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

ES 2 322 158 T3

DESCRIPTION

Derivatives of 1- (4-piperidinyl) -1,3-dihydro-2H-indol-2-one and related compounds such as nociceptin analogs and ORL-1 ligands for the treatment of pain.

This application claims the priority of the United States Provisional Applications having Nos. Deposit 60 / 284,666, 60 / 284,667, 60 / 284,668 and 60 / 284,669, all of which were filed on April 18, 2001.

Background of the invention

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

Until recently there was evidence for three main classes of opioid receptors in the central nervous system (CNS), with each class having receptors constituting subtypes. These classes of receptors were designated as μ, δ, and κ. Since opiates had a high affinity for these receptors without being endogenous to the body, further research was carried out to identify and isolate endogenous ligands for these receptors. These ligands were identified as enkephalins, endorphins, and dynorphins.

Recent experimentation has led to the identification of a cDNA encoding an opioid-like receptor (ORL 1) with a high degree of homology to known receptor classes. This newly discovered receptor was classified as an opioid receptor only on the basis of structural reasons, since the receptor had no pharmacological homology. Non-selective ligands having high affinity for μ, δ and κ receptors were initially shown to have low affinity for ORL 1. This characteristic, together with the fact that an endogenous ligand had not yet been discovered, led to the adoption of the term "orphan receptor".

Further investigation led to the isolation and determination of the structure of the endogenous ORL 1 receptor ligand. This ligand is a seventeen amino acid peptide that is structurally similar to members of the opioid peptide family.

The discovery of the ORL 1 receptor offers an opportunity within the field of drug discovery to obtain new compounds that can be administered for the management of pain or other syndromes modulated by this receptor.

WO 99/32481 A in the name of Alcon Laboratories, Inc. discloses a group of compounds having muscarinic activity. Said compounds can be used in the manufacture of a medicament for treating glaucoma, myopia, psychosis and various other conditions in which muscarinic receptors are involved.

US 5 789 402 in the name of the Eli Lilly Company discloses compounds that have effects on serotonin-related systems. Such hetero-oxy-alkanamine compounds are effective pharmaceuticals for the treatment of conditions related to or affected by serotonin reuptake and by the serotonin receptor 1.

WO 95/02405 A in the name of Merck & Co., Inc. discloses piperidinyl compounds of benzoxazinone and benzopyrimidinone. Such compounds are useful as antagonists of the oxytocin and vasopressin receptors.

US 3 325 499 in the name of Ireland Poos discloses certain substituted oxindole compounds [(1- (1-hydrocarbyl-4-piperidyl) -2-indolinones].

The publication of Klein et al., ARCHIV DER PHARMAZIE, VCH VERLAGSGESELLSCHAFT MBH, WEINHEIM, DE, vol. 307, No. 5, 1974, pages 360-366, describes the synthesis of 1- (piperidinyl-4) -indolinones- (2) and -3,4-dihydrocarbostyryls in order to obtain structural analogs of known analgesics.

The abstract of that article is also listed in Chemical Abstracts Database CA [online], Columbus, Ohio, USA [STN Database (Accession No. 1974: 477786)].

The publication of Lobbezoo and Soudijn, J.MED.CHEM., Vol. 24, 1981, pages 777-782, deals with the interaction with the opiate receptors of compounds derived from or structurally related to fentanyl. This publication discloses several compounds structurally related to fentanyl, and the authors determine the affinities of these compounds for the opiate receptor.

Another article by Kelin et al., ARCH. PHARMAZ., Vol. 308, no. 75, 1976, pages 910-916, discloses the synthesis and pharmacological activities of cyclic fentanyl analogs. The cyclization of the acyl group with C-2 of the aromatic ring produces a change in the stereochemical structure that results in a loss of analgesic activity.

ES 2 322 158 T3

WO 00 / 6157S A in the name of EISAI CO., LTD. discloses a process for the production of indole derivatives and intermediates thereof. Such derivatives are useful as drugs.

EP 0 976 732 in the name of EISAI CO., LTD. discloses 1,4-substituted cyclic amine derivatives. Such compounds exhibit antagonistic activity for serotonin and are clinically useful as medicaments to treat and e.g. ex. to improve and prevent spastic paralysis.

WO 99/09984 A in the name of Merck & Co., Inc. discloses certain pyrrolidine and piperidine compounds. These compounds can be useful as modulators of chemokine receptor activity.

WO 96/13265 A in the name of Merck & Co., Inc. discloses 4-heterocyclo-substituted piperidines. Such compounds promote the release of growth hormone in humans and animals, the property of which can be used to promote e.g. ex. the growth of animals for food or to treat conditions characterized by a deficiency in the secretion of growth hormone.

EP 0 355 663 in the name of BASF AG discloses 2,6-polyalkylpiperidine-substituted bislactams and their use for the stabilization of organic material.

US 5 760 054 in the name of Merck & Co., Inc. discloses alpha-1C-adrenergic receptor antagonists. In addition, its synthesis and its use as selective antagonists p. ex. for the treatment of benign prostatic hypertrophy.

WO 01/60796 A in the name of Meiji Seika Kaisha, LTD. discloses phenoxyalkylamine derivatives that are useful as δ-opioid receptor agonists.

WO 01/70689 A in the name of Meiji Seika Kaisha, LTD. discloses diphenylalkylamine derivatives that are useful as δ-opioid receptor agonists.

WO 02/14315 A in the name of Ortho McNeil Pharmaceutical, Inc. discloses substituted pyrazoles, methods of making them, compositions containing them, and methods of using them for the treatment of p. ex. autoimmune diseases mediated by cathepsin S.

WO 02/20011 A in the name of Ortho McNeil Pharmaceutical, Inc. also discloses substituted pyrazoles. Said pyrazoles are used in a method described there for treating an allergic condition including an atopic allergic condition.

The Forbes publication, TETRAHEDRON LETTERS, vol. 42, 2001, pages 6943-6945, describes the short and efficient synthesis of indol-2-ones N-substituents (oxindoles). Said synthesis strategy constitutes a general route to obtain N-substituted indole-2-ones.

Objects and brief exposition of the invention

It is consequently an object of certain embodiments of the present invention to provide new compounds that have affinity for the ORL 1 receptor.

It is an object of certain embodiments of the present invention to provide new compounds that have affinity for the ORL 1 receptor and one or more of the μ, δ or κ receptors.

It 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 an affinity for the ORL 1 receptor.

It is an object of certain embodiments of the present invention to provide new compounds that at μ, δ or κ receptors have an agonist activity that is greater than that of currently available compounds, such as p. ex. morphine.

It is an object of certain embodiments of the present invention to describe the use of new compounds according to the invention in the manufacture of a medicament for treating chronic and acute pain based on administering compounds that have a receptor at μ, δ and κ. agonist activity that is greater than that of currently available compounds.

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

It is an object of certain embodiments of the present invention to provide compounds that are useful as analgesics, anti-inflammatories, diuretics, anesthetics, and neuroprotective, antihypertensive, anti-anxiety agents;

ES 2 322 158 T3 appetite control agents; ear regulators; antitussives, antiasthmatics, locomotor activity modulators, learning and memory modulators, neurotransmitter and hormone release regulators, kidney function modulators, antidepressants, agents to treat memory loss due to Alzheimer's disease or others dementias, antiepileptics, anticonvulsants, agents to treat withdrawal from alcohol and drug addiction, agents to control fluid balance, agents for controlling sodium excretion and agents for controlling arterial blood pressure disorders, and methods for administering such compounds.

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

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

The present invention in certain embodiments comprises compounds having the formula (IIA):

<img file="ES2322158T3_D0001.tif" />

where the dotted line represents an optional double bond;

Z is selected from among the members of 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-, where the carbon and / or nitrogen atoms are unsubstituted or substituted with a lower alkyl, halogen, hydroxy or alkoxy group;

R and Q are the same or different and R is selected from the group consisting of halogen, C_1-10alkyl, C_1-10 alkenyl, C_1-10 alkylidene, C₃_₁₂ cycloalkyl, C_1-10 alkoxy and oxo;

and Q is selected from the group consisting of hydrogen, halogen, C_1-10 alkyl, C_1-10alkenyl, C1_10 alkylidene, C3_12 cycloalkyl, C1_10 alkoxy and oxo;

n is an integer ranging from 0 to 3;

ES 2 322 158 T3

R_i is selected from the group consisting of hydrogen, C_i-i0 alkyl, C₃__i2 cycloalkyl, C₂__i0 alkenyl, amino, C_1-10 alkylamino, C₃_₁₂ cycloalkylamino, benzyl, C₃_₁₂ cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, a bicyclic ring system and a spiro ring system of formula (V):

<img file="ES2322158T3_D0002.tif" />

where X_i and X₂ are independently selected from the group consisting of NH, O, S, and CH₂;

wherein said monocyclic aryl is preferably phenyl;

wherein said bicyclic aryl is preferably naphthyl;

where said alkyl, cycloalkyl, alkenyl, C_i-i0 alkylamino, C₃__i2 cycloalkylamino or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, Ci_i0 alkyl, C_i-i0 alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, and benzyloxy, said phenyl, benzyl, and benzyloxy being optionally substituted with 1-3 substituents selected from the group consisting of halogen, Ci-alkyl, C_i-i0 alkoxy and cyano;

where said C₃__i2 cycloalkyl, C₃__i2 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromoncyclic ring, heterobicyclic ring system and spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the members of the group consisting of halogen, Ci_i0 alkyl, C_{i_i0} alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy, and benzyloxy, wherein said phenyl, benzyl, phenyloxy, and benzyloxy are optionally substituted with 1-3 substituents selected from members of the group consisting of halogen, C_i-i0 alkyl, C_i-i0 alkoxy and cyano;

R₂ is selected from the group consisting of hydrogen, C_i-i0 alkyl, C₃__i2 cycloalkyl and halogen, said alkyl being optionally substituted with an oxo group;

but not to a compound of the following formula

<img file="ES2322158T3_D0003.tif" />

where X is CIIR⁴¹ and R ^ is Ci-5 alkyl and where Ar is a monocyclic aryl ring optionally substituted with halogen, Ci-5 alkoxy, Ci-i5 alkyl and cyano, and where R⁷ and R⁸ are independently hydrogen, Ci-5 alkyl and C | ₅ alkoxy or halogen; and alternatively R⁷ and R⁸ can be taken together to form a carbocyclic ring

ES 2 322 158 T3 or optionally substituted 5- to 7-membered heterocyclic, the ring of which may be saturated, unsaturated or aromatic;

and pharmaceutically acceptable salts thereof.

