1-(4-piperidinyl)-1,3-dihydro-2h-indole-2-one derivatives and related compounds as nociceptin analogs and orl1 ligands for the treatment of pain

0001This application claims priority from <patcit id="pcit0001" dnum="US284666P" dnum-type="L"><text>U.S. Provisional Application Serial Nos. 60/284,666</text></patcit>; <patcit id="pcit0002" dnum="US60284667P" dnum-type="L"><text>60/284,667</text></patcit>; <patcit id="pcit0003" dnum="US60284668P" dnum-type="L"><text>60/284,668</text></patcit>; <patcit id="pcit0004" dnum="US60284669P" dnum-type="L"><text>60/284,669</text></patcit> all filed April 18, 2001.

BACKGROUND OF THE INVENTION

0002Chronic pain is a major contributor to disability and is the cause of an untold amount of suffering. The successful treatment of severe and chronic pain is a primary goal of the physician with opioid analgesics being preferred drugs.

0003Until recently, there was evidence of three major classes of opioid receptors in the central nervous system (CNS), with each class having subtype receptors. These receptor classes were designated as µ, δ and κ. As opiates had a high affinity to these receptors while not being endogenous to the body, research followed in order to identify and isolate the endogenous ligands to these receptors. These ligands were identified as enkephalins, endorphins and dynorphins.

0004Recent experimentation has led to the identification of a cDNA encoding an opioid receptor-like (ORL1) receptor with a high degree of homology to the known receptor classes. This newly discovered receptor was classified as an opioid receptor based only on structural grounds, as the receptor did not exhibit pharmacological homology. It was initially demonstrated that non-selective ligands having a high affinity for µ, δ and κ receptors had low affinity, for the ORL1. This characteristic, along with the fact that an endogenous ligand had not yet been discovered, led to the term "orphan receptor".

0005Subsequent research led to the isolation and structure of the endogenous ligand of the ORL1 receptor. This ligand is a seventeen amino acid peptide structurally similar to members of the opioid peptide family.

0006The discovery of the ORL1 receptor presents an opportunity in drug discovery for novel compounds which can be administered for pain management or other syndromes modulated by this receptor.

0007<patcit id="pcit0005" dnum="WO9932481A"><text>WO 99/32481 A</text></patcit> in the name of Alcon Laboratories, Inc. discloses a group of compounds having muscarinic activity. Said compounds may be used in the manufacture of a medicament for treating glaucoma, myopia, psychosis and various other conditions involving muscarinic receptors.

0008<patcit id="pcit0006" dnum="US5789402A"><text>US 5 789 402</text></patcit> in the name of Eli Lilly Company discloses compounds having effects on serotonin-related systems. Such hetero-oxy alkanamine compounds are effective pharmaceuticals for the treatment of conditions related to or affected by the reuptake of serotonin and by the serotonin 1 receptor.

0009<patcit id="pcit0007" dnum="WO9502405A"><text>WO 95/02405 A</text></patcit> in the name of Merck &amp; Co., Inc. discloses benzoxazinone and benzopyrimidinone piperidinyl compounds. Said compounds are useful as oxytocin and vasopressin receptor antagonists.

0010<patcit id="pcit0008" dnum="US3325499A"><text>US 3 325 499</text></patcit> in the name of Ireland Poos discloses certain substituted oxindole compounds [(1-(1-hydrocarbyl-4-piperdyl)-2-indolinones].

0011The publication by <nplcit id="ncit0001" npl-type="b"><text>Klein et al., ARCHIV DER PHARMAZIE, VCH VERLAGSGESELLSCHAFT MBH, WEINHEIM, DE, vol. 307, no. 5, 1974, pages 360-366</text></nplcit> describes the synthesis of 1-(piperidinyl-4)-indolinones-(2) and-3,4-dihydrocarbostyriles in order to obtain structural analoga of known analgesics.

0012The abstract of said article is also listed in the Database CA [online] of chemical abstracts, Columbus, Ohio, US [<nplcit id="ncit0002" npl-type="e"><text>STN Database (accession no. 1974:477786</text></nplcit>)].

0013The publication by <nplcit id="ncit0003" npl-type="s"><text>Lobbezoo and Soudijn, J.MED.CHEM., vol. 24, 1981, pages 777-782</text></nplcit> is concerned with opiate receptor interaction of compounds derived from or structurally related to fentanyl. It discloses several compounds structurally related to fentanyl and the authors determine the affinities of said compounds towards the opiate receptor.

0014Another article by <nplcit id="ncit0004" npl-type="s"><text>Klein et al., ARCH. PHARMAZ., vol. 308, no. 75, 1976, pages 910-916</text></nplcit> discloses the synthesis and the pharmacological activities of cyclic analoga of fentanyl. Cyclisation of the acyl group with C-2 of the aromatic ring yields a change in stereochemical structure resulting in a loss of analgesic activity.

0015<patcit id="pcit0009" dnum="WO006157SA"><text>WO 00/6157S A</text></patcit> in the name of EISAI CO., LTD. discloses a process for the production of indole derivatives and intermediates thereof. Said derivatives are useful as drugs.

0016<patcit id="pcit0010" dnum="EP0976732A"><text>EP 0 976 732</text></patcit> in the name of EISAI CO., LTD. discloses 1,4-substituted cyclic amine derivatives. Such compounds show serotonin antagonistic activity and are clinically useful as medicaments for treating e.g. ameliorating and preventing spastic paralysis.

0017<patcit id="pcit0011" dnum="WO9909984A"><text>WO 99/09984 A</text></patcit> in the name of Merck &amp; Co., Inc discloses certain pyrrolidine and piperidine compounds. These compounds may be useful as modulators of chemokine receptor activity.

0018<patcit id="pcit0012" dnum="WO9613265A"><text>WO 96/13265 A</text></patcit> in the name of Merck &amp; Co., Inc discloses 4-heterocycle substituted piperidines. Such compounds promote the release of growth hormone in humans and animals, which property may be used to promote e.g. the growth of food animals or to treat conditions characterized by a deficiency in growth hormone secretion.

0019<patcit id="pcit0013" dnum="EP0355663A"><text>EP 0 355 663</text></patcit> in the name of BASF AG discloses 2,6-polyalkylpiperidin-substituted bislactames and their use for stabilization of organic material.

0020<patcit id="pcit0014" dnum="US5760054A"><text>US 5 760 054</text></patcit> in the name of Merck &amp; Co., Inc discloses alpha 1C adrenergic receptor antagonists. Furthermore, their synthesis and use as selective antagonists e.g. for the treatment of benign prostatic hypertrophy is disclosed.

0021<patcit id="pcit0015" dnum="WO0160796A"><text>WO 01/60796 A</text></patcit> in the name of Meiji Seika Kaisha, LTD. discloses phenoxyalkylamine derivatives useful as opioid δ receptor agonists.

0022<patcit id="pcit0016" dnum="WO0170689A"><text>WO 01/70689 A</text></patcit> in the name of Meiji Seika Kaisha, LTD. discloses diphenylalkylamine derivatives useful as opioid δ receptor agonists.

0023<patcit id="pcit0017" dnum="WO0214315A"><text>WO 02/14315 A</text></patcit> in the name of Ortho McNeil Pharmaceutical, Inc. discloses substituted pyrazoles, methods of manufacturing them, compositions containing them, and methods of using them for treatment of e.g. autoimmune diseases mediated by cathepsin S.

0024<patcit id="pcit0018" dnum="WO0220011A"><text>WO 02/20011 A</text></patcit> in the name of Ortho McNeil Pharmaceutical, Inc. also discloses substituted pyrazoles. Said pyrazoles are used in a method described therein for treating an allergic condition including an atopic allergic condition.

0025The publication by <nplcit id="ncit0005" npl-type="s"><text>Forbes, TETRAHEDRON LETTERS, vol. 42, 2001, pages 6943-6945</text></nplcit> describes the short and efficient synthesis of N-substituent indol-2-ones (oxindoles). Said synthesis strategy constitutes a general route to N-substituted inol-2-ones.

OBJECTS AND SUMMARY OF THE INVENTION

0026It is accordingly an object of certain embodiments of the present invention to provide new compounds which exhibit affinity for the ORL1 receptor.

0027It is an object of certain embodiments of the present invention to provide new compounds which exhibit affinity for the ORL1 receptor and one or more of the µ, δ or κ receptors.

0028It is an object of certain embodiments of the present invention to provide new compounds for treating a patient suffering from chronic or acute pain by administering a compound having affinity for the ORL1 receptor.

0029It is an object of certain embodiments of the present invention to provide new compounds which have agonist activity at the µ, δ and κ receptors which is greater than compounds currently available e.g. morphine.

0030It is an object of certain embodiments of the present invention to describe the use of new compounds in accordance with the invention in the manufacture of a medicament for treating chronic and acute pain by administering compounds which have agonist activity at the µ, δ and κ receptors which is greater than compounds currently available.

0031It is an object of certain embodiments of the present invention to describe the use of new compounds in accordance with the invention in the manufacture of a medicament for treating chronic and acute pain by administering non-opioid compounds which have agonist activity at the µ, δ and κ receptors and which produce less side effects than compounds currently available.

0032It is an object of certain embodiments of the present invention to provide compounds useful as analgesics, anti-inflammatories, diuretics, anesthetics and neuroprotective agents, anti-hypertensives, anti-anxioltics; agents for appetite control; hearing regulators; anti-tussives, anti-asthmatics, modulators of locomotor activity, modulators of learning and memory, regulators of neurotransmitter and hormone release, kidney function modulators, anti-depressants, agents to treat memory loss due to Alzheimer's disease or other dementias, anti-epileptics, anti-convulsants, agents to treat withdrawal from alcohol and drugs of addiction, agents to control water balance, agents to control sodium excretion and agents to control arterial blood-pressure disorders and methods for administering said compounds.

0033The compounds of the present invention are useful for modulating a pharmacodynamic response from one or more opioid receptors (ORL-1, µ, δ and κ) centrally and/or peripherally. The response can be attributed to the compound stimulating (agonist) or inhibiting (antagonist) the one or more receptors. Certain compounds can stimulate one receptor (e.g., a µ agonist) and inhibit a different receptor (e.g., an ORL-1 antagonist).

0034Other objects and advantages of the present invention will become apparent from the following detailed description thereof.

0035The present invention in certain embodiments comprises compounds having the formula (IIA): <chemistry id="chem0001" num="0001"><img file="EP1598338B1_D0001.tif" /></chemistry> wherein <ul id="ul0001" list-style="none" compact="compact"><li>the dotted line represents an optional double bond;</li><li>Z is selected from the group consisting of a bond, -CH₂-, -NH-, -CH₂O-, -CH₂CH₂- , -CH₂NH-, -CH₂N(CH₃)-, -NHCH₂-, -CH₂CONH-, -NHCH₂CO-, -CH₂CO-, -COCH₂-, - CH₂COCH₂-, -CH(CH₃)-, -CH=, and -HC=CH-, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with a lower alkyl, halogen, hydroxy or alkoxy groups;</li><li>R and Q are the same or different and R is selected from the group, consisting of halogen, C_1-10 alkyl, C_1-10 alkenyl, C_1-10 alkylidene, C_3-12 cycloalkyl, C_1-10 alkoxy, oxo;</li><li>and Q is selected from the group consisting of hydrogen, halogen, C_1-10 alkyl, C_1-10 alkenyl, C_1-10 alkylidene, C_3-12 cycloalkyl, C_1-10 alkoxy, and oxo;</li><li>n is an integer from 0 to 3;</li><li>R₁ is selected from the group consisting of hydrogen, C_1-10alkyl, C_3-12Cycloalkyl<b>,</b> C_2-10alkenyl, amino, C_1-10alkylamino, C_3-12cycloalkylamino, benzyl, C_3-12 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, a bicyclic ring system, and a spiro ring system of the formula (V): <chemistry id="chem0002" num="0002"><img file="EP1598338B1_D0002.tif" /></chemistry> wherein X₁ and X₂ are independently selected from the group consisting ofNH, O, S and CH₂; wherein said monocyclic aryl is preferably phenyl; wherein said bicyclic aryl is preferably naphthyl; wherein said alkyl, cycloalkyl, alkenyl, C_1-10alkylamino, C_3-12cycloalkylamino, or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C_1-10 alkyl, C_1-10 alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C_1-10 alkyl, C_1-10 alkoxy, and cyano; wherein said C_3-12 cycloalkyl, C_3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system, and spiro ring system of the formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C_1-10 alkyl, C_1-10 alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C_1-10 alkyl, C_1-10 alkoxy, and cyano;</li><li>R₂ is selected from the group consisting of hydrogen, C_1-10 alkyl, C_3-12cycloalkyl and halogen, said alkyl optionally substituted with an oxo group;</li><li>but not a compound of the following formula <chemistry id="chem0003" num="0003"><img file="EP1598338B1_D0003.tif" /></chemistry> wherein X is CHR⁴¹ and R⁴¹ is C_1-5 alkyl and wherein Ar is a monocyclic aryl ring optionally substituted with halogen, C_1-5alkoxy, C_1-5alkyl and cyano and wherein R⁷ and R⁸ independently are hydrogen, C_1-5 alkyl and C_1-5 alkoxy or halogen; alternatively, R⁷and R⁸ can be taken together to form an optionally substituted 5- to 7- membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic;</li></ul> and pharmaceutically acceptable salts thereof.

0036In certain preferred embodiments Q of formula (IIA), is hydrogen or methyl.

0037In certain preferred embodiments, R of formula (IIA), is methyl, ethyl, or ethylidene.

0038In certain preferred embodiments of formula (IIA), the R₁ alkyl is methyl, ethyl, propyl, butyl, pentyl, or hexyl.

0039In certain preferred embodiments of formula (IIA), the R_r cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, or norbornyl.

0040In other preferred embodiments of formula (IIA), the R₁ bicyclic ring system is naphthyl. In other preferred embodiments of formula (IIA), the R₁ bicyclic ring system is tetrahydronaphthyl, or decahydronaphthyl and the R₁ tricyclic ring system is dibenzocycloheptyl. In other preferred embodiments R₁ is phenyl or benzyl.

0041In other preferred embodiments of formula (IIA), the R₁ bicyclic aromatic ring is a 10-membered ring, preferably quinoline or naphthyl.

0042In other preferred embodiments of formula (IIA), the R₁ bicyclic aromatic ring is a 9-membered ring, preferably indenyl.

0043In certain embodiments of formula (IIA), Z is a bond, methyl, or ethyl.

0044In certain embodiments of formula (IIA), the Z group is maximally substituted as not to have any hydrogen substitution on the base Z group. For example, if the base Z group is -CH₂-, substitution with two methyl groups would remove hydrogens from the -CH₂- base Z group.

0045In other preferred embodiments of formula (IIA), n is 0.

0046In certain embodiments of formula (IIA), X₁ and X₂ are both O<b>.</b>

0047In other preferred embodiments, the dotted line is a double bond.

0048In certain embodiments of formula (IV), at least one of ZR₁ or R is -CH₂COOV₁, tetrazolylmethyl-, cyanomethyl-, NH₂SO₂methyl-, NH₂SOmethyl-, aminocarbonylmethyl-, C_1-4alkylaminonylmethyl-, or diC_1-4akylaminocarbonylmethyl-.

0049In certain embodiments of formula (IV), ZR₁ is 3,3 diphenylpropyl optionally substituted at the 3 carbon of the propyl with -COOV₁, tetrazolylC_0-4alkyl-, cyano-, aminocarbonyl-, C_1-4alkylaminocarbonyl-, or diC_1-4alkylaminocarbonyl-.

