MXPA01001025A - High affinity ligands for nociceptin receptor orl-1 - Google Patents

Abstract

Compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein:the dotted line represents an optional double bond;X1 is optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl;X2 is -CHO, -CN, optionally substituted amino, alkyl, or aryl;or X1 is optionally substituted benzofused heterocyclyl and X2 is hydrogen;or X1 and X2 together form an optionally benzofused spiro heterocyclyl group;R1, R2, R3 and R4 are independently H and 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;Z1 is optionally substitutedalkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, or -CO2(alkyl or substituted amino) or CN;Z2 is H or Z1;Z3 is H or alkyl;or Z1, Z2 and Z3, together with the carbon to which they are attached, form bicyclic saturated or unsaturated rings;pharmaceutical 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.

Description

HIGH-AFFINITY LIGANDS FOR NOCICEPTINE RECEIVER ORL-1 BACKGROUND OF THE INVENTION The nociceptin receptor ORL-1 has been shown to be involved with pain modulation in animal models. ORL-1 (nociceptin receptor) was discovered as an "orphan opioid receptor", ie a receptor whose ligand was unknown. The nociceptin receptor is a G-protein coupled receptor. Although it is closely related in structure to the three classical opioid receptors, ie the targets for traditional opioid analgesics, it is not activated by endogenous opioids. Similarly, endogenous opioids fail to activate the nociceptin receptor. As with classical opioid receptors, the nociceptin receptor has a wide distribution in the central nervous system. At the end of 1995, nociceptin was discovered and proved to be an endogenous peptide ligand that activates the nociceptin receptor. The data included in the initial publications suggested that nociceptin and its receptor were part of a newly discovered pathway involved in the perception of painful stimuli. Subsequent work from a number of laboratories showed that nociceptin, when administered intraspinally to rodents, is an analgesic. The efficacy of nociceptin is similar to that of endogenous opioid peptides. Recent data have shown that nociceptin acts as an anxiolytic when administered directly to the brain of rodents. When tested in models of anxiety in conventional animals, the efficacy of nociceptin was similar to that observed with classic benzodiazepine anxiolytics. These data suggest that a small molecule agonist of the nociceptin receptor could have significant analgesic or anxiolytic activity. Recent additional data (Rizzi, et al., Life Sci., 64 (1999), p 157-163) demonstrated that the activation of nociceptin receptors in isolated guinea pig bronchi inhibits non-adrenergic, non-cholinergic takinergic contraction, which indicates that nociceptin receptor agonists may be useful for the treatment of asthma. It was also reported (Ciccocioppo et al., Phvschpharmacoloqy, 141 (1999), p.220-224) that nociceptin reduces the gratification properties of ethanol in rats that prefer the alcohol msP which suggests that the intervention of nociceptin could be useful in the treatment of alcohol abuse. In European patent EP 856,514, 8,8-substituted derivatives 1, 3,8-triazespiro [4,5] decan-4-one are described as FQ orphanin agonists and / or antagonists (ie nociceptin), which are useful in the treatment of various disorders, including depression; 2-oxoimidazole derivatives described in WO98 / 54168 were described as possessing similar utility. ______! ___________, Previously, benzimidazolylpiperidines were described in U.S. Patent No. 3,318,900 as having analgesic activity. Potent analgesic agents such as traditional opioids, such as morphine, are significant side effects. Clinically relevant side effects include tolerance, physical dependence, respiratory depression, and a decrease in gastrointestinal motility. For many patients, particularly for those undergoing chronic opioid therapy, ie patients with cancer, these side effects limit the dose of opioid that can be administered. Clinical data suggest that more than a third of patients with cancer who have pain are very weakly controlled by the present agents. The data obtained with nociceptin suggest the potential of its advantages with respect to opioids. When administered chronically to rodents, nociceptin in contrast to morphine shows no addiction. Additionally, chronic treatment with morphine does not lead to a "cross-tolerance" with nociceptin, which suggests that these agents act in different ways. In view of the current interest for pain relief, a contribution to the technique that would be appreciated would be constituted by additional compounds useful for modifying the effect of nociceptin, a natural ligand of ORL-1 and which is therefore useful for manipulating the pain and anxiety. Said contribution is provided by the present invention.