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

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

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

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

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

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

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

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

In certain embodiments of formula (IIA), the Z group is maximally substituted so as to have no hydrogen substitution on the base Z group. For example, if the base group Z is -CH₂-, substitution with two methyl groups would remove the hydrogens from the base -CH group Z₂-.

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

In certain embodiments of formula (IIA), X1 and X2 are both O.

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

In certain embodiments of formula (IV), at least one member of the group consisting of ZR1 or R is -CH₂COOV₁, tetrazolylmethyl-, cyanomethyl-, NH₂SW₂methyl-, NH₂SOmethyl-, aminocarbonylmethyl-, C_1-4alkylaminonylmethyl- or diC_1-4alkylaminocarbonylmethyl-.

In certain embodiments of formula (IV), ZR1 is 3,3-diphenylpropyl optionally substituted at the 3-carbon of propyl with -COOV₁, tetrazolylC₀-₄alkyl-, cyano-, aminocarbonyl-, C_1-4alkylaminocarbonyl- or diC_1-4alkylaminocarbonyl-.

In alternative embodiments of formula (IIA), ZR1 can be the following

Y₂ where

Y₁ is R₃- (C₁-C₁₂) alkyl, R₄-aryl, R₅-heteroaryl, R₆- (C₃-C₁₂) cycloalkyl, R₇- (C₃-C₇) heterocycloalkyl, -CO₂(C₁C₆) alkyl, CN or -C (O) NR₈R₉; Y₂ is hydrogen or Y₁; Y₃ is hydrogen or (C₁-C₆)I rent; or Y₁, Y₂ and Y₃, together with the carbon to which they are attached, form one of the following structures:

ES 2 322 158 T3

<img file="ES2322158T3_D0004.tif" />

where r is 0 to 3; c and d are independently 1 or 2; s is 1 to 5; and ring E is a ring of R₄-phenyl or R₅-fused heteroaryl;

Rio is 1 to 3 substituents that are independently selected from the group consisting of H, (C₁ -C₆) alkyl, -OR₈, - (C₁-C₆) alkyl-OR₈, -NR₈R₉ and - (C₁-C₆) alkyl-NR₈R₉;

R₁₁ is 1 to 3 substituents that are independently selected from the group consisting of R₁₀, -CF₃, -OCF₃, DO NOT₂ and halo, or the R substituents₁₁ on adjacent cyclic carbon atoms they may together form a methylenedioxy or ethylenedioxy ring;

R₈ and R₉ are independently selected from among the members of the group consisting of hydrogen, (C₁-C₆) alkyl, (C₃-C₁₂) cycloalkyl, aryl and aryl (C₁-C₆)I rent;

R3 is 1 to 3 substituents that are independently selected from the group consisting of H, R₄-aryl, R₆- (C₃-C₁₂) cycloalkyl, R₅-heteroaryl, R₇- (C₃-C₇) heterocycloalkyl, -NR₈R₉, -OR₁₂ And so)_{0 2}^R12^;

R₆ is 1 to 3 substituents that are independently selected from the group consisting of H, (C₁-C₆) alkyl, R₄-aryl, -NR₈R₉, -OR₁₂ and -SR₁₂;

R4 is 1 to 3 substituents that are 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 -Co) alkyl-NR8R9, -NHSO2R8, -SOíN (R14) í, -SO2R8, -SOR8, -SR8, -NO2, -CONR8R9, -NR9COR8,

ES 2 322 158 T3

-COR₈, -COCK -OCOR₈, -OCO₂R₈, -COOR₈, - (Ci-C6) alkyl-NHCOOC (CH3) 3, - (Ci-CrJalkyl-NIICOOL, - (Ci-C₆) alkyl-NHSO₂- (C₁ -C₆) alkyl, - (C₁ -C₆) alkyl-NHCONH- (C₁-C₆) -alkyl and

<img file="ES2322158T3_D0005.tif" />

where f is 0 to 6; or the R substituents₄ on adjacent cyclic carbon atoms they may together form a methylenedioxy or ethylenedioxy ring;

R₅ is 1 to 3 substituents that are 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,

<img file="ES2322158T3_D0006.tif" />

R7 is H, (C1-C₆) alkyl, -OR8, - (C1-C₆) alkyl-OR «, -NR8R9 or - (C1-C6) alkyl-NR8R9;

R₁₂ is H, (C₁ -C₆) alkyl, R₄-aryl, - (C₁-C₆) alkyl-OR₈, - (C₁ -C₆) alkyl-NR₈R₉, - (C₁-C₆) alkyl-SR₈ or aril (C₁ -C₆) I rent;

R₁₃ is 1-3 substituents independently selected from members of the group consisting of H, (C₁C₆) alkyl, (C₁-C₆) alkoxy and halo;

R₁₄ is independently selected from among the members of the group consisting of H, (C₁-C₆) alkyl and R₁₃C6H4-CH2-.

As used herein, the term "alkyl" means a linear or branched saturated aliphatic hydrocarbon group having a single radical and 1-10 carbon atoms. Examples of alkyl groups include members of the group consisting of 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 substitute 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.

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

The term "cycloalkyl" means a non-aromatic mono- or multicyclic hydrocarbon ring system having a single radical and 3-12 carbon atoms. Examples of monocyclic cycloalkyl rings include members of the group consisting of cyclopropyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl rings include members of the group consisting of adamantyl and norbornyl.

The term "alkenyl" means a linear or branched aliphatic hydrocarbon group containing a carbon-carbon double bond having a single radical and 2-10 carbon atoms.

A "branched" alkenyl means that one or more alkyl groups such as methyl, ethyl or propyl substitute one or both hydrogens in a -CH group₂- or -CH = of a linear alkenyl chain. Examples of alkenyl groups include members of the group consisting of ethenyl, 1- and 2-propenyl, 1-, 2- and 3-butenyl, 3-methylbut-2enyl, 2-propenyl, heptenyl, octenyl, and decanyl.

The term "cycloalkenyl" means a non-aromatic monocyclic or multicyclic hydrocarbon ring system that contains a carbon-carbon double bond and has a single radical and 3 to 12 carbon atoms. Examples of monocyclic cycloalkenyl rings include members of the group consisting of cyclopropenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl. An example of a multicyclic cycloalkenyl ring is norbornenyl.

The term "aryl" means a carbocyclic aromatic ring system containing one, two or three rings which may be pendant or fused together and containing a single radical. Examples of aryl groups include members of the group consisting of phenyl, naphthyl, and acenaphthyl.

The term "heterocyclic" means cyclic compounds that have one or more heteroatoms (atoms other than carbon) in the ring, and that have a single radical. The ring can be saturated, partially saturated, or unsaturated, and the heteroatoms can be selected from the group consisting of nitrogen, sulfur, and oxygen. Examples of saturated heterocyclic radicals include saturated hetero-monocyclic groups.

3 to 6-membered ES 2 322 158 T3 containing 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino and piperazinyl; to saturated 3- to 6-membered hetero-monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl; and to 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 members of the group consisting of dihydrothiophene, dihydropyran, and dihydrofuran. Other heterocyclic groups can be rings of 7 to 10 carbons substituted with heteroatoms, such as oxokanyl and thiokanyl. When the heteroatom is sulfur, the sulfur can be a sulfur dioxide such as thiokanyl dioxide.

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

In the sense in which they are used here, the expressions “C_{i 4} heterocyclic alkyl "," C_i-4 heteroaromatic alkyl "and similar expressions refer to the ring structure attached to an alkyl radical of C_i-4.

All of the cyclic ring structures described herein can be joined at any point where such a connection is possible, as is known to one of ordinary skill in the art.

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

As used herein, the term "halogen" includes members of the group consisting of fluoride, bromide, chloride, iodide, or astatide.

The invention disclosed herein is intended to include all pharmaceutically acceptable salts of the disclosed compounds. Although not limited thereto, pharmaceutically acceptable salts include members of the group consisting of metal salts such as sodium salt, potassium salt, cesium salt, and the like; alkaline earth metal salts 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; and amino acid salts such as arginate, asparginate, glutamate, and the like.

The invention disclosed herein is also intended to include the disclosed compounds that are isotopically labeled as having one or more atoms substituted for an atom having a different mass number or atomic mass. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as²H, ³H, ⁱ³C, ⁱ⁴C, ⁱ⁵N, ⁱ⁸OR, ⁱ⁷OR, ⁱ³P, ³²P, ³⁵Yes, ⁱ⁸F and ³⁶Cl, respectively. Some of the compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastomers, and other stereoisomeric forms. The present invention also intends to include all possible forms of this type, 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, unless otherwise specified, geometric isomers of both E and Z configurations are intended to be included. They are also intended to be included herein. invention all tautomers.

As 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. This term includes the enantiomers and isomers of compounds with more than one chiral center that are not mirror images of each other (diastomers).

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

ES 2 322 158 T3

The term "enantiomer" or "enantiomeric" refers to a molecule that is not superimposable on its mirror image and that is therefore optically active, where the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of light polarized in the opposite direction.

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

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

As used herein with respect to the ORL-1 receptor, the term "modulate" means the mediation of a pharmacodynamic response (such as, eg, analgesia) in a subject based on (I) inhibit or activate the receptor, or (II) directly or indirectly affect the normal regulation of receptor activity. Compounds that modulate receptor activity include members of the group consisting of agonists, antagonists, mixed agonists / antagonists, and compounds that directly or indirectly affect the regulation of receptor activity.

Certain preferred compounds of formula (IIA) include the following:

3-ethylidene-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (4-propylcyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (naphth-2-yl-methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (p-benzyloxybenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (benzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (3,3-diphenylpropyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (p-cyanobenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- [4- (1-methylethyl) -cyclohexyl] -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (4-propylcyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (decahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1 [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (3,3-bis (phenyl) propyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (4-propylcyclohexyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (5-methylhex-2-yl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- [4- (1-methylethyl) cyclohexyl] -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (decahydro-2-naphthyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one; and pharmaceutically acceptable salts thereof and solvates thereof.

