Title of Invention

HIGH AFFINITY LIGANDS FOR NOCICEPTIN RECEPTOR ORL-1

Abstract

Compounds of fomlula (I) or a phamlaceutically acceptable salt or solvate thereof, wherein the dotted line represents an optional double bond Xl is optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; X2 if- CHO, -CN, optionally substituted amino, alkyl, or aryl; or Xl is optionally substituted benzofused heterocyclyl and X2 is hydrogen; or xl and X2 together fOml an optionally benzofused spiro heterocyclyl group; R 1, R2, R3 and R4. are independently H and alkyl, or (R 1 and R4) or (R 2 and R3) or (R 1 and R3) or (R2 and R4) together can fOml an alkylene bridge of I to 3 carbon atoms; ZI is optionally substituted alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, or-CO\alkyl or substituted amino) or CN; Z2 is H or ZI; Z3 is H or alkyl; or ZI, Z2 and Z3, together with the carbon to which they are attached, foml bicycle saturated or unsaturated rings; phamlaceutical compositions therefore, and the use of said compounds as nociceptin receptor inhibitors useful in the treatment of pain, anxiety, cough, asthma, depression and alcohol abuse are disclosed.

Full Text

HIGH AFFINITY LIGANDS FOR NOC1CEPTIN RECEPTOR ORL-1 BACKGROUND The noC1ceotm receptor ORL-1 has been shown to be involved with modulation of pain in animaf models. ORL-1 (the noC1ceptin receptor) was discovered as an "orphan opioid-like receptor" i.e. a receptor whose ligand was unknown. The noC1ceptin 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 noC1ceptin receptor. Like the classical opioid receptors, the noC1ceptin receptor has a broad distribution in the central nervous system. In late 1995, noC1ceptin was discovered and shown to be an endogenous peptide ligand that activates the noC1ceptin receptor. Data included in the initial publications suggested that noC1ceptin 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 noC1ceptin, when administered intraspinally to rodents, is an analgesic. The efficacy of noC1ceptin is similar to that of endogenous opioid peptides. Recent data has shown that noC1ceptin acts as an axiolytic when administered directly into the brain of rodents. When tested in standard animals models of anxiety, the efficacy of noC1ceptin is similar to that seen with classical benzodiazapine anxiolytics. These data suggest that a small molecule agonist of the noC1ceptin receptor could have significant analgesic or anxiolytic activity. Additional recent data (Rizzi, et al. Life ScL 64. (1999), p. 157-163) has shown that the activation of noC1ceptin receptors in isolated guinea pig bronchus inhibits tachykinergic non adrenergic-non cholinergic contraC1icn, indicating that noC1ceptin receptor agonists could be useful in the treatment of asthma. Also, it has been reported (C1ccoC1oppo et al, Phvschpharmacology, 141 (1999), p. 220-224) noC1ceptin reduces the rewarding properties of ethanol in msP alcohol preferring rats, suggesting that intervention of noC1ceptin 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., noC1ceptin) useful in the treatment of various disorders, including depression; 2-oxoimidazole derivatives disclosed in W098/54168 were desC1-ibed as having similar utility. Earlier, benzimidazoiyl piperidines were disclosed in U.S. 3,318,900 as having analgesic activity. 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 deC1-ease 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 noC1ceptin suggest the potential for advantages over opioids. When administered chronically to rodents, noC1ceptin, in contrast to morphine, showed no addiction liability. Additionally, chronic morphine treatment did not lead to a "C1-oss-tolerance" to noC1ceptin, suggesting that these agents act via distinct pathways. 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 noC1ceptin, a natural ligand to ORL-1 and therefore useful in the management of pain and anxiety. Such a contributioQ is provided by this invention. SUMMARY OF THE INVENTION Compounds of the present invention are represented by R19 and R20 are independently selected from the group consisting of hydrogen, (C1-CsJalkyl, (C3-C12)cycloalkyl, aryl and aryl(C1-C6)alkyl; R21 and R22 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C3-C12)cycloalky], (C3-C12)cycloalky[(C1-CsJalky!, (C3-C7)heterocyC1oalkyl. -(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-SR19r -(C1-CoJalkyl-NRiS-(C1-C6)alkyl-0-{C1-C6)alkyi and -(C1-Celalkyl-NR-fd-CgJalkyl-NR-(C1-C6)a!kyl; R18 is hydrogen or fC1-C6)alkyl; Z1 is R5-(C1-C12)alkyl, R7-aryl, RB-heteroaryl, R6-(C3-C12)cyclo-alkyl, R10-(C3-C1-)heterocycloalkyl, -C02(C1-C5)alkyl, CN or -C(O)NR19R20; Z2 IS hydrogen or Z1; 23 is hydrogen or (C1-C6)alkyl; or Z1, Z2 and Z3, together with the carbon to which they are attached, form 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-phenyf or R8-heteroaryl ring; R23 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl. -OR1 -(C1-C6)alkyl-OR19, -NR19R20 and -(C1-C6)aikyl-NRi9R20; R24 