0050In alternate embodiments of formula (IIA), ZR₁ can be the following <chemistry id="chem0004" num="0004"><img file="EP1598338B1_D0004.tif" /></chemistry> wherein <ul id="ul0002" list-style="none" compact="compact"><li>Y₁ is R₃-(C₁-C₁₂)alkyl, R₄-aryl, R₅-heteroaryl, R₆-(C₃-C₁₂)cyclo-alkyl, R₇-(C₃-C₇)heterocycloalkyl, -CO₂(C₁-C₆)alkyl, CN or -C(O)NR₈R₉; Y₂ is hydrogen or Y₁; Y₃ is hydrogen or (C₁-C₆)alkyl; or Y₁, Y₂ and Y₃, together with the carbon to which they are attached, form one of the following structures: <chemistry id="chem0005" num="0005"><img file="EP1598338B1_D0005.tif" /></chemistry><chemistry id="chem0006" num="0006"><img file="EP1598338B1_D0006.tif" /></chemistry> or <chemistry id="chem0007" num="0007"><img file="EP1598338B1_D0007.tif" /></chemistry> wherein r is 0 to 3; c and d are independently 1 or 2; s is 1 to 5; and ring E is a fused R₄-phenyl or R₅-heteroaryl ring;</li><li>R₁₀ is 1 to 3 substituents independently selected from the group consisting of H, (C₁-C₆)alkyl, -OR₈, -(C₁-C₆)alkyl-OR₈, -NR₈R₉ and -(C₁-C₆)alkyl-NR₈R₉;</li><li>R₁₁ is 1 to 3 substituents independently selected from the group consisting of R₁₀,-CF₃, -OCF₃, NO₂ and halo, or R₁₁ substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;</li><li>R₈ and R₉ are independently selected from the group consisting of hydrogen, (C₁-C₆) alkyl, (C₃-C₁₂)cycloalkyl, aryl and aryl(C₁-C₆)alkyl;</li><li>R₃ is 1 to 3 substituents independently selected from the group consisting of H, R₄-aryl, R₆-(C₃-C₁₂)cycloalkyl, R₅-heteroaryl, R₇-(C₃-C₇)heterocycloalkyl, -NR₈ R₉, -OR₁₂ and -S(O)_0-2R₁₂;</li><li>R₆ is 1 to 3 substituents independently selected from the group consisting of H, (C₁-C₆)alkyl, R₄-aryl, -NR₈R₉, -OR₁₂ and -SR₁₂;</li><li>R₄ is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C₁-C₆)alkyl, R₁₃-aryl, (C₃-C₁₂)cycloalkyl, -CN, -CF₃, -OR₈, -(C₁-C₆)alkyl-OR₈, -OCF₃, -NR₈R₉, -(C₁-C₆)alkyl-NR₈R₉, -NHSO₂R₈, -SO₂N(R₁₄)₂, -SO₂R₈, - SOR₈, -SR₈, -NO₂, -CONR₈R₉, -NR₉COR₈, -COR₈, -COCF₃, -OCOR₈, -OCO₂R₈,-COOR₈, -(C₁-C₆)alkyl-NHCOOC(CH₃)₃, -(C₁-C₆)alkyl-NHCOCF₃, -(C₁-C₆)alkyl-NHSO₂-(C₁-C₆)alkyl, -(C₁-C₆)alkyl-NHCONH-(C₁-C₆-alkyl and <chemistry id="chem0008" num="0008"><img file="EP1598338B1_D0008.tif" /></chemistry> wherein f is 0 to 6; or R₄ substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;</li><li>R₅ is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C₁-C₆)alkyl, R₁₃-aryl, (C₃-C₁₂)cycloalkyl, -CN, -CF₃, -OR₈, -(C₁-C₆)alkyl-OR₈, -OCF₃,-NR₈R₉, -(C₁-C₆)alkyl-NR₈R₉, -NHSO₂R₈, -SO₂N(R₁₄)₂, NO₂, -CONR₈R₉,-NR₉COR₈, -COR₈, -OCOR₈, -OCO₂R₈ and -COOR₈;</li><li>R₇ is H, (C₁-C₆)alkyl, -OR₈, -(C₁-C₆)alkyl-OR₈, -NR₈R₉ or -(C₁-C₆)alkyl-NR₈R₉;</li><li>R₁₂ is H, (C₁-C₆)alkyl, R₄-aryl, -(C₁-C₆)alkyl-OR₈, -(C₁-C₆)alkyl-NR₈R₉, -(C₁)-C₆)alkyl-SR₈, or aryl (C₁-C₆)alkyl;</li><li>R₁₃ is 1-3 substituents independently selected from the group consisting of H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy and halo;</li><li>R₁₄ is independently selected from the group consisting of H, (C₁-C₆)alkyl and R₁₃-C₆H₄-CH₂-.</li></ul>

0051As 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 -CH₂- group of a linear alkyl chain. The term "lower alkyl" means an alkyl of 1-3 carbon atoms.

0052The term "alkoxy" means an "alkyl" as defined above connected to an oxygen radical.

0053The term "cycloalkyl" means a non-aromatic mono- or multicyclic hydrocarbon ring system having a single radical and 3-12 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, and cyclohexyl. Exemplary multicyclic cycloalkyl rings include adamantyl and norbornyl<b>.</b>

0054The 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.

0055A "branched" alkenyl means that one or more alkyl groups such as methyl, ethyl or propyl replace one or both hydrogens in a -CH₂- 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.

0056The term "cycloalkenyl" means a non-aromatic monocyclic or multicyclic hydrocarbon ring system containing a carbon-carbon double bond having a single radical and 3 to 12 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopropenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. An exemplary multicyclic cycloalkenyl ring is norbornenyl.

0057The term "aryl" means a carbocyclic aromatic ring 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, naphthyl and acenaphthyl.

0058The term "heterocyclic' means cyclic compounds having one or more heteroatoms (atoms other than carbon) in the ring, and having a single radical. The ring may be saturated, partially saturated or unsaturated, and the heteroatoms may be selected from the group consisting of nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6- membered hetero-monocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl; saturated 3- to 6- membered hetero-monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3. nitrogen atoms, such as morpholinyl; saturated 3- to 6- membered hetero-monocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl. Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, and dihydrofuran. Other heterocyclic groups can be 7 to 10 carbon rings substituted with heteroatoms such as oxocanyl and thiocanyl. When the heteroatom is sulfur, the sulfur can be a sulfur dioxide such as thiocanyldioxide.

0059The term "heteroaryl" means unsaturated heterocyclic radicals, wherein "heterocyclic" is as previously described. Exemplary heteroaryl groups include unsaturated 3 to 6 membered hetero-monocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyridyl, pyrimidyl, and pyrazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, quinolyl and isoquinolyl; unsaturated 3 to 6- membered hetero-monocyclic groups containing an oxygen atom, such as furyl; unsaturated 3 to 6 membered hetero-monocyclic groups containing a sulfur atom, such as thienyl; unsaturated 3 to 6 membered hetero-monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl; unsaturated condensed, heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl; unsaturated 3 to 6 membered hetero-monocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl. The term "heteroaryl" also includes unsaturated heterocyclic radicals, wherein "heterocyclic" is as previously described, in which the heterocyclic group is fused with an aryl group, in which aryl is as previously described. Exemplary fused radicals include benzofuran, benzdioxole and benzothiophene.

0060As used herein, the term "heterocyclicC_1-4 alkyl", "heteroaromaticC_1-4alkyl" and the like refer to the ring structure bonded to a C_1-4 alkyl radical.

0061All of the cyclic ring structures disclosed herein can be attached at any point where such connection is possible, as recognized by one skilled in the art.

0062As used herein, the term "patient" includes a human or an animal such as a companion animal or livestock.

0063As used herein, the term "halogen" includes fluoride, bromide, chloride, iodide or alabamide.

0064The 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, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, fumarate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, asparginate, glutamate and the like.

0065The invention disclosed herein is also meant to encompass the disclosed compounds being isotopically-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 ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ¹³P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Some of the compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric 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 olefinic double bonds or other centers of geometric asymmetry, 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 invention as well

0066As used herein, the term "stereoisomers" is a general term for all isomers of individual 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).

0067The term "chiral center" refers to a carbon atom to which four different groups are attached.

0068The term "enantiomer" or "enantiomeric" refers to a molecule that is nonsuperimposeable 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.

0069The term "racemic" refers to a mixture of equal parts of enantiomers and which is optically inactive.

0070The term "resolution" refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.

0071The term "modulate" as used herein with respect to the ORL-1 receptor means the mediation of a pharmacodynamic response (e.g:, analgesia) in a subject from (i) inhibiting or activating the receptor, or (ii) directly or indirectly affecting the normal regulation of the receptor activity. Compounds which modulate the receptor activity include agonists, antagonists, mixed agonists/antagonists and compounds which directly or indirectly affect regulation of the receptor activity.

0072Certain preferred compounds of formula (IIA) include: <ul id="ul0003" list-style="none" compact="compact"><li>3-ethylidene-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethylidene-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethylidene-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethylidene-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethylidene-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethylidene-1-[1-(<i>p</i>-benzyloxybenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethylidene-1-[1-(benzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethylidene-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethylidene-1-[1-(norbornan-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethylidene-1-[1-(3,3-diphenylpropyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethylidene-1-[1-(<i>p</i>-cyanobenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethyl-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethyl-1-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethyl-1-[1-(1,2,3,4-tetrahydro-2-naphthyl-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethyl-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethyl-1-[1-(norbornan-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethyl-1-[1-(3,3-Bis(phenyl)propyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethyl-1-[1-(4-propylcyclohexyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethyl-1-[1-(5-methylhex-2-yl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethyl-1-[1-[4-(1-methylethyl)cyclohexyl]-3-methyl-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;</li><li>3-ethyl-1-[1-(decahydro-2-naphthyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;and</li><li>pharmaceutically acceptable salts thereof and solvates thereof.</li></ul>

0073The present invention also provides use of any of the disclosed compounds in the preparation of a medicament for treating pain and other disease states modulated by an opioid receptor, e.g., the ORL-1 receptor.

<u style="single">DETAILED DESCRIPTION OF THE INVENTION</u>

0074The compounds of the present invention can be administered to anyone requiring modulation of the opioid and ORL1 receptors: Administration may be orally, topically, by suppository, inhalation, or parenterally.

0075The 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.

0076Various 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, solubilizers, binders, disintegrants, preservatives, coloring agents, reconstitution as an injectable formulation.

0077In certain embodiments, the compounds of the present invention can be used in combination with at least one other therapeutic agent. Therapeutic agents include, but are not limited to, µ-opioid agonists; non-opioid analgesics; non-steroid antiinflammatory agents; Cox-II inhibitors; antiemetics; β-adrenergic blockers; anticonvulsants; antidepressants; Ca2+-channel blockers; anticancer agent and mixtures thereof.

0078In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with a µ-opioid agonist. µ-opioid agonists, which may be included in the formulations of the present invention include but are not limited to include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorpbanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine; phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.

0079In certain preferred embodiments, the µ-opioid agonist is selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone, pharmaceutically acceptable salts thereof, and mixtures thereof.

0080In another embodiment of the invention, the medicament comprises a mixture of a Cox-II inhibitor and an inhibitor of 5-lipoxygenase for the treatment of pain and/or inflammation. Suitable Cox-II inhibitors and 5-lipoxygenase inhibitors, as well as combinations thereof are described in <patcit id="pcit0019" dnum="US6136839A"><text>U.S. Patent No. 6,136,839</text></patcit>, which is hereby incorporated by reference in its entirety. Cox-II inhibitors include, but are not limited to rofecoxib (Vioxx), celecoxib (Celebrex), DUP-697, flosulide, meloxicam, 6-MNA, L-745337, nabumetone, nimesulide, NS-398, SC-5766, T-614, L-768277, GR-253035, JTE-522, RS-57067-000, SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367, SC-5766, PD-164387, etoricoxib, valdecoxib and parecoxib or pharmaceutically acceptable salts, enantiomers or tautomers thereof.

0081The compounds of the present invention can also be combined in dosage forms with non-opioid analgesics, e.g., non-steroidal anti-inflammatory agents, including aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, pharmaceutically acceptable salts thereof, and mixtures thereof. Other suitable non-opioid analgesics which may be included in the dosage forms of the present invention include the following, nonlimiting, chemical classes of analgesic, Antipyretic, nonsteroidal antifinflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; para-aminophennol derivatives including acetaminophen; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid, and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone); and alkanones, including nabumetone. For a more detailed description of the NSAIDs that may be included within the medicaments employed in the present invention, see Paul A. Insel Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the treatment of <nplcit id="ncit0006" npl-type="b"><text>Gout in Goodman &amp; Gilman's The Pharmacological Basis of Therapeutics, 617-57 (Perry B. Molinhoff and Raymond W. Ruddon, Eds., Ninth Edition, 1996</text></nplcit>), and <nplcit id="ncit0007" npl-type="b"><text>Glen R. Hanson Analgesic, Antipyretic and Anit-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol II, 1196-1221 (A. R. Gennaro, Ed. 19th Ed. 1995</text></nplcit>).

0082In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with antimigraine agents. Antimigraine agents include, but are not limited to, alpiropride, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine, ergot, ergotamine, flumedroxone acetate,fonazine,lisuride, lomerizine, methysergide oxetorone, pizotyline, and mixtures thereof.

0083The other therapeutic agent can also be an adjuvant to reduce any potential side effects such as, for example, an antiemetic agent. Suitable antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acethylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxypemdyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinols, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.

0084In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with β-adrenergic blockers. Suitable β-adrenergic blockers include, but are not limited to, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumotol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol, tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

0085In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with anticonvulsants. Suitable anticonvulsants include, but are not limited to, acetylpheneturide, albutoin, aloxidone, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide,beclamide, buramate, calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenitroin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenytoin, mephobarbital, metharbital, methetoin, methsuximide, 5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide, phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassium bromide, pregabaline, primidone, progabide, sodium bromide, solanum, strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, and zonisamide.

0086In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with antidepressants. Suitable antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, nortriptyline, noxiptilin, opipramol, pizotyline, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, adrafinil, benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, levophacetoperane, medifoxamine, milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride, sulpiride, tandospirone, thozalinone, tofenacin, toloxatone, tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

0087In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with Ca2+-channel blockers. Suitable Ca2+-channel blockers include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, and perhexiline.

0088In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with anticancer agents. Suitable anticancer agents include, but are not limited to, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1 ; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper, mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; varozole; zeniplatin; zinostatin; zorubicin hydrochloride. Other anti-cancer drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor, carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxitene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor, leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator, protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors;stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

0089The compounds of the present invention and the other therapeutic agent can act additively or, more preferably, synergistically. In a preferred embodiment, a composition comprising a compounds of the present invention is administered concurrently with the administration of another therapeutic agent, which can be part of the same composition or in a different composition from that comprising the compounds of the present invention. In another embodiment, a composition comprising the compounds of the present invention is administered prior to or subsequent to administration of another therapeutic agent.

0090The compounds of the present invention when administered, e.g., via the oral, parenteral or topical routes to mammals, can be in a dosage in the range of about 0.01 mg/kg to about 3000 mg/kg body weight of the patient per day, preferably about 0.01 mg/kg to about 1000 mg/kg body weight per day administered singly or as a divided dose. However, variations will necessarily occur depending upon the weight and physical condition (e.g., hepatic and renal function) of the subject being treated, the affliction to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the presence of any deleterious side-effects, and the particular compound utilized, among other things.

0091The compounds of the present invention preferably have a binding affinity K₁ for the human ORL-1 receptor of about 500 nM or less; 100 nM or less; 50 nM or less; 20 nM or less or 5 nM or less. The binding affinity K₁ can be measured by one skilled in the art by an assay utilizing membranes from recombinant HEK-293 cells expressing the human opioid receptor-like receptor (ORL-1) as described below.

REFERENCE EXAMPLE 1

SYNTHESIS OF BENZOXAZOLONE HEAD GROUPS.