ES 2 322 158 T3

The present invention also provides the 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, such as e.g. ex. the ORL-1 receptor.

Detailed description of the invention

The compounds of the present invention can be administered to anyone requiring modulation of opioid receptors and ENT 1. Administration can be effected orally, topically, by suppository, by inhalation or parenterally.

The present invention also includes all pharmaceutically acceptable salts of the above compounds. One skilled in the art will be aware that acid addition salts of the compounds claimed herein can be prepared by reacting the compounds with the appropriate acid by a variety of known methods.

Various oral dosage forms can be used including solid forms such as tablets, gel capsules, capsules, caplets, granules, lozenges, and bulk powders, and liquid forms such as emulsions, solutions, and suspensions. The compounds of the present invention can be administered alone or they 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 and reconstitution in the form of an injectable formulation.

In certain embodiments, the compounds of the present invention can be used in combination with at least one other therapeutic agent. Although not limited to these, therapeutic agents include members of the group consisting of μ-opioid agonists; non-opioid pain relievers; non-steroidal anti-inflammatory agents; Cox-II inhibitors; antiemetics; β-adrenergic blockers; anticonvulsants; antidepressants; Ca2 + channel blockers; anticancer agents and mixtures thereof.

In certain embodiments, the compounds of the present invention can be made into a pharmaceutical dosage form in combination with a µ-opioid agonist. Although not limited to these, the μ-opioid agonists that can be included in the formulations of the present invention include members of the group consisting of alfentanil, allylprodin, alphaprodin, anileridine, benzylmorphine, becitramide, buprenorphine, butorphanol, clonitacene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, dioxafethyl butyrate, dipipanone, eptazocin, ethoheptacin, ethylmethylthiambutene, ethylmorphine, etonitacene fentanyl, heroin, hydrocodone, hydromorphone, hydroxyypetidine, isomethadone, ketobemidone, levorphanol, levofenacylmorphan, lofentanyl, meperidine, methophanilorphine, methophaniline, methophenol, myrophanyne, methophenol, morphenine , normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenadoxone, phenomorphan, phenazocin, phenoperidine, piminodine, pyritramide, proheptacin, promedol, properidine, propyram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.

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

In another embodiment of the invention, the medicament comprises a mixture of a Cox-II inhibitor and a 5-lipoxygenase inhibitor for the treatment of pain and / or inflammation. Suitable CoxII inhibitors and 5-lipoxygenase inhibitors, as well as combinations thereof, are described in US Patent No. 6,136,839, which is incorporated herein by reference in its entirety. Although not limited to these, Cox-II inhibitors include members of the group consisting of 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, PD164387, etoricoxib, valdecoxib and parecoxib or enantiomers or tautomers or pharmaceutically acceptable salts thereof.

The compounds of the present invention can also be combined in dosage forms with non-opioid analgesics, such as e.g. ex. non-steroidal anti-inflammatory agents including members of the group consisting of aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, pyroxaprofen, carprofen, oxaprocin, trofenac, pramoprofen aminoprofen, tiaprophenic acid, fluprofen, bucoloxic acid, indomethacin, sulindac, tolmetin, zomepirac, thiopinac, cidomethacin, acemethacin, fenthiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxacam, sudoxicam or isoxicam, pharmaceutically acceptable salts thereof and mixtures thereof. Other suitable non-opioid analgesics that may be included in the dosage forms of the present invention include the following non-limiting chemical classes of non-steroidal analgesic, antipyretic, and anti-inflammatory drugs: salicylic acid derivatives, including members of the group consisting of aspirin, sodium salicylate, tri

ES 2 322 158 T3 Choline magnesium salicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine and olsalazine; derivatives of para-aminophenol, including acetaminophen; indoleacetic and indenoacetic acids, including members of the group consisting of indomethacin, sulindac, and etodolac; heteroarylacetic acids, including members of the group consisting of tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid and meclofenamic acid; enolic acids, including members of the group consisting of oxicams (piroxicam, tenoxicam) and pyrazolidinediones (phenylbutazone, oxyphentartazone); and alkanones, including nabumetone. For a more detailed description of the NSAIDs (NSAIDs = non-steroidal anti-inflammatory drugs) that can be included in the drugs used in the present invention, see Paul A. Insel Analgesic-Antipuretic and Antiinflammatory Agents and Drugs Employed in the treatment of Gout in Goodman &amp; Gilman's The Pharmacological Basis of Therapeutics, 617-57 (Editors Perry B. Molinhoff and Raymond W. Ruddon, Ninth Edition, 1996), and Glen R Hanson Analgesic, Antipyretic and Inti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol. II, 1196-1221 (editor-in-chief AR Gennaro, 19^to Ed. 1995).

In certain embodiments, the compounds of the present invention can be made into a pharmaceutical dosage form in combination with antimigraine agents. Although not limited to these, antimigraine agents include members of the group consisting of alpiropride, dihydroergotamine, dolasetron, ergochornine, ergochorninine, ergocriptine, ergot, ergotamine, flumedroxone acetate, fonazine, lisuride, lomericin, methysergide oxetiline, and mixtures of oxetiline pysergide. thereof.

The other therapeutic agent can also be an adjuvant to reduce any potential side effects, such as for example an antiemetic agent. Although not limited to these, suitable antiemetic agents include members of the group consisting of metoclopramide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine, monoethanolamine, alizapride, azasetron, benzinquinamine. bromopride, buclycine, clebopride, cyclicine, dimenhydrinate, diphenidol, dolasetron, meclycine, metalatal, mettopimazine, nabilone, oxyperndil, pipamazine, scopolamine, sulpiride, tetrahydrocannabiols, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.

In certain embodiments, the compounds of the present invention may be made into a pharmaceutical dosage form in combination with ^ -adrenergic blockers. Although not limited to these, suitable ^ -adrenergic blockers include members of the group consisting of acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumotol, bufetolol, bunoluralol, buffered bupranolol, butydrine hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, chloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, niphenalol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronetalol, propranolol, sotalol, sulfinalol, talinolol, tertatolol, tilisololol, timolol, and xylibenolol.

In certain embodiments, the compounds of the present invention can be made into a pharmaceutical dosage form in combination with anticonvulsants. Although not limited to these, suitable anticonvulsants include members of the group consisting of acetylpheneturide, albutoin, alloxidone, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, calcium bromide, carbamzepine, cinnazolromide, clomethiazolomide. , clonazepam, decimemide, diethadione, dimethadione, doxenitroin, eterobarb, etadione, ethosuximide, etotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, Magnesium sulfate, mephenytoin, mephobarbital, metharbital, methetoin, methsuximide, 5-methyl-5- (3-phenanthryl) -hydantoin, 3-methyl-5-phenylhydrantoin, narcobarbital, nimetazepam, nitrazepam, oxcarbanetazine, parametadione, pheuryacebitalide, parametadione , phenobarbital, phensuximide, phenylmethylbarbituric acid, phenytoin, sodium fetenilate, potassium bromide, pregabalin, primidone, progabide, sodium bromide, solanum, strontium bromide, suclofenide, sultiame, tetrantoin, thiagabine, topiramate trimethadione, valproic acid, valpromide, vigabatrin, and zonisamide.

In certain embodiments, the compounds of the present invention can be made into a pharmaceutical dosage form in combination with antidepressants. Although not limited to these, suitable antidepressants include members of the group consisting of bineladin, caroxazone, citalopram, dimethazan, phencamine, indalpine, indeloxacin hydrochloride, nefopam, nomifensine, oxytryptan, oxypertin, paroxetine, sertraline, thiacesim, trazodonacesim, benmoxine, iproclocide, iproniazide, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, roliciprin, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptyline, amoxapine, butryptyline, clomipramine, demexyptyline, desipramine, dibenzepine, dimetacrine, diotepine, doxepin, fluazizine, imipramine, imipramine N-oxide, iprindole, lofepramine, melitracene, protilipramine, propizotyline, non-propizotyline, pyrizine , tianeptine, trimipramine, adrafinil, benacticin, bupropione, butacetin, dioxadrol, duloxetine, ethoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, Hematoporphyrin, Hypericin, Levofacetoperan, Medifoxamine, Milnacipran, Minaprine, Moclobemide, Nefazodone, Oxaflozane, Piberaline, Prolintane, Pyrisuccideanol, Ritanserine, Roxindole, Rubidium Chloride, Sulpiride, Tandospyrone, Trypofonacin, Venanthromine, Trentinoxofonacin viloxacin and cimeldine.

In certain embodiments, the compounds of the present invention can be made into a pharmaceutical dosage form in combination with Ca2 + channel blockers. Although not limited to these, suitable Ca2 + channel blockers include members of the group consisting of bepridil, clentiazem, diltiazem, phendiline, galopamil, mibefradil, prenylamine, semothiadyl, terodiline, verapamil, amlodipine, aranidipine,

ES 2 322 158 T3 barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, cinnamon, nitricipine, ethandycin, lidycinofin, lidycinofin, lidycinofin and perhexiline.