is 1 to 3 substituents independently selected from the group consisting of R23, -CF;,, -OCF3, NO2 or halo, or R24 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring; R25 is 1-3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, (Cj-Cglalkoxy and halo; R2S is independently selected from the group consisting of H, (C1-C6)alkyl and R25-C6H4-CH2-; 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 In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceuticaliy acceptable carrier. The compounds of the present invention are agonists and/or antagonists of the ORL-1 receptor, and therefore, in another aspect, the invention relates to a method of treating pain, anxiety, 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. 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 noC1ceptin 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, leukotnene inhibitors, H3 inhibitors, B-adrenergic receptor agonists, xanthine derivatives, a-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NKi, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists. In still another aspect, the invention relates to a pharmaceutical composition comprising a noC1ceptin receptor ORL-1 agonist and a second agent selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, teukotriene inhibitors, H3 inhibitors, B-adrenergic receptor agonists, xanthine derivatives, a-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK,, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists. In other words, the invention relates to the use of compounds of claim 1 in the treatment of pain, anxiety, cough, asthma, alcohol abuse or depression, and to the use of a noC1ceptin receptor ORL-1 agonist, alone or in comoination with a second agent for treating cough, allergy Figures 2A and 2B show changes in Tidal Volume after administration of Compound A or baclofen, and Figure 2C shows changes in frequency of breaths after administration of Compound A or baclofen. DETAILED DESC1-IPTION OF THE INVENTION As used herein, the following terms are used as defined below uniess otherwise indicated: M+ represents the molecular ion of the molecule in the mass spectrum and MHT represents the molecular ion plus hydrogen of the molecule in the mass spectrum; Bu is butyl; Et is ethyl; We is methyl; and Ph is pnenyl; alkyi (including the aikyl portions of alkoxy. alkylamino and dialkyiamino) 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; 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; alkynyi represents an alkyl chain of 2 to 5 carbon atoms comprising one triple bond in the chain, e.g., ethynyi or propynyl; 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; 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-CV)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; 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; arylcxy 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; cycloalkyl represents saturated carbocyctic rings of frcm 3 to 12 carbon atoms, preferably 3 to 7 carbon atoms; wherein R6-cycloalkyl means that any of the available substttutable carbon atoms in said cycfoaikyl group is optionally and independently substituted, and wherein the cyC1oaiky! ring is substituted with 1-3 R6 groups; cycloalkylalkyi represents an alkyl group, as defined above, wherein one or mere hydrogen atoms of the alky] moiety have been substituted with one to three cyC1oalkyl groups, wherein cycloalkyl is as defined above; halo represents fluoro, chloro, bromo and iodo; heteroaryi 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 suffiC1ent number of delocalized pi electrons lo provide aromatic character, with the aromatic heterocyclic groups containing !rom 5 to 14 carbon atoms, wherein said heteroaryi group optionally can be fused with one or more aryl, cycloalkyl, heteroaryi or heterocycloalkyl rings; and wherein any of the available substitutable carbon or nitrogen atoms in said heteroaryi group and/or said fused ring"s) may be optionally and independently substituted, and wherein the heteroaryi ring can be substituted with 1-3 RB groups; representative neteroaryl groups can include, for example, furanyl, thienyl, imidazcyl, pyrimidinyl, triazolyl, 2~, 3- or 4-pyridyl or 2-, 3- or 4- j 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 -0-, -S- and -NR21-, wherein R~" is as defined above, and wherein optionally, said ring may contain one C1- 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- When the optional double bond in the pipendinyl ring of formula I is present, one of X1 and X2 forms the bond with the 3-posmon carbon and the remaining X1 or X2 is not hydrogen. When X1 and X2 form a spiro group as defined above, the wavy fines in the structures shown in the definition indicate the points of attachment to to the 4-position carbon of the piperidinyl ring, e.g., atropisomers) . The invention contemplates all such stereoisomers both in pure form and in mixture, including racemic mixtures. Certain compounds