAB: 523 (100)

530

531

C31H36N4Cl2O.2HCl FAB: 551 (100)

532

533

C30H34N4Cl2O.2HCl FAB: 537 (100)

534

535

C30H34N4Cl2O.2HCl FAB: 537 (100)

536

537

C29H38N4O.2HCl FAB: 459 (100)

538

539

C33H38N4Cl2O.2HCl ESI: 577 (56) 343 (100)

540

541

C33H38Cl2N4O ESI 577 (100), 343 (45)

542

543

C33H38Cl2N4O ESI 577 (100), 343 (45)

544

545

C34H40Cl2N4O ESI 591 (100), 357 (81)

546

547

C31H44N4O ESI 487 (100), 327 (51)

548

549

C33H39Cl2N5O ESI 592 (100), 358 (71), 235 (64)

550

551

C31H34Cl2N4O ESI 549 (100), 315 (52)

552

553

C31H42N4O ESI 487 (100), 329 (85)

554

555

C31H44N4O ESI 489 (100), 331 (99)

556

557

C33H38Cl2N4O2ESI 593 (100), 359 (45), 297 (45)

558

559

C34H40Cl2N4O ESI 591 (100), 357 (82), 235 (99)

560

561

C34H39Cl2N5O2ESI 620 (100), 386 (12), 235 (28)

562

563

C32H38Cl2N4O ESI 565 (100), 331 (56), 235 (52)

564

565

C32H36Cl2N4O2ESI 579 (100), 345 (51), 235 (76)

566

567

C33H38Cl2N4O2ESI 593 (100), 359 (63), 235 (90)

568

569

C35H42Cl2N4O ESI 605 (100), 371 (83)

570

571

C37H44Cl2N4O3FAB 663 (100), 234 (42)

572

573

C25H32Cl2N4O2ESI 491 (100), 333 (29)

574

575

C26H32Cl2N4O ESI 487 (100), 319 (31)

576

577

C26H34Cl2N4O ESI 489 (100), 331 (18)

578

579

C32H46N4O2ESI 519 (91), 361 (100)

580

581

C25H32N4Cl2O ESI 475 (100), 317 (24), 159 (69)

582

583

C28H38N4O FAB 447.3 (100), 289.2 (25), 242.2 (36)

584

585

C29H40N4O FAB 461.2 (100), 303.2 (20)

586

587

C31H42N4O2ESI 503.2 (100), 345.1 (95)

588

589

C30H42N4O ESI 475.1 (99), 317.1 (100)

590

591

C30H42N4O ESI 475.1 (89), 317.1 (100)

592

593

C33H48N4O2ESI 519.1 (95), 361.1 (100) 256.1 (12)

594

595

C29H40N4O2ESI 477.1 (100), 319.1 (100)

596

597

C31H42N4O ESI 487.10 (100), 329.1 (88)

598

599

C28H38N4O FAB 447 (100), 391 (30), 317 (20)

600

601

C29H41N5O FAB 476 (100), 346 (40)

602

603

C29H40N4O FAB 461 (100), 391 (40), 167 (22)

604

605

C28H38N4O FAB 447 (100), 391 (60)

606

607

C31H42N4O ESI 487.1 (100), 329.1 (86)

608

609

C30H42N4O2ESI 491.1 (63), 333.10 (100)

610

611

C34H48N4O ESI 529.1 (79), 371.1 (100)

612

613

C31H45N5O ESI 504.1 (99), 358.1 (100)

614

615

C32H45N5O ESI 516.1 (92), 358.1 (100), 251.1 (28)

616

617

C25H32Cl2N4O ESI 475 (100), 317 (16)

618

619

C24H30Cl2N4O ESI 461 (100), 303 (25)

620

621

C23H28Cl2N4O ESI 447 (100), 224 (64)

622

623

C26H34Cl2N4O ESI 489 (100), 331 (33)

624

625

C27H25F4N3O ESI 484 (100)

626

627

C26H32Cl2N4O ESI 487 (100), 433 (39)

628

629

C26H32Cl2N4O ESI 487 (100), 433 (46)

630

631

C31H44N4O ESI 489.1 (100), 331.1 (68)

632

633

C30H40N4O ESI 473.1 (100), 315.1 (55)

634

635

C32H46N4O ESI 503.1 (100), 345.1 (834)