BRIEF DESCRIPTION OF THE INVENTION The compounds of the present invention are represented by the formula I or by a pharmaceutically acceptable salt or solvate thereof, wherein: the dotted line represents an optional double bond, X1 is R5- (C? -Ci2) alkyl, R6- (C3-C? 2) cycloalkyl, R7-aryl , R8-heteroaryl or R10- (C3-C7) heterocycloalkyl, X2 is -CHO, -CN, NHC (= NR26) NHR26, -CH (= NOR26), -NHOR26, R7-aryl, R7-aryl (C? -C6) alkyl, R7-aryl (CrC6) alkenyl, R7-aplo (d-C6) alkynyl, - (CH2) vOR13, - (CH2) vCOOR27, - (CH2 ) vCONR14R15, - (CH2) VNR21R22 0 -. 0 - (CH2) vNHC (O) R21, where v is zero, 1, 2 or 3 and where q is 1 to 3 and a is 1 or 2; or X1 is and X2 is hydrogen; or X1 and X2 together form a spiro group that has the formula m is 1 or 2; n is 1, 2 or 3, with the proviso that when n is 1, one of R16 and R17 is -C (O) R28; p is 0 or 1, Q is -CH2-, -O-, -S-, -SO-, -SO-2 or -NR17-; R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen and (CrC6) alk, or (R1 and R4) or (R2 and R3) or (R and R3) or (R2 and R4) together can forming an alkylene bridge of 1 to 3 carbon atoms; R5 represents from 1 to 3 substituents independently selected from the group consisting of H, R7-aryl, R6- (C3-C? 2) cycloalkyl, R8-heteroaryl, R10- (C3-C7) heterocycloalkyl, -NR19R20, -OR13 and -S (O) o- R13; R6 is 1 to 3 substituents independently selected from the group consisting of H, (d-Ce.alkyl, R7-aryl, -NR19R20, -OR13-SR13; • - * "-" - »---- - ~ ^ R7 represents from 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (CrCßJalkyl, R25-aryl, (C3-C12) cycloalkyl, - CN, -CF3, -OR19, - (C6) Alkyl-OR19, -OCF3, -NR19R20, - (C6) Alkyl-NR19-R20, -NHS02R19, -S02N (R26) 2, -S02R19 , -SOR19, -SR19, -N02, -CONR19R20, -NR20COR19, -COR19, -COCF3, -OCOR19, -OC02R19, -COOR19, - (C? -C6) alkyl-NHCOOC (CH3) 3, - (C C6) alkyl-NHCOCF3, - (C? -C6) alkyl-NHS? 2- (C? -C6) alkyl, - (C.-C6) alkyl-NHCONH- (CrC? J-alkyl or - (CH2) f - NN-R19, where f is 0 to 6, or the substituents R7 on the adjacent carbon atoms of the ring may together form a methylenedioxy or ethylenedioxy ring; R8 represents from 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (Ci-CβJalkyl, Rianyl, (C3-C12) cycloalkyl, -CN, CF3, -OR19, - (CrC6) alkyl-OR19, -OCF3, -NR19R20, - (C? -C6) alkyl-NR19R20, -NHS02R19, -S02N (R26) 2> -N02, -CONR19R20, -NR20COR19, -COR19, -OCOR19, -OC02R19, -COOR19; R9 is hydrogen, (C -, - C6) alkyl, halo, -OR19, -NR19R20, -NHCN, -SR19 or - (CrC6) alkyl-NR19R20; R10 is H, (C? -C6) alkyl, -OR19, - (C? -C6) alkyl-OR19, -NR19R20, or (C6) alkyl-NR19R20; R11 is independently selected from the group consisting of H, R5- (CrC6) alkyl, R6- (C3-C-? 2) cycloalkyl, - (CrC6) alkyl (C3-C12) cycloalkyl, - (CrC6) alkyl-OR19, - (C C6) alkyl-NR19R20 and where - (CH2) q- N? 'a q and a are as defined above; _____________ R12 is H, (CrCß) alkyl, halo, -N02, -CF3, -OCF3, -OR19, (d-C6) alkyl-OR19, -NR19R20, or (d-C6.alkyl-NR19R20; R13 is H, (CrC6) alkyl, R7-aryl, - (CrC6) alkyl-OR19, - (d-C6) alkyl-NR19R20, - (d-C6) alkyl-SR19, or aryl (C6) alkyl; R4 and R15 are independently selected from the group which consists of H, R 5 - (C C 6) alkyl, R 7 -aryl and where q and a are as defined above; R16 and R17 are independently selected from the group consisting of hydrogen, R5- (C? -C6) alkyl, R7-aryl, (C3-C? 2) cycloalkyl, R8-heteroaryl, R8-heteroaryl (C? -C6) alkyl , -C (0) R28, - (d-C6) alkyl (C3-C7) -heterocycloalkyl, - (C? -C6) alkyl-OR19 and (C6) alkyl-SR19; R19 and R20 are independently selected from the group consisting of hydrogen, (C? -C6) alkyl, (C3-C? 2) cycloalkyl, aryl and aryl (d-C6) alkyl; R21 and R22 are independently selected from the group consisting of hydrogen, (C? -C6) alkyl, (C3-C? 2) cycloalkyl, (C3-C? 2) cycloalkyl- (C? -C6) alkyl, - (C3) -C7) heterocycloalkyl, (C6C) alkyl- (C3C7) -heterocycloalkyl, R7-aryl, R7-aryl- (CrC6) alkyl, R8-heteroaryl (CC? 2) alkyl, - (d-C6) alkyl-OR19; - (C C6) alkyl-NR19R20, - (d-C6) alkyl-SR19, alkyl ________ i_ | ___ - (C? -C6) alkyl-NR1β- (CrC6) alkyl-0- (C? -C6) alkyl and - (C? -C6) alkyl-NR18- (C? -C6) alkyl- NR18- (CrC6) alkyl; R18 is hydrogen or alkyl (d-C6), Z1 is R5- (d-C12) alkyl, R7-aryl, R8-heteroaryl, R6- (C3-C12) cycloalkyl, R10- (C3-C7) heterocycloalkyl, -C02 (d-C6) alkyl, CN or -C (0) NR19R20; Z2 is hydrogen or Z1; Z3 is hydrogen or (C? -C6) alkyl; or Z1, Z2 and Z3, together with the carbon atom to which they are attached, forms the group where r is 0 to 3; w and u are each 0-3, with the proviso 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 ring R7-phenyl or R8-heteroaryl: R23 represents 1 to 3 substituents independently selected from the group consisting of H, (d-C6) alkyl, OR19, - (d-Cd) .alkyl-OR19, -NR19R20 and - (CrC6) alkyl-NR19R20; R24 represents 1 to 3 substituents independently selected from the group consisting of R23, -CF3> -OCF3, N02 or halo, or the substituents R24 on the adjacent carbon of the ring can jointly form a methylenedioxy or ethylenedioxy ring; R25 represents 1 to 3 substituents independently selected from the group consisting of H, (CrC6) alkyl, (d-CßJalkoxy and halo; R26 is independently selected from the group consisting of H (C C6) alkyl and R25-C6H4-CH2-; R27 is H, (d-C6) alkyl, R7-aryl (C6-C6) alkyl, or (C3-C2) cycloalkyl; R28 is (CrC @ Jalkyl, - (CrC6) (C3-C2) cycloalkyl, R7-aryl, R7-aryl- (d-C6) alkyl, R8-heteroaryl, - (d-C6) alkyl-NR19R20, - ( C C6) alkyl-OR19, or (C C6) alkyl -SR19, X1 or X2 and Z1 is R7-phenyl, Z2 is not hydrogen or (d-C3) alkyl; with the proviso that when Z1, Z2 and Z3 together with the carbon to which they are attached, form and X1 and X2 together are , R11 is not H, (d-C6) alkyl, (C1-C6) alkoxy (CrC6) alkyl or (CrCßJhydroxyalkyl, with the proviso that when R2 and R4 form an alkylene bridge, Z1 and Z2 and Z3 together with the carbon to which they are attached, are not C12) cycloalkyl, Z2 is not H. The preferred compounds of the invention are those in which Z1 and Z2 are each R7-aryl, particularly R7-phenyl. Preferred R7 substituents are (CrC6) alkyl and halo, with ortho substitution being the most preferred. The compounds in which R1, R2, R3 and R4 are each hydrogen are the preferred compounds as well as the compounds in which R1 and R3 are each hydrogen and R3 and R4 are an alkylene bridge of 2 or 3 carbons.