0092The head groups of the present invention were synthesized according to the following procedure: <chemistry id="chem0009" num="0009"><img file="EP1598338B1_D0009.tif" /></chemistry>

Procedure:

0093To a mixture of 1 (1.09 g,10 mmol), 2 (1.99 g, 10 mmol) and acetic acid (0.60 g,10 mmol) in 50 mL of dichloroethane, was added sodium triacetoxyborohydride (2.97 g, 14 mmol). The mixture was stirred at room temperature overnight. The mixture was filtered through Celite and 1 N NaOH (50 mL) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over K₂CO₃, filtered and evaporated in vacuum to give crude 3 as a brown solid (2.75 g, yield: 94%). ¹H NMR (CDCl₃): d 1.20-1.60. (m, 11 H), 2,00 (dd, 2H), 2.9 (m, 2H), 3.40 (m, 1H), 4.00 (m, 2H), 6.60-6.85 (m, 4H).

0094To an ice cooled solution of crude 3 (12.0 g, 40 mmol) and DIEA (20.8 mL, 120 mmol) in 200 mL of THF, was added a solution of triphosgene (4.32 g,14.4 mmol) in 200 mL of THF. After the addition was complete the ice bath was removed and the mixture stirred at room temperature overnight. The solids were filtered off and the filtrate evaporated in vacuum. The residual brown oil was dissolved in EtOAc and washed with saturated aqueous K₂CO₃. The organic phase was dried over K₂CO₃, filtered and evaporated in vacuum to give a red oil which was filtered through a column of silica gel eluting with a mixture of 5% Et₃N, 25% EtOAc and 70% hexane. The selected fractions were combined and the solvent evaporated in vacuum to give a brown solid which was crystallized from EtOAc to give pure 4 (10.0 g, 78% yield). ¹H NMR (CDCl₃): d 1.50 (s, 9H), 1.85 (d, 2H), 2.25 (m, 2H), 2.85 (m, 2H); 4.20-4.45 (m, 3H), 7.00-7.25 (m, 4H).

0095A solution of 4 (4.0 g, 17.2 mmol) in 30% TFA%dichloromethane (25 mL) was stirred at room temperature for 3 h. The solvent was evaporated in vacuum and saturated aqueous K₂CO₃ was added to the oily residue. The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic extracts were dried over K₂CO₃, filtered and evaporated in vacuum to give the crude product. Chromatography on silica gel eluting with a mixture of 10% Et₃N, 60% EtOAc and 30% hexane gave 5 as a yellow solid (1.82 g, 66% yield). MS: m/z 450 ¹H NMR (CDCl₃): d 1.75-2.10 (m, 3H), 2.30 (d, 2H), 2.80 (m, 2H), 3.20 (m, 2H), 4.25 (m, 1H), 7.00-7.25 (m, 4H).

REFERENCE EXAMPLE 2

ATTACHMENT OF TAIL GROUPS

0096Tail groups were attached to the head groups according to the following procedures: . <chemistry id="chem0010" num="0010"><img file="EP1598338B1_D0010.tif" /></chemistry>

General procedure for alkylation:

0097To a solution of the amine (1eq) and triethylamine (1eq) in dimethylformamide, was added 1 eq of alkyl bromide or chloride in one portion. The mixture was stirred and heated at 80°C over night. TLC indicated the reaction was complete. The reaction was quenched by the addition of water followed by 1 N NaOH to pH 10. The mixture was extracted 2x with Et₂O. The combined organic extracts were dried over potassium carbonate and the solvent evaporated, followed by chromatography to give the pure product.

General procedure for reductive amination:

0098To a mixture of ketone or aldehyde (1 eq), amine (1 eq), and acetic acid (1 eq) in methanol, was added sodium cyanoborohydride (1.4 eq) in one portion. The mixture was stirred over night at room temperature. TLC indicated the reaction was complete. The reaction was quenched by the addition of water followed by 1 N NaOH to pH 10. The mixture was extracted 2x with Et₂O. The combined organic extracts were dried over potassium carbonate and the solvent evaporated, followed by chromatography to give the pure product.

0099The following reference compounds were prepared by attaching the tail groups using the general procedures described: <ul id="ul0004" list-style="none"><li>3-[1-(naphth-2-yl-methyl)-4-piperidinyl]-2H-benzoxazol-2-one</li><li>3-[1-(naphth-1-yl-methyl)-4-piperidinyl]-2H-benzoxazol-2-one</li><li>3-[1-(<i>p</i>-phenylbenzyl)-4-piperidinyl]-2H-benzoxazol-2-one</li><li>3-[1-(<i>p</i>-benzyloxybenzyl)-4-piperidinyl]-2H-benzoxazol-2-one</li><li>3-[1-(<i>p</i>-cyanobenzyl)-4-piperidinyl]-2H-benzoxazol-2-one MS: m/z 334.4 (M+1)</li><li>3-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2H-benzoxazol-2-one</li><li>3-[1-[4,4-Bis-(4-fluorophenyl)butyl]-4-piperidinyl]-2H-benzoxazol-2-one MS: m/z 463.6 (M+1).</li><li>3-[1-(2-phenylethyl)-4-piperidinyl]-2H-benzoxazol-2-one</li><li>3-[1-(cyclooctymethyl)-4-piperidinyl]-2H-benzoxazol-2-one LC: 100% MS: m/z 343.6 (M+1). ¹H-NMR (CDCl₃): d 1.25 (m, 2H), 1.40-1.7 (m,17H), 2.10 (m, 4H), 3.10 (m, 2H), 4.20 (m, 1H), 7.10-7.20 (4H). 13C-NMR (CDCl3): d 26.02, 26.87, 27.55, 29.27, 31.23, 35.31, 53.39, 53.70, 66.28, 110.45, 110.51, 122.45, 123.96, 130.45, 143.08, 154.51.</li><li>3-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-2H-benzoxazol-2-one LC: 100% MS: 349.6 (M+1) 1H-NMR (CDCl3): d 1.70 (m, 1H), 2.00 (b, 2H), 2.10 (b, 1H), 2.40 (m, 4H), 2.90 (m, 5H), 3.10 (m, 2H), 4.20 (m, 1H), 7.10-7.3 0 (m, 8H).</li><li>3-[1-(5-methylhex-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one LC:100% MS: 317.4 (M+1) ¹H-NMR (CDCl₃): d 0.90 (d, 6H), 1.00 (d, 3H), 1.20 (m, 3H), 1.50-1.60 (m, 4H), 1.80 (m, 2H), 2.20-2.60 (m, 5H), 2.90 (b, 2H), 4.2 (m, 1H), 6.90-7.30 (m, 4H).</li><li>3-[1-(10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-4-piperidinyl]-2H-benzoxazol-2-one LC: 96.4% ¹H-NMR (CDCl₃): d 1.80 (dd, 2H), 2.00 (dt, 2H), 2.30 (dq, 2H), 2.80-2.95 (m, 4H), 4.01 (s, 1H), 4.05-4.22 (m, 3H), 7.05-7.25 (m, 12H).</li><li>3-[1-(4-propyl-cyclohexyl)-4-piperidinyl]-2H-benzoxazol-2-one MS: m/z 343.0</li><li>3-[1-(norbornan-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one LC: 97% MS: m/z 313.41 (M+1) ¹H-NMR (CDCl₃): d 0.90 (m,1H), 1.30-2.50 (m,17H), 3.20 (m,2H), 4.3 (m, 1 H), 6.90-7.30 (m,4H).</li><li>3-[1-(decahydro-2-naphthyl)-4-piperidinyl]-2H-benzoxazol-2-one MS: m/z 355.4</li><li>3-[1-(3,3-dimethyl-1,5-dioxaspiro[5.5]undeca-9-yl)-4-piperidinyl]-2H-benzoxazol-2-one MS: m/z 401.3</li><li>3-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-2H-benzoxazol-2-one MS: m/z 343.0</li><li>3-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one LC: 100% MS: m/z 335.4 (M+1) ¹H-NMR (CDCl₃): d 1.90 (m, 1H), 2.40 (m, 2H), 2.50 (m, 2H), 2.90 (m, 2H), 3.10-3.40 (m, 6H), 4.20 (m, 1H), 7.10-7.30 (m, 8H).</li><li>3-[1-(cyclooctyl)-4-piperidinyl]-2H-benzoxazol-2-one LC: 100% MS: m/z 329.2 (M+1) ¹H-NMR (CDCl₃): d 1.40-2.00 (m, 16H), 2.40-2.65 (m, 4H), 2.80 (m, 1H), 3.05 (m, 2H), 4.25 (m, 1H), 7.10-7.40 (m, 4H).</li></ul>

REFERENCE EXAMPLE 3

0100Nociceptin affinity at the ORL 1 receptor for preferred compounds was obtained using the following assay: Membranes from recombinant HEK-293 cells expressing the human opioid receptor-like receptor (ORL-1) (Receptor Biology) were prepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES, pH 7.4) (10 ml/10 cm dish) hollowed by homogenization with a tissue grinder/teflon pestle. Membranes were collected by centrifugation at 30,000 x g for 15 min at 4°C and pellets resuspended in hypotonic buffer to a final concentration of 1-3 mg/ml. Protein concentrations were determined using the BioRad protein assay reagent with bovine serum albumen as standard. Aliquots of the ORL-1 receptor membranes were stored at-80°C. Functional SGTPgS binding assays were conducted as follows. ORL-1 membrane solution was prepared by sequentially adding final concentrations of 0.066 mg/ml ORL-1 membrane protein, 10 mg/ml saponin, 3 mM GDP and 0.20 nM [³⁵S]GTPgS to binding buffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 ml/well) was transferred to 96-shallow well polypropylene plates containing 10 ml of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at room temperature with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GF/B filter plates (Packard) using a 96-well tissue harvester (Brandel) and followed by three filtration washes with 200 ml ice-cold binding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates were subsequently dried at 50°C for 2-3 hours. Fifty ml/well scintillation cocktail (BetaScint; Wallac) was added and plates were counted in a Packard Top-Count for 1 min/well. Data was analyzed using the curve fitting functions in GraphPad PRISMÔ, v. 3.0 and the results are set forth in table 1. below: <tables id="tabl0001" num="0001"><table frame="all"><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="133mm" /><colspec colnum="2" colname="col2" colwidth="22mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top"><b>TABLE 1</b></entry></row><row><entry namest="col1" nameend="col2" align="left" valign="top"><b>Nociceptin Affinity</b></entry></row><row><entry valign="top"><b>REFERENCE Compound</b></entry><entry valign="top"><b>calc K_l(nM)</b></entry></row></thead><tbody><row><entry>3-[1-(naphth-2-yl-methyl)-4-piperidinyl]-2H-benzoxazol-2-one</entry><entry>3030</entry></row><row><entry>3-(1-(naphth-1-yl-methyl)-4-piperidinyl]-2H-benzoxazol-2-one</entry><entry>370</entry></row><row><entry>3-[1-(<i>p</i>-phenylbenzyl)-4-piperidinyl]-2H-benzoxazol-2-one</entry><entry>>10,000</entry></row><row><entry>3-[1-(<i>p</i>-benzyloxybenzyl)-4-piperidinyl]-2H-benzoxazol-2-one</entry><entry>2173</entry></row><row><entry>3-[1-(<i>p</i>-cyanobenzyl)-4-piperidinyl]-2H-benzoxazol-2-one</entry><entry>>10,000</entry></row><row><entry>3-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2H-benzoxazol-2-one</entry><entry>726</entry></row><row><entry>3-[1-[4,4-Bis-(4-fluorophenyl)butyl]-4-piperidinyl]-2Hbenzoxazol-2-one</entry><entry>3070</entry></row><row><entry>3-[1-(2-phenylethyl)-4-piperidinyl]-2H-benzoxazol-2-one</entry><entry>7087</entry></row><row><entry>3-[1-(cyclooctylmethyl)-4-piperidinyl]-2H-benzoxazol-2-one</entry><entry>64</entry></row><row><entry>3-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-2Hbenzoxazol-2-one</entry><entry>93</entry></row><row><entry>3-[1-(5-methylhex-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one</entry><entry>60</entry></row><row><entry>3-[1-(10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-4-piperidinyl]-2H-benzoxazol-2-one</entry><entry>>10,000</entry></row><row><entry>3-[1-(3,3-dimethyl-1,5-dioxaspiro[5.5]undeca-9-yl)-4-piperidinyl]-2H-benzoxazol-2-one</entry><entry>>10,000</entry></row><row><entry>3-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one</entry><entry>512</entry></row><row><entry>3-[1-(cyclooctyl)-4-piperidinyl]-2H-benzoxazol-2-one</entry><entry>16</entry></row></tbody></tgroup></table></tables>

EXAMPLE 4

SYNTHESIS OF SUBSTITUTED INDOLE HEAD GROUPS

0101<chemistry id="chem0011" num="0011"><img file="EP1598338B1_D0011.tif" /></chemistry>

Procedure:

0102To a mixture of 2 (23.3 g, 0.25 mol), 1 (47.3 g, 0.25 mol), acetic acid (15 g, 0.25 mol) and molecular sieves (15 g) in 500 mL of dichloroethane, sodium triacetoxyborohydride (74.2 g, 0.35 mol) was added in one portion and the mixture stirred overnight. The molecular sieves were filtered off and 1 N NaOH (500 mL) was added to quench the reaction. The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 300 mL). The combined organic extracts were dried over K₂CO₃, filtered and the solvent evaporated under vacuum to give crude 3 as a brown solid which was directly used in next step.

Compound 3

0103¹H-NMR (CDCl₃): d 1.50 (m, 2H), 2.05 (m, 2H), 2.20 (bt, 2H), 2.85 (m, 2H), 3.30 (m, 1H), 3.52 (s, 2H), 6.60 (d, 2H), 6.70 (t, 1H), 7.20 (m, 2H), 7.25-7.40 (m, 5H),

0104To an ice cooled solution of crude 3 (0.25 mol,100% yield assumed) and DIEA (48.4 g, 0.38 mol) in 500 mL of dichloromethane, was added dropwise chloroacetyl chloride (42.4 g, 0.375 mol). After the addition was complete the ice bath was removed and the reaction mixture stirred overnight The solvent was removed in vacuum and the residue dissolved in dichloromethane. The organic phase was washed with saturated aqueous K₂CO₃, dried over K₂CO₃, filtered and the solvent removed in vaccum to give a brown gum which was filtered through a column of silica gel eluting with a mixture of 10% Et₃N, 40% EtOAc and 50% hexane. The selected fractions were combined and the solvent evaporated in vacuum to give a brown solid which was further crystallized from EtOAc to give 42.2 g of 4 (49.2%, 2 steps).

Compound 4

0105¹H NMR (DMSO): d 1.22 (m, 2H), 1.70 (b, 2H), 2.00 (t, 2H), 2.80 (b, 2H), 3.40 (s, 2H), 3.80 (s, 2H), 4.40 (m, 1H), 7.15-7.30 (m, 7H), 7.45 (m, 3H).

0106A mixture of 4 (42.2 g, 0.12 mol) and AlCl₃ (49.2 g, 0.369 mol) was mixed in a flask by rapid stirring. The mixture was then heated in an oil bath at 130 °C. Within a few minutes the solids melted and became a dark liquid with concomitant gas evolution. After heating for 1 h the reaction mixture was cooled somewhat and while still mobile poured into a beaker containing 500 mL of ice water. The solution was basified and extracted with dichloromethane. The organic layer was dried over Na₂SO₄, filtered and the solvent evaporated in vacuum to give a dark oil which was filtered through a column of silica gel eluting with a mixture of 10% Et₃N, 40% EtOAc and 50% hexane. The selected fractions were combined and the solvent evaporated in vacuum to give 5 as a red oil which set to a pale solid (22.0 g, 58.5%).

Compound 5

0107¹H NMR (CDCl₃): d 1.70 (m, 2H), 2.17 (m 2H), 2.50 (m, 2H), 3.05 (m, 2H), 3.55 (s, 2H), 3.60 (s, 2H), 4.33 (m, 1H), 7.00-7.40 (m, 9H).

