BENZIMIDAZOLE COMPOUNDS HAVING NOCICEPTIN RECEPTOR AFFINITY

Abstract: Disclosed are compounds of formula (I), wherein A, R1, R2, R3, R4 and X1 are as disclosed herein. The compounds have affinity for the ORL1 receptor and are useful in the treatment of chronic and acute pain.

Description: BENZIMIDAZOLE COMPOUNDS HAVING NOCICEPTIN RECEPTOR AFFINITY This application claims the benefit of U S provisional no 60/169.394 filed December 6, 1999. the disclosure of which is hereby incorporated by reference BACKGROUND OF THE INVENTION Chronic pam is a major contributor to disability m the industrialized world and is the cause of an untold amount of suffeπng The successful treatment of severe and chronic pam is a primary goal of the physician with opioid analgesics being the current drugs of choice Lnfortunately. this class of compounds produces several undesirable side effects including respiratory depression, constipation, and the development of tolerance and dependence Opioids are deπved from the opium poppy papa\ a sommferwn and include drugs such as morphine, codeine and semi-synthetic compounds deπved from them and from thebame, another component of the opium poppy It was hypothesized that the opioids deπved their therapeutic effect b\ interacting with specific receptor sites in the body Later expeπments led to the belief that there were more than one receptor site in the body, in explanation for the fact that the synthetic compound nalorphine provides analgesic activity while at the same time, antagonizes the analgesic effect of morphine I til recently, there was ewdence of three major classes of opioid receptors in the central nervous system (CNS). w ith each class having subtype receptors These receptor classes were designated as u. δ and k As opiates had a high affinity to these receptors while not being endogenous to the bod\ . research followed m order to identify and isolate the endogenous gands to these receptors These hgands were identified as enkepha ns endorphms and dynorphms Recent expeπmentation has led to the identification of a cDNA encoding an opioid receptor-like (ORLl) receptor with a high degree of homology to the known receptor classes This newly discovered receptor w as classified as an opioid receptor based only on structural grounds, as the receptor did not exhibit pharmacological homology It was lnitialK demonstrated that e hgands having a high affinity for μ, δ and k receptors had low affinity for the ORLl This characteπstic. along with the fact that an endogenous hgand had not yet been discovered, led to the term "orphan receptor" Subsequent research led to the isolation and structure of the endogenous gand of the ORLl receptor. This gand is a seventeen amino acid peptide structurally similar to members of the opioid peptide family The discovery of the ORLl receptor presents an opportunity in drug discovery for novel compounds which can be administered for pam management or other syndromes modulated by this receptor Given the close structural homology of hgands to the ORLl receptor to hgands of the other opioid receptors, such drug ery could also lead to compounds having a higher affinity for the μ, δ and k receptors than known compounds, while producing less side effects OBJECTS AND SUMMARY OF THE INVENTION It is accordingly an object of the present invention to provide new compounds which exhibit affinity for the ORLl receptor It is another object of the present invention to provide new compounds hich exhibit affinity for the ORLl receptor and one or more of the μ, δ or k receptors It is another object of the present invention to provide new compounds for treating a patient suffering from chronic or acute pam by administering a compound having affinity for the ORLl receptor It is another object of the invention to provide new compounds which have agonist activity at the μ, δ and k receptors which is greater than compounds currently available e.g morphine It is another object of the invention to provide methods of treating chronic and acute pam admimsteπng compounds which have agonist activity at the μ, δ and k receptors which is greater than compounds currently a\ ailable It is another object of the invention to provide methods of