It is preferred that the compounds in which X1 is R7-aryl, for example R7-phenyl, and X2 is OH (ie, X2 is - (CH2) vOR13, where v is 0 and R13 is H) or -NC compounds ( 0) where R12 is hydrogen and R11 is (CrC6) alkyl, - (CrC6) (C3-C? 2) cycloalkyl, - (d-C6) alkyl-OR19 or - (d-C6) alkyl-NR19R20: and compounds in which X1 and X2 together form the spirocyclic group , where m is 1, R17 is phenyl and R11 is - (d-C6) alkyl-OR19 or - (C6C6) alkyl-NR> 1? 99_R_ 2¿, or _ a "? Lq" .u.; I? Lo / (C-, - r C> 6 \) -. N / A In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. The compounds of the present invention are agonists and / or antagonists of the ORL-1 receptor and therefore, in another aspect, the invention relates to a method for treating pain, anxiety, cough, asthma, alcohol abuse or depression, which comprises 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 for treating cough, which comprises administering to a mammal in need of said treatment (a) an effective amount of a nociceptin receptor ORL-1 agonist; and (b) an effective amount of a second agent to treat cough, allergy or -n- -i-iM-i-a-M-? idiiii asthma symptoms selected from the group consisting of: antihistamines, 5-hypoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, ß-adrenergic receptor agonists, xanthine derivatives, agonists -adrenergic receptors, stabilizers of the mastoid cell, anti-tusivo, expectorants, tachykinin receptor antagonist NK-i, NK2 and NK3 and GABAB agonists. In another aspect, the invention relates to a pharmaceutical composition comprising an ORL-1 nociceptin receptor agonist and a second agent selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, agonists ß-adrenergic receptors, xanthine derivatives, α-adrenergic receptor agonists, mastoid cell stabilizers, antitussives, expectorants, tachykinin receptor antagonists NK-i, NK2 and NK3 and GABAB agonists. In other words, the invention relates to the use of compounds of claim 1 for the treatment of pain, anxiety, cough, asthma, alcohol abuse or depression, and the use of an ORL-1 nociceptin receptor agonist, alone or in combination with a second agent for the treatment of cough, allergy or asthma symptoms. In another aspect, the present invention relates to a new compound that is not included in the structure of formula (I), wherein said compound is: BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the effect in guinea pigs of compounds A and B (see example 12), as compared to baclofen in cough induced by capsaicin. Figures 2A and 2B show the changes in the volume of the flow after the administration of compound A or baclofen and figure 2C shows the changes in respiration frequency after the administration of compound A or baclofen.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms are used as defined below unless otherwise indicated: 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; Bu is butyl, Et is ethyl; It is methyl; and Ph is phenyl; 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, isopropyl, 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, for example vinyl, propenyl or butenyl; alkynyl, represents an alkyl chain of 2 to 6 carbon atoms comprising a triple bond in the chain, for example ethynyl or propynyl; alkoxy represents an alkyl portion, covalently linked 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 which contains from 6 to 15 carbon atoms and which has at least one aromatic ring (for example, aryl is phenyl), wherein said aryl group can be optionally fused with aryl, (C3-C7) cycloalkyl, heteroaryl or hetero rings ( C3-C7) cycloalkyl; and wherein R7-aryl means that any of the substitutable carbon and nitrogen atoms available in said aryl group and / or said fused rings are optionally and independently substituted, and wherein the aryl ring is substituted with 1-3 R7 groups. Examples of aryl groups are phenyl, naphthyl or anthryl; Arylalkyl represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl portion have been substituted with one to three aryl groups, where aryl is as defined above, aryloxy represents an aryl group such , as defined above, wherein said aryl group is covalently linked to an adjacent structural element through an oxygen atom, for example phenoxy; cycloalkyl represents saturated carbocyclic rings of 3 to 12 carbon atoms, preferably 3 to 7 carbon atoms, where R 6 -cycloalkyl means that any of the substitutable carbon atoms available in said cycloalkyl group is optionally and independently substituted and where the cycloalkyl ring is substituted with 1-3 R6 groups, cycloalkylalkyl represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl portion have been substituted with one to three cycloalkyl groups, where cycloalkyl is as defined higher; halo represents fluorine, chlorine, bromine and iodine; heteroaryl represents cyclic groups, having one to three heteroatoms selected from O, S and N, interrupting said ^^^ heteroatoms a carbocyclic ring structure and having a sufficient amount of delocalized pi electrons to provide aromatic character, with aromatic heterocyclic groups containing from 5 to 14 carbon atoms, wherein said heteroaryl group may be optionally fused with one or more rings aryl, cycloalkyl, heteroaryl or heterocycloalkyl; and wherein any of the nitrogen or carbon atoms available in said heteroaryl group and / or said fused rings may be optionally and independently substituted and wherein the heteroaryl ring may be substituted with 1-3 R8 groups; Representative heteroaryl groups may include, for example, furanyl, thienyl, imidazolyl, pyrimidinyl, triazolyl, 2-, 3- or 4-pyridyl or 2-, 3- or 4- pyridyl N-oxide where the pyridyl N-oxide It can be represented as: heteroarylalkyl represents an alkyl group such as defined above in which one or more hydrogen atoms have been replaced by one or more heteroaryl groups, such as those defined above; heterocycloalkyl represents a saturated ring containing from 3-7 carbon atoms, preferably from 4 to 6 carbon atoms, interrupted by 1 to 3 heteroatoms selected from -O-, -S- and NR21, where R > 21 is as defined above and where optionally, said ring may contain one or two unsaturated bonds that impart no aromatic character to the ring; and wherein any of the substitutable carbon atoms available in the ring may be substituted and wherein the heterocycloalkyl ring may be substituted with 1-3 R10 groups; Representative heterocycloalkyl groups include 2- or 3-tetrahydro-tertiary, 2- or 3-tetrahydrothienyl, 1-, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 1-, 2-, or 3-piperizinyl, 2- or 4-dioxanyl, morpholinyl, ("° ') tl d -.o-n_d-.e- R r-, 1177 is as defined above and t is 0, 1 or 2 When the optional double bond is present in the piperidinyl ring of the formula 1, one of X1 and X2 form the bond with the carbon in position 3 and the remaining X1 or X2 is not hydrogen.When X1 and X2 form a spiro group as defined above, the wavy lines in the structures shown in the definition, they indicate the points of adhesion to the carbon in position 4 of the piperidinyl ring, that is to say, the compounds of the following formulas are formed: Some of the compounds of the invention can exist in different stereoisomeric forms (for example, enantiomers, diastereoisomers and atropisomers) The invention contemplates all said stereoisomers both in pure form and in racemic mixtures. the compounds are acidic in nature, for example those compounds which possess a carboxyl or phenolic hydroxyl group These compounds can form pharmaceutically acceptable salts Examples of said salts may include sodium, potassium, calcium, aluminum, gold and silver salts. the salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, N-methylglucamine and the like are contemplated Some basic compounds also form pharmaceutically acceptable salts, for example, acid addition salts, for example the pyrido-nitrogen atoms can form salts with strong acids, while Compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of acids suitable for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and other mineral and carboxylic acids which are well known in the field. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in a conventional manner. The free base forms can be regenerated by treating the salt with an appropriate diluted 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 terms of some physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for the purposes of the invention. All such base salts and acids are comprised within the pharmaceutically acceptable salts within the scope of the invention and all acidic and basic salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention. The compounds of the invention can be prepared by known methods from starting materials known in the art or prepared by methods known in the art. Examples of general procedures and specific preparatory examples are those given below. Typically, X1, X2-substituted piperidines are alkylated with halides substituted with Z1, Z2, Z3 in the presence of excess bases such as K2C03 and Et3N, in solvents such as DMF, THF or CH3CN, at room temperature or at elevated temperatures. X1, X2"-substituted piperidines are commercially available or prepared by known procedures, for example 4-hydroxy-4-phenyl-piperidine can be converted to 4-tBoc-amino-4-phenylpiperidine in accordance ^^ * 5 ^^ > gS j? j ^ á ^^ sV with the following reaction scheme, where Bn is benzyl, Ph is phenyl and tBoc is t-butoxycarbonyl: The commercially available 4-phenyl-4-piperidinol is protected with a benzyl group and the resulting intermediate is then treated with Me 3 SiCN. The resulting amide is hydrolyzed with aqueous HCl in CH 3 OH 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. The 4- (protected) amino-piperidine can then be reacted with a Z1, Z2, Z3-halomethane and the protecting group can be removed. The amine (ie X2 is -NH2) can be subjected to several conventional conversions to obtain the amine derivatives. For example, the amine of formula 1 can react with R22-carboxaldehyde in the presence of a mild reducing agent such as Na (OAc) 3BH or with a compound of formula R22-L, where L is a leaving group such as Cl or Br, in the presence of a base such as Et3NI. ._ »- --'--- v An alternative method for the preparation of compounds of formula 1 in which X1 is R7-aryl, and X2 is OH, involves alkylating a 4-piperidone hydrochloride with a Z1, Z2, Z3-halomethane and then reacting the ketone with an appropriately substituted R7-phenylmagnesium bromide or with a compound of formula X1-L1, wherein L1 is Br or I, and n-butyllithium. The X1, X2-substituted compounds of formula I can be converted to other compounds of formula I by carrying out reactions that are well known in the art on substituents X1 and / or X2. For example, the carboxaldehyde substituted pyperidine (ie X2 is -CHO) can be converted to a substituted piperidine in which X2 is R13-0-CH2, as shown in the following procedure for a compound of formula I in which X1 is phenyl, Z1 and Z2 are each phenyl, and R1, R2, R3 and R4 and Z3 are H: A piperidine substituted with cyano (ie, X2 is -CN) can be converted to a substituted piperidine in which X is R 21 Ro22? Ns -CH2-o X is R > 28 C (0) NH-CH2-, as shown in the following procedure for tia____tf___________________________i obtain a compound of formula I in which X1 is phenyl, R21, R1, R2, R3, and R4, and Z3 are H and L is a leaving group such as Cl or Br: The compounds of formula 1 in which X1 is a benzofused nitrogen containing heterocycle having a substituent R11 other than hydrogen, are prepared by the reaction of the corresponding compounds in which R11 is hydrogen with a compound having the formula R11L (R11 it is not H and L is as defined above). * - ** •• '- * - * - • •' • ..-_-_. . ..- ^ Alternatively, the piperidine starting materials substituted with X1, X2 can be converted to other piperidines substituted with X1, X2 by similar procedures before reacting with the halomethane substituted with Z1, Z2, Z3. For the compounds of the formula I in which R1, R2, R3 and R4 variably form alkylene bridges, the commercially available N-protected 4-piperiones are treated with phenylthio and the resulting intermediate is deprotected to produce the desired compounds, for example where Pr is a protecting group N, Ph is phenyl z is 1-2. The derivatives of Z1, Z2, Z3-halomethyl in which Z1 and Z2 are R7-phenyl are available commercially or can be prepared using the procedure shown in the following reaction scheme.

Similar procedures, or other methods known in the art, can be used to prepare compounds in which Z substituents are other than phenyl. The compounds of the present invention and the preparation starting materials thereof are exemplified by the following examples, which should not be considered as limiting the scope of the description. The following solvents and reagents are defined herein by the indicated abbreviations: tetrahydrofuran (THF), ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N, N-dimethylformamide (DMF); and diethyl ether (Et20). Ambient temperature is abbreviated as t.a.