In certain embodiments, the compounds of the present invention can be made into a pharmaceutical dosage form in combination with anticancer agents. Although not limited to these, suitable anticancer agents include members of the group consisting of acivicin; aclarubicin; acodazole hydrochloride; acronin; adocelesin; aldesleuquina; altretamine; ambomycin; methantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; acetepa; azotomycin; bathymastat; benzodepa; bicalutamide; bisanthrene hydrochloride; bisnafide dimesylate; bicelesin; bleomycin sulfate; brequinar sodium; bropyrimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carcelesin; cedefingol; chlorambucil; Cyrolemycin; cisplatin; cladribine; chrysnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; Daunorubicin Hydrochloride; decitabine; dexormaplatin; dezaguanine; Dezaguanine Mesylate; diacyuone; docetaxel; doxorubicin; Doxorubicin Hydrochloride; droloxifene; Droloxifene Citrate; Dromostanolone Propionate; duazomycin; edatrexate; Eflornithine Hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; Epirubicin Hydrochloride; erbulozole; Esorubicin Hydrochloride; estramustine; estramustine sodium phosphate; ethanidazole; etoposide; Etoposide Phosphate; ethoprine; Fadrozole Hydrochloride; fazarabine; fenretinide; floxuridine; Fludarabine Phosphate; fluorouracil; flurocitabine; phoschidone; sodium phostriecin; gemcitabine; Gemcitabine Hydrochloride; hydroxyurea; Idarubicin Hydrochloride; ifosfamide; ilmophosine; interleukin II (including recombinant interleukin II or rII2), interferon alpha-2a; interferon alfa-2b; interferon alpha-n1; interferon alpha-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; sodium methotrexate; metoprine; meturedepa; mitindomide; mitocarcin; mitochromin; mitogyline; mitomalcin; mitomycin; mitosper; mitotane; Mitoxantrone Hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxysuran; paclitaxel; pegaspargasa; peliomycin; pentamustine; Peplomycin Sulfate; perfosphamide; pipobroman; piposulfan; Pyroxantrone Hydrochloride; plicamycin; plomestane; porfimer sodium; porphyromycin; prednimustine; Procarbazine Hydrochloride; puromycin; Puromycin Hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; Safingol Hydrochloride; semustine; simtracene; sodium sparphosate; sparsomycin; Spirogermanium Hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; sodium tecogalan; tegafur; Teloxantrone Hydrochloride; temoporfin; teniposide; teroxyrone; testolactone; thiamiprine; thioguanine; thiotepa; thiazofurine; 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; ceniplatin; cinostatin and zorubicin hydrochloride. Although not limited to these, other anticancer drugs include members of the group consisting of: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adeyphenol; adocelesin; aldesleuquina; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; G antagonist; antarelix; Morphogenetic protein 1 anti-spill; antiandrogen, prostatic carcinoma; antiestrogen; antineoplastone; antisense oligonucleotides; aphidicolin glycinate; modulators of apoptosis genes; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azathyrosine; Baccatin III derivatives; balanol; bathymastat; BCR / ABL antagonists; benzochlorines; benzoylstaurosporine; derivatives of beta-lactam; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantreno; bisacidinyl permine; bisnafide; bistratene A; bizelesin; breflate; bropyrimine; budotitan; butionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; Capecitabine; carboxamine-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carcelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorines; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; Clomiphene Analogs; clotrimazole; colismycin A; colismycin B; combretastatin A4; Combretastatin Analog; conagenina; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; Cytarabine Ophosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexyphosphamide; dexrazoxane; dexverapamil; diacyuone; didemnin B; didox; diethylnospermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenylpyromustine; docetaxel; docosanol; dolasetron; doxyfluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelphosine; edrecolomab; eflornithine; elemene; emitter; epirubicin; epristerida; estramustine analog; estrogen agonists; estrogen antagonists; ethanidazole; Etoposide Phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flecelastin; fluasterone; fludarabine; Fluorodaunorunicin Hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocytabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; Hexamethylene Bisacetamide; hypericin; Ibandronic acid; idarubicin; idoxitene; idramantone; ilmophosine; ilomastat; imidazoacridones; imiquimod; immunostimulating peptides; insulin-like growth factor 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguan; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazol; isohomohalicondrin B; itasetron; jasplaquinolide; cahalalide F; lamelarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolestatin; letrozole; leukemia inhibitory factor, leukocyte interferon alpha; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analog; lipophilic disaccharide peptide; lipophilic platinum compounds; lysoclinamide 7; lobaplatin; earthworm; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysophylline; lytic peptides; maytansine; mannostatin

ES 2 322 158 T3

TO; marimastat; masoprocol; maspina; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarona; meterilin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; Mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogs; mitonafida; mitotoxin fibroblast growth factor-saporin; mitoxantrone; Mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A + myobacterial cell wall streptokinase; mopidamole; inhibitor of multidrug resistance genes; tumor multisuppressant-based therapy 1; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavine; nafterpine; nartograstim; nedaplatin; nemorubicin; Neridronic Acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrulline; O6-benzylguanine; octreotide; oquicenone; oligonucleotides; onapristone; ondansetron; orazine; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogs; derivatives of paclitaxel; palauamina; palmitoylrizoxin; Pamidronic acid; panaxytriol; panomiphene; parabactin; paceliptin; pegaspargasa; peldesine; Pentosan Sodium Polysulfate; pentostatin; pentrozole; perflubron; perfosphamide, perilyl alcohol; phenacinomycin; phenyl acetate; phosphatase inhibitors; picibanil; Pilocarpine Hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porphyromycin; 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; glitter; pyrazoloacridine; conjugate of polyoxyethylene and pyridoxylated hemoglobin; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; demethylated reteliptin; Rhenium etidronate Re 186; rhizoxin; ribozymes; retinamide RII; rogletimide; rohituquine; romurtida; roquinimex; rubiginone B1; ruboxil; safingol; saintopine; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescene-derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; modulators of signal transduction; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate, solverol; somatomedin binding protein; sonermina; sparphosic acid; spicamycinD; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonin; synthetic glycosaminoglycans; talimustine; Tamoxifen Metiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrillium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; taliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; timotrinan; thyroid stimulating hormone; ethyl tin ethiopurpurine; tirapazamine; titanocene dichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; typhostines; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramin; verdinas; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb and zinostatin stimalamer.

The compounds of the present invention and the other therapeutic agent may act additively or, more preferably, synergistically. In a preferred embodiment, a composition comprising a compound of the present invention is administered concurrently with the administration of another therapeutic agent that may be part of the same composition or may be in a different composition from that comprising the compound of the present invention. present invention. In another embodiment, a composition comprising the compounds of the present invention is administered before or after the administration of another therapeutic agent.

When they are administered p. ex. By oral, parenteral, or topical routes to mammals, the compounds of the present invention may be in a dosage within the range of dosages from about 0.01 mg / kg to about 3000 mg / kg of patient body weight. per day, and preferably from about 0.01 mg / kg to about 1000 mg / kg of body weight per day, said dosage being administered as a single dose or as a divided dose. However, there will necessarily be variations depending on the weight and physical state (such as liver and kidney function) of the subject in question, the condition in question, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the presence of any deleterious side effects, and the specific compound used, among other things.

The compounds of the present invention preferably have a K1 binding affinity for the human ORL1 receptor of about 500 nM or less, 100 nM or less, 50 nM or less, 20 nM or less, or 5 nM or less. K1 binding affinity can be measured by a person skilled in the art using an assay using recombinant HEK-293 cell membranes expressing the human opioid-like receptor (ORL-1) as described below.

ES 2 322 158 T3

Reference example 1

Synthesis of the benzoxazolone head groups

The head groups of the present invention were synthesized according to the following procedure:

<img file="ES2322158T3_D0007.tif" />

Process

To 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 kept stirring at room temperature overnight. The mixture was filtered through Celite, and 1N 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 with K₂CO₃, filtered and evaporated in vacuo to obtain crude 3 as a brown solid (2.75 g, yield: 94%).

¹H NMR (¹H NMR = nuclear magnetic resonance of ¹H) (CDCl₃) (CDCl₃ = deuterated chloroform): d 1.20-1.60 (m, 11H), 2.00 (dd, 2H), 2.9 (m, 2H), 3.40 (m, 1H), 4.00 ( m, 2H), 6.60-6.85 (m, 4H).

To an ice-cold solution of crude 3 (12.0 g, 40 mmol) and DIEA (DIEA = diisopropylethylamine) (20.8 ml, 120 mmol) in 200 ml of THF (THF = tetrahydrofuran) 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 was allowed to stir at room temperature overnight. The solids were filtered off and the filtrate was evaporated in vacuo. The residual brown oil was dissolved in EtOAc (EtOAc = ethyl acetate) and washed with saturated aqueous K2CO3. The organic phase was dried with K2CO3, filtered and evaporated in vacuo to obtain a red oil that 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 was evaporated in vacuo to obtain a brown solid that was crystallized from EtOAc to obtain 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).

A solution of 4 (4.0 g, 17.2 mmol) in 30% TFA (TFA = trifluoroacetic acid) in dichloromethane (25 ml) was stirred at room temperature for 3 h. The solvent was evaporated in vacuo, 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 vacuo to obtain the crude product. By chromatography on silica gel eluting with a mixture of 10% Et3N, 60% EtOAc and 30% hexane, 5 was obtained as a yellow solid (1.82 g, 66% yield).

MS (MS = mass spectrometry): 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).

ES 2 322 158 T3

Reference example 2

Union of the tail groups

The tail groups were joined to the head groups according to the following procedures:

<img file="ES2322158T3_D0008.tif" />

General procedure for alkylation

To 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 kept stirred and heated at 80 ° C overnight. TLC (TLC = thin layer chromatography) indicated that the reaction was complete. The reaction was quenched by the addition of water followed by 1N NaOH until pH 10. The mixture was extracted 2 times with Et₂O. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to obtain the pure product.

General procedure for reductive amination

To 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 overnight at room temperature. TLC indicated that the reaction was complete. The reaction was quenched by the addition of water followed by 1N NaOH until pH 10. The mixture was extracted 2 times with Et₂O. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, after which chromatography was carried out to obtain the pure product.

The following reference compounds were prepared by linking the tail groups using the general procedures described:

3- [1- (naphth-2-yl-methyl) -4-piperidinyl] -2H-benzoxazol-2-one

3- [1- (naphth-1-yl-methyl) -4-piperidinyl] -2H-benzoxazol-2-one

3- [1- (p-phenylbenzyl) -4-piperidinyl] -2H-benzoxazol-2-one

3- [1- (p-benzyloxybenzyl) -4-piperidinyl] -2H-benzoxazol-2-one

3- [1- (p-cyanobenzyl) -4-piperidinyl] -2H-benzoxazol-2-one

MS: m / z 334.4 (M + 1)

3- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2H-benzoxazol-2-one

3- [1- [4,4-bis- (4-fluorophenyl) butyl] -4-piperidinyl] -2H-benzoxazol-2-one

MS: m / z 463.6 (M + 1)

3- [1- (2-phenylethyl) -4-piperidinyl] -2H-benzoxazol-2-one

3- [1- (cyclooctylmethyl) -4-piperidinyl] -2H-benzoxazol-2-one

ES 2 322 158 T3

LC (LC = liquid chromatography): 100%

MS: m / z 343.6 (M + 1)

Ή 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 (13C-NMR = 13C Nuclear Magnetic Resonance), (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.

3- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -2H-benzoxazol-2-one

LC: 100%

MS: 349.6 (M + 1)

Ή 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), 7.10-7.30 (m, 8H).

3- [1- (5-methylhex-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one

LC: 100%

MS: 317.4 (M + 1)

Ή 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).