will be aC1dic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxy! group. These compounds may form pharmaceutical acceptable salts. Examples of such salts may include sodium, potassium, calC1um, aluminum, gold and silver salts. Aiso contemplated are salts formed with pharmaceutically acceptabfe amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like. Certain basic compounds also form pharmaceutically acceptable salts, e.g., aC1d addition salts. For example, pyrido-nitrogen atoms may form salts with strong aC1d, white compounds having basic substituents such as amino groups also form salts with weaker aC1ds. Examples of suitable aC1ds for salt formation are hydrochloric, sulfuric, phosphoric, acetic, C1tric, oxalic, malonic, salicylic, malic, fumaric, sucC1nic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic aC1ds well known to those skilled in the art. The salts are prepared by contacting the free base form with a suffiC1ent amount of the desired aC1d 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 soa/um bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the aC1d and base salts are otherwise equivalent to their respective free base forms for purposes of the invention. All such aC1d and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all aC1d and base salts are considered equivalent to the free forms of the corresponding compounds for purpopses of the invention. 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 speC1fic preparative examples are given below. 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. X1 ,X2-substituted piperidines are either commerC1ally available or made by known procedures. For example, 4-hydroxy-4-phenyl-piperidine can be converted to a 4-ffioc-amino-4-phenylpiperidine according to the following reaction scheme, wherein Bn is benzyl, Ph is phenyl and fBoc is t-butoxycarbonyl: group and the resulting intermediate is then treated with MeaSiCN. The resultant amide is hydrolyzed with aqueous HC! 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-ptperidine derivative. 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 miid reduC1ng agent such as Na(OAc)3BH or with a compound of the formula R22-L, wherein L is a leaving group such as C1 or Br, in the presence of a base such as Et3N. 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-ha!omethane, then reacting the ketone with an appropriately substituted R7-pheny(magnesium bromide or with a compound of the formula X1-!.1, wherein L1 is Br or I, and n-butyl-lithium. X1,X2-substituted campounds 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 R13-0-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 7? are H : 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). 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. For compounds of formula I wherein R1, R2, R3 and R4 variously form alkylene bridges, commerC1ally available N-protected 4- prepare compounds wherein the Z substnuents are other than phenyl. 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- The following solvents and reagents are referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic aC1d (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); and diethyl ether (Et20). Room A mixture of 4-hydroxy-4-phenyl piperidine (1.5 g. 8.-37 mmoll and K2CO3 (3.0 g, 21.73 mmol) in CH3CN was stirred at n. To this was added a-bromo-diphenylmethane (2-5 g, TO.12 mmol) and !ne reaction was stirred overnight. The reaction mixture was concentrated. redissolved in CH2Ct2.wash.ed with water, dried (MgSO) and concentrated. Chromatography (SiOo, 9:1 nexane/EtOAc) gave the title compound (2.6g, 90%). H NMR (CDC13): 5 1.80 (m, 2Hj, 2.25 (m, 2H). mmol) in CH3C1-\i was alkylated using She procedure descnoed in Example 1. Chromatography of the residue on silica (95:5 hexane/ EtOAc) gave the desired compound. Step 2: 4-Methyiphenylrnagnesium bromide (0.5 M in THF, 1.75 ml, 0.87 mmol) was added to a solution ot product ot Step 1 (191 mg, 0.72 mmol) in THF dropwise at OX The solution was stirred at 0C for 2h, quenched with ice-H20, extracted with EtOAc, washed with H2O and bnne, 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 (CDC13) 5 7.5 (rn. 6H, ArH), 7 3 (t, 4H, ArH), 7.2 (t, 4H, ArH), 4.35 fs, 1H), 2.8 (d, 2H). 2 4 (m. 5H), 2.2 (td, 2H). 1.75 (d, 2H); MS (C1) 358 (M+1): Elemental analysis for C25H27NO 1.2 H20. calcd: C 79.2, H 7.82, N 3.59; observed: C 73.90, H 8.02, N 3.85. Example 3 Ul OH Add n-BuLi (2.5 M, 0.38 ml. 0.95 mmol) to a solution of 3-bromo-thiophene (0.15g, 0.95 mmol) in Et20 dropwise at -70°C and stir for 2h. Add a solution of the product of Step 1 of Example 2 (230 mg, 0.87 mmol) in Et20 (4 ml) to the reaction mixture, slowly warm to rt over a period of 3 h, quench with ice-cooled NH4C1 (aq), extract with Et20, wash with H2O and brine, dry, and concentrate. Chromatograph the residue (95:5 hexane/EtOAc) to give the title compound (90 mg). 