EXAMPLE 1 A mixture of 4-hydroxy-4-phenylpiperidine (1.5g, 8.47mmol) and K2CO3 (3.0 g, 21.73 mmol) in CH3CN was stirred at r.t. To this was added a-bromo-diphenylmethane (2.5 g, 10.12 mmol) and the reaction was stirred overnight. The reaction mixture was concentrated and redissolved in CH 2 Cl 2, washed with water, dried (MgSO 4) and concentrated. Chromatography (Si02, 9: 1 hexane / EtOAc) gave the title compound (2 g, 90%). 1 H NMR (CDCl 3): d 1.80 (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 Step 1 A solution of 4-piperidone monohydrate hydrochloride (5 g, 32. 6 mmole) in CH3CN was rented using the procedure described in example 1. Chromatography of the residue on silica (95: 5 hexane / EtOAc) gave the desired compound. Step 2 4-Methylphenylmagnesium bromide (0.5 M in THF, 1.75 ml, 0.87 mmol) was added to a solution of the product from step 1 (191 mg, 172 mmol) in THF by dripping at 0 ° C. The solution was stirred at 0 ° for two hours, quenched with ice H20, extracted with EtOAc, washed with H20 and brine, * - «-» --- K-Jft-- 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%). 1 H NMR (CDCl 3): d 7.5 (m, 6 H, Ar H), 7.3 (t, 4 H, Ar H), 7.2 (t, 4 H, Ar H), 4.35 (s, 1 H), 2.8 (d, 2 H), 2.4 (m, 5H), 2.2 (td, 2H), 1.75 (d, 2H); MS (Cl) 358 (M + 1). Elemental analysis for C25H27NO. 1.2 H20: caled: C 79.2, H 7.82, N, 3.69; observed C 78.90, H 8.02, N 3.85.

EXAMPLE 3 N-BuLi (2.5 M, 0.38 mL 0.95 mmol) is added to a solution of 3-bromo-thiophene (0.15 g, 0.95 mmol) in Et20 by dripping at -70 ° C and stirred for two hours. A solution of the product of step 1, Example 2 (230 mg, 0.87 mmol) in Et20 (4 ml) is added to the reaction mixture, heated slowly to t.a. over a period of three hours, quench with NH4CI cooled with ice (aqueous), extract with ET20, wash with H2O and brine, dry and concentrate. Chromatography of the residue (95: 5 hexane / EtOAc) gives the title compound (90 mg). 1 H NMR (CDCl 3): d 7.5 (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, 2H), 2.3 (t, 2H), 2.0 (d, 2H); MS (Cl) 350 (M + 1). Elemental analysis for C22H22NOS. 1.1 HCl 0.9 H20: caled: 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 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%) 1 H NMR (CDCb): d 2.40 (m, 4H), 2.50 (m, 2H), 2.85 (m, 2H), 4.25 (s, 1 H), 7.20-7.50 (m, 15H), 9.42 (s, 1 H). _____________________ - '•• "- •' *" • --- Stage 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 hours the 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) yielded the desired primary alcohol. 1 H NMR (CDCb): d 2.00 (m, 2H), 2.25 (m, 4H), 2.65 (m, 2H), 3.65 (d, 2H), 4.20 (s, 1 H), 4.25 (d, 1 H) , 7.2-7.6 (m, 15H).

Step 3 The product from step 2 was treated with NaH in DMF at 0 ° C for 0.5 hours. CH3I was added and the reaction warmed to t.a. After stirring overnight, the reaction mixture was poured onto ice, extracted with ET20, dried (MgSO4) and evaporated. Column chromatography of the residue afforded the title compound. 1 H NMR (CDC b): d 2.10 (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, 15H).

EXAMPLE 5 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 was waved to ta under N2 for 20 hours. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and H20. The organic layer was washed with water twice, then with brine and dried (MgSO 4), filtered and concentrated. Chromatography (Si02, 19: 1 hexane / EtOAc) gave 6.0 g (76%) the desired 1 H NMR product (CDCb): d 2.21 (m, 4H), 2.49 (t, J = 12.3 Hz, 2H), 3.11 ( d, J = 12.5 Hz, 2H), 4.46 (s, 1 H), 7.45 (m, 15H).

Step 2 A solution of the product (6.0 g, 17 mM) from step 1 in Et20 (40 ml) was cooled to 0 ° C, treated with a 1 M solution of LAH (34.10 ml, 34 mM) by dripping under N2. , for 0.5 hours. The reaction mixture was allowed to warm to room temperature and then refluxed for four hours. The reaction mixture was cooled to 0 ° C and treated with water (8 eq). The reaction mixture was allowed to warm to t.a. and stirred for one hour. The resulting solid was separated by filtration and rinsed with Et20, and the filtrate was concentrated to provide 5.45 g (90%) of the desired product. 1 H NMR (CD 3 OD): d 1.84 (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).

Step 3 A solution of the product (0.2 g, 0.56 mM) from 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 t.a. for 18 hours under N2. The reaction mixture was concentrated, then partitioned between H2O and CH2Cl2. The organic layer was washed with water (2x) and brine, then dried (MgSO), filtered and concentrated. Chromatography (S02, 3: 1 hexane / EtOAc) gave 0.2 g (77%) of the desired product. 1 H NMR (CD 3 OD): d 2.13 (m, 6 H), 2.66 (m, 4 H), 3.50 (s, 2 H), 4. 07 (s, 1 H), 7.1 1-7.65 (m, 20H).

Step 4 A solution of the product (0.075 g, 0.16 mM) from step 3 in THF (3 ml) was cooled to 0 ° C under stirring. LAH (solid, 0.025 g, 0. 65 mM) under N2 and continued stirring for 0.25 hours. The reaction mixture was refluxed for five hours and then stirred at r.t. for 18 hours. The reaction mixture was cooled to 0 ° C and quenched with water (8eq). The reaction mixture was allowed to warm to t.a. and stirred for one hour. The resulting solid was separated by filtration and rinsed with Et20, the filtrate was dried (MgSO4) and concentrated. Chromatography (neutral Al203, CH2CI2 > and then 3: 1 CH2Cl2: EtOAc) provided 0.014 g (20%) of the title compound. 1 H NMR (CD 3 OD): d 1.90 (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, 20H). EXAMPLE 6 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 t.a. for 18 hours. The reaction mixture was concentrated and partitioned between H20 and CH2Cl2. The organic layer was washed with water (twice), brine, then dried (MgSO 4), filtered and concentrated to give 0.214 g (95%) of the title compound. 1 H NMR (CD 3 OD): d 1.87 (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 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 he shook low under N2 for 20 hours. The reaction mixture was concentrated in vacuo, basified to pH 8 with saturated NaHCO3 and partitioned between EtOAc and H20. The organic layer was washed twice with water, then with brine, and dried (MgSO 4), filtered and concentrated. Chromatography (neutral Al203, hexane, and then 1: 1 hexane: EtOAc) provided 11.95 g (80%) of the desired product.

Step 2 To a mixture of the product (30.0 g, 0.112 mole) from step 1 and (CH3) 3 SiCN (59.94 ml, 0.448 mole) cooled to -15 ° C in an ethylene glycol / C02 bath under N2 was added Glacial acOH (47 ml) per drop, while maintaining an internal temperature of -15 ° C. Concentrated H2SO4 (47 ml, 0.34 M) was added by dripping with vigorous stirring, while maintaining an internal temperature of -15 ° C. The cooling bath was then removed and the reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was poured into an ice bath and adjusted to pH 7 with a 50% solution of NaOH while maintaining a temperature of 25 ° C. The reaction mixture was then extracted with CH 2 Cl 2 and the organic layer was washed with water (twice) then with brine and dried (MgSO 4), filtered and concentrated. Recrystallization from EtOAc / hexane (1:10 gave 22.35 g (68%) of the desired compound.1H NMR (CD3OD): d 2.10 (m, 2H), 2.40 (m, 4H), 2.82 (d, J = 11.50 Hz , 2H), 3.57 (s, 2H), 7.20-7.43 (m, 10H), 8.05 (s, 1 H).