3. [1- (10,11-dihydro-5H-dibenzo [a, d] -cyclohepten-5-yl) -4-piperidinyl] -2H-benzoxazol-2-one

LC: 96.4%

Ή 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).

3- [1- (4-propyl-cyclohexyl) -4-piperidinyl] -2H-benzoxazol-2-one

MS: m / z 343.0

3- [1- (norbornan-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one

LC: 97%

MS: m / z 313.41 (M + 1)

Ή NMR (CDCl₃): d 0.90 (m, 1H), 1.30-2.50 (m, 17H), 3.20 (m, 2H), 4.3 (m, 1H), 6.90-7.30 (m, 4H).

3- [1- (decahydro-2-naphthyl) -4-piperidinyl] -2H-benzoxazol-2-one

MS: m / z 355.4

3- [1- (3,3-dimethyl-1,5-dioxaspiro [5.5] undeca-9-yl]) - 4-piperidinyl] -2H-benzoxazol-2-one

MS: m / z 401.3

3- [1- [4- (1-methylethyl) -cyclohexyl] -4-piperidinyl] -2H-benzoxazol-2-one

MS: m / z 343.0

3- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one

LC: 100%

MS: m / z 335.4 (M + 1)

Ή 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).

3- [1- (cyclooctyl) -4-piperidinyl] -2H-benzoxazol-2-one

LC: 100%

MS: m / z 329.2 (M + 1)

ES 2 322 158 T3

Ή 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).

Reference example 3

The nociceptin affinity at the ORL 1 receptor for preferred compounds was obtained using the following assay:

Membranes of recombinant HEK-293 cells expressing the human opioid-like receptor (ORL1) (Receptor-Biology) were prepared by lysing cells in ice-cold hypotonic buffer (MgCl₂ 2.5 mM, 50 mM HEPES, pH 7.4) (10 ml / 10 cm plate) followed by homogenization with a Teflon tissue grinder / pestle. The membranes were harvested by centrifugation at 30,000 xg for 15 min. at 4 ° C, and the pellets were 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 Albumin as a standard. Aliquots of the ORL-1 receptor membranes were stored at -80 ° C.

Functional SGTPgS binding assays were carried out 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 [³⁵S] 0.20 nM GTPgS to binding buffer (100 mM NaCl, MgCl₂ 10 mM, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 ml / well) was transferred to shallow 96-well polypropylene plates containing 10 ml of 20x concentrated solutions of agonist prepared in DMSO. The plates were incubated for 30 min. at room temperature with shaking. Reactions were terminated by rapid filtration on Unifilter GF / B 96-well filter plates (Packard) using a 96-well tissue harvester (Brandel) followed by three filter washes with 200 ml of ice-cold binding buffer. (NaH₂PO₄ 10 mM, Na₂HPO₄ 10 mM, pH 7.4). The 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 on a Packard TopCount for 1 min / well.

The data were analyzed using the curve fitting functions in GraphPad PRISMO, v. 3.0, and the results are indicated in the following table 1:

<td colspan="2">TABLE 1</td>

<td colspan="2">Nociceptin Affinity</td>

<td>REFERENCE compound</td><td>Ki (nM) cale</td>

<td>3- (1- (naphth-2-yl-methyl) -4-piperid¡n¡l] -2H-benzoxazol-2-one</td><td> 3030</td>

<td>3- [1- (naphth-1-yl-methyl) -4-piperidinl] -2H-benzoxazol-2-one</td><td> 370</td>

<td>3- (1- (p-phenylbenzyl) -4-piperidinyl] -2H-benzoxazol-2-one</td><td> &gt;10.000</td>

<td>3- [1- (p-benzyloxybenzyl) -4-piperidinl] -2H-benzoxazol-2-one</td><td> 2173</td>

<td>3- [1- (p-cyanobenzyl) -4-piperidinyl] -2H-benzoxazol-2-one</td><td> &gt;10.000</td>

<td>3- (1- (3,3-diphenylpropyl) -4-piperidinyl] -2H-benzoxazol-2-one</td><td> 726</td>

<td>3- (1- (4,4-b¡s- (4-fluorophenyl) but¡l] -4-piperidin¡l] -2H-benzoxazol-2-one</td><td> 3070</td>

<td>3- [1- (2-phenylethyl) -4-piperidinyl] -2H-benzoxazol-2-one</td><td> 7087</td>

<td>3- [1- (cyclooctylmethyl) -4-piperdinyl] -2H-benzoxazol-2-one</td><td> 64</td>

<td>3- [1- (1,2,3,4-tetrahydro-2-naphthil) -4-piperidinyl] -2H-benzoxazol-2-one</td><td> 93</td>

<td>3- [1- (5-methylhex-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one</td><td> 60</td>

<td>3- (1- (10,11 -dihydro-5H-dibenzo [a, d] -cyclohepten-5-yl) -4-piperidinyl] -2Hbenzoxazol-2-one</td><td> &gt;10.000</td>

<td>3- (1- (3,3-dimethyl-1,5-dioxaspiro [5.5] undeca-9-yl]) - 4-piperidinyl] -2H- benzoxazol-2-one</td><td> &gt;10.000</td>

<td>3- (1- (1,3-dihydroinden-2-¡l) -4-piper¡d¡n¡l] -2H-benzoxazol-2-one</td><td> 512</td>

<td>3- [1- (cyclooctyl) -4-piperidinl] -2H-benzoxazol-2-one</td><td> 16</td>

ES 2 322 158 T3

Example 4

Synthesis of the Head Substituted Indole Groups

<img file="ES2322158T3_D0009.tif" />

Process

To a mixture of 2 (23.3 g, 0.25 mol), 1 (47.3 g, 0.25 mol), acetic acid (15 g, 025 mol) and molecular sieves (15 g) in 500 ml of Dichloroethane was added to sodium triacetoxyborohydride (74.2 g, 0.35 mole) in one portion, and the mixture was kept stirring overnight. The molecular sieves were filtered off and 1N NaOH (500 ml) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 300 ml). The combined organic extracts were dried over K2CO3 and filtered, and the solvent was evaporated under vacuum to obtain crude 3 as a brown solid which was used directly in the next step.

Compound 3 ¹H 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).

To an ice-cold solution of crude 3 (0.25 mol, 100% yield assumption) 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 was allowed to stir overnight. The solvent was removed in vacuo and the residue was dissolved in dichloromethane. The organic phase was washed with K₂CO₃ saturated aqueous, dried over K₂CO₃ and filtered, and the solvent was removed in vacuo to obtain a brown gum which was filtered through a column of silica gel eluting with a mixture of 10% Et₃N, 40% of

ES 2 322 158 T3

EtOAc and 50% hexane. The selected fractions were combined and the solvent was evaporated in vacuo to obtain a brown solid that was further crystallized from EtOAc to obtain 42.2 g of 4 (49.2%, steps).

Compound 4 ¹H 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).

A 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 into a dark liquid with concomitant evolution of gas. After heating for 1 h, the reaction mixture was cooled somewhat, and while it was still mobile, it was poured into a beaker containing 500 ml of ice water. The solution was made basic and extracted with dichloromethane. The organic layer was dried over Na₂SW₄ and filtered, and the solvent was evaporated in vacuo to obtain a dark colored oil that was filtered through a column of silica gel eluting with a mixture of 10% Et3N, 40% EtOAc and 50% of hexane. The selected fractions were combined, and the solvent was evaporated in vacuo to obtain 5 as a red oil which solidified to a pale colored solid (22.0 g, 58.5%).

Compound 5 ¹H 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).

To 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 (psi = pounds / inch²) for 12 h at room temperature. The solution was filtered through a pad of Celite and the pad was washed with methanol (2 x 20 ml). By evaporation of the solvent in vacuo, 6 was obtained as a pale solid (11.2 g, 100%).

Compound 6

LC: 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).

To 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 butoxycarbonyl anhydride (BOC) (8.87 g, 40.7 mmol). After stirring for h, K was added₂CO₃ saturated aqueous solution and the layers were separated. The aqueous phase was extracted with dichloromethane (2 x 50 ml). The combined organic phase was dried over K2CO3, filtered and evaporated in vacuo to obtain a brown oil which was filtered through a column of silica gel eluting with a mixture of 10% Et3N, 40% EtOAc and a 50% hexane. The selected fractions were combined and the solvent was evaporated in vacuo to obtain 7 as an off-white solid (8.50 g, 73%).

Compound 7 ¹H 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).

Acetaldehyde (1.67 g, 38.0 mmol) was added to a mixture of 7 (6.0 g, 19.0 mmol) and sodium acetate (2.58 g, 19.0 mmol) in 150 ml of methanol. . The mixture was refluxed for 2 h. The solvent was evaporated in vacuo to obtain 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 was evaporated in vacuo to obtain 8 as a red oil (5.90 g, 91%).

Compound 8

LC: 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).

A solution of 8 (5.90 g, 17.2 mmol) in 30% TFA in dichloromethane (100 ml) was stirred at room temperature for 3 h. The solvent was evaporated in vacuo, and saturated aqueous K2CO3 was added to the oily residue. The resulting mixture was extracted with dichloromethane (3 x 150 ml). The extracts

ES 2 322 158 T3 organics combined were dried with K₂CO₃, filtered and evaporated in vacuo to obtain the crude product. By chromatography on silica gel eluting with a mixture of 10% Et₃N, 50% EtOAc and 40% hexane gave 9 (E / Z configuration isomers) as a yellow foam (3.60 g, 82%).

Compound 9

LC: 2 isomers in a ratio of 2: 1

MS: m / z 243.1 (M + 1) ⁱH 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

<img file="ES2322158T3_D0010.tif" />

To a mixture of 5 (55.0 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 vacuo to obtain 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 was evaporated in vacuo to obtain 10 as a red oil (5.90 g, 98%).

Compound 10

LC: 2 isomers in a ratio of 2: 1.

MS: m / z 333.2 (M + 1) ⁱH 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).

To 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 was washed with methanol (2 x 20 ml). By evaporating the solvent in vacuo, a pale colored solid was obtained which was purified by chromatography on silica gel eluting with a mixture of 10% methanol and 90% EtOAc to obtain 11 as an off-white solid ( 2.02 g, 50%).