treating chronic and acute pam by admmisteπng non-opioid compounds which have agonist activity at the μ, δ and k receptors and which produce less side effects than compounds currently available It is another object of the present invention to provide compounds useful as analgesics, antimflammatoπes, diuretics, anesthetics and neuroprotective agents and methods for administeπng said compounds It is another object of the present invention to provide a method of modulating a response from opioid receptors comprising administeπng a compound having a binding affinity for the ORLl receptor of less than 500 K, (nM) and a binding affinity for the mu receptor of less than 25 K, (nM) It is another object of the invention to provide a method of reducing side effects associated with the administration of opioid analgesics in a human patient compπsing administeπng to a human patient an analgesically effective amount of a non-opioid compound which exhibits a binding affinity for the ORLl receptor of less than 500 K, (nM) In other embodiments, the compound has a binding affinity for the mu receptor of less than 25 K, (nM) Other objects and advantages of the present invention ill become apparent from the following detailed description thereof With the abo\ e and other objects in view , the present invention in certain embodiments comprises compounds having the general formula (I) wherein A is a saturated, unsaturated or partially unsaturated πng Xi is selected from the group consisting of a bond, C \ ιo branched or straight alkyl, alkenyl. alkynylene optionally substituted with 1-3 halogen, oxo or phenyl groups, said phenyl group optionally substituted with 1-3 halogen or C, ιo alkyl groups, Ri is selected from the group consisting of hydrogen, C 12 cycloalkyl, C 3 12 cycloalkenyl, a monocychc, bicychc or tπcychc aryl or heteroaryl πng, a heteromonocychc πng, and a heterobicyc c ring system, wherein said C 3 12 cycloalkyl, C-, 12 cycloalkenyl, monocychc. bicychc or tπcyclic aryl or heteroaryl ring, heteromonocychc ring, and heterobicychc ring system are optionally substituted with 1 -3 substituents selected from the group consisting of halogen, C 0 alkyl, nitro, tπfluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxv are optionally substituted with halogen or C \ 10 alkyl, R 2 is selected from the group consisting of C M O alkyl, C^ ι 2 cycloalkyl and halogen, said alkyl and cycloalkyl substituted with an oxo group, and R 3 and R4 are independently selected from the group consisting of hydrogen, hydroxy, C alkyl, Ci 3 alkoxy. Ci 1 carbonyl and halogen; and pharmaceutically acceptable salts thereof In preferred embodiments, A has one double bond at the 1 ,2 position In preferred embodiments, X 1 R 1 is not hydrogen In preferred embodiments, A has one double bond at the 1,2 position In other preferred embodiments Xi is selected from a bond, methyl, ethyl or propyl In other preferred embodiments X] is substituted with fluorophenyl In other preferred embodiments Ri is a tπcyclic aryl πng, preferably dibenzocycloheptyl In other preferred embodiments Ri is a cycloalkyl, preferably cyclopentyl, cyclohexyl or cycloheptyl, wherein the cycloalkyl is optionally substituted with a C \ 3 alkyl. In other prefeπed embodiments Ri is a monocychc aryl πng, preferably phenyl, wherein the aryl ring is optionally substituted with a halogen, alkyl, phenyl or benzyloxy In other preferred embodiments, Ri is selected from napthyl, benzyloxyphenyl, decahydronaphyl, 1.3 hydro-mdene, propylhexane, cyclodecyl, biphenylmethyl, phenylethyl, cyclooctyl, l,2,3,4,hydro-napthyl, 1-3 dimethyl-pentyl In other preferred embodiments, R 2 is a methyl, ethyl or propyl wherein the methyl ethyl and propyl are optionally substituted with an oxo group In other preferred embodiments, Ri and R 4 are both hydrogen As used herein, the term "alkyl" means a linear or branched saturated aliphatic hydrocarbon group having a single radical and 1 -10 carbon atoms Examples of alkyl groups include methyl, propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl A branched alkyl means that one or more alkyl groups such as methyl, ethyl or propyl, replace one or both hydrogens in a -CLL- group of a linear alkyl chain The term "cycloalkyl" means a non-aromatic mono- or multicyc c hydrocarbon ring system having a single radical and 3-12 carbon atoms Exemplary monocychc cycloalkyl πngs include cyclopropyl, cyclopentyl, and cyclohexyl Exemplary multicychc cycloalkyl πngs include adamantyl and norbornyl The term "alkenyl" means a linear or branched aliphatic hydrocarbon group containing a carbon-carbon double bond having a single radical and 2-10 carbon atoms A "branched" alkenyl means that one or more alkyl groups such as methyl, ethyl or propyl replace one or both hydrogens in a -CH 2 - or -CH= linear alkenyl chain Exemplary alkenyl groups include ethenyl, 1- and 2- propenyl, 1-, 2- and 3- butenyl, 3-methylbut-2-enyl, 2- propenyl, heptenyl, octenyl and decenyl The term "cycloalkenyl" means a non-aromatic monocychc or multicychc hydrocarbon ring system containing a carbon-carbon double bond having a single radical and 3 to 12 carbon atoms Exemplary monocychc cycloalkenyl πngs include cyclopropenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl An exemplary multicychc cycloalkenyl ring is norbornenyl The term "aryl" means a carbocychc aromatic πng system containing one, two or three rings which may be attached together in a pendent manner or fused, and containing a single radical Exemplary aryl groups include phenyl and naphthyl The term "heterocychc" means cyclic compounds having one or more heteroatoms (atoms other than carbon) in the πng, and having a single radical The ring may be saturated, partially saturated and unsaturated. and the heteroatoms may be selected from the group consisting of nitrogen, sulfur and oxygen Examples of saturated heterocychc radicals include saturated 3 to 6- membered heteromonocychc groups containing 1 to 4 nitrogen atoms, such as pyrrohdmyl, lmidazolidmyl, pipeπdino, piperazmyl, saturated 3- to 6- membered heteromonocychc groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morphohnyl, saturated 3- to 6- membered heteromonocychc groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazohdmyl Examples of partially saturated heterocychc radicals include dihydrothiophene, dihydropyran, and dihydrofuran The term "heteroaryl" means unsaturated heterocychc radicals, wherein heterocychc is as previously descπbed Exemplary heteroaryl groups include unsaturated 3 to 6 membered heteromonocychc groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyπdyl, pyπmidyl, and pyrazmyl, unsaturated condensed heterocychc groups containing 1 to 5 nitrogen atoms, such as mdolyl, qumolyl, isoquinolyl. unsaturated 3 to 6- membered heteromonocychc groups containing an oxygen atom, such as furyl, unsaturated 3 to 6 membered heteromonocychc groups containing a sulfur atom, such as thienyl, unsaturated 3 to 6 membered heteromonocychc groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, unsaturated condensed heterocychc groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl, unsaturated 3 to 6 membered heteromonocychc groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, unsaturated condensed heterocychc group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl The term "heteroaryl" also includes unsaturated heterocychc radicals, wherein heterocychc is as previously described, in which the heterocychc group is fused with an aryl group, in which aryl is as previously descπbed Exemplary fused radicals include benzofuran. benzdioxole and benzothiophene As used herein, the term "patient" includes both human and other mammals As used herein, the term "halogen" includes fluoride, bromide, chloride, iodide or alabamide The invention disclosed herein is meant to encompass all pharmaceutically acceptable salts thereof of the disclosed compounds The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, secium salt and the like, alkaline earth metals such as calcium salt, magnesium salt and the like, organic amine salts such as tπethylamme salt, pyπdine salt, picolme salt, ethanolamine salt, tπethanolamme salt, dicyclohexylamme salt, N,N'-dιbenzylethylenedιamme salt and the like, inorganic acid salts such as hydrochloπde, hydrobromide, sulfate, phosphate and the like, organic acid salts such as formate, acetate, tπfluoroacetate, maleate, tartrate and the like, sulfonates