Step 3 The product of step 2 (20 g, 67.9 mM) and 5% (w / w) concentrated HCl (aqueous) / CH 3 OH (350 ml) were stirred under N 2 for 48 hours. The mixture was concentrated to provide a foam which was suspended in Et20 and concentrated to remove excess HCl. The resulting solid was resuspended in Et20, collected by vacuum filtration, washed with Et20 and dried under vacuum to give (23 g, 100%) of the desired product. 1H NMR (CD3OD): salt di-HCl: d 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 = 13.50 Hz, 2H), 4.26 (s, 2H), 7.56 (m, 10H).

Step 4 The product from step 3 (24.10 g, 71 mM) CH2Cl2 (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 18 hours. The reaction mixture was partitioned between CH2Cl2 and H20, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water (2 times), then with brine, and dried (MgSO), filtered and concentrated. The resulting solid was suspended in Et20 and sonicated, filtered and dried to yield the desired compound (21.98 g, 90%). 1 H NMR (CD 3 OD): d 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), CH 3 OH (430 ml). Pd (OH) 2 / C (3.0 g) and NH 4 COOH (18.86 g, 0.298 M) were combined and refluxed under N 2 for 8 hours: The reaction mixture was filtered using celite, washed with CH 3 OH. The combined filtrates were concentrated to produce (3.90 g, 97%) of the desired product. 1 H NMR (CD 3 OD): d 1.10 (bs, 2H), 1.39 (s, 7H), 1.90 (m, 2H), 2.26 (m, 4H), 2.92 (m, 4H), 7.17-7.41 (m, 5H) .

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 under t.a. under N for 18 hours. The mixture was concentrated and the resulting residue was partitioned between H20 and EtOAc. The EtOAc layer was washed with water (twice), brine, then dried (MgSO 4), filtered and concentrated. Chromatography (neutral Al203, hexane, then 4: 1 hexane: EtOAc) gave 2.85 g (65%) of the desired product. 1 H NMR (CD3OD): d 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, 1 H), 7.10-7.47 (m, 15H).

Step 7 The product from step 6 (4.6, 10 mM), 1,4-dioxane (38 ml) and 4 M HCl in 1,4-dioxane (25 ml, 101 mM) were combined and stirred at r.t. under N2 for 4 hours. The mixture was concentrated and the residue was suspended in Et20 and re-concentrated. The resulting solid was resuspended in Et20, sonicated and the product was collected by vacuum filtration and dried to give 3.27 g (80%) of the desired product. 1 H NMR (CD3OD) of di-HCl salt: d 2.91 (m, 8H), 5.34 (s, 1 H), 7. 37-7.77 (m, 15H).

Step 8: To a suspension of the product from step 7 (0.3 g, 0.722 mM) in CH2Cl2 (3 ml), under N2 at t.a. 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 hour. Then Na (OAc) 3BH (0.230 g, 1.08 mM) was added and the reaction mixture was stirred at r.t. under N2 for three hours. The reaction was quenched with saturated NaHC03 (aqueous) and partitioned between Et20 and H20. The organic layer was washed with H20 (2 times) brine, dried (MgSO4), filtered and concentrated. Chromatography (SiO2, toluene, then 1.19 EtOAc / toluene) gave 0.158 g (50%) of the desired product. 1 H NMR (CD 3 OD): d 1.96 (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, 16H).

EXAMPLE 8 Step 1 A solution of 4- (2-oxo-1-benzamidazolyl) -piperidine in CH 3 CN was alkylated using the procedure described in step 1 of example 1 to produce the desired compound.

Step 2: NaH was added to a solution of 3- [1- (diphenylmethyl) -4-pipepdinyl] -1,3-dihydro-2H-benzimidazo-1-one (2.5 g, 6.6 mmoles) in DMF (25 ml) and he stirred to ta for 1 hour. N-Butyl iodide was added to the mixture at t.a. and stirred during the night. It was quenched with ice-H20, extracted with EtOAc, washed with H20 and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica (1: 9 EtOAc / hexane) to obtain the title compound (2.35 g). The title compound Et20 was dissolved, HCl in Et20 (8 mL, 1 M) was added, stirred for 1 hour and filtered to obtain the HCl salt. 1 H NMR (CD 3 OD): d 7.55 (m, 4 H, Ar H), 7.35 (m, 5 H, Ar H), 7.25 (m, 2 H, Ar H), 7.15 (m, 2 H, Ar H), 7.1 (m, 1 H, ArH), 4.4 (m, 2H), 3.95 (t, 2H), 3.15 (d, 2H), 2.6 (dq, 2H), 2.1 (t, 2H, 1.8, m, 4H), 1.5 (m, 2H) , 1.0 (t, 3H); ESI-MS 440 (M + 1); Elemental analysis for C29H33N3O.HCI.H20: caled: 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 SOCI2 (247 mg, 2.07 mmol) was added to a solution of 2- (chlorophenyl) phenylmethanol (300 mg, 1.38 mmol) in CH 2 Cl 2 at r.t., stirred at r.t. for five hours and concentrated. The residue was dissolved in CH3CN, K2C03, 4-hydroxy-4-phenylpiperidine and Nal. The solution was stirred at reflux overnight, filtered and concentrated. The residue was chromatographed on silica (9: 1 hexane / EtOAc) to give the title compound. 1 H NMR (CDCl 3): d 7.91 (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, 3H), 5.0 (s, 1 H), 2.8 (dd, 2H), 2.5 (dq, 2H), 2.2 (dt, 2H), 1.75 (d, 2H). The title compound was dissolved in ether, HCl / Et20 (1M) was added to obtain the HCl salt. MS Cl (378 (M + 1); Elemental analysis for C24H24NOCI.HCI.0.2H2O: caled: 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 Step 1 A solution of 4-piperidone monohydrate hydrochloride (880 mg, 5 ml) in CH3CN was alkylated with mandelonitrile (1 g, 7.51 mmol) using the procedure described in example 9. The residue was chromatographed on silica followed by recrystallization (EtOAc) to obtain the desired compound (630 mg).

Step 2 A solution of 2-methoxyphenylmagnesium bromide in THF (24 ml, 0.5 M, 11.85 mmol) was added to a solution of the product from step 1 (330 mg, 1185 mmol) in THF at 0 ° C. The ice bath was removed and the reaction mixture was stirred at reflux for six hours. The reaction was quenched with NH 4 Cl (aqueous), extracted with EtOAc, washed with brine, dried and concentrated. Chromatography of the residue (95: 5, 9: 1 hexane / EtOAc) provided the title compound (330 mg). 1 H NMR (CDCl 3): d 7.76 (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, 2H), 4.88 (s, 1 H), 3.89 (s, 3H), 2.94 (d, 1 H), 2.82 (d, 1 H), 2.45 ( td, 2H), 2.26 (t, 2H), 1.78 (d, 2H). The title compound was dissolved in Et20, HCl in Et20 was added, stirred for one hour and filtered to obtain the HCl salt. MS FAB 374.1 (M + 1); Elemental analysis for C25H27NO2.HCI.0.15H2O: caled: C 72.76, H 6.91, N 3.59, Cl 8.59; observed: C 72.76, H 7.02, N 3.59, Cl 8.83.

EXAMPLE 11 Step 1 A solution of 1-phenyl-1,3,8-triazaspirole [4,5] decan-4-one (0.5 g) in CH 3 CN was alkylated using the procedure described in step 1 of Example 1 to produce the desired compound .

Step 2: The product from step 1, 1-phenyl-8- (diphenylmetyl) -1,3,8-triazaspirole [4,5] decan-4-one (0.4 g) was alkylated with CH 3 I using the procedure described in step 2 of example 1 to produce the title compound (0.25 g). 1 H NMR (CDCl 3): d1.70 (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, 2H), 7.20-7.60 (m, 12H). Using the procedures of Examples 1 to 11, using the appropriate starting material, the compounds shown in the following tables were prepared.