Compound 11

LC: 97%

MS: m / z 245.2 (M + 1) ⁱH NMR (CDCl₃): d 0.85 (t, 3H), 1.26 (m, 2H), 2.20 (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).

ES 2 322 158 T3

Reference example 6

<img file="ES2322158T3_D0011.tif" />

<img file="ES2322158T3_D0012.tif" />

Process

Compound 16 was prepared in a similar manner to Preparation 6.

Compound 13

LC: 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

MS 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

LC: 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

LC: 92.5%

MS m / z 231.2 (M + 1)

ES 2 322 158 T3 ¹H NMR (CDCl₃): dd 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

<img file="ES2322158T3_D0013.tif" />

Process

Compound 18 was prepared in a similar manner to preparation 11.

Compound 17

MS: M / Z 347.3 (m + 1)

Compound 18

LC: 82.6%

MS m / z 259.3 (M + 1) ¹H NMR (CDCl₃): d 0.80 (t, 3H), 1.20 (d, 3H), 2.00 (m, 2H), 2.30 (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, 1H), 6.90 (d, 1H), 7.05 (t, 1H), 7.25 (m, 2H).

Example 8

Union of the tail groups

The tail groups were joined to the head groups according to the following procedures:

<img file="ES2322158T3_D0014.tif" />

ES 2 322 158 T3

General procedure for alkylation

To 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 kept stirred and heated at 80 ° C overnight. TLC indicated that the reaction was complete. The reaction was quenched by the addition of water followed by 1N NaOH until pH 10. The mixture was extracted 2 times with Et2O. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, after which chromatography was carried out to obtain the pure product.

General procedure for reductive amination

To 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 overnight at room temperature. TLC indicated that the reaction was complete. The reaction was quenched by the addition of water followed by 1N NaOH until pH 10. The mixture was extracted 2 times with Et2O. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to obtain the pure product.

The following compounds were prepared by linking the tail groups using the general procedures described:

1- [1- (naphth-1-yl-methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one *

MS: mlz 357.2 (M + 1).

1- [1- (naphth-2-yl-methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one *

MS: mlz 357.3 (M + 1).

1- [1- (p-phenylbenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one *

MS: mlz 383.2 (M + 1).

1- [1- (3,3-bis (phenyl) propyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one *

LC: 98.7%

MS: mlz 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).

1- [1- (p-cyanobenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one *

MS: m / z 332.2 (M + 1).

3- [1- (p-benzyloxybenzyl) -4-piperidinyl] -1,3-dihydro -2H-indol-2-one *

MS: mlz 413.3 (M + 1).

1- [1- (1,2,3,4-tetrahydronaphth-2-yl) -4-piperidinyl] -1,3-dihydro -2H-indol-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).

1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro -2H-indol-2-one *

LC: 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).

1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one *

LC: 97%

ES 2 322 158 T3

MS: m / z 311.41 (M + 1)

Ή 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).

1- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one *

LC: 100%

MS: m / z 332.4 (M + 1)

Ή 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).

1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro -2H-indol-2-one *

LC: 97%

MS: m / z 341.50 (M + 1)

Ή 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 (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.

3-ethyl-1- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

MS: m / z 375.3 (M + 1)

3-ethyl-1- [1- (4-propylcyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

MS: m / z 369.2 (M + 1)

3-ethyl-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC: 100%

MS: m / z 342.4 (M + 1) ¹H NMR (CDCl₃): d 0.80 (t, 3H), 0.90 (d, 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).

3-ethyl-1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-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).

3-ethyl-1- [1- (decahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

MS: m / z 381.3 (M + 1)

3-ethyl-1- [1- [4- (1-methylethyl) -cyclohexyl] -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

MS: m / z 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).

3-ethyl-1 [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

MS: m / z 361.2 (M + 1)

3-ethyl-1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

ES 2 322 158 T3

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).

3-ethylidene-1- [1- (benzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-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 (d, 1H).

3-ethylidene-1- [1- (naphth-2-yl-methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

MS: m / z 405.2

3-ethylidene-1- [1- (3,3-diphenylpropyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC:&gt; 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).

3-ethylidene-1- [1- (p-cyanobenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC:&gt; 97% (2 isomers combined)

MS: m / z 358.5 (M + 1) ¹H NMR (CDCl₃): d 1.80 (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).

3-ethylidene-1- [1- (p-benzyloxybenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

MS: m / z 405.2.

3-ethylidene-1- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC:&gt; 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).

3-ethylidene-1- [1- (4-propylcyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC:&gt; 97% (2 isomers combined)

MS: m / z 367.5 (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, 5H).

3-ethylidene-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC:&gt; 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).

3-ethylidene-1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC:&gt; 97% (2 isomers combined)

ES 2 322 158 T3

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).

3-ethylidene-1- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC:&gt; 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).

3-ethylidene-1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC:&gt; 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).

1- [1- (3,3-bis (phenyl) propyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one *

LC: 100%

MS: mlz 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 0.00 (t, 1H), 7.10-7.30 (m, 12H).

1- [1- (benzyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro -2H-indol-2-one *

LC: 100%

MS: mlz 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).

1- [1- (4-propylcyclohexyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-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).

1- [1- (5-methylhex-2-yl) -3- (methyl) -4-piperidinyl] -1,3-dihydro -2H-indol-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).

1- [1- (decahydro-2-naphthyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one *

LC: 95.3%

MS: m / z 367.2 (M + 1) ¹H NMR (CDCl₃): d 1.11 (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).

1- [1- (4- (1-methylethyl) cyclohexyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one *

ES 2 322 158 T3

LC: 96.1%

MS: m / z 355.2 (M + 1) ⁱH 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), 2.953.25 (m, 2H), 3.50 (s, 2H), 4.10 (m, 1H), 6.95 (m, 2H), 7.22 ( m, 2H).

1- [1- (cyclooctylmethyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one *

LC: 100%

MS: m / z 355.2 (M + 1) ⁱH NMR (CDCl₃): d 1.12 (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, 1H), 3.12 (dq, 1H), 3.50 (s, 2H), 4.05 (dt, 1H), 6.99 (m, 2H) , 7.20 (m, 2H).

3-ethyl-1- [1- (3,3-bis (phenyl) propyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC: 96.3%

MS: mlz 453.3 (M + 1).

ⁱH 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, 1H ), 7.02 (t, 1H), 7.12-7.32 (m, 12H).

3-ethyl-1- [1- (4-propylcyclohexyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC: 93.2%

MS: mlz 383.3 (M + 1).

ⁱH 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).

3-ethyl-1- [1- (5-methylhex-2-yl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

LC: 92.3%

MS: mlz 357.4 (M + 1).

ⁱH 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).

3-ethyl-1- [1- [4- (1-methylethyl) cyclohexyl] -3-methyl-4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC: 94.7%

MS: mlz 383.4 (M + 1).

ⁱH 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).

3-ethyl-1- [1- (decahydro-2-naphthyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC: 94.3%

MS: mlz 395.3 (M + 1).

ⁱH 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).

* Reference compounds

ES 2 322 158 T3

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

Example 9

The nociceptin affinity at the ORL-1 receptor for preferred compounds was obtained using the following assay:

Membranes of recombinant HEK-293 cells expressing the human opioid-like receptor (ORL1) (Receptor-Biology) were prepared by lysing cells in ice-cold hypotonic buffer (MgCl₂ 2.5 mM, 50 mM HEPES, pH 7.4) (10 ml / 10 cm plate) followed by homogenization with a Teflon tissue grinder / pestle. The membranes were harvested by centrifugation at 30,000 xg for 15 min. at 4 ° C, and the pellets were 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 Albumin as a standard. Aliquots of the ORL-1 receptor membranes were stored at -80 ° C.

Functional SGTPgS binding assays were carried out 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 [³⁵S] 0.20 nM 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 shallow 96-well polypropylene plates containing 10 ml of 20x concentrated solutions of agonist prepared in DMSO. The plates were incubated for 30 min. at room temperature with shaking. Reactions were terminated by rapid filtration on Unifilter GF / B 96-well filter plates (Packard) using a 96-well tissue harvester (Brandel) followed by three filter washes with 200 ml of ice-cold binding buffer. (NaH₂PO₄ 10 mM, Na₂HPO₄ 10 mM, pH 7.4). The 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 on a Packard TopCount for 1 min / well.

The data were analyzed using the curve fitting functions in GraphPad PRISMO, v. 3.0, and the results are indicated in the following table 2:

(Table goes to next page)

ES 2 322 158 T3

<td colspan="2">TABLE 2</td>

<td colspan="2">Nociceptin Affinity</td>

<td>Compound</td><td>Ki (nlVI) stall</td>

<td>3-ethyl ¡deno-1 - [1 - (5-methi I hex-2-yl) -4-piperid¡ ni I] -1,3-dihydro-2H-¡ndol-2-one</td><td> 11,1</td>

<td>3-ethylidene-1- [1- (4-propylcyclohexyl) -4-pyridyl] -1,3-dihydro-2H-andol-2-one</td><td> 19</td>

<td>3-ethylidene-1 - [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indole- 2-one</td><td> 16,7</td>

<td>3-ethylidene-1 - [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indole-2one</td><td> 20,7</td>

<td>3-ethylidene-1 - [1- (naphth-2-¡l-methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one</td><td> 630</td>

<td>3-eti I iden o-1 - [1 - (p-benzylox¡ be nci l) -4-p¡ peridin i I] -1,3-dihydro-2H-indol-2-one</td><td> 516</td>

<td>3-ethyldene-1- [1- (benzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one</td><td> 1854</td>

<td>3-et¡ I ¡deno-1 - [1 - (cidoocti I methyl) -4-pi perid ini I] -1,3-dihydro-2H-indol-2-one</td><td> 22,3</td>

<td>3-ethyl ideno-1 - [1 - (3,3-d ifeni Ipropi l) -4-p¡peridin i I] -1,3-dihydro-2H-indol-2-one</td><td> 100,7</td>

<td>3-eth¡l¡deno-1- [1- (norbornan-2-¡l) -4-p¡perid¡n¡l] -1,3-d¡h¡dro-2H-¡ndol-2- ona</td><td> 922</td>

<td>3-ethylidene-1 - [1 - (p-cyanobenzyl) -4-piperidin i I] -1,3-dihydro-2H-indol-2-one</td><td> 7652</td>