1H NMR (CDC13) 5 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 (C1) 350 (M+1); Elemental analysis for C22H22NOS.LI HC1.0.9 H20: calcd: C 65.11, H 6.43, N 3.54, S 7.8, C1 9.61; observed: C 65.27, H 6.54, N 3.45, alkylated using the procedure of Example 1, Step 1, to obtain the desired product (1.69g, 90%). 1H NMR (CDC13): 5 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 Stepl (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 HC1 and concentrated. The residue was extracted with CH2C12, dried (MgS04) and evaporated. Column chromatography on the residue (4:1 hexane:EtOAc) produced desired primary alcohol. 1H NMR (CDC13): 5 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). Sjep_3: The product of Step 2 was treated with NaH in DMF at 0DC for . 0.5h. CH3I was added and reaction was warmed up to rt. After stirring overnight, the reaction mixture was poured on ice, extracted with Et20, dried (MgSCU) and evaporated. Column chromatography on the residue produced the title compound. 1H NMR (CDC13): 8 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). (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 20h. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and H20. The organic layer was washed with twice with water, then brine, and dried (MgS04), filtered and concentrated. Chromatography (SiC>2, 19:1 hexane/EtOAc) gave 6.0 g (76%) of the desired product. 1H NMR (CDC13): 5 2.21 (m, 4H), 2.49 (t, J=12.3Hz, 2H), 3.11 (d, J=12.5Hz, 2H), 4.46 (s, 1H),7.45(m. 15H). Step 2: A solution of the product (6.0 g, 17 mM) of Step 1 in Et20 (40 ml) was cooled to 0"C and treated with a 1M solution of of LAH (34.10 ml, 34 mM), dropwise, under N2, over 0.5 h. The reaction mixture was allowed to warm to rt and then refluxed for 4h. 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 Et20, and the filtrate was concentrated to yield 5.45 g (90%) of desired product. 1H NMR {CD3OD): 6 1.84 (m, 2H), 2.16 (m, 4H), 2.56 (m,2H), 2.68 (m,2H), 4.07 (s, 1H), 7.25 (m, 15H). Step 3: A solution of the product (0.2 g, 0.56 mM) of Step 2 in CH2C12 (3 ml) was treated with benzoyl chloride (0.078 ml, 0.673 mM) and pyridine (0.045g, 0.568 mM) at rt for 18 h under N2. The reaction mixture was concentrated, then partitioned between H2O and CH2C12- The organic layer was washed with water (2x) and brine, then dried (MgS04), filtered and concentrated. Chromatography (SiC>2, 3:1 hexane/EtOAc) gave 0.2 g (77%) of the desired product. 1H NMR (CD3OD): 5 2.13 (m, 6H), 2.66 (m, 4H), 3.50 (s, 2H), 4.07 (s, 1H). 7.11-7.65 (m, 20H). 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 0.25h. The reaction mixture was then refluxed for 5 h, then stirred at rt for 18h. The reaction mixture was cooled to 0CC 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 oft and rinsed with E12O, the filtrate was dried 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 reactfon mixture was concentrated in vacuo, basified to pH 8 with saturated NaHCC>3 and partitioned between EtOAc and H2O. The organic layer was washed twice with water, then brine, and dried (MgSCU), filtered and concentrated. Chromatography (neutral AI2O3, hexane, then 1:1 hexane:EtOAc) gave 11.95 g (80%) of the desired product. 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 giycol/C02 bath, under N2, is added glaC1al 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 18h. 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 CH2C12, and the organic layer was washed with water (2x), then brine, and dried (MgSCM), filtered and concentrated. ReC1-ystaiization with EtOAc/hexane (1:10) gave 22.35 g (68%) of desired compound. 1H NMR (CD3OD): 5 2.10 (m, 2H), 2.40 (m, 4H), 2.82 (d, J=11.50Hz, 2H), 3.57 (s, 2H), 7.20-7.43 (m, 10H), 8.05 (s, 1H). Step 3: The product of Step 2 (20 g, 67.9 mM) and 5% (w/w) concentrated HC1 (aq)/CH30H (350 ml) were stirred under N2 for 48 h. The mixture was concentrated to yield a foam which was suspended in Et20 and concentrated to remove excess HC1. The resultant solid was resuspended in Et20, collected by vacuum filtration, washed with EtO and dried under vacuum to give (23 g, 100%) of desired product. "H NMR (CD3OD) of di-HC1 salt: 6 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). Step 4: The product of Step 3 (24.10 g. 71 mM), CH2C12 (300 ml), (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 18hrs. The reaction mixture was partitioned between CH2C12 and H2O, and the aqueous layer was extracted with CH2C12. The combined organic layers were washed with water (2x), then brine, and dried (MgSCU), filtered and concentrated. The resulting solid was suspended in EtgO and sonicated, filtered and dried to produce the desired compound (21.98 g, 90%). H NMR {CD3OD): 8 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). 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 refiuxed under N2 for 8h. 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 fCD3OD): 5 1.10(bs,2H). 