TABLE 1 where X1 is as defined below: TABLE 2 where X is as defined below TABLE 3 where Z 7. Y. Z72 are as defined below -Jtaas-A * • '.S-QB-? G TABLE 4 where X1, X2, Z1 and Z2 are as defined below - «« - &, ^ ^ «Saa», - TABLE 5 where R11, Z and Z2 are as defined in the following table where Ac is acetyl, Me is methyl and Et is ethyl.

TABLE 6 where R) 11, Z 71. and, Z72 are as defined in the following table: Mh - rf-.

TABLE 7 Compounds of the formulas shown in which Ph is phenyl TABLE 8 where Z-i and Z2 are as defined in the following table: TESTS Nociceptin adhesion assay A preparation of CHO cell membranes expressing the ORL-1 receptor (2 mg) was incubated with varying concentrations of [125 l] [Tyr14] nociceptin (3-500 pM) in a buffer containing 50 mM HEPES (pH 7.4), 10 mM NaCl, 1 mM MgCl 2, 2.5 mM CaCl 2, 1 mg / ml bovine serum albumin, and 0.025% bacitrin. In a variety of studies, assays were carried out in 50 mM tris-HCl buffer (pH 7.4), 1 mg / ml bovine serum albumin and 0.025% bacitracin. The samples were incubated for one hour at room temperature (22 ° C). The radiolabel ligand adhered to the membrane was harvested on GF / B filters pre-refreshed in 0.1% polyethyleneimine using a Brandell cell harvester and washed five times with 5 ml of cold distilled water. The non-specific adhesion was determined in parallel by similar tests that were carried out in the presence of 1 μm of nociceptin. All the test points were made in duplicate of total and non-specific adhesion. Ki calculations were performed using methods well known in the art. For the compounds of this invention, the ki values were determined to be in the range of 0.6 to 3000 nM, with compounds having a ki value of less than 10 nM being preferred. The ki values for the representative compounds of the invention are the following: Using the procedures described in European Journal of Pharmacoloqv, 336 (1997), p.233-242, the agonist activity of the compounds of the invention was determined: EXAMPLE 12 Study on cough Effects of the nociceptin agonist compound A (0.3-10 mg / kg, p.o) and compound B (10 mg / kg, p.o).

COMPOSITE TO COMPOUND B were evaluated in cough induced by capsaicin in a guinea pig according to the methods of Bolser et al., British Journal of Pharmacoloqv (1995) 114, 735-738. This model is a widely used method to evaluate the activity of potential antitussive drugs. The guinea pigs of the male Hartley breed kept fasting overnight (350-450 g, Charles River, Bloomington, MA, USA) were placed in a transparent chamber of 30.48 cm by 35.56 cm. The animals were exposed to aerosolised capsaicin (300 μM, for 4 minutes) produced by a jet nebulizer (Puritan Bennett, Lenexa, KS, USA) to produce a cough reflex. Each of the guinea pigs were exposed only once to capsaicin. The amount of coughs was detected by a microphone placed in the camera and verified by a trained observer. The signal from the microphone was traced by a polygraph that provided a record of the number of coughs. Either vehicle (methyl cellulose 1 ml / kg, p.o) or compound A or compound B were administered two hours before the 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 of Figure 1.

EXAMPLE 13 Respiratory measurements Studies were conducted on Hartley guinea pigs weighing 450 to 550 g. The animals were fasted during the night but were given water and libitum. The guinea pigs were placed in a full-body, upper-body plethysmograph, and a rubber collar was placed over the head of the animal to provide an air-tight seal between the guinea pig and the plethysmograph. The air flow was measured as differential pressure through a wire mesh screen covering a 2.54 cm hole in the wall of the plethysmograph. The air flow signal was integrated into a signal provided to the volume using a preamplifier circuit and a pulmonary function computer (Buxco Electronics, Sharon, CT model XA). A head chamber was added to the plethysmograph and air was circulated from a source of compressed gas (21% of 02)., being the rest N2) through the head of the camera during the entire duration of the study. All respiratory measurements were made while the guinea pigs breathed this circulating air. The volume signal of each animal was fed to a data acquisition / analysis system (Buxco Electronics, model XA) that calculated the flow volume and respiration rate on a breath-by-breath basis. Those signals were visually displayed on a monitor. The volume of flow and the respiratory regime were recorded as an average value per minute. The guinea pigs were allowed to equilibrate in the plethysmograph for 30 minutes. The baseline measurements were obtained at the end of this thirty minute period. The guinea pigs were taken out of the plethysmograph and orally dosed with the compound A of example 12 (10 mg / kg po), baclofen (3 mg / kg, po) or with a placebo consisting of a methylcellulose vehicle (2). ml / kg po). Immediately after dosing the guinea pigs were placed in the plethysmograph, the chamber head and circulating air were reconnected and the respiratory variables were measured at 30, 60, 90 and 120 minutes after treatment. This study was carried out under the ACUC? 960103 protocol.

Data analysis Data for the volume of flow (Vt), respiratory rate (f) and volume per minute (MV = VT X f) were made for the baseline condition and at each time point after the drug or the vehicle. The results were expressed as mean ± SEM. The results are shown in Figures 2A, 2B and 2C. Figure 2 A shows the flow volume change. Figure 2 B shows the change in flow volume and Figure 2C shows the change in breathing frequency. We have surprisingly discovered that nociceptin receptor ORL-1 agonists exhibit anti-tussion vity, which makes them useful for suppressing cough in mammals. Non-limiting examples of nociceptin receptor ORL-1 agonists include the nociceptin receptor ORL-1 agonist compounds described herein. For mammals that are treated for coughing, the ORL-1 receptor, nociceptin agonists may be administered along with one or more additional agents for treating cough, allergy or symptoms selected asthma between antihistamines, 5-lipoxygenase, leukotriene inhibitors, H3 inhibitors, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, mastoid cell stabilizers, antitussives, expectorants, tachykinine receptor antagonists NKi, NK2 and NK3 and GABAB agonists. Non-limiting examples of antihistamines include astemizole, azathidine, azelastine, acrivastine, brompheniramine, certirizine, chlorpheniramine, > . "& - * & * - &A ^ ^^ ^^ A- 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, tripelenennamina, temelastine, trimeprazine and triprolidine. Nonlimiting examples of receptor antagonists Histamine H3 include: thioperamide, impromidine, burimamide, clobenpropit, impentamine, mifetidine, S-sopromidine, R-sopromidine, SKF-91486, GR-175737, GT-2016, UCL-1199 and clozapine. Other compounds can be easily evaluated for the vity of the H3 receptors by known methods including the guinea pig brain membrane assay and the guinea pig neuronal ileal contron test both being described in US Pat. No. 5,352,707 . Another useful assay utilizes the rat brain membranes and has been described 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, restricts, retards or inter in any other way with the on or vity of the leukotrienes. Non-limiting examples of leukotriene inhibitors include montelukast acid [R- (E)] - 1 [[[1- [3- [2- (7-chloro-2-quinolinyl) -ethenyl] pheny] -3 [2 - (1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropanoacetic acid and its sodium salt described in European patent 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 US Patent No. 5,270,324; 1 - ((1 (R) -3 (3- (2- (2,3-dichlorothien [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 in U.S. Patent No. 5,472,964; pranlukast, N- [4-oxo-2- (1 H-tetrazol-5-yl) -4H-1-benzopyran-8-yl] -p- (4-phenylbutoxy) benzamide) described in WO 97/28797 and in European Patent No. 173,617; zafirlukast, (cyclopentyl-3- [2-methoxy] -4 - [(o-tolyl-sulfonyl) carbamoyl] benzyl] -1-methylindol-5-carbamate) described in WO 97/28797 and in the European patent No. 199,543; and [2 - [[2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl] oxomethyl] phenyl] acetic acid, described in US Pat. No. 5,296,495 and Japanese Patent JP08325265 A. The term "inhibitor 5" "lipoxygenase" or "5-LO inhibitor" includes any agent or compound that inhibits, restricts, retards or interacts in any other way with the enzymatic action of 5-lipoxygenase. Non-limiting examples of 5-lipoxygenase include zileuton, docebenone, piripost, ICI-D2318 and ABT 761. Non-limiting examples of β-adrenergic receptor agonists include: albuterol, bitolterol, isoetharine, mataproterenol, perbuterol, salmeterol, terbutaline, soproterenol, ephedrine and epinephrine. A non-limiting example of a xanthine derivative is theophylline.