0108To a solution of 5 (16.0 g, 0.052 mol) in 35 mL of methanol was added Pd(OH)₂ (4.0 g). The resulting suspension was hydrogenated at 50 psi for 12 h at room temperature. The solution was filtered through a pad of Celite and the pad washed with methanol (2 x 20 mL). Evaporation of the solvent in vacuum gave 6 as a pale solid (11.2 g, 100%).

Compound 6

0109LC: 100% MS: m/z 217 (M+1). ¹H NMR (CDCl₃): d 1.75 (m, 3H), 2.35 (m 2H), 2.75 (m, 2H), 3.25 (m, 2H), 3.50 (s, 2H), 4.33 (m, 1H), 7.00-7.30 (m, 4H)

0110To a solution of 6 (8.0 g, 37.0 mmol) in 50 mL of dichloromethane was added Et₃N (4.07 g, 40.7 mmol) and BOC anhydride (8.87 g, 40.7 mmol). After stirring for 3 h saturated aqueous K₂CO₃ was added and the layers separated. The aqueous phase was extracted with dichloromethane (2 x 50 mL). The combined organic phase was dried over K₂CO₃, filtered and evaporated in vacuum to give a brown oil which was filtered through a column of silica gel eluting with a mixture of 10% Et₃N, 40% EtOAc and 50% hexane. The selected fractions were combined and the solvent evaporated in vacuum to give 7 as an off white solid (8.50 g, 73%).

Compound 7

0111¹H NMR (CDCl₃): d 1.50 (m, 9H), 1.70 (m 2H), 2.20-2.50 (m, 2H), 2.80-3.00 (m, 2H), 3.50 (s, 2H), 4.20-4.50 (m, 3H), 6.90-7.60 (m, 5H).

0112To a mixture of 7 (6.0 g, 19.0 mmol) and sodium acetate (2.58 g, 19.0 mmol) in 150 mL of methanol was added acetaldehyde (1.67 g, 38.0 mmol). The mixture was refluxed for 2 h. The solvent was evaporated in vacuum to give a dark oil which was filtered through a column of silica gel eluting with a mixture of 10% Et₃N, 40% EtOAc and 50% hexane. The selected fractions were combined and the solvent evaporated in vacuum to give 8 as a red oil (5.90 g, 91 %).

Compound 8

0113LC: 2 isomers in a ratio of 2:1. ¹H NMR (CDCl₃): (mixture of 2 isomers) d 1.50 (m, 9H), 1.70 (m 2H), 2.20-2.50 (m, 6H), 2.60-3.00 (m, 2H), 4.20-4.50 (m, 3H), 6.90-7.60 (m, 5H).

0114A solution of 8 (5.90 g, 17.2 mmol) in 30% TFA/dichloromethane (100 mL) was stirred at room temperature for 3 h. The solvent was evaporated in vacuum and saturated aqueous K₂CO₃ was added to the oily residue. The resulting mixture was extracted with dichloromethane (3 x 150 mL). The combined organic extracts were dried over K₂CO₃, filtered and evaporated in vacuum to give the crude product. Chromatography on silica gel eluting with a mixture of 10% Et₃N, 50% EtOAc and 40% hexane gave 9 (E/Z isomers) as a yellow foam (3.60 g, 82%).

Compound 9

0115LC: 2 isomers in a ratio of 2:1. MS: m/z 243.1 (M+1). ¹H NMR (CDCl₃): (mixture of 2 isomers) d 0.85 (m, 1H), 1.50 -2.00 (m, 4H), 2.20-2.50 (m, 5H), 2.60 (m, 1H), 3.10-3.50 (m, 2H), 4,30 (m, 1H), 6.90-7.60 (m, 5H).

EXAMPLE 5

0116<chemistry id="chem0012" num="0012"><img file="EP1598338B1_D0012.tif" /></chemistry>

0117To a mixture of 5 (5.50 g, 18 mmol) and sodium acetate (2.45 g,18 mmol) in 150 mL of methanol was added acetaldehyde (1.58 g, 36 mmol). The mixture was refluxed for 2 h. The solvent was evaporated in vacuum to give a dark oil which was filtered through a column of silica gel eluting with a mixture of 10% Et₃N, 40% EtOAc and 50% hexane. The selected fractions were combined and the solvent evaporated in vacuum to give 10 as a red oil (5.90 g, 98%).

Compound 10

0118LC: 2 isomers in a ratio of 2:1. MS: m/z 333.2 (M+1). ¹H NMR (CDCl₃): d 1.70 (m, 2H), 2.17 (m 2H), 2.30 (d, 3H), 2.50 (m, 2H), 3.05 (m, 2H), 3.55 (s, 2H), 4.33 (m, 1H), 7.00-7.40 (m, 9H), 7.6 (d, 1H).

0119To a solution of 10 (5.90 g, 17.7 mmol) in 30 mL of methanol was added Pd(OH)₂ (3.0 g). The resulting suspension was hydrogenated at 50 psi for 12 h at room temperature. The solution was filtered through a pad of Celite and the pad washed with methanol (2 x 20 mL). Evaporation of the solvent in vacuum gave a pale solid which was purified by chromatography on silica gel eluting with a mixture of 10% methanol and 90% EtOAc to give 11 as an off white solid (2.02 g, 50%).

Compound 11

0120LC: 97% MS: m/z 245.2 (M+1) ¹H NMR (CDCl₃): d 0.85 (t, 3H), 1.26 (m, 2H), 2.00 (m, 2H), 2.43 (m, 2H), 2.90 (m, 2H), 3.3 (m, 2H), 3.4 (m, 1H), 4.4 (m, 1H), 7.05 (m, 1H), 7.15-7.30 (m, 3H).

REFERENCE EXAMPLE 6

0121<chemistry id="chem0013" num="0013"><img file="EP1598338B1_D0013.tif" /></chemistry>

Procedure:

0122In a manner similar to the preparation of 6, compound 16 was prepared.

Compound 13

0123LC: 89.4% MS: m/z 281.2 (M+1) ¹H-NMR (mixture of trans and cis) (CDCl₃): d 0.95 (m, 3H), 1.50-2.75 (m, 5H), 2.80-3.20 (m, 1H), 3.50 (m, 2H), 3.60 (minor)+3,70 (major) (two s, 2H), 6.55-6.80 (m, 2H), 7.05-7.45 (m, 8H).

Compound 14

0124MS: m/z 357.2 (M+1) ¹H-NMR (mixture of trans and cis) (CDCl₃): d 1.10 (m, 3H), 1.40-4.20 (m, 11H), 4.40 (m,1H), 7.05-7.50 (m, 10H).

Compound 15

0125LC:90.0% MS: m/z 321.2 (M+1) ¹H-NMR (CDCl₃): d 1.20 (d, 3H),1.75 (m, 1H), 2.10 (dt, 1H), 2.25 (b, 1H), 2.30 (dd, 1H), 2.75 (dd, 1H), 3.05 (m, 1H), 3.20 (m, 1H), 3.50 (m, 4H), 4.10 (m, 1H), 6.99 (m, 2H), 7.23 (m, 3H), 7.37 (m, 4H).

Compound 16

0126LC: 92.5% MS: m/z 231.2 (M+1) 1H-NMR (CDCl3): d d 1.20 (d, 3H), 1.75 (m, 1H), 2.10 (dt, 1H), 2.25 (b, 1H), 2.30 (dd, 1H), 2.75 (dd, 1H), 3.05 (m,1H), 3.20 (m, 1H), 3.50 (m, 2H), 4.10 (m, 1H), 6.99 (m, 2H), 7.23 (m, 3H), 7.37 (m, 4H).

EXAMPLE 7

0127<chemistry id="chem0014" num="0014"><img file="EP1598338B1_D0014.tif" /></chemistry>

Procedure:

0128In a manner similar to the preparation of 11, compound 18 was prepared.

Compound 17

0129MS: m/z 347.3 (M+1)

Compound 18

LC: 82.6%

0130MS: m/z 259.3 (M+1) ¹H-NMR (CDCl₃): d 0.80 (t, 3H), 1.20 (d, 3H), 2.00 (m, 2H), 2.3,0 (m, 1H), 2.65 (m, 1H), 2.82 (m, 1H), 3.15-3.25 (m, 1H), 3.32 (m, 1H), 3.45 (m, 1H), 3.65 (m, 1H), 3.75 (m, 1H), 4.25 (m, 1 H), 6.90 (d, 1H), 7.05 (t, 1H), 7.25 (m, 2H).

EXAMPLE 8

ATTACHMENT OF TAIL GROUPS

0131Tail groups were attached to the head groups according to the following procedures: <chemistry id="chem0015" num="0015"><img file="EP1598338B1_D0015.tif" /></chemistry>

General procedure for alkylation:

0132To a solution of the amine (1 eq) and triethylamine (1 eq) in dimethylformamide, was added 1 eq of alkyl bromide or chloride in one portion. The mixture was stirred and heated at 80°C over night. TLC indicated the reaction was complete. The reaction was quenched by the addition of water followed by 1 N NaOH to pH 10. The mixture was extracted 2x with Et₂O. The combined organic extracts were dried over potassium carbonate and the solvent evaporated, followed by chromatography to give the pure product.

General procedure for reductive amination:

0133To a mixture of ketone or aldehyde (1 eq), amine (1 eq), and acetic acid (1 eq) in methanol, was added sodium cyanoborohydride (1.4 eq) in one portion. The mixture was stirred over night at room temperature. TLC indicated the reaction was complete. The reaction was quenched by the addition of water followed by 1N NaOH to pH 10. The mixture was extracted 2x with Et₂O. The combined organic extracts were dried over potassium carbonate and the solvent evaporated, followed by chromatography to give the pure product.