1.39 (s, 7H), 1.90 (m, 2H), 2.26 (m, 4H), 2.92 im. 4H), 7.17-7.41 (m, 5H). Step 6: The product of Step 5 (2.74 g, 9.91 mM), CH3CN (85 mi), Et3N (1.75 ml, 12.40 mM) and bromodiphenylmethane (2.70 g, 10.9 mM) were combined and stirred at rt under N2 for 18hrs. The mixture was concentrated and the resultant residue was partitioned between H2O and EtOAc. The EtOAc layer was washed with water (2x), brine, then dried (MgSO.4), filtered and concentrated. Chromatography (neutral AI2O3, hexane, then 4:1 hexane:EtOAc) gave 2.85 g (65%) of the desired product. 1H NMR (CD3OD): 5 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). Step 7: The product of Step 6 (4.6 g, 10 mM), 1,4-dioxane (38 ml) and 4 M HC1 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 Et20 and re-concentrated. The resultant solid was resuspended in EtjO, sonicated and the product was collected by vacuum filtration and dried to give 3.27 g (60% of the desired product. 1HNMR(CD3OD) of di-HC1 salt: S2.91(m. 8H), 5.34 (s, 1H), 7.37-7.77 (m, 15H). Step 8: To a suspension of the product of Step 7 (0.3 g, 0.722 mM) in CH2C12 (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 NaHCOafaq) and partitioned between Et20 and H2O. The organic layer was washed with H2O (2x), brine, dried (MgSO), filtered and concentrated. Chromatography (Si02. toluene, then 1:19 EtOAc: toluene) gave 0.158 g (50%) of the desired product. 1H NMR (CD3OD): 6 1.96 (m, 2HJ.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). Step 1: Alkylate a solution of 4-(2-oxo-1-benzimidazolyl)-piperidine in CH3CN using the procedure desC1-ibed in Step 1 of Example 1 to produce the desired compound. 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-H20, extract with EtOAc, wash with H2O and brine, dry (MgS04) and concentrate. Chromatograph the residue on silica (1:9 EtOAc/hexane) to give the title compound {2.35 g). Dissolve the title compound in Et20, add HC1 in Et.20 (8 ml, 1 M), stir for 1 h and filter to give the HC1 salt. 1H NMR {CDC13) 5 7.55 (m, 4H, ArH), 7.35 (m, 5H, phenyl)phen"ylmethanol (300 mg, 1.38 mmol) in CH2C12 at rt, stir at rt for 5 h and concentrate. Dissolve the residue in CH3CN, add K2CO3, 4-hydroxy-4-phenyipiperidine and Nal. Stir the solution at refiux overnight, filter and concentrate. Chromatograph the residue on silica (9:1 hexane/EtOAc) to give the title compound. 1H NMR (CDC13) 5 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, $tep 1: Alkylate a solution of 4-piperidone monohydrate hydrochloride (880 mg, 5 mmo!) in CH3CN with mandelonitrile (1 g, 7.51 mmoi) using the procedure desC1-ibed in Example 9. Chromatography of the residue on silica followed by reC1-ystallization (EtOAc) gives the desired compound (630 mg). 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 NH4C1 (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). !H NMR (CDC13) 5 7.76 (d. 1H).7.62{d, 1H). 7.55 (d, 1H),7.45(t, 1H), Step 1 Alkylate a solution of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (0.5g) in CH3CN using the procedure desC1-ibed in Step 1 of Example 1 to produce desired compound. Step 2 Alkylate the product from Step 1, 1-phenyl-8-(diphenylmethyl)-1,3,8-triazaspiro[4,5]decan-4-one (0.4 g) with CH3I using the procedure desC1-ibed in Step 2 of Example 1 to produce the title compound (0.25 g). 1H NMR (CDC13) 5 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). Using the procedures of Examples 1 to 11, employing the appropriate starting material, compounds shown in the following tables ASSAYS NoC1ceptin binding assay CHO cell membrane preparation expressing the ORL-1 receptor (2 mg) was incubated with varying concentrations of [125 l][Tyru]noC1ceptin (3-500 pM) in a buffer containing 50 mM HEPES (pH7.4), 10 mM NaC!, ImM MgCl2, 2.5 mM CaCl2. 1 mg/ml bovine serum albumin and 0.025% baC1traC1n. In a number of studies, assays were carried out in buffer 50 mM tris-HC1 (pH 7.4), 1 mg/ml bovine serum alumbin and 0.025% baC1traC1n. Samples were incubated for 1h 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. NonspeC1fic binding was determined in parallel by similar assays performed in the presence of 1 p.M noC1ceptin. All assay points were performed in duplicates of total and non-speC1fic binding. Calculations of Ki were made using methods well known in the art. 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 Using the procedures desC1-ibed in the European Journal of Pharmacology. 336 (1997), p. 233-242, the agonist activity of EXAMPLE 12 Cough Studies The effects of noC1ceptin agonist Compound A (0.3 - 10 mg/kg, p.o.) and Compound B (10 mg/kg, p.o.) were evaluated in capsaiC1n-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 wideiy used method to evaluate the activity of potential antitussive drugs. Overnight fasted male Hartley guinea pigs (350-450 g, Charles River, Bloomington, MA, USA) were placed in a 12" x 14" transparent chamber. The animals were exposed to aerosolized capsaiC1n (300 p.M, for 4 min) produced by a jet nebulizer (Puritan Bennett, Lenexa, KS, USA) to eliC1t the cough reflex. Each guinea pig was exposed only once to capsaiC1n. The number of coughs were detected by a miC1-ophone placed in the chamber and verified by a trained observer. The signal from the miC1-ophone was relayed to a polygraph which provided a record of the number of coughs. Either vehicle (methylceltuiose \ ml/kg, p.o.) or Compound A or Compound B were given 2 hours before aerosolized capsaiC1n. 