such as methanesulfonate. benzenesulfonate, p-toluenesulfonate, and the like, ammo acid salts such as argmate, aspargmate, glutamate and the like The invention disclosed herein is also meant to encompass all prodrugs of the disclosed compounds Prodrugs are considered to be any covalently bonded earners which release the active parent drug in vivo The invention disclosed herein is also meant to encompass the m vivo metabolic products of the disclosed compounds Such products may result for example from the oxidation, reduction, hydrolysis, amidation. esteπfication and the like of the administered compound, pπmaπly due to enzymatic processes Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a peπod of time sufficient to yield a metabolic product thereof Such products typically are identified by prepaπng a radiolabelled compound of the invention, administeπng it parenterally in a detectable dose to an animal such as rat, mouse, guinea pig. monkey, or to man, allowing sufficient time for metabolism to occur and isolating its conversion products from the uπne, blood or other biological samples The invention disclosed herein is also meant to encompass the disclosed compounds being lsotcpically-labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, Η, ' C, 14 C. 1 J N, 18 0, r O, j I P, j2 P, 3 'S, 1 F, and 3ό Cl, respectively Some of the compounds disclosed herein may contain one or more asymmetπc centers and may thus give rise to enantiomers, diastereomers. and other stereoiscmeπc forms The present invention is also meant to encompass all such possible forms as well as their racemic and resolved forms and mixtures thereof When the compounds described herein contain olefmic double bonds or other centers of geometric asymmetr , and unless specified otherwise, it is intended to include both E and Z geometric isomers All tautomers are intended to be encompassed by the present ιn\ ention as well As used herein, the term "stereoisomers" is a general term for all isomers of indiv idual molecules that differ only in the orientation of their atoms in space It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers) The term "chiral center" refers to a carbon atom to which four different groups are attached The term "enantiomer" or "enantiomeπc" refers to a molecule that is nonsupeπmposeable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction The term "racemic" refers to a mixture of equal parts of enantiomers and which is optically inactive The term "resolution" refers to the separation or concentration or depletion of one of the two enantiomeπc forms of a molecule Certain preferred compounds of fonnula I according to the invention include 1 -[ 1 -dιbenzocycloheptyl-4-pιpeπdmyl]- 3-[ 1 -oxo-ethyl]- 1 ,3-dιhydro-2H- 1.3-benzamιdazol- 2-one, l-[l-(4-propylcyclohexane)-4-pιpeπdιnyl]- 3-[l -oxo-propyl]-l,3-dιhydro-2H-l,3- benzamιdazol-2-one, l-[l-(4-propylcyclohexane)-4-pιpeπdmyl]-3-[l-oxo-ethyl]-l,3-dιhydro-2H-l,3- benzamιdazol-2-one, l-[l-(4-propylcyclohexane)-4-pιpeπdιnyl]- 3-[2-oxo-cyclopropyl]-l,3-dιhydro-2H-l,3- benzamιdazol-2-one, 1 -[ 1 -(4-propyl- 1 ,2-cyclohexene)-4-pιpeπdmyl-3-[ 1 -oxo-ethyl]- 1 ,3-dιhydro-2H- 1 ,3- benzamιdazol-2-one, l-[l-(4,4-dιfluorophenylbutyl)-4-pιpeπdmyl]- 3-[l -oxo-ethyl]- l ,3-dιhydro-2H- 1,3- benzamιdazol-2-one, and l-[ l-(4-phenyl-phenylmethyl)-4-pιpeπdmyl]- 3-[l -oxo-ethyl]- l,3-dιhydro-2H- 1,3- benzamιdazol-2-one 1 -[ 1 l-methyl)-4-pιpeπdmyl]-3-[ 1 -oxo-ethyl]- 1 ,3-dιhydro-2H- 1 ,3-benzamιdazol-2- one, l-[l-(4-benzyloxy-benzyl)-4-pιpeπdmyl]-3-[l -oxo-ethyl]- l,3-dιhydro-2H- 1 ,3-benzamιdazol- 2-one, l-[l-(decahydronaphyl)-4-pιpeπdmyl]-3-[l -oxo-ethyl]- l,3-dιhydro-2H- l ,3-benzamιdazol-2- one, 1 -[ 1 -(2[ 1.3 dιhvdro-mdene])-4-pιpeπdmyl]-3-[ 1 -oxo-eth\ 1]- 1.3-dιhydro-2H- 1.3- benzamιdazol-2-one, l-[l-(4-ιsopropylhexane)-4-pιpeπdmyl]-3-[ l -oxo-ethyl]- 1.3-dιhydro-2H- 1,3-benzamιdazol- 2-one, 1 -[ 1 -(4-[ 1 -methyl-ethyl]hexane)-4-pιpeπdmyl]-3-[ 1 -oxo-ethyl]- 1 ,3-dιhydro-2H- 1 ,3- benzamιdazol-2-one, 1 -[ 1 -cyclodecyl -4-pιpeπdmyl]-3-[ 1 -oxo-ethyl]- 1 ,3-dιhydro-2H- 1 ,3-benzamιdazol-2-one, l-[l-(3-dιphenylpropyl)-4-pιpeπdmyl]-3-[l -oxo-ethyl]- l,3-dιhydro-2H- l,3-benzamιdazol-2- one, 1 -[ 1 -(2- phenylethyl)-4-pιpeπdmyl]-3-[ 