0134The following compounds were prepare by attaching the tail groups using the general procedures described: <ul id="ul0005" list-style="none"><li>1-[1-(naphth-1-yl-methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * MS: m/z 357.2 (M+1).</li><li>1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * MS: m/z 357.3 (M+1).</li><li>1-[1-(<i>p</i>-phenylbenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * MS: m/z 383.2 (M+1).</li><li>1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * LC: 98.7% MS: m/z 411.2 (M+1) ¹H-NMR (CDCl₃): d 1.65 (bd, 2H), 2.05 (bt, 2H), 2.30 (m, 4H), 2.45 (m, 2H), 3.02 (bd, 2H), 3.50 (s, 2H), 4.01 (1, 1H), 4.30 (m; 1H), 7.00 (t, 1H), 7.15-7.35 (m, 13H).</li><li>1-[1-(<i>p</i>-cyanobenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * MS: m/z 332.2 (M+1).</li><li>1-[1-(<i>p</i>-benzyloxybenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * MS: m/z 413.3 (M+1)</li><li>1-[1-(1,2,3,4-tetrahydronaphth-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * LC: 100% MS: m/z 347.5 (M+1). ¹H NMR (CDCl₃): d 1.70 (m, 3H), 2,10 (m, 1H), 2.40 (m, 4H), 2.90-3.00(m, 5H), 3.10 (m, 2H), 3.60 (s, 2H), 4.3 (m, 1H), 7.00-7.30 (m, 8H).</li><li>1-[1-(5-methylhex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * 100% MS: m/z 315.4 (M+1). ¹H NMR (CDCl₃): d 0.90 (m, 6H),1.00 (m, 3H),1.20 (m, 3H),1.5-1.8 (m, 2H), 2.2-2.6 (m, 5H), 2.90 (m, 2H), 3.60 (s, 2H), 4.2 (m,1H), 6.90-7.30 (m, 4H).</li><li>1-[1-(norbornan-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * LC: 97% MS: m/z 311.41 (M+1). ¹H NMR (CDCl₃): d 0.90 (m, 1H), 1.30-2.00(m, 7H), 2.10-2.30 (m, 5H), 3.20 (m, 2H), 3.60 (s, 2H), 4.3 (m, 1H), 6.90-7.30 (m, 4H).</li><li>1-[1-1,3-dihydroinden-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * LC: 100% MS: m/z 332.4 (M+1). ¹H NMR (CDCl₃): d 1.80 (m, 2H), 2,40 (m, 2H), 2.50 (m, 2H), 2.90 (m, 2H), 3.10-3,40 (m, 5H), 3.60 (s, 2H), 4.20 (m, 1H), 7.10-7.30 (m, 8H).</li><li>1-[1-(cycooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indolo-2-one * LC: 97% MS: m/z 341.50 (M+1). ¹H NMR (CDCl₃): d 1.25 (m, 3H),1-4-1.7 (m, 14H), 2.10 (m, 4H), 2.50(m, 2H), 3.10 (m, 2H), 3.60 (s, 2H), 4.3 (m, 1H), 7.10-7.20 (m, 4H). ¹³C-NMR (CDCl₃): d 23.07, 26.04, 26.89, 27.56, 28.63, 31.27, 32.00, 35.30, 36.33, 46.63, 50.65, 54.06, 66.47, 110.90, 122.17, 124.90,125.26, 127.94, 144.25, 175.31.</li><li>3-ethyl-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one MS: m/z 375.3 (M+1).</li><li>3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one MS: m/z 369.2 (M+1).</li><li>3-ethyl-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one LC: 100% MS: m/z 342.4 (M+1). ¹H NMR (CDCl₃): d 0.80 (t, 3H), 0.90 (m, 6H), 1.00 (m, 3H), 1.20 (m, 3H), 1.5-1.8 (m, 2H), 2.2-2.6 (m, 5H), 2.90 (m, 2H), 3.40 (m, 1H), 4.3 (m, 1H), 6.90-7.30 (m, 4H).</li><li>3-ethyl-1-[1-(norbornan-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one LC: 100% MS: m/z 339.41 (M+1). ¹H NMR (CDCl₃): d 0.80 (m,3H), 0.90 (m, 1H), 1.30-1.45 (m, 5H), 1.50-2.05 (m, 8H), 2.10 (m, 1H), 2.20 (m, 2H), 2.50 (m, 2H), 3.10 (m, 2H), 3.40 (m, 1H), 4.3 (m, 1H), 6.90-7.30 (m, 4H).</li><li>3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one MS: m/z 381.3 (M+1). 3-ethyl-1-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-1,3-dihydro-2H-indole-2-one MS: <i>mlz</i> 369.3 (M+1) ¹H-NMR (CDCl₃): d 0.88 (t, 3H), 0.92 (d, 6H),1.17 (m, 1H), 1.40 (m, 2H), 1.50-1.70 (m, 9H), 2.05 (m, 2H), 2.25 (m, 2H), 2.32-2.55 (m, 3H), 3.15 (b, 2H), 3.43 (t, 1H), 4.35 (m, 1H), 7.05 (t, 1H), 7.22 (d, 1H), 7.28 (m, 2H).</li><li>3-ethyl-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one MS: m/z 361.2 (M+1).</li><li>3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one LC: 97% MS: m/z 369.50 (M+1). ¹H NMR (CDCl₃): d 0.80 (t, 3H), 1.25 (m, 3H), 1-4-1.7 (m, 14H), 2.10 (m, 6H), 2.50(m, 2H); 3.10 (m, 2H), 3.40 (m, 1H), 4.3 (m, 1H), 7.10-7.20 (m, 4H).</li><li>3-ethylidene-1-[1-(benzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one MS: m/z 333.2 (M+1) ¹H-NMR (CDCl₃): d 1.70 (m, 2H), 2.1 (dt, 2H), 2.28 (d, 3H), 2.47 (m, 2H), 3.05 (b, 2H), 3.57 (s, 2H), 4.34 (m, 1H), 7.02 (t, 1H), 7.08-7.40 (m, 8H), 7.58 (d, 1H).</li><li>3-ethylidene-1-[1-(naphth-2-yl-methy)-4-piperidinyl]-1,3-dihydro-2H-indole-2one MS: m/z 405.2</li><li>3-ethylidene-1-[1-(3,3-diphenylpropyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one LC: >97% (2 isomers combined). MS: m/z 437.5 (M+1). ¹H NMR (CDCl₃): d 1.70 -1.80 (m, 3H), 2,10 (m, 2H), 2.20 - 2.40 (m, 8H), 3.10 (m, 2H), 4.10 (M, 1H), 4.3 (m, 1H), 7.00-7.30 (m, 15H).</li><li>3-ethylidene-1-[1-(<i>p</i>-cyanobenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one LC: >97% (2 isomers combined). MS: m/z 358.5 (M+1). ¹H NMR (CDCl₃): d1.80 (m, 4H), 2.10-2.60 (m, 5H), 3.10 (m, 2H), 3.70 (s, 2H), 4.3 (m, 1H), 6.90-7.60 (m, 8H).</li><li>3-ethylidene-1-[1-(<i>p</i>-benzyloxybenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one MS: m/z 405.2.</li><li>3-ethylidene-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one LC: >97% (2 isomers combined). MS: m/z 373:5.(M+1). ¹H NMR (CDCl₃): d 1.70 - 3.10 (m, 18H), 4.3 (m, 1H), 7.00-7.30 (m, 9H).</li><li>3-ethylidene-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one LC: >97% (2 isomers combined). MS: m/z 367.5 (M+1). ¹HNMR (CDCl₃): d 0.90 (m, 1H), 1.30-2.00(m, 7H), 2.10-2.30 (m, 5H), 3.20 (m, 2H), 3.60 (s, 2H), 4.3 (m, 1H), 6.90-7.30 (m, 5H).</li><li>3-ethylidene-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-1,3 -dihydro-2H-indole-2-one LC: >97% (2 isomers combined). MS: m/z 341.4 (M+1). ¹H NMR (CDCl₃): d 0.90 -2.6 (m, 24H), 2.90 (m, 2H), 4.2 (m, 1H), 6.90-7.30 (m, 3H).</li><li>3-ethylidene-1-[1-(norboman-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one LC: >97% (2 isomers combined). MS: m/z 337.41 (M+1). ¹H NMR (CDCl₃): d 0.90 (m, 1H),1.30-2.50(m, 17H), 3.10 (m, 2H), 4.3 (m, 1H), 6.90-7.30 (m, 5H).</li><li>3-ethylidene-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one LC: >97% (2 isomers combined). MS: m/z 359.4 (M+1). ¹H NMR (CDCl₃): d 1.80 - 3.10 (m, 17H), 4.20 (m, 1H), 7.10-7.30 (m, 9H).</li><li>3-ethylidene-1-[1-(cyclooctylmethyl)-4-pipendinyl]-1,3-dihydro-2H-indole-2-one LC: >97% (2 isomers combined). MS: m/z 367.50 (M+1). ¹H NMR (CDCl₃): d 1.25 (m, 3H),1.4-1.7 (m, 21H), 2.10 - 2.50(m, 2H), 3.10 (m, 2H), 4.3 (m, 1H), 6.90-7.60 (m, 5H).</li><li>1-[1-(3,3-Bis(phenyl)propyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * LC:100% MS: m/z 425.3 (M+1) ¹H-NMR (CDCl₃): d 1.20 (d, 3H),1.69 (bd, 1H), 1.95 (dt,1H), 2.13-2.30 (m, 5H), 2.72 (bd, 1H), 2.98 (bd, 1H), 3.15 5 (dq, 1H), 3.50 (s, 2H), 4.03 (dt, 1H), 4.12 (t, 11-1), 6.94 (d,1 1H), 7.00 (t, 1H), 7.10-7.30 (m, 12H).</li><li>1-[1-(benzyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * LC: 100% MS: m/z 321.2 (M+1) ¹H-NMR (CDCl₃): d 1.20 (d, 3H),1.70 (m,1H), 2.10 (dt,1H), 2.23 (m, 1H), 2.35 (dd,1H), 2.78 (d, 1H), 3.05 (m, 1H), 3.20 (dq, 1H), 3.51 (m, 4H), 4.10 (dt, 1H), 7.00 (m, 2H), 7.25 (m, 3H), 7.38 (m, 4H).</li><li>1-[1-(4-propyl-cyclohexyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * LC:96.2% MS: m/z 355.2 (M+1) ¹H-NMR (CDCl₃): d 0.85 (m, 3H), 1.15 (m, 3H), 1.22-1.85 (m, 13H), 2.05-2.90 (m, 6H), 2.95-3.20 (m, 2H), 3.50 (s, 2H), 4.05 (m, 1H), 7.00 (m, 2H), 7.22 (m, 2H).</li><li>1-[1-(5-methylhex-2-yl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * LC: 100% MS: m/z 329.2 (M+1) ¹H-NMR (CDCl₃): d 0.85 (m, 9H), 1.1 (m, 3H), 1.20-1.75 (m,6H), 2.25 (m, 1H), 2.45-2.75 (m, 4H), 2.88 (m, 1H), 3.10 (m, 1H), 3.50 (s, 2H), 4.05 (m, 1H), 6.98 (m, 2H), 7.25 (m, 2H).</li><li>1-[1-(decahydro-2-naphthyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * LC:95.3% MS: m/z 367.2 (M+1) ¹H-NMR (CDCl₃): d1.11 (d, 3H), 1.16-1.85 (m, 16H), 2.20 (m,1H), 2.35 (m, 2H), 2.52 (m, 2H), 2.75 (m, 1H), 3.02 (m, 2H), 3.50 (s, 2H), 4.05 (m, 1H), 6.96 (m, 2H), 7.20 (m, 2H).</li><li>1-[1-(4-(1-methylethyl)cyclohexyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * LC: 96.1% MS: m/z 355.2 (M+1) ¹H-NMR (CDCl₃): d 0.80 (m, 6H), 1.15 (m, 3H), 1.22-1.48 (m, 3H), 1.50-1.90 (m, 6H), 2.15-2.90 (m, 4H), 2.95-3.25 (m, 2H). 3.50 (s, 2H), 4.10 (m, 1H), 6.95 (m, 2H), 7.22 (m, 2H).</li><li>1-[1-(cyclooctylmethyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one * LC:100% MS: m/z 355.2 (M+1) ¹H-NMR (CDCl₃): d 1.1.2 (d, 3H), 1.15-1.75 (m, 16H), 1.92-2.10 (m, 3H), 2.20 (m, 2H), 2.73 (m, 1H), 3.00 (m, 1 H), 3.12 (dq, 1H), 3.50 (s, 2H), 4.05 (dt, 1H), 6.99 (m, 2H), 7.20 (m, 2H).</li><li>3-ethyl-1-[1-(3,3-Bis(phenyl)propyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one LC: 96.3% MS: m/z 453.3 (M+1) ¹H-NMR (CDCl₃): d (two t, 3H),1.18 (d, 3H), 1.70 (m, 1H), 1.90-2.05 (m, 3H), 2.12-2.30 (m, 5H). 7.73 (m, 1H), 2.97 (bd, 1H), 3.10-3.30 (m, 1H), 3.38 (t, 1H), 3.90-4.05 (m, 1H), 4.12 (q, 1H), 6.90-7.00 (two d, 1 H), 7.02 (t, 1 H), 7.12-7.32 (m, 12H).</li><li>3-ethyl-1-[1-(4-propylcylohexyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one LC: 93.2% MS: m/z 383.3 (M+1) ¹H-NMR (CDCl₃): d 0.75-0.95 (m, 6H), 1.05-1.20 (m, 5H), 1.20-1.35 (m, 4H), 1.35-1.75 (m, 6H), 1.75-1.90 (m, 2H), 1.95-2.05 (m, 2H), 2.15-2.45 (m, 3H), 2.55 (d, 0.5H), 2.75 (d, 0.5H), 2.95-3.15 (m, 2H), 3.38 (t, 1H), 3.90-4.10 (m, 1H), 6.90-7.05 (2H), 7.20-7.25 (m, 2H).</li><li>3-ethyl-1-[1-(5-methylhex-2-yl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one; LC: 92.3% MS: m/z 357.4 (M+1) ¹H-NMR (CDCl₃): d 0.75-0.95 (m, 10H), 1.10 (d, 3H), 1.15-1.40 (m, 3H), 1.40-1.75 (m, 4H), 1.97-2.10 (m, 2H), 2.20 (m, 1H), 2.43-2.75 (m, 4H), 2.80-2.95 (m, 1H). 3.00-3.25 (m,1H), 3.40 (t, 1H), 3.90-4.10 (m, 1H), 6.90-7.05 (m, 2H), 7.25 (m, 2H).</li><li>3-ethyl-1-[1-[4-(1-methylethyl)cyclohexyl]-3-methyl-4-piperidinyl]-1,3-dihydro-2H-indole-2-one LC: 94.7% MS: m/z 383.4 (M+1) ¹H-NMR (CDCl₃): d 0.75-1.05 (m, 8H), 1.10-1.50 (m, 7H), 1.50-1.90 (m, 7H), 1.90-2.10 (m, 2H), 2.15-2.43 (m, 3H), 2.55 (d, 0.5H), 2.75 (d, 0.5H), 2.90-3.25 (m, 3H), 3.40 (t,1H), 3.90-4.10 (m, 1H), 6.90-7.01 (m, 2H), 7.25 (m, 2H).</li><li>3-ethyl-1-[1-(decahydro-2-naphthyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one LC: 94.3% MS: m/z 395.3 (M+1) ¹H-NMR(CDCl₃): d 1.75-1.90 (two t, 3H),1.10 (d, 3H), 1.15-1.90 (m, 15H), 2.00 (m, 2H), 2.20 (bs, 1H), 2.40 (m, 2H), 2.45-1.60 (m, 2H), 2.75 (m, 1H), 2.90-3.20 (m, 2H), 3.40 (bs, 1H), 3.90-4.15 (m, 1H), 6.90-7.05 (m, 2H), 7.25 (m, 2H).</li></ul> * REFERENCE COMPOUNDS

0135Other compounds within the scope of formula (II) or (IIA) of the present invention can be synthesized by analogous techniques.

EXAMPLE 9

0136Nociceptin affinity at the ORL1 receptor for preferred compounds was obtained using the following assay: Membranes from recombinant HEK-293 cells expressing the human opioid receptor-like receptor (ORL-1) (Receptor Biology) were prepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES, pH 7.4) (10ml/10 cm dish) followed by homogenization with a tissue grinder/teflon pestle. Membranes were collected by centrifugation at 30,000 x g for 15 min at 4°C and pellets resuspended in hypotonic buffer to a final concentration of 1-3 mg/ml. Protein concentrations were determined using the BioRad protein assay reagent with bovine serum albumen as standard. Aliquots of the ORL-1 receptor membranes were stored at-80°C. Functional SGTPgS binding assays were conducted as follows. ORL-1 membrane solution was prepared by sequentially adding final concentrations of 0.066 mg/ml ORL-1 membrane protein, 10 mg/ml saponin, 3 mM GDP and 0.20 nM [³⁵S]GTPgS to binding buffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH J.4) on ice. The prepared membrane solution (190 ml/well) was transferred to 96-shallow well polypropylene plates containing 10 ml of20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at room temperature with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GF/B filter plates (Packard) using a 96-well tissue harvester (Brandel) and followed by three filtration washes with 200 ml ice-cold binding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates were subsequently dried at 50°C for 2-3 hours. Fifty ml/well scintillation cocktail (BetaScint; Wallac) was added and plates were counted in a Packard Top-Count for 1 min/well. Data was analyzed using the curve fitting functions in GraphPad PRISMÔ, v. 3.0 and the results are set forth in table 2 below: <tables id="tabl0002" num="0002"><table frame="all"><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="132mm" /><colspec colnum="2" colname="col2" colwidth="23mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top"><b>TABLE 2</b></entry></row><row><entry namest="col1" nameend="col2" align="left" valign="top"><b>Nociceptin Affinity</b></entry></row><row><entry valign="top"><b>Compound</b></entry><entry valign="top"><b>calc K₁ (nM)</b></entry></row></thead><tbody><row><entry>3-ethylidene-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>11.1</entry></row><row><entry>3-ethylidene-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>19</entry></row><row><entry>3-ethylidene-1-[1-(1,2,3,4-tetrahydro-2-naphtyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>16.7</entry></row><row><entry>3-ethylidene-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>20.7</entry></row><row><entry>3-ethylidene-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>630</entry></row><row><entry>3-ethylidene-1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>516</entry></row><row><entry>3-ethylidene-1-[1-(benzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>1854</entry></row><row><entry>3-ethylidene-1-[1-(cyclooctymethyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>22.3</entry></row><row><entry>3-ethylidene-1-[1-(3,3-diphenylpropyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2 one</entry><entry>100.7</entry></row><row><entry>3-ethylidene-1-[1-(norboman-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>922</entry></row><row><entry>3-ethylidene-1-[1-(<i>p</i>-cyanobenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>7652</entry></row><row><entry>3-ethyl-1-[1-(5-methylhex-2-yl)]-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>4</entry></row><row><entry>3-ethyl-1-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>.86</entry></row><row><entry>3-ethyl-1-[1-(4-ptopylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>40</entry></row><row><entry>3-ethyl-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>124</entry></row><row><entry>3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]- 1,3-dihydro-2H-indole-2-one</entry><entry>3.6</entry></row><row><entry>3-ethyl-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>43</entry></row><row><entry>3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>9</entry></row><row><entry>3-ethyl-1-[1-(norboman-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>82.7</entry></row><row><entry>1-[1-(naphth-1-ylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one*</entry><entry>92</entry></row><row><entry>1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one*</entry><entry>107</entry></row><row><entry>1-[1-(<i>p</i>-phenylbenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2one*</entry><entry>1362</entry></row><row><entry>1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one*</entry><entry>12.5</entry></row><row><entry>1-[1-(<i>p</i>-cyanobenzyl)-4-piperidinyl]-1,3-dihydio-2H-indole-2-one*</entry><entry>1267</entry></row><row><entry>1 [1(<i>p</i>-benzyloxybenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one*</entry><entry>32</entry></row><row><entry>1-[1-(1,2,3,4-tetrahydronaphth-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one*</entry><entry>28.7</entry></row><row><entry>1-[1-(5-methylhex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one*</entry><entry>7.4</entry></row><row><entry>1-[1-(norbornan-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one*</entry><entry>215</entry></row><row><entry>1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one*</entry><entry>18.7</entry></row><row><entry>1-[1-(cycooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one*</entry><entry>54.3</entry></row><row><entry>1-[1-(benzyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one*</entry><entry>> 10,000</entry></row><row><entry>1-[1-(4-propyl-cyclohexyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one*</entry><entry>2435</entry></row><row><entry>1-[1-(5-methylhex-2-yl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one*</entry><entry>4335</entry></row><row><entry>1-[1-(decahydro-2-naphthyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one*</entry><entry>366</entry></row><row><entry>1-[1-(4-(1-methylethyl)-cyclohexyl)-3-(methyl)-4-piperidinyl]-1,3-dihycdro-2H-indole-2-one*</entry><entry>167</entry></row><row><entry>1-[1-(cyclooctylmethyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one*</entry><entry>189</entry></row></tbody></tgroup><tgroup cols="2" rowsep="0"><colspec colnum="1" colname="col1" colwidth="132mm" /><colspec colnum="2" colname="col2" colwidth="23mm" /><tbody><row><entry namest="col1" nameend="col2" align="justify">*REFERENCE COMPOUNDS</entry></row></tbody></tgroup></table></tables>

REFERENCE EXAMPLE 10

SYNTHESIS OF CERTAIN HEAD GROUPS.