636

637

C33H46N4O ESI 515.1 (73), 357.1 (100), 258.1 (9)

638

639

C32H40N4OS ESI 433.1 (22), 371.1 (83)

640

641

C32H44N4O ESI 501.1 (80), 343.1 (100), 251.1 (7), 159.1 (69)

642

643

C32H40N4O2ESI 513.1 (87), 433.1 (32), 355.1 (100), 275.1 (12)

644

645

C34H42N4O ESI 523.1 (91), 365.1 (100)

646

647

C32H38Cl2N4O ESI 565 (100), 331 (56), 235 (52)

H

648

C26H27N3O ESI 398 (100), 397 (4)

649

650

C26H34FN4O ESI 457 (92), 229 (100)

651

652

C29H40N4O ESI 461 (99), 231 (100)

653

654

C30H42N4O2ESI 491.1 (90), 331.1 (65), 61 (100)

655

656

C31H43ClN4O ESI 525.1 (42), 524.1 (53), 523.1 (65), 331.1 (60), 193.1 (100)

657

658

C28H38N4O2ESI 463 (100), 331 (38)

659

660

C29H40N4O3ESI 494 (100), 247 (95)

661

662

C26H34Cl2N4O ESI 491 (86) 489 (100), 245 (72)

663

664

C28H38N4O ESI 447 (88), 224 (100)

665

666

C26H35ClN4O ESI 455 (100), 228 (85)

667

668

C26H35ClN4O ESI 455 (100), 228 (60)

669

670

C24H31ClN4O ESI 427 (100), 303 (10), 214 (48)

671

672

C23H29BrN4O ESI 459 (99), 457 (100), 230 (45)

673

674

C26H35BrN4O FAB 501 (99), 499 (100), 235 (40)

675

676

C26H35BrN4O FAB 501 (99), 499 (100), 171 (28)

677

678

C26H35BrN4O FAB 499 (99), 497 (100), 171 (20)

679

680

C26H33FN4O FAB 439 (100), 220 (7)

681

682

C26H35FN4O FAB 439 (100), 220 (40)

H

683

C21H25N3O FAB 336 (100), 171 (100)

684

685

C23H29FN4O FAB 397 (100), 242 (100)

686

687

C24H31FN4O FAB 411 (100), 242 (90)

H

688

C19H27N3O FAB 314 (100), 247 (7)

689

690

C29H39FN4O ESI 479.1 (100), 424.1 (31), 331.1 (43), 203.1 (61)

691

692

C29H39FN4O ESI 479.1 (100), 424.1 (11), 331.1 (39), 203.1 (38)

693

694

C29H39ClN4O ESI 495.1 (70), 345.1 (37), 65.0 (100)

H

695

C24H25N3O ESI 372.1 (100), 200.1 (4)

696

697

C30H38N4O ESI 471.1 (100), 331.1 (36)

H

698

C20H29N3O ESI 328 (100)

H

699

C21H31N3O ESI 342 (100)

H

700

C22H33N3O ESI 356.1 (100), 171.1 (5)

701

702

C24H37N3O ESI 370.1 (100), 247.1 (20)

[0148]

8

TABLE 7

compounds of the formula shown, wherein Ph is phenyl

Compound
Physical Data

703

C25H27NO.HCl ESI 358.1 (44.50), 167.0 (100)

704

C25H27NO.HCl FAB 358.2 (100), 232.1 (23.70)

705

C27H29NO.HCl Cl 348.20 (58), 366.25 (48)

706

C26H27NO.HCl FAB 370.1 (100), 167.0 (100)

707

C28H31NO.HCl FAB 398.1 (100), 195.1 (98)

708

C26H25NOCl2.HCl FAB 440.1 (65), 438.0 (100), 236.9 (38), 234.9 (60)

709

C25H23NO2.HCl FAB 370.2 (100), 292.2 (18)

710

C25H25NO.HCl ESI 356.1 (14.77), 168 (20.98), 167 (100)

711

C26H27N.HCl ESI 354.1 (55.06), 167.1 (100),

712

C26H25N.HCl ESI 352.1 (41.94), 167.1 (100)

713

C25H25NO2.HCl ESI 372.1 (15.42), 167 (100)