Non-limiting examples of α-adrenergic receptor agonists include arialkylamines (for example phenylpropanolamine and pseudoephedrine), imidazoles (for example, naphazoline, oxymetazoline, tetrahydrozoline, and xylometazoline), and cycloalkylamines (for example, propylhexedrine). A non-limiting example of a mastoid cell stabilizer is nedocromil sodium. Non-limiting examples of anti-tussous agents include codeine dextromethorphan, benzonatate, clofendianol and noscapine. A non-limiting example of an expectorant is guaifenesin. Non-limiting examples of tachykinin receptor antagonists, NK-i, NK2 and NK3 include CP-99,994 and SR 48968. Non-limiting examples of GABAB agonists include baclofen and 3-aminopropyl-phosphinic acid. For the preparation of the pharmaceutical compositions from the compounds described in this invention, the inert pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, seals and suppositories. The powders and tablets may comprise from about 5 to about 70% of the active ingredient. Suitable solid carriers are known in the art, for example magnesium carbonate, magnesium stearate, talc, sugar, lactose. The tablets, powders, seals and capsules can be used as solid dosage forms suitable for oral administration.

To prepare 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 by stirring. The molten homogeneous mixture is then poured into molds of a suitable size and allowed to cool and thus solidify. Liquid form preparations include solutions, suspensions and emulsions. As an example, water or water-propylene glycol solutions for parenteral injection may be mentioned. The 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 combined with a pharmaceutically acceptable carrier, such as an inert compressed gas. Also included are preparations in solid form, to be converted, shortly before being used, to liquid form preparations for oral or parenteral administration. Said liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be administered transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and / or emulsions may be included in a transdermal dressing of the matrix or reservoir type conventional in the art for this purpose.

Preferably, the compound is administered orally. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into unit doses containing the appropriate amounts of active component, for example an effective amount to achieve the desired purpose. The amount of active compound in a unit dose of preparation may vary or be 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 used may vary depending on the requirements of the patient and the severity of the condition being treated. The determination of the appropriate dosage for a particular situation is within the skill of the person skilled in the art. In general, treatment starts with smaller dosages that are less than the optimal dose of the compound. Next, the doses are increased in small increments until the optimum effect is reached under certain circumstances. For reasons of convenience, the total daily dosage can 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 pharmaceutically acceptable salts thereof will be regulated according to the opinion of the attending physician considering factors such as age, condition and size of the patient as well as the severity of the symptoms that are treated. A typical recommended dosage regimen is oral administration of 10 mg to 2000 mg / day preferably 10 to 1000 mg / day in two to four divided doses to provide relief for pain, anxiety, depression, asthma or alcohol abuse. The compounds are non-toxic when administered within this dosing scale. For treating cough, the amount of nociceptin receptor ORL-1 agonist in a unit dose is preferably between about 0.1 mg to 1000 mg, more preferably, about 1 mg to 300 mg. A typical recommended dosage regimen is oral administration of 1 mg to 2000 mg / day, preferably 1 to 1000 mg / day in two to four divided doses. When the cough is treated, the nociceptin receptor ORL-1 agonist can be administered with one or more additional agents to treat cough, allergy, or asthma symptoms, selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, inhibitors of leukotriene, H3 inhibitors, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, mastoid cell stabilizers, antitussives, expectorants, tachykinin receptor antagonists NK ^ NK2 and NK3 and GABA_ agonists. The nociceptin receptor ORL-1 agonist and additional agents are preferably administered in a combined dosage form (e.g., in a single tablet), although they may be administered separately. Additional agents are administered in amounts that are effective to provide relief for cough, allergy, or asthmatic 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 from 1 mg to 1000 mg / day in two to four divided doses. The following are examples of pharmaceutical dosage forms containing a compound of the invention. The scope of the invention in its pharmaceutical composition aspect is not limited by the examples provided.

EXAMPLES OF PHARMACEUTICAL DOSAGE FORMS EXAMPLE A PICTURE Manufacturing Method Articles 1 and 2 are mixed in an appropriate mixer for 10-15 minutes. The mixture is granulated with article No. 3. The wet granules are crushed through a coarse sieve (eg 1/4", 0.63 cm) if necessary.The wet granules are dried The dried granules are sieved if necessary and mixed with article No. 4 and Mixing continues for 10-15 minutes Add item No. 5 and mix for 1-3 minutes Compress the mixture to the appropriate size and weigh in an appropriate tablet machine.

EXAMPLE B Capsules Manufacturing method Articles 1, 2 and 3 are mixed in an appropriate mixer for 10-15 minutes. Item No. 4 is added and mixed for 1-3 minutes. The mixture is filled into appropriate two-piece hard gelatin capsules in an appropriate encapsulating machine. Although the present invention has been described in conjunction with the specific embodiments indicated above, many alternatives, modifications and variations thereof will be apparent to those skilled in the art. All said alternatives, modifications and variations will be within the spirit and scope of the present invention.