1 -oxo-ethyl]- 1 ,3-dιhydro-2H- 1 ,3-benzamιdazol-2- one. 1 -[ 1 -(cyclooctylmethyl)-4-pιpeπdmyl]-3-[ 1 -oxo-ethyl]- 1 ,3-dιhydro-2H- 1 ,3-benzamιdazol-2- one. 1 -[ 1 -(4-[ 1 ,2,3,4,hydro-napthyl])-4-pιpeπdmyl]-3-[ 1 -oxo-ethyl]- 1 ,3-dιhydro-2H- 1 ,3- benzamιdazol-2-one, l-[l -(4-[l-3 dιmethyl-pentyl])-4-pιpeπdmyl]-3-[l-oxo-ethyl]-l ,3-dιhydro-2H-1.3- benzamιdazol-2-one, and pharmaceutically acceptable salts thereof The present invention is also directed to the following compounds l-[4-dιbenzocycloheptyl-4-pιpeπdmyl]-l ,3-dιhydro-2H-l,3-benzamιdazol-2-one, 1 -[4-(4-propylcyclohexane)-4-pιpeπdmyl]- 1 ,3-dιhydro-2H- 1 ,3-benzamιdazol-2-one, l-[4-(4-propyl-l ,2-cyclohexene)-4-pιpendmyl-l,3-dιhydro-2H-l,3-benzamιdazol-2-one, l-[4-(4,4-dιfluorophenylbutyl)-4-pιpeπdmyl]-l,3-dιhydro-2H-l ,3-benzamιdazol-2-one, l-[4-(4-phenyl-phenylmethyl)-4-pιpeπdιnyl]-l,3-dιhydro-2H-l ,3-benzamιdazol-2-one, and pharmaceutically acceptable salts thereof DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention can be administered to anyone requiring modulation of the opioid and ORLl receptors Administration may be orally, topically, by suppository, inhalation, or parenterally The present invention also encompasses all pharmaceutically acceptable salts of the foregoing compounds One skilled in the art will recognize that acid addition salts of the presently claimed compounds may be prepared by reaction of the compounds with the appropriate acid via a variety of known methods Various oral dosage forms can be used, including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders and liquid forms such as emulsions, solution and suspensions The compounds of the present invention can be administered alone or can be combined with various pharmaceutically acceptable carriers and excipients known to those skilled in the art. including but not limited to diluents, suspending agents. solubihzers, binders, dismtegrants, preservatives, coloπng agents, lubπcants and the like When the compounds of the present invention are incorporated into oral tablets, such tablets can be compressed, tablet tπturates, enteric-coated, sugar-coated, film-coated, multiply compressed or multiply layered Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions, suspensions, and solutions and/or suspensions reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, coloπng agents, and flavoπng agents When the compounds of the present invention are to be injected parenterally, they may be, e g , in the form of an lsotonic steπle solution Alternatively, when the compounds of the present invention are to be inhaled, they mav be formulated into a dry aerosol or may be formulated into an aqueous or partially aqueous solution In addition, when the compounds of the present invention are incorporated into oral dosage forms, it is contemplated that such dosage forms may provide an immediate release of the compound in the gastrointestinal tract, or alternatively may provide a controlled and/or sustained release through the gastrointestinal tract A wide vaπety of controlled and/or sustained release formulations are well known to those skilled in the art, and are contemplated for use m connection with the formulations of the present invention The controlled and/or sustained release may be provided by, e g , a coating on the oral dosage form or by incorporating the compound(s) of the invention into a controlled and/or sustained release matrix Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms, are described in the Handbook of Pharmaceutical Excipients, Amencan Pharmaceutical Association (1986), incorporated by reference herein Techniques and compositions for making solid oral dosage forms are descπbed in Pharmaceutical Dosage Forms Tablets (Lieberman, Lachman and Schwartz, editors) 2nd edition, published by Marcel Dekker, Inc , incorporated by reference herein Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also descπbed in Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553B1593 (1980), incorporated herein by reference Techniques and composition for making liquid oral dosage forms are descπbed in Pharmaceutical Dosage Forms Disperse Systems. (Lieberman. Rieger and Banker, editors) published by Marcel Dekker. Inc , incorporated herein by reference When the compounds of the present inv ention are incorporated for parenteral administration by injection (e g , continuous infusion or bolus injection), the formulation for parenteral administration may be in the form of suspensions, solutions, emulsions in oily or aqueous vehicles, and such formulations may further compπse pharmaceutically necessary additives such as stabilizing agents, suspending agents, dispersing agents, and the like The compounds of the invention may also be in the form of a powder for reconstitution as an injectable formulation The dose of the compounds of the present invention is dependent upon the affliction to be treated, the seventy of the symptoms, the route of administration, the frequency of the dosage interval, the presence of any deleteπous side-effects, and the particular compound utilized, among other things. The following examples illustrate various aspects of the present invention, and are not to be construed to limit the claims m any manner whatsoever. Example 1 l-[4-(4-propylcyclohexane)-4-pιpendmyl]-3-[l -oxo-ethyl]- l ,3-dιhydro-2H- 1,3- benzamιdazol-2-one. The above compound was synthesized according to the following synthetic scheme and general procedure: General Procedure for Reductive Coupling. A solution containing the amine and ketone in toluene was refluxed in the presence of molecular sieves for 5-6 hours. The reaction mixture was cooled and filtered through Celite and the Celite cake was washed with Dichloromethane. The combined filtrate was concentrated to dryness. The residue was dissolved m a mixture of THF and methanol(10: l) To the solution was then added 1 eq of NaCNBH3 in one portion and a few drops of acetic acid to adjust pH=4-5 The reaction was stirred at room temperature for 12 hours The reaction mixture was diluted with EtOAc and washed with IN NaOH solution The aqueous was extracted with additional EtOAc and the combined organic was dned with MgS04, filtered and concentrated The desired product was purified either by recrystahzation or flash chromatography on silica gel Preparation of Example 1 To a solution of 380 mg of example 1 in 10 ml dichloromethane was added 236 mg Et 3 N, 99 mg acetyl chloride and a catalytic amount of DMAP The reaction was stirred at room temperature for 12 hours After diluting with dichloromethane the mixture was washed with brme and the aqueous phase extracted w ith additional dichloromethane The combined organic extracts were dried over MgS04, filtered and concentrated The residue was purified via flash chromatography(sιhca, EtOAc) to give desired product 1HNMR m CDCL(ppm) 7 35 (t, 2H), 7 10 (m, 7H), 5 05 (s, 2H), 3 13-2 80 (m, 9H), 2 62 (s, 3H), 2 40 (m, 2H), 2 13 (m, 1H), 1 89 (bd, 2H), 1 70 (m. 1H) LCMS 404(M+1) The general procedures disclosed abov e can be modified in order to synthesize the other preferred compounds of the invention Example 2 Nociceptin affinity at the ORLl receptor for prefeπed compounds was obtained using the following assay Membranes from recombmant HEK-293 cells expressing the human opioid receptorlike receptor (ORL-1 ) (Receptor Biology) were prepared by lysing cells in ice-cold hypotomc buffer (2 5 mM MgCk 50 mM HEPES, pH 7 4) (10 ml/10 cm dish) followed by homogemzation with a tissue gπnder/teflon pestle Membranes were collected by centπfugation at 30,000 x g for 15 mm at 4°C and pellets resuspended m hypotomc buffer to a final concentration of 1-3 mg/ml Protein concentrations were determined using the BioRad protein assay reagent w ith bovine serum albumen as standard Ahquots of the ORL-1 receptor membranes were stored at -80°C Functional SGTPγS binding assays were conducted as follows ORL-1 membrane solution was prepared by sequentially adding final concentrations of 0 066 μg/μl ORL-1 membrane protein. 