<td>3-ethyl-1- [1- (5-methylhex-2-yl) -4-p¡perid¡n¡l] -1,3-dihydro-2H-indol-2-one</td><td> 4</td>

<td>3-ethyl-1 - [1- [4- (1-methylethyl) -cyclohexyl] -4-p¡perid¡n¡l] -1,3-dihydro-2H-indol-2-one</td><td> 0,86</td>

<td>3-ethyl-1 - [1- (4-propylcyclohexyl) -4-piperid¡n¡l] -1,3-dihydro-2H-indol-2-one</td><td> 40</td>

<td>3-ethyl-1 - [1— (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinl] -1,3-dihydro-2H-indol-2-one</td><td> 124</td>

<td>3-ethyl-1 - [1 - (decah id ro-2-naphth¡ l) -4-p¡perid in ¡I] -1,3-dihydro-2H-indol-2-one</td><td> 3,6</td>

<td>3-ethyl-1 [1 - (1,3-dihydroinden-2-¡l) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one</td><td> 43</td>

<td>3-ethyl-1- [1 - (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one</td><td> 9</td>

<td>3-et¡ I-1 - [1 - (norbornan-2-yl) -4-piperid¡n¡l] -1,3-dihydro-2H-¡ndol-2-one</td><td> 82,7</td>

<td>1- [1- (naphth-1-¡lmet¡l) -4-p¡perid¡nyl] -1,3-d¡h¡dro-2H-¡ndol-2-one *</td><td> 92</td>

<td>1- [1- (naphth-2-yl-methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one *</td><td> 107</td>

<td>1- [1- (p-phenylbenzyl) -4-p¡per¡d¡nyl] -1,3-dihydro-2H-indol-2-one *</td><td> 1362</td>

<td>1- [1- (3,3-bis (phenyl) propyl) -4-piperid¡n¡l] -1,3-dihydro-2H-indol-2-one *</td><td> 12,5</td>

<td>1- [1- (p¡anobenzyl) -4-p¡perid¡nyl] -1,3-dihydro-2H-¡ndol-2-one *</td><td> 1267</td>

<td>1- [1- (p-benzylox¡benzl) -4-p¡per¡d¡n¡l] -1,3-dihydro-2H-andol-2-one *</td><td> 32</td>

<td>1- [1 - (1,2,3,4-tetrahydronaphth-2-¡l) -4-piperidinyl] -1,3-dihydro -2H-indol-2-one *</td><td> 28,7</td>

<td>1 - [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one *</td><td> 7,4</td>

<td>1 - [1- (norbornan-2-yl) -4-piperid¡n¡l] -1,3-dihydro-2H-indol-2-one *</td><td> 215</td>

<td>1 - [1 - (1,3-dihydroinde η-2-yl) -4-p¡perid¡ ni I] -1,3-dihydro-2H-indol-2-one *</td><td> 18,7</td>

<td>1 - [1 - (cyclooctilmethyl) -4-piperidinyl] -1,3-dihydro -2H-indol-2-one *</td><td> 54,3</td>

<td>1 ¿1 - (benzyl) -3- (methyl) -4-piper¡dnyl] -1,3-dihydro-2H-andol-one *</td><td> &gt; 10.000</td>

<td>1- [1- (4-prop¡lc¡clohex¡l) -3- (methyl) -4-piperid¡nyl] -1,3-dihydro-2H-indol-2-one *</td><td> 2435</td>

<td>1 - [1 - (5-meth¡ I hex-2-¡l) -3- (methyl) -4-pi peridinyl] -1,3-dihydro-2H-andol-2-one *</td><td> 4335</td>

<td>1 - [1 - (decah idro-2-η afthyl) -3- (methyl) -4-pi peridinyl] -1,3-dihydro-2H-indol-2-one *</td><td> 366</td>

ES 2 322 158 T3

<td>1- (1- (4- (1-methylethyl) -cyclohexyl) -3- (methyl) -4-p¡per¡d¡nyl] -1,3-d¡hydro- 2H-andol-2one *</td><td> 167</td>

<td>1- [1- (cyclooctylmethyl) -3- (methyl) -4-piperidinl] -1,3-dihydro-2H-indol-2-one *</td><td> 189</td>

<td colspan="2">'REFERENCE COMPOUNDS</td>

Reference Example 10

Synthesis of certain head groups

Scheme 1

<img file="ES2322158T3_D0015.tif" />

Process

At a mixture of 4 (21.6 g, 0.2 mol), 5 (15.6 g, 0.1 mol) and acetic acid (6 g, 0.1 mol) in 500 ml of dichloroethane (DCE) gave 29.7 g of sodium triacetoxyborohydride (0.14 mole, 1.4 eq) were added in one portion. Gas is evolved for a period of time between 30 min. and 1 h. The mixture was kept stirring overnight. TLC indicated that 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 by EtOAc (300 ml x 2). The combined organic substances were dried with potassium carbonate and the solvent was evaporated in order to obtain a red oil that was filtered in a column (5% Et₃N, 25% EtOAc and 70% hexane) to obtain 14 g of product 6 as a white solid (54%).

ES 2 322 158 T3

Compound 6

MS: mlz 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).

To a solution of 13.5 g of 6 (54.5 mmol) in 50 ml of acetonitrile was added in one portion 11.02 g of carbonyldiimidazole. The mixture was kept stirring overnight. A solid precipitated, separating from the solution, which was filtered and washed with H₂O and TBUG (TBUG = tert-butylglycine) to obtain 7.5 g of product. The filtrate was evaporated and the crude material was dissolved in EtOAc and washed with water and saturated potassium carbonate solution. The organic substances were dried with potassium carbonate. The solvent was evaporated to obtain a second batch of pink solid which was filtered in a column (10% Et₃N, 40% EtOAc and 50% hexane) to obtain another 4.5 g of product 7 (81%, combined).

Compound 7

MS: mlz 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).

A mixture of 7 (7.5 g, 27.4 mmol) and 8.26 g of PPTS (PPTS = pyridinium p-toluenesulfonate) in 50 ml of acetone and H was stirred and refluxed overnight.₂Or (10: 1). The mixture was cooled to room temperature, and acetone was evaporated. By adding water to the mixture, crystallization was started to obtain 3 g of product 8 (47.4%).

Compound 8

MS: 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).

At a mixture of 8 (7.75 g, 33.65 mmol), benzylamine (3.61 g, 33.65 mmol) and acetic acid (2.0 g, 33.65 mmol) in 150 ml of dichloroethane were 10.3 g of sodium triacetoxyborohydride (47.1 mmol, 1.4 eq) were added in one portion. Gas is evolved for a period of time between 30 min. and 1 h. The mixture was kept stirring overnight. TLC indicated that 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 x 2). The combined organic substances were dried with potassium carbonate and the solvent was evaporated in order to obtain a brown solid that was filtered in a column (of 5% Et₃N, 25% EtOAc and 70% hexane to 10% Et₃N, 40% EtOAc and 50% hexane) to obtain 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

MS: 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

MS: 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).

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

ES 2 322 158 T3

Compound 11

MS: m / z 232 (M + 1).

Ή NMR (CDCl₃): d 1.50-1.85 (m, 8H), 2.60 (m, 2H), 4.30 (m, 1H), 7.10 (m, 3H), 7.30 (m, 1H ).

To a mixture of 11 (1.7 g, 7.4 mmol) and acetaldehyde (0.33 g, 7.4 mmol) in 50 ml of dichloroethane was added in one portion 2.2 g of sodium triacetoxyborohydride (10, 36 mmol, 1.4 eq). Gas is evolved for a period of time between 30 min. and 1 h. The mixture was kept stirring overnight. TLC indicated that 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 x 2). The combined organic substances were dried with potassium carbonate and the solvent was evaporated to obtain a brown oil that was chromatographed (10% Et₃N, 40% EtOAc and 50% hexane) to obtain 1.5 g of product 2 in the form of a sticky oil that was recrystallized from TBME (TBME = tert-butyl methyl ether) to obtain a white solid (78%).

Compound 2

MS: mlz 259.7 (M + 1).

Ή NMR (CDCl₃): d 1.15 (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).

1.5 g of Pd (OH)₂ were added to a 30 ml methanol solution containing 3.01 g of compound 9. The resulting suspension was hydrogenated at 50 psi for 12 h at room temperature. TLC indicated that the reaction was complete overnight. The solution was filtered through a pad of celite to remove the catalyst. The celite was washed with methanol twice (20 ml). The organic substances were combined and the solvent was removed to obtain a pale colored solid that was purified by chromatography (10% MeOH, 90% EtOAc) to obtain an off-white product 1 (1.68 g, 77.4 %).

Compound 1

MS: m / z 232 (M + 1).

Ή NMR (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).

Scheme 2

<img file="ES2322158T3_D0016.tif" />

ES 2 322 158 T3

Process

About 2.5 g of NaH were washed by THF twice and suspended in 100 ml of DMF (DMF = dimethylformamide), and 8.15 g of 7 (38 mmol) was added to the mixture. Gas is evolved, and after 5 minutes, 7.13 g of ethyl iodide (45.7 moles) were added. The mixture was kept stirring overnight. LC / MS (LC / MS = liquid chromatography coupled to mass spectrometry) indicated that the starting material had been completely consumed. The reaction mixture was cooled and H2O was added to the mixture. The product began to precipitate separating from the solution. The crystals were collected by filtration to obtain 9.7 g of 12 (84.7%).

Compound 12

MS: mlz 303.3 (M + 1).

Ή 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).

A mixture of 12 (9.7 g, 32.2 mmol) and 9.72 g of EPPTS in 50 ml of acetone and H was refluxed overnight.₂Or (10: 1). The mixture was cooled to room temperature and acetone was evaporated. By adding water to the mixture, crystallization was initiated in order to obtain 6.85 g of product 13 (82.3%).

Compound 13

MS: mlz 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).

At a mixture of 13 (6.85 g, 26.5 mmol), benzylamine (2.84 g, 26.5 mmol) and acetic acid (1.59 g, 26.5 mmol) in 150 ml of dichloroethane were 7.86 g of sodium triacetoxyborohydride (37.1 mmol, 1.4 eq) were added in one portion. Gas is evolved for a period of time between 30 min. and 1 h. The mixture was kept stirring overnight. TLC indicated that 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 x 2). The combined organic substances were dried with potassium carbonate and the solvent was evaporated in order to obtain a brown solid that was filtered in a column (of 5% Et₃N, 25% EtOAc and 70% hexane to 10% Et₃N, 40% EtOAc and 50% hexane) to obtain 1.52 g of product 14 as a white solid and 1.08 g of product 15 as a white solid.