Claims (13)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound represented by the formula or a pharmaceutically acceptable salt or solvate thereof where: the dotted line represents an optional double bond, X1 is R5- (dC-? 2) alkyl, R6- (C3-C? 2) cycloalkyl, R7-aryl, R8-heteroaryl or R10- (C3-C7) heterocycloalkyl, X2 is -CHO, -CN, -NHC (= NR26) NHR26, -CH (= NOR26), -NHOR26, R7-aryl, R7-aryl (d-C6) ) alkyl, R ^ aryloyl-Cejalkenyl, R7-aryl (C? -C6) alkynyl, - (CH2) vOR13, - (CH2) vCOOR27, - (CH2) vCONR14R15, - (CH2) VNR21NR22 or - (CH2) vNHC ( 0) R21 where v is zero, 1, 2 or 3 and where q is 1 to 3 and is 1 or 2; or X1 is • - '- and X2 is hydrogen; or X1 and X2 together form a spiro group that has the formula m is 1 or 2; n is 1, 2, or 3, with the proviso that when n is 1, one of R16 and R17 is -C (0) R28; p is 0 or 1, Q is -CH2-, -O-, -S-, -SO-, -S02-, or -NR17-, R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen and (d-C6) alkyl, or (R1 and R4) or (R2 and R + 3 +) or (R1 and R3) or (R2 and R4) together can form an alkylene bridge of 1 to 3 carbon atoms; R5 represents from 1 to 3 substituents independently selected from the group consisting of H, R7-aryl, R6- (C3-C12) cycloalkyl, R8-heteroaryl, R10- (C3-C7) heterocycloalkyl, -NR19R20, -OR13 and -S (O)? 0-2R13; R6 is 1 to 3 substituents independently selected from the group consisting of H, (Ci-Ce.alkyl, R7-aryl, -NR19R20, -OR13-SR13; R7 represents from 1 to 3 substituents independently selected from the group consisting of hydrogen , halo, (d-Cß.alkyl, R25-aryl, (C3-C? 2) cycloalkyl, -CN, -CF3, -OR19- (C6) alkylo-OR19, -OCF3, -NR19R20, - ( d-C6) alkyl-NR19R20, -NHS02R19, -S02N (R26) 2, -S02R19, -SOR19, -SR19, -N02, -CONR19R20, NR20COR19, -COR19, -COCF3, -OCOR19, -OC02R19, -COOR19, - (d-C6) alkyl-NHCOOC (CH3) 3, - (C C6) alkyl-NHCOCF3, - (C? -C6) alkyl-NHSOr (Cr C6) alkyl, - (dd alkyl-NHCONH- Ci-d- alkyl or - (CH ^ -N N-R19 where f is 0 to 6; or the substituents R7 on the adjacent carbon atoms of the ring can together form a methylenedioxy or ethylenedioxy ring; R8 represents from 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C? -C6) alk, R25-aryl (C3-C? 2) cycloalkyl, -CN, -CF3, -OR19 , - (d-C6) alkyl-OR19, -OCF3, -NR 9R20, - (C C6) alkyl-NR19R20, -NHS02R19, -S02N (R26) 2, -N02, -CONR19R20, -NR20COR19, -COR19, - OCOR19, -OC02R19 and -COOR19; R9 is hydrogen, (C Ce.alkyl, halo, -OR19, -NR19R20, -NHCN, -SR19 or (d-C6) alkyl-NR19R20; R10 is H, (d-Ce.alkyl, -OR19, - (d-C6) alkyl-OR19, -NR19R20, or - (C6) alkyl-NR19R20; R11 is independently selected from the group consisting of H, R5- (C6) alkyl, R6- (C3-C12) cycloalkyl, - (C? -C6) (C3-C12) alkyl, cycloalkyl, - (d-C6) alkyl-OR19, - (d-C6) alkyl-NR19R20 and where - (CH2) q- N? Aqya are such as have been defined above, R12 is H, (CrC6) alkyl, halo, -N02, -CF3, -OCF3, -OR19, - (C6) alkyl-OR19, -NR19R20, or (d-C6) alkyl-NR19R20; R13 is H, (C C6) alkyl, R7-ryl, - (d-C6) alkyl-OR19, - (d-C6) alkyl-NR19R20, or - (CrC6) alkyl-SR19; R14 and R15 are independently selected from the group consisting of H, R5- (dC6) alkyl, R7-aryl and where q and a are as defined above; R16 and R17 are independently selected from the group consisting of hydrogen, R5- (CrC6) alkyl, R7-aryl, (C3-C12) cycloalkyl, R8-heteroaryl, R8-heteroaryl (d-C6) alkyl, -C ( 0) R28, - (d-C6) alkyl- (C3-C7) -heterocycloalkyl, - (C6) alkyl-OR19 and - (d-C6) alkyl-SR19; R19 and R20 are independently selected from the group consisting of hydrogen, (dC6_alkyl, (C3-C12) cycloalkyl, aryl, and aryl (d-C6) alkyl; R21 and R22 are independently selected from the group consisting of hydrogen , (C? -C6.alkyl, (C3-Ci2) cycloalkyl, (C3-C? 2) cycloalkyl (d-C6) alkyl, - (C3C7) heterocycloalkyl, - (C? -C6) alkyl- (C3-C7) ) -heterocycloalkyl, R7-aryl, R7-aryl- (C? -C6) alkyl, R8-heteroaryl- (CrC? 2) alkyl, (C? -C6) alkyl-OR19; - (C? -C6) alkyl, NR19R20, - (C C6) alkyl-SR19, - (C C6) alkyl-NR18- (C? -C?) Alkyl-0- (C C6) alkyl and (C? -C6) alkyl-NR18- (C? -C6) alkyl-NR18- (C? -C6) alkyl; R18 is hydrogen or alkyl (CrC6), Z1 is R5- (dC? 2) alkyl, R7-aryl, R8-heteroaryl, R6- (C3-C? 2) cycloalkyl, R10- (C3-C7) heterocycloalkyl, -C02 (CrC6) alkyl, CN or -C (0) NR19R20; Z2 is hydrogen or Z1; Z3 is hydrogen or (C? -C6) alkyl; or Z1, Z2 and Z3, together with the carbon to which it is attached, form the group the condition 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 ring R7-phenyl or R8-heteroaryl: R23 represents 1 to 3 substituents independently selected from the group consisting of H, (d-C6) alkyl, OR19, - (C6) alkyl-OR19, - NR19R20 and - (d-C6) alkyl-NR19R20; R24 represents 1 to 3 substituents independently selected from the group consisting of R23, -CF3, OCF3, N02 or halo, or the substituents R24 on the adjacent carbon atoms of the ring may together form a methylenedioxy or ethylenedioxy ring; R25 represents 1 to 3 substituents independently selected from the group consisting of H, (d-C6) alkyl, (d-C6) alkoxy, and halo; R26 is independently selected from the group consisting of H, (d-CβJalkyl, and R25-C8H-CH2-; R27 is H, (C?-C6) alkyl, R7-aryl (CrC6) alkyl, or (C3-C? 2) cycloalkyl, R28 is (d-C6) alkyl, (C? -C6) (C3-C? 2) alkyl cycloalkyl, R7-aryl, R7-aryl- (C? -C6) alkyl, R8-heteroaryl , - (d-C6) alky1-NR19R20, - (d-C6) alkyl-OR19, or (C -C.alkyl-SR19, with the proviso that when X1 is or X1 or X2 together and Z 1 is R 7 -phenyl, Z 2 is not hydrogen or (C C 3) alkyl; with the proviso that when Z Z2 and Z3 together with the carbon to which they are attached form and X, y, X v2 together are R11 is not H, (d-C6) alkyl, (C.-C6) alkoxy (C6) alkyl or (C6) hydroxyalkyl; with the proviso that when R2 and R4 form an alkylene bridge, Z1, Z2 and Z3 together with the carbon to which they are attached, are not with the co and Z1 is R6 - (C3-C? 2) -cycloalkyl, Z2 is not H.

2. The compound according to claim 1, wherein Z1 and Z2 are each R7-aryl.

3. The compound according to claim 2, wherein R7 is selected from the group consisting of (d-Cß) alkyl and halo.

4. The compound according to claim 1, wherein X1 is R7-aryl and X2 is OH or -NC (0) R28.

5. The compound according to claim 1, wherein and X2 is hydrogen.

6. - The compound according to claim 5, wherein R12 is hydrogen and R11 is (d-C6) alkyl, (d-Cß) alkyl, (C3-d2) cycloalkyl, (d-C6) alkyl-OR19 or (d-) C6) alkyl -NR19R20.

7. The compound according to claim 1, wherein X1 and X2 together form a spirocyclic group.

8. The compound according to claim 7, wherein m is 1, R17 is phenyl and R16 is (d-C6) alkyl-OR19 or (C6) alkyl-NR19R20.

9. - The compound selected from the group consisting of:

10. - A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutically effective carrier.

11. - A pharmaceutical composition comprising: a therapeutically effective amount of a nociceptin receptor ORL-1 agonist; a therapeutically effective amount of a second agent selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, cell stabilizers mastoids, antitussives, expectorants, tachykinin receptor antagonists NK-i, NK2 and NK3 and GABA agonists and a pharmaceutically acceptable carrier.

12. The use of a compound as claimed in claim 1 for the manufacture of a medicament for the treatment of pain, anxiety, asthma, depression or alcohol abuse.

13. The use of a nociceptin receptor ORL-1 agonist, alone or in combination with a second agent for the manufacture of a medicament for treating cough, allergy or asthma symptoms, said second agent is selected from the group consisting of: antihistamines, inhibitors 5-lipoxygenase, leukotriene inhibitors, H3 inhibitors, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, mastoid cell stabilizers, antitussives, expectorants, tachykinin receptor antagonists NK-i, NK2 and NK3 and agonists GABAB. i ^^ U ^^^^ SUMMARY OF THE INVENTION New compounds of formula or a pharmaceutically acceptable salt or solvate thereof in which: the dotted line represents an optional double bond; X1 is optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; X2 is -CHO, -CN, amino, alkyl or optionally substituted aryl; or X1 is optionally substituted benzofused heterocyclyl and X2 is hydrogen; or X1 or X2 together form an optionally benzofused spiro heterocyclyl group; R1, R2, R3 and R4 are independently H or 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; Z1 is optionally substituted alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl or -C02 (alkyl or substituted amino) or CN; Z2 is H or Z1; Z3 is H or alkyl; or Z1, Z2 and Z3 together with the carbon to which they are attached form saturated or unsaturated bicyclic rings; pharmaceutical compositions including the same and the use of said compounds as inhibitors, nociceptin receptors useful for the treatment, anxiety, cough, asthma, depression and alcohol abuse. SHERING / all P00 / 1843F ^^^^^^^^ gÉ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^ j ^^^