10 μg/ml saponin, 3 μM GDP and 0 20 nM [ 3S S]GTPγS to binding buffer (100 mM NaCl, 10 mM MgCl 2 , 20 mM HEPES, pH 7 4) on ice The prepared membrane solution (190 μl/well) was transfened to 96-shallow well polypropylene plates containing 10 μl of 20x concentrated stock solutions of agonist prepared m DMSO Plates were incubated for 30 mm at room temperature with shaking Reactions were terminated by rapid filtration onto 96-well Umfilter GF/B filter plates (Packard) using a 96-well tissue harvester (Brandel) and followed by three filtration washes with 200 μl ice-cold binding buffer (10 mM NaH 2 P0 4 , 10 mM Na 2 HP0 4 , pH 7 4) Filter plates were subsequently dned at 50°C for 2-3 hours Fifty μl/well scintillation cocktail (BetaScmt, Wallac) was added and plates were counted m a Packard Top-Count for 1 mm/well Data was analyzed using the curve fitting functions in GraphPad PRISM™, v 3 0 and the results are set forth in table 1 below Example 3 Affinity at the μ, k and δ receptors for preferred compounds was obtained according to the following assays Mu, kappa or delta opioid receptor membrane solution w as prepared by sequentially adding final concentrations of 0 075 μg/μl of the desired membrane protein. 10 μg/ml saponm, 3 μM GDP and 0 20 nM [ 35 S]GTPγS to binding buffer (100 mM NaCl, 10 mM MgCl 2 , 20 mM HEPES, pH 7 4) on ice The prepared membrane solution (190 μl/well) was transfeπed to 96-shallow well polypropylene plates containing 10 μl of 20x concentrated stock solutions of agonist prepared in DMSO Plates were incubated for 30 mm at room temperature with shaking Reactions were terminated by rapid filtration onto 96-well Umfilter GF/B filter plates (Packard) using a 96-well tissue harvester (Brandel) and followed by three filtration washes with 200 μl ice-cold binding buffer (10 mM NaH 2 P0 , 10 mM Na 2 HP0 4 , pH 7 4) Filter plates were subsequently dried at 50°C for 2-3 hours Fifty μl/well scintillation cocktail (MιcroScιnt20, Packard) was added and plates were counted in a Packard Top-Count for 1 mm/well Data were analyzed using the curv e fitting functions in GraphPad PRISM™, v 3 0 and the results are set forth in table 2 below

Claims: What is claimed is 1 A compound of the formula (I) wherein A is a saturated, unsaturated or partially unsaturated ring Xi is selected from the group consisting of a bond, Ci 10 branched or straight alkyl, alkenyl, alkynylene optionally substituted with 1-3 halogen, oxo or phenyl groups, said phenyl group optionally substituted with 1-3 halogen or Ci iπ alkvl groups, Ri is selected from the group consisting of hydrogen, C 12 cycloalkyl, Ci 12 cycloalkenyl, a monocychc, bicychc or tncychc aryl or heteroaryl ring, a heteromonocychc πng, and a heterobicychc ring system, wherein said 12 cycloalkyl, C 3 12 cycloalkenyl, monocychc, bicychc or tncychc aryl or heteroaryl πng, heteromonocychc nng, and heterobicychc nng system are optionally substituted with 1 -3 substituents selected from the group consisting of halogen, Ci 10 alkyl, nitro, tπfluoromethyl. phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenvloxy and benzyloxy are optionally substituted with halogen or Ci 10 alkyl, R 2 is selected from the group consisting of hydrogen. Ci 10 alkyl, C 3 12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group, and Ri and R4 are independently selected from the group consisting of hydrogen, hydroxy, Cι_ 3 alkyl, Cι_ 3 alkoxy, Ci 1 carbonyl and halogen; and pharmaceutically acceptable salt thereof 2. A compound of claim 1 wherein A has a double bond at the 1,2 position. 3 A compound of claim 1 wherein Xi is selected from a bond, methyl, ethyl or propyl. 4 A compound of claim 1 wherein Xi is methyl 5 A compound of claim 1 wherein X] is substituted with fluorophenyl 6 A compound of claim 1 wherein R] is a tncychc aryl ring 7 A compound of claim 1 wherein R] is a cycloalkyl 8 A compound of claim 1 wherein R] is a monocychc aryl πng, wherein the aryl πng is optionally substituted with a halogen, C \ i alkyl, phenyl or benzyloxy 9 A compound of claim 1 wherein Ri is selected from napthyl, benzyloxyphenyl, decahydronaphyl 1.3 hydro-mdene. propylhexane, cyclodecyl, biphenylmethyl, phenylethyl, cyclooctyl, 1.2,3,4.hydro-napthyl, 1-3 dim ethyl -pentyl 10 A compound of claim 4 wherein Ri is selected from napthyl, benzyloxyphenyl, decahydronaphyl, 1,3 hydro-mdene, propylhexane, cyclodecyl, biphenylmethyl, phenylethyl, cyclooctyl, l ,2,3,4.hydro-napthyl, 1-3 dimethyl-pentyl 1 1 A compound of claim 1 wherein Ri and R 4 are both hydrogen 12 A compound of claim 1 selected from l-[l-dιbenzocycloheptyl-4-pιpendιnyl]- 3-[l -oxo-ethyl]- l,3-dιhydro-2H- 