0137<chemistry id="chem0016" num="0016"><img file="EP1598338B1_D0016.tif" /></chemistry>

Procedure:

0138To a mixture of 4 (21.6 g, 0.2 mole), 5 (15.6 g, 0.1 mole), acetic acid (6 g, 0.1mole) in 500 ml of dichloroethane, 29.7 g of sodium triacetoxyborohydride (0.14 mol,1.4 eq) was added in one portion. Gas evolves between 30 min and 1 hr. The mixture was stirred over night. TLC indicated the reaction is complete. 1 N NaOH (500 ml) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted by EtOAC (300 ml x2). The combined organics were dried over potassium carbonate and the solvent evaporated to give a red oil which was column filtrated (5%Et3N, 25%EtOAc and 70%Hexane) to give 14 g of product 6 as a white solid (54%).

Compound 6

0139MS: m/z 249.3 (M+1). ¹H NMR (CDCl₃): d 1.50 -1.90 (m, 6H), 2.05 (m, 2H), 3.30 (m, 4H), 3.95 (s. 4H), 6.60 -6.80 (m, 4H).

0140To a solution of 13.5 g of 6 (54.4 mmol) in 50 ml of acetonitrile, 11.02 g of carbonyldiimidazole was added in one portion. The mixture was stirred over night. Solid precipitated out of solution which was filtered and washed by H₂O and TBUG to give 7.5 g of product. The filtrate was evaporated and the crude material was dissolved in EtOAc, washed with water and saturated potassium carbonate solution. The organics were dried over potassium carbonate. The solvent was evaporated to give a second batch of solid with a pink color which was column filtrated (10%Et3N, 40%EtOAc and 50%Hexane) to give another 4.5 g of product 7 (81%, combined).

Compound 7

0141MS: m/z 274.7 (M+1). ¹H NMR (CDCl₃): d 1.50 -1.90 (m, 7H), 2.50 (m, 2H), 4.00 (m, 4H), 4.50 (m, 1H), 7.10 (m, 3H), 7.25 (m, 1H).

0142A mixture of 7 (7.5 g, 27.4 mmole) and 8.26 g of PPTS in 50 ml of acetone and H₂O (10:1) was stirred in refluxed over night. The mixture was cooled to room temperature and acetone was evaporated. Addition of water to the mixture initiated crystalization to give 3 g of product 8 (47.4%).

Compound 8

0143MS: m/z 231 (M+1). ¹H NMR (CDCl₃): d 2.20 (m, 2H), 2.60 (m, 2H), 4.50 (m, 1H), 7.10 (m, 4H), 9.5 (br, 1H).

0144To a mixture of 8 (7.75 g, 33.65 mmole), benzylamine (3.61 g, 33.65 mmole), acetic acid (2.0 g, 33.65 mmole) in 150 ml of dichloroethane,10.3 g of sodium triacetoxyborohydride (47.1 mmol, 1.4 eq) was added in one portion. Gas evolves between 30 min and 1 hr. The mixture was stirred over night. TLC indicated the reaction was complete. 1N NaOH (500 ml) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (300 ml x2). The combined organics were dried over potassium carbonate and the solvent was evaporated to give a brown solid, which was column filtrated (5%Et3N, 25%EtOAc and .70%Hexane to 10%Et3N, 40%EtOAc and 50%Hexane) to give 4.7 g of product 10 as a white solid (53.4%) and 3.01 g of product 9 as a white solid (34.2%).

Compound 9

0145MS: m/z 322 (M+1). ¹H NMR (CDCl₃): d 1.40 (m, 2H), 1.80-2.35 (m, 61-1),2.-70 (m, 1H), 3.86 (s, 2H), 4.30 (m, 1H), 7.10 -7.50 (m, 9H), 9.6 (br, 1H).

Compound 10

0146MS: m/z 322 (M+1). ¹H NMR (CDCl₃): d 1.60 (m, 4H), 1.90 (m, 2H), 2.60 (m, 2H), 3,10 (m, 1H), 3.84 (s, 2H), 4.50 (m, 1H), 7.10-7.50 (m, 9H), 9.6 (br, 1H).

01472 g of Pd(OH)2 was added into a solution of 30 ml of methanol containing 4.7 g of compound 10. The resulting suspension was hydrogenated at 50 psi for 12 hrs at room temperature. TLC indicated the reaction was complete over night. The solution was filtered through a pad of celite to remove the catalyst The celite was washed with methanol twice (20 ml). The organics were combined and solvent was removed to give a pale solid which was purified by chromatography (10% MeOH, 90% EtOAc) to give an off white product 11 (1.79 g, 50.7%).

Compound 11

0148MS: m/z 232 (M+1). ¹H NMR (CDCl₃): d1.50-1.85 (m,8H), 2.60 (m, 2H), 4.30 (m,1H), 7.10 (m, 3H), 7.30 (m,1H).

0149To a mixture of 11 (1.7 g, 7.4 mmole), acetaldehyde (0.33 g, 7.4 mmole) in 50 ml of dichloroethane, 2.2 g of sodium triacetoxyborohydride (10.36 mmol, 1.4 eq) was added in one portion. Gas evolves between 30 min and 1 hr. The mixture was stirred over night. TLC indicated the reaction was complete. 1N NaOH (500 ml) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (300 ml x2). The combined organics were dried over potassium carbonate and the solvent was evaporated to give a brown oil which was chromatographed (10%Et3N, 40%EtOAc and 50%Hexane) to give 1.5 g of product 2 as a sticky oil which recrystalized from TBME to give a white solid (78%).

Compound 2

0150MS: m/z 259.7 (M+1). ¹H NMR (CDCl₃): d1.15(t,3H),1.50-1.95(m,6H),2.40-2.75(m, 4H). 2.95(m,1H), 4.35 (m; 1H), 7.10 (m, 3H), 7.35 (m, 1H).

01511.5 g of Pd(OH)₂ was added into a solution of 30 ml ofmethanol containing 3.01 g of compound 9. The resulting suspension was hydrogenated at 50 psi for 12 hrs at room temperature. TLC indicated the reaction was complete over night. The solution was filtered through a pad of celite to remove the catalyst. The celite was washed with methanol twice (20 ml). The organics were combined and solvent was removed to give a pale solid which was purified by chromatography (10% MeOH, 90% EtOAc) to give an off white product 1(1.68 g 77.4%).

Compound 1

0152MS: m/z 232 (M+1). ¹HNMR (CDCl₃): d 1.50 (m, 2H), 1.90-2.35 (m, 6H), 3.00 (m, 1H), 4.30 (m,1H), 7.10-7.30 (m, 4H). <chemistry id="chem0017" num="0017"><img file="EP1598338B1_D0017.tif" /></chemistry>

Procedure:

0153About 2.5 g of NaH was washed by THF twice, suspended in 100 ml of DMF, then 8.15 g of 7 (38 mmole) was added to the mixture. Gas evolves, and after 5 minutes, 7.13 g of ethyl iodide (45.7 mole) was added. The mixture was stirred over night. LC/MS indicated that the starting material was completely consumed. The reaction was cooled down and H₂O was added to the mixture. The product started to precipitated out of solution. The crystals was collected by filtration to give 9.7 g of 12 (84.7%).

Compound 12

0154MS: m/z 303.3 (M+1). ¹H NMR (CDCl₃): d 1.30 (t, 3H), 1.70-1.90 (m, 6H), 2.50 (m, 2H), 3.85-4.00 (m, 6H), 4.50 (m, 1H), 7.05 (m, 3H), 7.25 (m, 1H).

0155A mixture of 12 (9.7 g, 32.2 mmole) and 9.72 g of EPPTS in 50 ml of acetone and H2O (10:1) was refluxed over night. The mixture was cooled to room temperature and acetone was evaporated. Addition of water to the mixture initiated crystalization to give 6.85 g of product 13 (82.3%).

Compound 13

0156MS: m/z 259 (M+1). ¹H NMR (CDCl₃): d 1.35 (t, 3H), 2.20 (m, 2H), 2.60 (m, 6H), 3.95 (q, 2H), 4.85 (m, 1H), 7.10 (m, 4H).

0157To a mixture of 13 (6.85 g, 26.5 mmole), benzylamine (2.84 g, 26.5 mmole), acetic acid (1.59 g, 26.5 mmole) in 150 ml of dichloroethane, 7.86 g of sodium tracetoxyborohydride (37.1 mmol, 1.4 eq) was added in one portion. Gas evolves between 30 min and 1 hr. The mixture was stirred over night. TLC indicated the reaction was complete. 1N NaOH (500 ml) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (300 ml x2). The combined organics were dried over potassium carbonate and the solvent was evaporated to give a brown solid, which was column filtrated (5%Et3-N; 25%EtOAc and 70%Hexane to 10%Et3N, 40%EtOAc and 50%Hexane) to give 1.52g of product 14 as a white solid and 1.08 g of product 15 as a white solid.

Compound 14

0158MS: m/z 350 (M+1). ¹H NMR (CDCl₃): d 1.35 (t, 3H), 1.50 (m, 2H), 1.65 (m, 4H),1.95 (m, 2H), 2.60 (m, 2H), 3,02 (m, 1H), 3.83 (s,2H), 3.95 (ddd, 2H), 4.45 (m, 1H), 7.00-7.50 (m, 9H).

Compound 15

0159MS: m/z 350 (M+1). ¹H NMR (CDCl₃): d 1.35 (m, 5H), 1.90 (m, 2H), 2.10-2.35 (m, 4H), 2.70 (m,1H), 3.83 (s, 2H), 3.95 (ddd, 2H), 4.40 (m, 1H), 7.00-7.50 (m, 9H).

01600.3 g of Pd(OH)2 was added into a solution of 20 ml of methanol containing 0.5 g of compound 14. The resulting suspension was hydrogenated at 50 psi for 12 hr at room temperature. TLC indicated the reaction was complete over night. The solution was filtered through a pad of celite to remove the catalyst. The celite was washed with methanol twice (20 ml). The organics were combined and solvent was removed to give a pale solid which was purified by chromatography (10% MeOH, 90% EtOAc) to give an off white product 3 (300 mg, 50%).

Compound 3

0161MS: m/z 232 (M+1). ¹H NMR (CDCl₃): d 1.35 (t, 3H), 1.50-1.85 (m, 8H); 2.60 (m, 2H), 3.20 (m, 1H), 3.95 (ddd, 2H), 4.30 (m, 1H), 7.10 (m, 3H), 7.30 (m, 1H).

REFERENCE EXAMPLE 11

A

TTACHMENT OF TAIL GROUPS

0162Tail groups were attached to the head groups according to the following procedures: <chemistry id="chem0018" num="0018"><img file="EP1598338B1_D0018.tif" /></chemistry>

General procedure for alkylation:

0163To a solution of the amine (1 eq) and triethylamine (1 eq) in dimethylformamide, was added 1 eq of alkyl bromide or chloride in one portion. The mixture was stirred and heated at 80°C over night. TLC indicated the reaction was complete. The reaction was quenched by the addition of water followed by 1 N NaOH to pH 10. The mixture was extracted 2x with Et₂O. The combined organic extracts were dried over potassium carbonate and the solvent evaporated, followed by chromatography to give the pure product.

General procedure for reductive amination:

0164To a mixture of ketone or aldehyde (1 eq), amine (1 eq), and acetic acid (1 eq) in methanol, was added sodium cyanoborohydride (1.4 eq) in one portion. The mixture was stirred over night at room temperature. TLC indicated the reaction was complete. The reaction was quenched by the addition of water followed by 1 N NaOH to pH 10. The mixture was extracted 2x with Et₂O. The combined organic extracts were dried over potassium carbonate and the solvent evaporated, followed by chromatography to give the pure product.

0165The following reference compounds were prepared by attaching the tail groups using the general procedures described: <ul id="ul0006" list-style="none"><li>1-[4-(benzylamino)-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one</li><li>1-[4-(benzylamino)-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one</li><li>1-[4-[(naphth-2-yl-methyl)ethylamino]-cyclohexyl]-1,3-dihydro-2H-benziriiidazol-2-one MS: m/z 400.2 (M+1)</li><li>1-[4-(norboman-2-ylamino)-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one MS: m/z 326.3 (M+1)</li><li>1-[4-[[4-(1-methylethyl)-cyclohexyl]amino]-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one MS: m/z 356.4 (M+1)</li><li>1-[4-[(decahydro-2-naphthyl)amino]-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one MS: m/z 368.2 (M+1)</li><li>1-[4-(ethylamino)-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one</li><li>1-[4-(benzylamino)-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one</li><li>1-[4-(benzylamino)-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one</li><li>1-[4-[(indan-2-yl)benzylamino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one MS: m/z 466.3 (M+1) ¹H-NMR (CDCl₃): d 1.30 (t, 3H), 1,50-1.75 (m, 2H), 1.90 (b, 2H), 2.02 (b, 2H), 2.20 (m, 2H), 2.80 (m, 1H), 2.99 (m, 4H), 3.75 (s, 2H), 3.90 (m, 3H), 4.25 (m, 1H), 6.95-7.45 (m, 13H).</li><li>1-[4-[(cyclooclylmethyl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one LC: 99% MS: m/z 384.5 ¹H NMR (CDCl₃): d1.40 -1.90 (m, 24H), 2.30 (m, 2H), 2.50(m, 2H), 2.90(m,1H), 3.90(ddd, 2H), 4.20(m, 1H), 7:10(m, 3H), 7.30(m, 1H).</li><li>1-[4-[(naphth-2-yl)aminol-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one LC: 97% MS: m/z 399 : ¹H NMR (CDCl₃): d 1.50 (t, 3H), 1.80 (m, 5H), 2.0 (m, 2H), 2.70(m, 2H), 3.10(m, 1H), 3.90(m, 2H), 4.0(m, 2H), 4.40(m, 1H), 7.10(m, 3H), 7.50(m, 4H), 7.90(m, 4H).</li><li>1-[4-[(<i>p</i>-benzyloxybenzyl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one LC: 97% MS: m/z 455 ¹NMR (CDCl₃): d 1.40 (t, 3H), 1.70 (m, 2H), 1.90 (m, 3H), 2.60(m, 4H), 3.10(m, 1H), 3.80(s, 2H), 4.0(m, 2H), 4.50(m, 1H), 5.10(s, 2H), 7.10(m, 6H), 7.50(m, 6H), 7.90(m, 1H).</li><li>1-[4-[(cyclooctylmethyl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one TLC:99% MS: m/z 369 ¹H NMR (CDCl₃): d1.40 (t, 3H), 1.70(m, 5H), 1.90(m, 12H), 2.10(m,3H), 2.40(m, 2H), 2.50(d, 2H), 3.30(m, 1H), 3.90(m, 2H), 4.20(m, 1H), 7.10(m, 1H), 7.30(m, 3H).</li><li>1-[4-[(decahydro-2-naphthyl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one LC:99% MS: m/z 395 ¹H NMR (CDCl₃): d1.40 (t, 3H), 1.70(m, 3H),1.80(m, 3H),1.90(m,12H), 2.20(m, 2H), 2.30(m, 3H), 2.50(q, 2H), 3.10(m, 1H), 3.90(m, 2H), 4.20(m,1H), 4.30(m,1H), 7.0(m,1H), 7.30(m, 3H).</li><li>1-[4-[(p-phenylbenzyl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one LC:100% MS: m/z 440.8 (M+1) ¹H-NMR (MeOH-d₄): d 1.75 (m, 2H), 2.00 (m, 2H), 2.40-2.55 (m, 4H), 3.35-3.52 (m, 2H), 4.35 (s, 2H), 7.40 (m, 2H), 7.59 (t, 2H), 7.60-7.72 (m, 6H), 7.78 (d, 2H).</li><li>1-[4-[(1,2,3,4-tetrahydronaphthyl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one LC:93.9% MS: m/z 405.7 (M+1) ¹H-NMR (MeOH-d₄): d 1.70 (m, 2H), 1.85 (m, 1H), 2.02 (m, 2H), 2.39 (b, 3H), 2.50 (m, 2H), 2.90 (m, 1H), 3.00 (b, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.72 (b, 1H), 4.35 (m, 1H), 7.15 (b, 4H), 7.40 (d, 1H), 7.60 (s, 1H), 7.65 (d, 1H).</li><li>1-[4-[(4-propyl-cyclohexyl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one TLC:100% MS: m/z 399.6 (M+1) ¹H-NMR (MeOH-d₄): d 0.95 (t, 3H), 1.10 (m, 1H), 1.20-1.60 (m, 6H), 1.70 (b, 5H), 1.80-2.00 (m, 4H), 2.10 (m, 1H), 2.30 (b, 2H), 2.45 (m, 2H), 3.25 (m, 1H), 3.50 (m, 1H), 4.40 (m, 1H), 7.40 (d, 1H), 7.60 (s, 1H), 7.65 (d, 1H).</li><li>1-[4-[(5-methylhex-2-yl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one LC: 100% MS: m/z 373.5 (M+1) ¹H-NMR(MeOH-d₄): d 0.95 (d, 6H), 1.25-1.40 (m, 5H),1.50-1.75 (m, 4H), 1.85 (m, 1H), 1.95 (b, 2H), 2.30 (m, 2H), 2.40-2.55 (m, 2H), 3.35-3.55 (m, 2H), 4.38 (m, 1H), 7.40 (d, 1H), 7.60 (s, 1H), 7.70 (d, 1H).</li><li>1-[4-[(decahydro-2-naphthyl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one LC:100% MS: m/z 411:7 (M+1) ¹H-NMR (MeOH-d₄): d 0.90-2.10 (m, 18H), 2.10-2.50 (m, 5H), 2.82 (m,1H), 3.50 (m, 2H), 4.35 (m, 1H), 7.42 (d, 1H), 7.60 (s, 1H), 7.70 (d, 1H).</li><li>1-[4-(cyclooctylamino)-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one; LC: 95.4% MS: m/z 385.7 (M+1). ¹H-NMR (MeOH-d₄): d 1.50-2.10 (m, 13H), 2.30(m, 2H), 2.40-2.52 (m, 3H), 2.80-2.95 (m, 3H), 3.45 (m, 2H), 3.70 (m, 1H), 4.38 (m,1H), 7.40 (d,1H), 7.63 (s, 1H), 7.70 (d,1H).</li><li>1-[4-[(indan-2-yl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one LC:100% MS: m/z 391.6 (M+1) ¹H-NMR (MeOH-d₄): d 1.70 (m, 2H), 2.00 (m, 2H), 2.40-2.60 (m, 4H), 3.10-3.20 (m, 2H), 3.50 (m, 3H), 4.30-4.45 (m, 2H), 7.25 (m, 2H), 7.35 (m, 2H), 7.42 (d, 1H), 7.60 (s,1H), 7.72 (d,1H).</li><li>1-[4-(benzylamino)-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one LC: 100% MS: m/z 399.5 (M+1) ¹H-NMR (MeOH-d₄): d 1.40-1.85 (m, 15H), 2.00 (m, 4H), 2.25-2.50 (m, 4H), 2.93 (d, 2H), 3.30 (m, 1H), 4.30 (m, 1H), 7.36 (d, 1H), 7.60 (s, 1H), 7.65 (d, 1H).</li><li>1-[4-[(4-phenyl-cyclobexyl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one LC:100% MS: m/z 433.7 (M+1) ¹H-NMR(MeOH-d₄): d 1.65 (m, 2H), 1.85-2.20 (m, 8H), 2.25-2.50 (m, 5H), 3.90 (m, 1H), 3.50 (m, 2H), 3.58 (m, 1H), 4.30 (m,1H), 7.15-7.40 (m, 6H), 7.60 (s, 1H), 7.65 (d, 1H).</li><li>1-[4-(dibenzylamino)-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one LC: 100% MS: m/z 455.6 (M+1) ¹H-NMR (MdOH-d₄): d 2.00-2.25 (m, 4H), 2.40 (m, 4H), 3.52 (m, 2H), 4.25-4.65 (m, 4H), 7.30 (d, 1H), 7.45-7.58 (m,10H), 7.60 (s, 1H), 7.65 (d, 1H).</li><li>1-[4-[(5-methylhex-2-yl)amino]-cyclohexyl]-7-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one LC: 99.1 % MS: m/z 373.3 (M+1) ¹H-NMR (MeOH-d₄): d 0.95 (d, 6H), 1.30 (d, 3H), 1.45-1.68 (m, 5H), 1.75 (m, 1H), 2.00 (m, 2H), 2.18-2.32 (m, 3H), 2.60 (m, 2H), 3.20-3.40 (m, 2H), 4.30 (m, 1H), 7.05-7.20 (m, 3H).</li></ul>