714

C26H27NO2.HCl Cl 386.10 (73), 354.05 (88), 167.25 (100),

715

C25H24N3Cl.HCl Cl 402 (55), 366.20 (77), 250.15 (34), 167.25 (100),

716

C24H27N3O.HCl Cl 398.05 (100), 232.10 (19), 167.25 (74),

717

C25H26N2Cl 356.2 (26) 355.2 (100), 167 (28)

718

C26H25N3O2:HCl ESI 412 (20), 167.1 (100)

719

C26H25F2NO ESI 406.1 (100), 203.1 (89.11)

720

C26H26ClNO ESI 406.1 (34.35), 404.10 (81.42), 201.10 (100)

721

C27H29NO ESI 384.1 (54.52), 181 (100)

722

C27H28Cl2N2O ESI 399.1 (13.87), 398.1 (56.98), 397.1 (100)

723

C26H26FNO ESI 388.2 (90), 185.0 (100)

724

C29H34N2O ESI 429.1 (8.33) 428.10 (36.55), 427.1 (74.28)

725

C24H31NO FAB 350.4 (100), 204.3 (18)

726

C25H33NO FAB 364.40 (100), 204.3 (20)

727

C27H28F2N2O FAB 435.2 (100), 203.1 (55)

728

C26H26BrNO FAB 448.1 (100), 247.0 (58), 166.1 (38)

729

C26H25Br2NO ESI 528 (100), 325.1 (54.35)

730

C27H28Br2N2O FAB 560 (20), 557 (100), 324.8 (60)

731

C27H27NO3Cl 414.20 (100), 396.20 (34), 211.15 (47), 186.15 (30)

732

C19H19N3O ESI 306.1 (100)

733

C21H29N3O ESI 341.1 (30.27), 340.1 (100)

734

C23H33N3O ESI 369.1 (39.66), 368.1 (100)

735

C28H31NO3ESI 430.1 (100), 204.1 (52.46)

736

C28H27NO3FAB 426.3 (100), 225.0 (18), 195 (18)

737

C30H35NO ESI 426.1 (100), 408 (11), 223.0 (43)

738

C28H31NO3ESI 430.1 (100), 412.1 (11.0) 227.0 (24.2)

739

C25H33NO ESI 364.10 (100), 346 (7)

740

C21H23NO3FAB 338.1 (100)

741

C21H21F4NO2ESI 396.1 (100)

742

C22H27NO3Cl 354 (100), 336 (78)

743

C21H21F4NO ESI 380.1 (100)

[0149]

9

TABLE 8

744

wherein Z1 and Z2 are as defined in the following table:

Z1
Z2
Physical Data

745

746

C25H24N2O.HCl FAB 369.2 (75), 167.1 (100)

747

748

C27H28N2O.HCl FAB 397.2 (40), 195.1 (100)

749

750

C26H26N2O.HCl ESI 383.1 (11.64), 181.1 (100)

751

752

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)

753

754

C25H25N2OF2.HCl FAB 405.2 (100), 203.1 (76)

755

756

C25H23ClN2O:HCl FAB 403.1 (100) 201 (70)

ASSAYS

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 (pH 7.4), 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:

10CompoundsKi (nM)

757

758

200

759

760

0.6

761

2.3

762

763

764

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.

11% Stimulationof [35S]-GTPγSbinding to hu-man ORL-1 re-ceptor @Compound100 nM

765

766

767

768

102

769

770

771

772

773

107

774

120

775

776

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.)

777

[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-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).

[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-(1 H-tetrazol-5-yl)-4 H-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.

12Pharmaceutical Dosage Form ExamplesEXAMPLE A-TabletsNo.Ingredientsmg/tabletmg/tablet1.Active compound1005002.Lactose USP1221133.Corn Starch, Food Grade, as a 30 4010% paste in Purified Water4.Corn Starch, Food Grade 45 405.Magnesium Stearate 3 7Total300700

Method of Manufacture

[0190] 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.

13EXAMPLE B-CapsulesNo.Ingredientmg/capsulemg/capsule1.Active compound1005002.Lactose USP1061233.Corn Starch, Food Grade 40 704.Magnesium Stearate NF 7 7Total253700

[0191] Method of Manufacture

[0192] 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.

[0193] 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.

	Number	Date	Country
Parent	09359771	Jul 1999	US
Child	09769824	Jan 2001	US

High affinity ligands for nociceptin receptor ORL-1

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Provisional Applications (1)

Divisions (1)