1,3- benzamιdazol-2-one, l-[l-(4-propylcyclohexane)-4-pιpeπdmyl]- 3-[l-oxo-propyl]-l ,3-dιhydro-2H-l,3- benzamιdazol-2-one, l-[l -(4-propylcyclohexane)-4-pιpendιnyl]-3-[l -oxo-ethyl]-l,3-dιhydro-2H-l,3- benzamιdazol-2-one, l-[l-(4-propylcyclohexane)-4-pιpeπdmyl]- 3-[2-oxo-cyclopropyl]-l,3-dιhydro-2H- 1 ,3-benzamιdazol-2-one, 1 -[ 1 -(4-propyl- 1 ,2-cyclohexene)-4-pιpeπdιnyl-3-[ 1 -oxo-ethyl]- 1 ,3-dιhydro-2H- 1 ,3- benzamιdazol-2-one, l-[l-(4,4-dιfluorophenylbutyl)-4-pιpendιnyl]- 3-[l-oxo-ethyl]-l,3-dιhydro-2H-l,3- benzamιdazol-2-one, and l-[l-(4-phenyl-phenylmethyl)-4-pιpeπdmyl]- 3-[l -oxo-ethyl]-l ,3-dιhydro-2H-l,3- benzamιdazol-2-one l-[l-(2-napthyl-methyl)-4-pιpeπdmyl]-3-[ l -oxo-ethyl]- 1.3-dιhydro-2H- 1,3- benzamιdazol-2-one, 1 -[ 1 -(4-benzyloxy-benzyl)-4-pιpeπdιnyl]-3-[ 1 -oxo-ethyl]- 1 ,3-dιhydro-2H- 1 ,3- benzamιdazol-2-one, l-[l-(decahydronaphyl)-4-pιpendmyl]-3-[l -oxo-ethyl]- l,3-dιhydro-2H-l, 3- benzamιdazol-2-one, 1 -[1 -(2[ 1 ,3 dιhydro-mdene])-4-pιpeπdmyl]-3-[ 1 -oxo-ethyl]- 1 ,3-dιhydro-2H- 1 ,3- benzamιdazol-2-one, l-[l-(4-ιsopropylhexane)-4-pιpeπdιnyl]-3-[l -oxo-ethyl]- 1.3-dιhydro-2H-l, 3- benzamιdazol-2-one, l-[l-(4-[l-methyl-ethyl]hexane)-4-pιpendmyl]-3-[l-oxo-ethyl]-l,3-dιhydro-2H-l,3- benzamιdazol-2-one, 1-[1 -cyclodecyl -4-pιpeπdmyl]-3-[l -oxo-ethyl]- 1.3-dιhydro-2H-l,3-benzamιdazol-2- one, l-[l-(3-dιphenylpropyl)-4-pιpeπdιnyl]-3-[l -oxo-ethyl]- l ,3-dιhydro-2H-l, 3- benzamιdazol-2-one, 1 -[1 -(2- phenylethyl)-4-pιpeπdmyl]-3-[l -oxo-ethyl]- l ,3-dιhydro-2H- 1,3- benzamιdazol-2-one, l-[l-(cyclooctylmethyl)-4-pιpeπdιnyl]-3-[l -oxo-ethyl]- l,3-dιhydro-2H- 1,3- benzamιdazol-2-one, 1 -[ 1 -(4- [ 1 ,2,3 ,4,hydro-napthyl] )-4-piperidinyl] -3 - [ 1 -oxo-ethyl] - 1 ,3 -dihydro-2H- 1,3- benzamidazol-2-one; 1 -[ 1 -(4-[ 1 -3 dimethyl-pentyl])-4-piperidinyl]-3-[ 1 -oxo-ethyl]-l ,3-dihydro-2H- 1 ,3- benzamidazol-2-one; and pharmaceutically acceptable salts thereof. 13. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient. 14. A method of treating pain comprising administering to a patient in need thereof, an effective amount of a compound according to claim 1. 15. A method of modulating a pharmacological response from the ORLl receptor comprising administering an effective amount of a compound according to claim 1. 16. A compound selected from the group consisting of 1 -[4-dibenzocycloheptyl-4-piperidinyl]-l ,3-dihydro-2H-l ,3-benzamidazol-2-one; l-[4-(4-propylcyclohexane)-4-piperidinyl]-l,3-dihydro-2H-l,3-benzamidazol-2-one; 1 -[4-(4-propyl- 1 ,2-cyclohexene)-4-piperidinyl- 1 ,3-dihydro-2H- 1 ,3-benzamidazol-2- one; l -[4-(4,4-difluorophenylbutyl)-4-piperidinyl]-l,3-dihydro-2H-l ,3-benzamidazol-2- one; l -[4-(4-phenyl-phenylmethyl)-4-piperidinyl]-l ,3-dihydro-2H-l,3-benzamidazol-2- one; and pharmaceutically acceptable salts thereof. 17. A pharmaceutical composition comprising a compound of claim 16 and at least one pharmaceutically acceptable excipient. 18. A method of treating pain comprising administering to a patient in need thereof, an eff ective amount of a compound according to claim 16. 19. A method of modulating a pharmacological response from the ORLl receptor comprising administering an effective amount of a compound according to claim 16. 20. A method of modulating a response from opioid receptors comprising administering a compound having a binding affinity for the ORLl receptor of less than 500 Kj (nM) and a binding affinity for the mu receptor of less than 25 K, (nM). 21. A method of reducing side effects associated with the administration of opioid analgesics in a human patient comprising administering to said human patient an analgesically effective amount of a non-opioid compound which exhibits a binding affinity for the ORLl receptor of less than 500 K; (nM). 22. The method of claim 21 wherein said compound has a binding affinity for the mu eceptor of less than 25 K, (nM).

Inventors: GOEHRING RICHARD R, KYLE DONALD, SHAO BIN, GOEHRING, RICHARD, R., KYLE, DONALD, SHAO, BIN
Applicants: EURO CELTIQUE SA, GOEHRING RICHARD R, KYLE DONALD, SHAO BIN, EURO-CELTIQUE, S.A., GOEHRING, RICHARD, R., KYLE, DONALD, SHAO, BIN
Application year: 2000
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P25, A61P29, A61P43, C07D401