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 Respiratory Measurements 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. Airfiow was measured as a differential pressure aC1-oss a wire mesh sC1-een 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 C1rcuit and a pulmonary function computer (Buxco Electronics, Sharon, CT., model XA). A head chamber was attached to the plethysmograph and air from a compressed gas source (21%C>2, balance N2) was C1rculated through the head chamber for the duration of study. All respiratory measurements were made while the guinea pigs breathed this C1rculating air. 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. 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 C1rculating 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. Data Analysis The data for tidal volume (Vj), respiratory rate (f) and minute volume (MV ~ Vj X 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 Figures 2A, 2B and 2C. Fig. 2A shows the change in Tidal Volume, Fig. 2B shows the change in Tidal Volume and Fig. 20 shows the change in frequency of breaths. ■ We have surprisingly discovered that noC1ceptin receptor ORL-1 agonists exhibit anti-tussive activity, making them useful for suppressing coughing in mammals. Non-limitative examples of noC1ceptin receptor ORL-1 agonists include the noC1ceptin receptor ORL-1 agonist compounds desC1-ibed herein. For mammals treated for coughing, the noC1ceptin 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, 13-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. Non limitative examples of antihistamines include: astemizole, azatadine, azelastine, aC1-ivastine, brompheniramine, certirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine (also known as SCH-34117), doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizoiastine, equitazine, mianserin, noberastine, meclizine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine. 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 desC1-ibed in U.S. Patent 5,352,707. Another useful assay utilizes rat brain membranes and is desC1-ibed by West et al., "Identification of Two-H3-Histamine Receptor Subtypes," Molecular Pharmacology, Vol. 38, pages 610-613 (1990). 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]propyI]thio]methyl]cyclo-propaneacetic aC1d and its sodium salt, desC1-ibed in EP 0 480 717; 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio) methylcyclopropaneacettc aC1d, and its sodium salt, desC1-ibed in WO 97/28797 and U.S. Patent 5,270,324; 1-(((1(R)-3(3-(2- {2,3-dichlorothJeno[3,2-b]pyridin-5-yl)-{E)-ethenyl)phenyl)-3-{2-(1-hydroxy-1-methylethyl)phenyl) propyl)thio) methyl)cyC1opropaneacetic aC1d, and its sodium salt, desC1-ibed in WO 97/28797 and U.S. Patent 5,472,964; pranfukast, N-[4-oxo-2-(1 H-tetrazol-5-yl)-4H-1 -benzopyran-8-yl]-p-(4-phenylbutoxy) benzamide) desC1-ibed in WO 97/28797 and EP 173,516; zafirlukast, (cyclopentyl-3-[2-methoxy-4-[(o-tolylsulfonyl) carbamoyl]benzyl]-1-methylindole-5-carbamate) desC1-ibed in WO 97/28797 and EP 199,543; and [2-[[2{4-ferf-butyl-2-thiazolyl}-5-benzofuranyl] oxymethyl]phenyi]acetic aC1d, desC1-ibed in U.S. Patent 5,296,495 and Japanese patent JP08325265 A. 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, IC1-D2318, and ABT 761. Non-limitative examples of B-adrenergic receptor agonists include: albuterol, bitolterol, isoetharine, mataproterenol, perbuterol, saimeterol, terbutaline, isoproterenol, ephedrine and epinephrine. A non-limitative example of a xanthine derivative is theophylline. Non-limitative examples of a-adrenergic receptor agonists include arylalkylamines, (e.g., phenylpropanolamine and pseudephedrine), imidazoles (e.g., naphazoiine, oxymetazoline, tetrahydrozoiine, and xylometazoline), and cycloalkylamines (e.g., propylhexedrine). A non-limitative example of a mast cell stabilizer is nedoC1-omil sodium. Non-limitative examples of anti-tussive agents include codeine, dextromethorphan, benzonatate, chiophedianol, and noscapine. A non-1 imitative example of an expectorant is guaifenesin. Non-limitative examples of NK,, NK2 and NK3 tachykinin receptor antagonists include CP-99,994 and SR 48968. Non-limitatve examples of GABAB agonists include baclofen and 3-aminopropyl-phosphinic aC1d. For preparing pharmaceutical compositions from the compounds desC1-ibed by this invention, inert, pharmaceutical 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. For preparing suppositories, a low melting wax such as a mixture of fatty aC1d 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. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid form preparations may also include solutions for intranasal. administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutical acceptable carrier, such as an inert compressed gas. 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. The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of C1-eams, 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. Preferably the compound is administered orally. 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. 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. 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 inC1-eased by small inC1-ements until the optimum effect under the C1rcumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. The amount and frequency of administration of the compounds of the invention and the pharmaceutical acceptable salts thereof will be regulated according to the judgment of the attending cliniC1an 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. For treating cough, the amount of noC1ceptin 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 noC1ceptin 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, B-adrenergic receptor agonists, xanthine derivatives, a-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NKi, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists! The noC1ceptin 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. 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 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 sC1-een (e.g., 1/4", 0.63 cm} if necessary. Dry the damp granules. SC1-een 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 Method of Manufacture 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. While the present invention has been desC1-ibed in conjunction with the speC1fic 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 fail within the spirit and scope of the present invention. WE CLAIM: or a pharmaceutically acceptable salt or solvate thereof, wherein: the dotted line represents an optional double bond; X1 is R5-(C1-C12)alkyl, R6-(C3-C12)cycloalkyl, R?-aryl, R8-heteroaryl or R10-(C3-C7)heterocycloalkyl; X2 is -CHO. -CK -NHC(-NR26)NHR26, -CH(=NOR26), -NHOR26, R7. aryl, R7-aryl(Cl-C6)alkyl. R7-aryl(Cl-C6)alkenyl, R7-aryl(C1-C6)-aIkynyl, - and x2 is hydrogen; or Xl and x2 together form a spiro group of the formula R1,R2.R3andR4 are independently selected from the group consisting of hydrogen and (Cl-C6)alkyl, or (R1 and R4) or (R2 and R3) or (R1 andR3)or(R2 and R ) together can form an alkylene bridge of 1 to 3 carbon atoms; R5 is 1 to 3 substituents independently selected from the group consisting of H. R7-aryl, R6-(C3-C12)cycloalkyl, R8-heteroaryl, R1()-(C3-C7)heterocycloa!kyl, -NR19R20, _QR13 and -S(O)0-2R13; R6 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, R7-aryl, -NR19R20, -OR13 and -SR13; R7 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl. R25-aryl, (C3-C12)cycloalkyl, -CN, -CF3, -OR19, -(C1-C6)aJky]-ORl9 -OCF3, -NR19R20, -(C]-C6)alkyl-NRl9R20i . wherein f is 0 to 6; or R7 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring; R8 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R25-aryL (C3-C12)cycloalkyl, -CN, -CF3, - OR19, -(C1-C6)alkyl-OR19, -OCF3, -NR19R20% -(C1-C6)alkyl-NRl9R205 . NHS02R19. -S02N(R26)2, HN02. -CONR19R20, -NR20cORl9, -COR*9, . OCORl9, -OCO2R19 and -COOR*9; R9 is hydrogen, (C1-C6)alkyl> halo, -ORI9, -NR"9R205 -NHCN, -SR*9 or -(Cl-C6)alkyl-NRl9R20; Rl° is H, (C1-C6)alkyl. -ORI9, -(Cl-C6)alkyl-OR"9 -NR19R20 or _(Cl_ C6)alkyl-NR19R20; R is independently selected from the group consisting of H, R5-(Cl-C6)alkyl, R6-(C3-Cl2)cycloalkyl, -(C1-C6)alkyl(C3-C12)cycloalkyl, -(Cl-C6)alkyl-ORl9, -(C1-C6)alkyl-NR19R20 and wherein q and a are as defined above; Rl2 is H, (C1-C6)alkyl. halo, -NO2, -CF3, -OCF3, -OR19, -(C1-C6)alkyl-ORI9, -NRl9R20 or -(C1-C6)alkyl-NRl9R20; Rl3 is H, (C1-C6)alkyl, R7-aryl, -(C1-C6)alkyl-ORl9 -(C1-C6)alkyl-NRl9R20or-(C1-C6)alkyl-SR19; R"4 and R1^ are independently selected from the group consisting of H, R5-(C1-C6)alkyl, R7-aryl and wherein q is 1 to 3 and a is 1 or 2: R"6 and R*7 are independently selected from the group consisting of hydrogen, R5-(C 1-C6)alkyl, R7-aryl, (C3-C12)cycloalkyl, R8-heteroaryl, R8-heteroaryl(C1-C6)alkyl, -C(0)R28, -(C1-C6)alkyl(C3-C7)-heterocycloalkyl, -(C1-C6)alkyl-OR19 and -(C|-C6)alkyl-SRl9; Rl9 and R20 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C3-Cl2)cycloalkyl, aryl and aryl(C1-C6)alkyl; R21 and R22 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl. (C3-C12)cycloalkyl, (C3-C12)cycloalkyl(C1-C6)alkyl, (C3-C7)heterocycloalkyl, -(Cl-C6)alkyl(C3-C7)-heterocycloalkyl, R7-aryl, R7- and 7} and Z are each R^-phenyl, R is not -OC1-^aryl and at least one R is ortho- halo or ortho-C1-C6 alkyl; 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 hctero(C rC 7)cycloalkyl rings; and wherein R -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; 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 suffiC1ent 