REFERENCE EXAMPLE 12

0166Nociceptin affinity at the ORL1 receptor for preferred compounds was obtained using the following assay: <ul id="ul0007" list-style="none" compact="compact"><li>Membranes from recombinant HEK-293 cells expressing the human opioid receptor-like receptor (ORL-1) (Receptor Biology) were prepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES, pH 7.4) (10 ml/10 cm dish) followed by homogenization with a tissue grinder/teflon pestle. Membranes were collected by centrifugation at 30,000 x g for 15 min at 4°C and pellets resuspended in hypotonic buffer to a final concentration of 1-3 mg/ml. Protein concentrations were determined using the BioRad protein assay reagent with bovine serum albumen as standard. Aliquots of the ORL-1 receptor membranes were stored at -80°C.</li><li>Functional SGTPgS binding assays were conducted as,follows. ORL-1 membrane solution was prepared by sequentially adding final concentrations of 0.066 mg/ml ORL-1 membrane protein, 10 mg/ml saponin, 3 mM GDP and 0.20 nM [³⁵S]GTPgS to binding buffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution(190 ml/well) was transferred to 96-shallow well polypropylene plates containing 10 ml of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at room temperature with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GFB filter plates (Packard) using a 96-well tissue harvester (Brandel) and followed by three filtration washes with 200 ml ice-cold binding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates were subsequently dried at 50°C for 2-3 hours. Fifty ml/well scintillation cocktail (BetaScint; Wallac) was added and plates were counted in a Packard Top-Count for 1 min/well.</li></ul>

0167Data was analyzed using the curve fitting functions in GraphPad PRISMÔ, v. 3.0 and the results are set forth in table 3 below: <tables id="tabl0003" num="0003"><table frame="all"><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="144mm" /><colspec colnum="2" colname="col2" colwidth="22mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top"><b>TABLE 3</b></entry></row><row><entry namest="col1" nameend="col2" align="left" valign="top"><b>Nociceptin Affinity</b></entry></row><row><entry valign="top"><b>REFERENCE Compound</b></entry><entry valign="top"><b>calc K₁(nM)</b></entry></row></thead><tbody><row><entry>3-ethyl-1-(<i>p</i>-phenylbenzyl)-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>509</entry></row><row><entry>3-ethyl-1-(5-methylhex-2-yl)-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>23</entry></row><row><entry>3-ethyl-1-(4-propylcyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>68</entry></row><row><entry>3-ethyl-1-(decahydro-2-naphthyl)-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>1.6</entry></row><row><entry>3-ethyl-1-(naphth-2-yl-methyl)-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>198</entry></row><row><entry>1-(<i>p</i>-benzyloxybenzyl)-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>438</entry></row><row><entry>1-benzyl-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>296</entry></row><row><entry>1-[4-(benzylamino)-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>trans:112 cis: >10,000</entry></row><row><entry>3-ethyl-1-(naphthylmethyl)-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>39</entry></row><row><entry>3-ethyl-1-[5-(3-fluorophenyl)-5-(4-fluorophenyl)-hexyl]-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>148</entry></row><row><entry>1-[4-[(naphth-2-yl-methyl)ethylamino]-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>3598</entry></row><row><entry>1-[4-(norbornan-2-ylamino)-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>>10000</entry></row><row><entry>1-[4-[[4-(1-methylethyl)-cyclohexyl]amino]-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>>10000</entry></row><row><entry>1-[4-[(decahydro-2-naphthyl)anino]-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>>10000</entry></row><row><entry>1-[4-(ethylamino)-cyclohexyl]-1,3-dihydro-2H-beuzimidazol-2-one</entry><entry>9179</entry></row><row><entry>1-[4-(benzylamino)-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>trans: 273 cis: >10000</entry></row><row><entry>1-[4-[(indan-2-yl)benzylamino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>>10000</entry></row><row><entry>1-[4-[(cyclooctylmethyl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>115</entry></row><row><entry>1-[4-[(naphth-2-yl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-dne</entry><entry>961</entry></row><row><entry>1-[4-[(<i>p</i>-benzyloxybenzyl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>2935</entry></row><row><entry>1-[4-[(cyclooctylmethyl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>286</entry></row><row><entry>1-[4-[(decahydro-2-naphthyl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>288</entry></row><row><entry>1-[4-(benzylamino)-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>>10000</entry></row><row><entry>1-[4-(dibenzylamino)-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>>10000</entry></row><row><entry>1-[4-[(<i>p</i>-phenylbenzyl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>>10000</entry></row><row><entry>1-[4-[(1,2,3,4-tetrahydronaphthyl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>>10000</entry></row><row><entry>1-[4-[(4-propyl-cyclohexyl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidaiol-2-one</entry><entry>>10000</entry></row><row><entry>1-[4-[(5-methylhex-2-yl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>>10000</entry></row><row><entry>1-[4-[(decahydro-2-naphthyl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>>10000</entry></row><row><entry>1-[4-(cyclooctylamino)-cyclohoxyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one.</entry><entry>>10000</entry></row><row><entry>1-[4-[(indan-2-yl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>>10000</entry></row><row><entry>1-[4-[(4-phenyl-cyclohexyl)amino]-cyclohaxyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>>10000</entry></row><row><entry>1-[4-[(5-methylhex-2-yl)amino]-cyclohexyl]-7-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one</entry><entry>>10000</entry></row></tbody></tgroup></table></tables>

REFERENCE EXAMPLE 13

SYNTHESIS OF SUBSTITUTED BENZIMIDAZOLE HEAD GROUPS.

0168<chemistry id="chem0019" num="0019"><img file="EP1598338B1_D0019.tif" /></chemistry>

Procedure:

0169Sodium hydride 60% dispersion in mineral oil (0.67 g,16.7 mmol) was washed with dry pentane and then suspended in 80 mL of dry THF under N₂. Compound 1 (European patent <patcit id="pcit0020" dnum="EP0029707A"><text>0029707</text></patcit>) (3.80 g,11.1 mmol) was added, the mixture stirred at room temperature for 15 min and then warmed to 50°C. Ethyl bromide (1.06 mL,13.3 mmol) was added and the resulting mixture stirred at 50°C for 18 hr. TLC (SiO₂, CH₂Cl₂:MeOH 96:4) showed that the reaction was ca 40% complete. Additional sodium hydride (0.67 g) and ethyl bromide (1.06 mL) were added. After heating at 50°C for an additional 24 hr the reaction mixture was cooled to room temperature and quenched with water. The layers were separated and the aqueous layer extracted with ethyl acetate (1x). The combined organic extracts were washed with aqueous sodium bicarbonate solution (1x), dried over MgSO₄ and the solvent was evaporated to give the crude product as a yellow solid. Trituration with diethyl ether gave pure 2 as a white solid (3.38 g, 82%). ¹H-NMR (CDCl₃): d 1.45-1.55 (m; 12H), 1.82 (bs, 2H), 2.30 (m, 2H), 2.87 (m, 2H), 4.30 (bs, 2H), 4.41 (q, 2H), 4.82 (m, 1H), 7.10-7.30 (m, 4H).

0170To a solution of 2 (3.60 g, 9.74 mmol) in 100 mL of ethyl acetate was added a 25 mL of a 1:1 mixture of ethyl acetate and concentrated HCl. The mixture was stirred vigorously at room. , temperature for 2hr. and evaporated to dryness. The residue was neutralized with 50 mL of methanolic ammonia 10:1 and again evaporated to dryness. The residue was suspended in 100 mL a 1:1 mixture of MeOH and CH₂Cl₂, filtered and the filtrate evaporated to dryness to leave an off-white solid. Flash chromatography on silica gel, eluting with CH₂Cl₂:MeOH:NH₃ (300:10:1) gave pure 3 as a white crystalline solid (1.98 g, 76%). ¹H-NMR (CDCl₃): d .1.45 (t, 3H), 1.82 (bs, 2H), 2.33 (m, 2H), 2.80 (m, 2H), 4.40 (q, 2H), 4.80 (m, 1H), 7.10-7.30 (m, 3H), 7.45 (d,1H).

REFERENCE EXAMPLE 14

ATTACHMENT OF TAIL GROUPS

0171Tail groups were attached to the head groups according to the following procedures: <chemistry id="chem0020" num="0020"><img file="EP1598338B1_D0020.tif" /></chemistry>

General procedure for alkylation:

0172To a solution of the amine (1 eq) and triethylamine (1 eq) in dimethylformamide, was added 1 eq of alkyl bromide or chloride in one portion. The mixture was stirred and heated at 80°C over night. TLC indicated the reaction was complete. The reaction was quenched by the addition of water followed by 1 N NaOH to pH 10. The mixture was extracted 2x with Et₂O. The combined organic extracts were dried over potassium carbonate and the solvent evaporated, followed by chromatography to give the pure product.

General procedure for reductive amination:

0173To a mixture of ketone or aldehyde (1 eq), amine (1 eq), and acetic acid (1 eq) in methanol, was added sodium cyanoborohydride (1.4 eq) in one portion. The mixture was stirred over night at room temperature. TLC indicated the reaction was complete. The reaction was quenched by the addition of water followed by 1N NaOH to pH 10. The mixture was extracted 2x with Et₂O. The combined organic extracts were dried over potassium carbonate and the solvent evaporated, followed by chromatography to give the pure product.