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; and 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 -0-, -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, or a pharmaceutically acceptable salt or solvate thereof, wherein: the dotted line represents an optional double bond; X1 is R5-(C,-C|2) alkyl, R6- (C3-C12)cycloalkyl, R 7-aryl, R8-heteroaryl or R,0-(C1-C7) heterocycloalkvl; X2 is -CHO, -CK - NHC orX"is m is I or 2; n is 1, 2 or 3, provided that when n is 1, one of R l6 and R17 is -C(0)R28; p is 0 or 1; Q is -CH 2; -0-, -S-. -SO-, -SO2- or - NR l7-; R1, R2, R3 and R4 arc 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 R ) together can form an alkylene bridge of 1 to 3 carbon atoms; R5 is 1 to 3 substitui"nts independently selected from the group consisting of H, R 7-aryl. R6-(C ,- C12)cycloalkyl, R8-heteroaryl, R l0-(C 3-C7) heterocycloalkyl, -NR19 R20. - OR13 and -S(O)0.2R "3; R6 is 1 to 3 substitucnts independently selected from the group consisting of H; (C rC6)alkyl, R7- aryl. -NR,9Rio, -OR13 and -SR13; R7 is 1 to 3 substitucnts independently selected from the group consisting wherein f is 0 to 6; or R subiitituents on adjacent ring carbon atoms may together form a methyienedioxy or ethylenedioxy ring; RK is 1 to 3 substituents independently selected from the group consisting wherein q is 1 to 3 and a is 1 o 2; RIC and R17 are independently selected from the group consisting of hydrogen, R5-(C,-C 6) alky], R7- aryl, (C3-C12) cycloalky], R Mieteroaryl, R8-heleroaryl(C rC6)alkyl, -C(0)R28, -(C1-C 6)alkyl(C3-C 7)-heterocycloalkyI, -(C r C6)alkyl-OR19and-(C1-C6)alkyl-SR19; R and R are independently selected from the group consisting of hydrogen. (C,-C6)alkyl, (C 3-C >)cycloalkyl, aryl and aryl(C ,-C6) alkyl; R" and R22 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C 3-C12)cycloalkyl, (C3-C 12) cycloalkyl(C rC6)alkyl, (C3-C7) hcterocycloalkyl, -(CL-C6)alkyl(C 3-C 7)- heterocycloalkyl, R7-aryl, R 7-aryl(C ,-C6)a]kyl, R 8-heteroaiyl(C,-C ,2)alkyl, - (C,-C 6)alkyl-OR l9, -(C ,-C6)alk>l-NR19R?0, -(C1- C(l)alkyl-SR ,9, -(d -C6)alkvl- NR,8-(C rC6)alkyl-0-(C1-C fi)alkyl and -(C1-C 6)alkyl-NR1K-(C ,-C 6)alkyl-NRlg-(C1- C6) alkyl; R1S is hydrogen or (C,-C1-,J alkyl; wherein Z1 and Z2 are each R - aryl wherein R7 is independently ortho-(C1-C 6) alkyl or ortho-halo; Z3 is hydrogen or (C|-C6)alkyl; 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-C 7) cycloalkyl, heteroaryl or hetero(C3-C 7) 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; 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 suffiC1ent 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 R groups; and 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 -0-, -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-tetrahyi.rothienyl, 1-, 2-, 3- or 4-piperidinyl. 2- or 3-pyrrolidinyl, 1-, 2- or 3-piperi7; ivl, 2- or 4-dioxanyl, morpholinyl, wherC1" Rl7 is as defined above and t is 0, 1 or 2. 3. \ compound of claim 1 wherein z" and 7?- are each R"7-phenyl. 4. A compound of claim 1 wherein R7 is selected from the group consisting of (C1-C6)alkyl and halo. 5. A compound of claim 1 wherein X* is R7-aryl and and X^ is OH or -NC(0)R28. 6. A compound of claim 1 wherein Xl is 7. A compound of claim 6 wherein RJ2 is hydrogen and R11 is (C1-C6)alkyl, -(C1-C6) alkyl(C3-C12)cycloalkyl. -(C|-C6)alkyl-OR19 or -(Cl-C6)alkyl- NR19R20. 8. A compound of claim 1 wherein X" and X^ together form the spirocyclic group 9. A compound of claim 8 wherein m is 1, R"7 is phenyl and Ri6 is -(C\- C6)alkyl-OR19 or -(C1-C6)alkyl-NR19R20- 10. A compound selected from the group consisting of 11. A pharmaceutical composition comprising a therapeutically effective amount of compound of claim 1 or claim 2 in combination with a pharmaceutically acceptable carrier. 12. A pharmaceutical composition comprising: a therapeutically effective amount of a noC1ceptin receptor ORL-1 agonist of claim 1 or claim 2; a therapeutically effective amount of a second agent selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, B-adrenergic receptor agonists, xanthine derivatives, ot-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NKl, NK2 and NK3 tachykinin receptor antagonists, and GABAR agonists; and a pharmaceutically acceptable carrier.

Documents:

in-pct-2001-0085-che abstract duplicate.pdf

in-pct-2001-0085-che abstract.pdf

in-pct-2001-0085-che assignment.pdf

in-pct-2001-0085-che claims duplicate.pdf

in-pct-2001-0085-che claims.pdf

in-pct-2001-0085-che correspondence others.pdf

in-pct-2001-0085-che correspondence po.pdf

in-pct-2001-0085-che description (complete) duplicate.pdf

in-pct-2001-0085-che description (complete).pdf

in-pct-2001-0085-che drawings duplicate.pdf

in-pct-2001-0085-che drawings.pdf

in-pct-2001-0085-che form-1.pdf

in-pct-2001-0085-che form-26.pdf

in-pct-2001-0085-che form-3.pdf

in-pct-2001-0085-che form-4.pdf

in-pct-2001-0085-che form-5.pdf

in-pct-2001-0085-che pct.pdf

in-pct-2001-0085-che petition.pdf