0174The following reference compounds were prepared by attaching the tail groups using the general procedures described: <ul id="ul0008" list-style="none"><li>2-cyanoimino-3-ethyl-1-[1-(<i>p</i>-phenylbenzyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole ¹H-NMR (CDCl₃): d 1.50 (t, 3H), 1.88 (m, 2H), 2.28 (m, 2H), 2.62 (m, 2H), 3.12 (m, 2H), 3.65 (s, 2H), 4.48 (q, 2H), 4.80 (m, 1H), 7.15-7.70 (m, 13H).</li><li>2-cyanoimino-3-ethyl-1-[1-(p-benzyloxybenzyl)-4-piperidinyl] 1,3-dihydro-2H-benzimidazole LC: 96.5% MS: m/z 466.5 (M+1) ¹H-NMR (CDCl₃): d 1.55 (t, 3H), 1.82 (m, 2H), 2.25 (m, 2H), 2.50 (m, 2H), 3.10 (m, 2H), 3.55 (s, 2H), 4.48 (q, 2H), 4.78 (m, 1H), 5.20 (s, 2H), 7.00 (d, 2H), 7.15-7.65 (m, 11H).</li><li>2-cyanoimino-3-ethyl-1-[1-(naphth-2-yl-methyl)-4-pipendinyl] 1,3-dihydro-2H-benzimidazole LC: 93.9% MS: m/z ¹H-NNM (CDCl₃): d 1.55 (t, 3H), 1.80 (m, 2H), 2.30 (t, 2H), 2.52 (m, 2H), 3.18.(bd, 2H), 3.78 (s, 2H), 4.50 (q,2H), 4.80 (m,1H), 7.20-7.90 (m.11H).</li><li>2-cyanoimino-3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole MS: m/z 394.4 (M+1) ¹H-NMR (CDCl₃): d 0.90-2.28 (m, 21H), 3.10 (m, 4H), 3.62 (m, 2H), 4.42 (q. 2H), 5.15 (m, 1H), 7.20 (d, 1H), 7.30 (m, 1H). 7.50 (t, 1H), 7.80 (b,1H).</li><li>2-cyanoimino-3-ethyl-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazole LC: 100% MS:m/z 394.5 (M+1) ¹H-NMR (CDCl₃): d 0.90.(d, 3H), 0.98 (d, 3H), 1.15-2.35 (m, 14H), 3.10 (m, 5H), 3.70 (m, 2H), 3.92 (bs, 1H), 4.40 (q. 2H), 5.20 (m, 1H), 7.20 (d, 1H), 7.38 (d, 1H), 7.52 (t, 1H), 7.80 (m,1H).</li><li>2-cyanoimino-3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole LC:93.9% MS: m/z 406.6 (M+1) ¹H-NMR (CDCl₃): d 1.25-2.35 (m, 24H), 1.15 (m, 4H), 3.60 (m, 2H), 4.40 (m, 2H), 4.20 (m, 1H), 7.20-7.80 (m, 4H).</li><li>2-cyanoimmo-3-ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole LC:100% MS: m/z 380.3 (M+1) ¹H-NMR (CDCl₃): 1.50-1.80 (m,13H), 1.90 (m, 2H), 2.10 (m, 4H), 3.05 (m, 3H), 3.30 (m, 1H), 3.45 (m, 2H), 3.90 (m, 1H), 4.42 (q, 2H), 5.15 (m, 1H), 7.20 (d, 1H), 7.35 (d, 1H), (m,1H), 7.78(m,1H).</li><li>2-cyanoimino-3-ethyl-1-[1-(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole LC:94.5% MS: m/z 462.2 (M+1) ¹H-NMR (CDCl₃): d 1.40 (t, 3H), 1.70 (bs, 2H), 2.01 (m, 2H), 2.28 (m, 2H), 2.80 (m, 4H), 3.95 (s, 1H), 4.02 (m, 2H), 4.32 (q, 2H), 4.65 (m, 1H), 7.00-7.32 (m,12H).</li><li>2-cyanoimino-3-ethyl-1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole MS: m/z 464.2 (M+1) ¹H-NMR (CDCl₃): d 1.40 (t, 3H), 1.73 (bs, 2H), 2.09 (m, 2H), 2.18-2.45 (m, 6H), 2.98 (b, 2H), 3.93 (t, 1H), 4.35 (q, 2H), 4.63 (m, 1H), 7.10-7.30 (m, 13H), 7.40 (d, 1H).</li><li>2-cyanoimino-3-ethyl-1-[1-(1,2,3,4-tetrahydronaphthyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole LC:94.0% MS:m/z400.2(M+1) ¹H-NMR (CDCl₃): d 1.30-1.70 (m, 6H), 1.85 (m, 2H), 2.05 (m, 1H), 2.45 (m, 3H), 2.85 (m, 4H), 3.10 (m, 2H), 4.35 (q, 2H), 4.71 (m, 1H); 7.00-7.60 (m, 8H).</li><li>2-cyanoimino-3-ethyl-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole LC: 94.9% MS: m/z 368.3 (M+1) ¹H-NMR (CDCl₃): d 0.85 (d, 6H), 0.95 (d, 3H), 1.12-1.65 (m, 8H), 1.80 (m, 2H), 2.27-2.60 (m, 5H), 2.85 (m, 2H), 4.38 (m, 2H), 4.62 (m, 1H), 7.08-7.30 (m, 3H), 7.45 (m, 1H).</li><li>2-cyanoimino-3-ethyl-1-[1-(norbornan-2-yl)-4-piperidinyl]-1,3-dilxydro-2H-benzimidazole LC: 99.2% MS: m/z 364.7 (M+1) ¹H-NMR (CDCl₃): d 1.10-2.10 (m, 13H), 2.35 (m, 1H), 2.50-2.70 (m, 3H), 2.70-2.90 (m, 3H), 3.50 (m, 2H), 4.50 (q, 2H), 4.80 (m, 1H), 7.35 (m, 2H), 7.48 (m, 1H), 7.75 (m, 1H).</li><li>2-cyanoimino-3-ethyl-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole LC: 92.1 % MS: m/z 386.2 (M+1) ¹H-NMR (CDCl₃): d 1.42 (t, 3H), 1.82 (m, 2H), 2.21 (m, 2H), 2.43 (m, 2H), 2.88 (m, 2H), ' 3.02-3.19 (m, 4H), 3.23 (m, 1H), 4.38 (q, 2H), 4.80 (m, 1H), 7.08-7.30 (m, 7H), 7.45 (d, 1H).</li><li>2-cyanoimino-3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole LC: 100% . MS: m/z 394.7 (M+1) ¹H-NMR (MeOH): d 1.35-2.00 (m, 20H), 2.60-2.85 (m, 6H), 3.40 (m, 2H), 2.52 (q, 2H), 4.90 (m, 1H), 7.35 (m, 2H), 7.48 (m, 1H), 7.70 (m, 1H).</li><li>2-cyanoimino-3-(2-hydroxy)ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole TLC:100% MS: m/z 396.3 (M+1) ¹H-NMR (DMSO): 7.52 (dt, 1H), 7.45 (dt, 1H), 7.21 (m, 2H), 4.97 (t, 1H), 4.55 (m, 1H), 4.38 (t, 2H), 3.76 (q, 2H), 2.88 (m, 2H), 2.61 (bt, 1H), 2.33 (m, 4H), 1.76-1.37 (m, 16H).</li><li>2-cyanoimino-3-methoxycarbonylmethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole LC: 98.3% MS: m/z 424.2 (M+1) ¹H-NMR (DMSO): 7.56 (dd, 1H), 7.51 (dd, 1H), 7.25 (m, 2H), 5.26 (s, 2H), 4.56 (m, 1H), 3.72 (s, 3H), 3.34.(m, 2H), 2.78 (m, 2H), 2.62 (bt, 1H), 2.32 (m, 4H), 1.80-1.35 (m, 16H).</li><li>2-cyanoimino-3-cyanomethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole LC: 100% MS: m/z 391.2 (M+1) ¹H-NMR (DMSO): 7.60 (m, 2H), 7.31 (m, 2H), 5,48 (s, 2H), 4.77 9m, 1H), 3.33 (d, 2H), 2.88 (m, 2H), 2.62 (bt,1H), 2.33 (m, 4H),1.86-1.37 (m, 16H).</li><li>2-cyanoimino-3-butyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole LC:95.4% MS: m/z 352.2 (M+1) ¹H-NMR (DMSO): 7.58 (dd,1H), 7.49 (dd, 1H), 7.24 (m, 2H), 6.55 (s, 2H), 4.59 (m,1H), 4.34 (t, 2H), 2.97 (m, 2H), 2.80 (m,1H), 2.55 (m, 2H), 2.38 (m, 2H),1.80-1.30 (m,18H), 0.90 (t, 3H).</li><li>2-cyanoimino-3-(2-methanesulfonamido)ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole LC:100% MS:m/z473.2(M+1) ¹H-NMR (DMSO): 7.53 (dd, 1H), 7.44 (dd, 1H), 7.23 (m, 2H), 4.60 (m,1H), 4.35 (t, 2H), 3.37 (t, 2H), 2.87 (m, 2H), 2.82 (s, 3H), 2.60 (bt, 1H), 2.31 (m, 4H), 1.76-1.37 (m, 15H).</li><li>2-cyanoimino-3-acetomido-1-[1-(cyclooctyl)-4-pipendinyl]-1,3-dihydro-2H-benzimidazole LC: 100% MS: m/z 409.2 (M+1) ¹H-NMR (DMSO): 7.75 (s, 1H), 7.52 (dd, 1H), 7.37 (s. 1H), 7.30 (dd, 1H), 7.20 (m, 2H), 4.96 (s, 2H), 4.55 (m, 1H), 3.33 (d, 2H), 2.88 (m, 2H), 2.62 (bt, 1H), 2.30 (m, 4H), 1.80-1.37 (m, 15H).</li><li>2-cyanoimino-3-carboxymethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole LC: 97.5% MS: m/z 409.9 (M+1) ¹H-NMR (DMSO): 7.45 (dd, 1H), 7.14 (m, 3H), 4.57 (s, 2H), 4.50-(m, 1H), 2.87 (m, 2H), 2.61 (bt, 1H), 2.33 (m, 4H), 1.75-1.37 (m, 15H).</li><li>2-cyanoimino-3-(2-dimethylamino)ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole LC: 100% MS: m/z 423.3 (M+1) ¹H-NMR (DMSO): 7.60-6.96 (m, 4H), 6.54 (2H, s), 4.65 (m,1H), 4.40 (t, 2H), 3.90 (t, 2H), 3.05 (m, 4H), 2.90 (m, 1H), 2.63 (m, 3H), 2.56-2.37 (m, 4H), 1.85-1.35 (m, 15H).</li><li>2-cyanoimino-1-[1-(cyclooctyl)-3-hydroxymethyl-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</li><li>2-cyanoimino-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-7-azabenzimidazole;</li><li>2-cyanoimino-1-[1-(cyclooctyl)-2,6-ethano-4-one-4-piperidinyl]-1,3,-dihydro-2H-benzimidazole</li></ul>

REFERENCE EXAMPLE 15

0175Nociceptin affinity at the ORL1 receptor for preferred compounds was obtained using the following assay: <ul id="ul0009" list-style="none" compact="compact"><li>Membranes from recombinant HEK-293 cells expressing the human opioid receptor-like receptor (ORL-1) (receptor Biology) were prepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES, pH 7.4) (10 ml/10 cm dish) followed by homogenization with a tissue grinder/teflon pestle. Membranes were collected by centrifugation at 30,000 x g for 15 min at 4°C and pellets resuspended in hypotonic buffer to a final concentration of 1-3 mg/ml. Protein concentrations were determined using the BioRad protein assay reagent with bovine serum albumen as standard. Aliquots of the ORL-1 receptor membranes were stored at -80°C.</li><li>Functional SGTPgS binding assays were conducted as follows. ORL-1 membrane solution was prepared by sequentially adding final concentrations of 0.066 mg/ml ORL-1 membrane protein, 10 mg/ml saponin, 3 mM GDP and 0.20 nM [³³S]GTPgS to binding buffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 ml/well) was transferred to 96-shallow well polypropylene plates containing 10 ml of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at room temperature with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GF/B filter plates (Packard) using a 96-well tissue harvester (Brandel) and followed by three filtration washes with 200 ml ice-cold binding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates were subsequently dried at 50°C for 2-3 hours. Fifty ml/well scintillation cocktail (BetaScint; Wallac) was added and plates were counted in a Packard Top-Count for 1 min/well.</li></ul>

0176Data was analyzed using the curve fitting functions in GraphPad PRISMÔ, v. 3.0 and the results are set forth in table 4 below: <tables id="tabl0004" num="0004"><table frame="all"><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="144mm" /><colspec colnum="2" colname="col2" colwidth="22mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top"><b>TABLE 45</b></entry></row><row><entry namest="col1" nameend="col2" align="left" valign="top"><b>Nociceptin Affinity</b></entry></row><row><entry valign="top"><b>REFERENCE Compound</b></entry><entry valign="top"><b>calc K₁(nM)</b></entry></row></thead><tbody><row><entry>2-cyanoimino-3-ethyl-1-[1-(<i>p</i>-phenylbenzyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</entry><entry>5558</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(<i>p</i>-benzyloxybenzyl)-4-piperidinyl] 1,3-dihydro-2H-benzimidazole</entry><entry>1660</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(naphth-2-yl-methyl)-4-piperidinyl] 1,3-dihydro-2H-benzimidazole</entry><entry>882</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</entry><entry>241</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</entry><entry>6.9</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</entry><entry>6.6</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</entry><entry>5.57</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(10, 11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;</entry><entry>> 10,000</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;</entry><entry>80</entry></row><row><entry>2-cyanoimino-3-ethyl-1-(1-(1,2,3,4-tetrahydronaphthyl)-4-piperidinyl)-1,3-dihydro-2H-benzimidazole;</entry><entry>157</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;</entry><entry>76</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(norbornan-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;</entry><entry>323</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole; and</entry><entry>89</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole.</entry><entry>7.1</entry></row><row><entry>2-cyanoimino-3-(2-hydroxy)ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</entry><entry>6.4</entry></row><row><entry>2-cyanoimino-3-methoxycarbonylmethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</entry><entry>3.3</entry></row><row><entry>2-cyanoimino-3-cyanomethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</entry><entry>.97</entry></row><row><entry>2-cyanoimino-3-butyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3dihydro-2H-benzimidazole</entry><entry>1.36</entry></row><row><entry>2-cyanoimino-3-(2-methanesulfonamido)ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</entry><entry>78</entry></row><row><entry>2-cyanoimino-3-acetomido-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</entry><entry>11</entry></row><row><entry>2-cyanoimino-3-carboxymethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</entry><entry>201</entry></row><row><entry>2-cyanoimino-3-(2-dimethylamino)ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</entry><entry>18</entry></row><row><entry>2-cyanoimino-1-[1-(cyclooctyl)-3-hydroxymethyl-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</entry><entry>473</entry></row><row><entry>2-cyanoimino-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-7-azabenzimidazole</entry><entry>3743</entry></row><row><entry>2-cyanoimino-1-[1-(cyclooctyl)-2,6-ethano-4-one-4-piperidinyl]-1,3-dihydro-2H-benzimidazole</entry><entry>19</entry></row></tbody></tgroup></table></tables>

Example 16

0177Affinity at the µ receptor for compounds was obtained according to the following assay: Mu opioid receptor membrane solution was prepared by sequentially adding final concentrations of 0.075 µg/µl of the desired membrane protein, 10 µg/ml saponin, 3 µM GDP and 0.20 nM [³⁵S]GTP_ΥS to binding buffer (100°mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 µl/well) was transferred to 96-shallow well polypropylene plates containing 10 µl of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at room temperature with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter 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 NaH₂PO₄,10 mM Na,HPO₄, pH 7.4). Filter plates were subsequently dried at 50° C for 2-3 hours. Fifty µl/well scintillation cocktail (MicroScint20, Packard) was added and plates were counted in a Packard Top-Count for 1 min/well.

0178Data were analyzed using the curve fitting functions in GraphP ad PRISM^™,v. 3.0 and the results for several compounds are set forth in table 5 below: <tables id="tabl0005" num="0005"><table frame="all"><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="143mm" /><colspec colnum="2" colname="col2" colwidth="23mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top"><b>TABLE 5</b></entry></row><row><entry namest="col1" nameend="col2" align="left" valign="top"><b>Mu Receptor Affinity</b></entry></row><row><entry valign="top"><b>Compound</b></entry><entry valign="top"><b>calc K₁ (nM)</b></entry></row></thead><tbody><row><entry>3-[1-(naphth-1-yl-methyl)-4-piperidinyl]-2H-benzoxazol-2-one*</entry><entry>340</entry></row><row><entry>3-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2H-benzoxazol-2-one*</entry><entry>726</entry></row><row><entry>3-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-2H-benzolazol-2-one*</entry><entry>343</entry></row><row><entry>3-[1-(4-propyl-cyclohexyl)-4-piperidinyl]-2H-benzoxazol-2-one*</entry><entry>145</entry></row><row><entry>3-ethylidene-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>23.3</entry></row><row><entry>3-ethylidene-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>137</entry></row><row><entry>3-ethylidene-1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>1150</entry></row><row><entry>3-ethylidene-1-[1-(3,3-diphenylpropyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one</entry><entry>24</entry></row><row><entry>1-[4-[(naphth-2-yl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one*</entry><entry>2.1</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole*</entry><entry>46</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(1,2,3,4-tetrahydronaphthyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole*</entry><entry>458</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole*</entry><entry>15</entry></row><row><entry>2-cyanoimino-3-ethyl-1-[1-(norborman-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole*</entry><entry>1653</entry></row></tbody></tgroup><tgroup cols="2" rowsep="0"><colspec colnum="1" colname="col1" colwidth="143mm" /><colspec colnum="2" colname="col2" colwidth="23mm" /><tbody><row><entry namest="col1" nameend="col2" align="justify">*REFERENCE COMPOUNDS</entry></row></tbody></tgroup></table></tables>