Compound 14

MS: mlz 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

MS: mlz 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).

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

Compound 3

MS: 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).

ES 2 322 158 T3

Reference example 11

Union of the tail groups

The tail groups were joined to the head groups according to the following procedures:

<img file="ES2322158T3_D0017.tif" />

General procedure for alkylation

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

General procedure for reductive amination

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

The following reference compounds were prepared by linking the tail groups using the general procedures described:

1- [4- (benzylamino) -cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

1- [4- (benzylamino) -cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

1- [4 - [(naphth-2-yl-methyl) ethylamino] -cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one

MS: m / z 400.2 (M + 1)

1- [4- (norbornan-2-ylamino) -cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one

MS: m / z 326.3 (M + 1)

1- [4 - [[4- (1-methylethyl) -cyclohexyl] amino] -cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one

ES 2 322 158 T3

MS: m / z 356.4 (M + 1)

1- [4 - [(decahydro-2-naphthyl) amino] -cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one

MS: m / z 368.2 (M + 1)

1- [4- (ethylamino) -cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one

1- [4- (benzylamino) -cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one

1- [4- (benzylamino) -cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one

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).

1- [4 - [(cyclooctylmethyl) amino] -cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 99%

MS: m / z 384.5 ¹H NMR (CDCl₃): d 1.40-1.90 (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).

1- [4 - [(naphth-2-yl) amino] -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 ).

1- [4 - [(p-benzylolxybenzyl) amino] -cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 97%

MS: m / z 455 ¹H NMR (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).

1- [4 - [(cyclooclylmethyl) amino] -cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

TLC: 99%

MS: m / z 369 ¹H NMR (CDCl₃): d 1.40 (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 ).

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): d 1.40 (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).

1- [4 - [(p-phenylbenzyl) amino] -cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 100%

ES 2 322 158 T3

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).

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).

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).

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).

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).

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).

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), 4.304.45 (m, 2H), 7.25 (m, 2H), 7.35 (m, 2H), 7.42 (d, 1H), 7.60 (s, 1H) , 7.72 (d, 1H).

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).

ES 2 322 158 T3

1- [4 - [(4-phenyl-cyclohexyl)) amino] -cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 100%

MS: m / z 433.7 (M + 1)

Ή 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).

1- [4- (dibenzylamino) -cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 100%

MS: m / z 455.6 (M + 1) 'H NMR (MeOH-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).

1- [4 - [(5-methylhex-2-yl)) amino] -cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 99.1%

MS: m / z 373.3 (M + 1) 'H 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).

Reference example 12

The nociceptin affinity at the ORL-1 receptor for preferred compounds was obtained using the following assay:

Membranes of recombinant HEK-293 cells expressing the human opioid-like receptor (ORL1) (Receptor-Biology) were prepared by lysing cells in ice-cold hypotonic buffer (MgCl₂ 2.5 mM, 50 mM HEPES, pH 7.4) (10 ml / 10 cm plate) followed by homogenization with a Teflon tissue grinder / pestle. The membranes were harvested by centrifugation at 30,000 xg for 15 min. at 4 ° C, and the pellets were 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 Albumin as a standard. Aliquots of the ORL-1 receptor membranes were stored at -80 ° C.

Functional SGTPgS binding assays were carried out 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 [³⁵S] 0.20 nM 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 shallow 96-well polypropylene plates containing 10 ml of 20x concentrated solutions of agonist prepared in DMSO. The plates were incubated for 30 min. at room temperature with shaking. Reactions were terminated by rapid filtration on Unifilter GFB 96-well filter plates (Packard) using a 96-well tissue harvester (Brandel) followed by three filter washes with 200 ml of ice-cold binding buffer (NaH₂PO₄ 10 mM, Na₂HPO₄ 10 mM, pH 7.4). The 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 on a Packard TopCount for 1 min / well.

The data were analyzed using the curve fitting functions in GraphPad PRISMO, v. 3.0, and the results are indicated in the following table 3:

ES 2 322 158 T3

<td colspan="2">TABLE 3</td>

<td colspan="2">Nociceptin Affinity</td>

<td>REFERENCE compound</td><td>Ki (nM) cale</td>

<td>3-ethyl-1- (p-phenylbenzyl) -1,3-dihydro-2H-benzimidazol-2-one</td><td> 509</td>

<td>3-ethyl-1 - (5-methylhex-2-yl) -1,3-dihydro-2H-benzimidazol-2-one</td><td> 23</td>

<td>3-ethyl-1- (4-propylcyclohexyl) -1,3-dihydro-2H-benzimidazol-2-one</td><td> 68</td>

<td>3-ethyl-1- (decahydro-2-naphthyl) -1,3-dihydro-2H-benzimidazol-2-one</td><td> 1,6</td>

<td>3-ethi I-1 - (naphth-2-yl-methyl) -1,3-dihydro-2H-benzimidazol-2-one</td><td> 198</td>

<td>1- (p-benzyloxybenzyl) 3-ethyl-1,3-dihydro-2H-benzimidazol-2-one</td><td> 438</td>

<td>1 -benzyl-3-ethyl-1,3-dihydro-2H-benzimidazol -2-one</td><td> 296</td>

<td>1 - [4- (benzylamino) -cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol -2-one</td><td>trans: 112 cis:&gt; 10,000</td>

<td>3-ethyl-1- (naphthylmethyl) -1,3-dihydro-2H-benzimidazol-2-one</td><td> 39</td>

<td>3-ethyl-1- [5- (fluorophenyl) -5- (4-fluorophenyl) -hexyl] -1,3-dihydro-2H-benzimidazole- 2-one</td><td> 148</td>

<td>1- [4 - [(naphth-2-yl-methyl) ethylamino] -cyclohexyl] -1,3-dihydro-2H-benzimidazole-2- ona</td><td> 3598</td>

<td>1- [4- (norbornan-2-ylaminol) -cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one</td><td> &gt;10000</td>

<td>1 - [4 - [[4- (1 -methylethyl) -cyclohexyl] amino] -cyclohexyl] -1,3-dihydro-2Hbenzimidazol-2-one</td><td> &gt;10000</td>

<td>1- [4 - [(decahydro-2-naphthyl (amino] -cyclohexyl] -1,3-dihydro-2H-benzimidazole-2- ona</td><td> &gt;10000</td>

<td>1- [4- (ethylamine) -cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one</td><td> 9179</td>

<td>1 - [4- (benzylarnino) -cyclohexyl] -1,3-dihydro-2H-benzimidazol -2-one</td><td>trans: 273 cis:&gt; 10,000</td>

<td>1- [4 - [(Indan-2-yl) benzylamino] -cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazole- 2- one</td><td> &gt;10000</td>

<td>1- [4 - [(cyclooctylmethyl) amino] -cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazole-2- ona</td><td> 115</td>

<td>1- [4 - [(naphth-2-yl) amino] -cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one</td><td> 961</td>

<td>1- [4 - [(p-benzyloxybenzyl) amino] -cyclohexyl] -3-ethyl-1,3-dihydro-2H- benzimidazol-2-one</td><td> 2935</td>

<td>1- [4 - [(cyclooctylmethyl) amine] -cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazole-2- ona</td><td> 286</td>

<td>1- [4 - [(decahydro-2-naphthyl) amino] -cyclohexyl] -3-ethyl-1,3-dihydro-2H- benzimidazol-2-one</td><td> 288</td>

<td>1- [4- (benzylamino) -cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazole-2- ona</td><td> &gt;10000</td>

<td>1- [4- (dibenzylamino) -cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazole-2-</td><td> &gt;10000</td>

ES 2 322 158 T3

<td colspan="2">ona</td>

<td>1- [4 - [(p-phenylbenzyl) amino] -cyclohexyl] -5-carbamoyl-1,3-dihydro-2H- benzimidazol-2-one</td><td> &gt;10000</td>

<td>1 - [4 - [(1,2,3,4-tetrahydronaphthyl) amino] -cyclohexyl] -5-carbamoyl-1,3-dihydro-2Hbenzimidazol-2-one</td><td> &gt;10000</td>

<td>1- [4 - [(4-propyl-cyclohexyl) amino] -cyclohexyl] -5-carbamoyl-1,3-dihydro-2H- benzimidazol-2-one</td><td> &gt;10000</td>

<td>1- [4 - [(5-methylhex-2-yl) amino] -cyclohexyl] -5-carbamoyl-1,3-dihydro-2H- benzimidazol-2-one</td><td> &gt;10000</td>

<td>1- [4 - [(decahydro-2-naphthyl) amino] -cyclohexyl] -5-carbamoyl-1,3-dihydro-2H- benzimidazol-2-one</td><td> &gt;10000</td>

<td>1- [4- (cyclooctylamino) -cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazole- 2- one</td><td> &gt;10000</td>

<td>1- [4 - [(indan-2-yl) amino] -cyclohexyl] -5-carbamoyl-1,3-dihydro-2Hbenzimidazol-2-one</td><td> &gt;10000</td>

<td>1- [4 - [(4-phenyl-cyclohexyl) amino] -cyclohexyl] -5-carbamoyl-1,3-dihydro-2H- benzimidazol-2-one</td><td> &gt;10000</td>

<td>1- [4 - [(5-methylhex-2-yl) amino] -cyclohexyl] -7-carbamoyl-1,3-dihydro-2H- benzimidazol-2-one</td><td> &gt;10000</td>

Reference Example 13

Synthesis of the Head Substituted Benzimidalzole Groups

<img file="ES2322158T3_D0018.tif" />

Process

A dispersion of 60% sodium hydride 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 0029707) (3.80 g, 11.1 mmol) was added, and the mixture was allowed to stir at room temperature for 15 min. and was then heated to 50 ° C. Ethyl bromide (1.06 ml, 13.3 mmol) was added and the resulting mixture was stirred at 50 ° C for 18 h. TLC (SiO₂, CH₂Cl₂: MeOH 96: 4) indicated that the reaction was about 40% complete. Additional sodium hydride (0.67 g) and ethyl bromide (1.06 ml) were added. After heating at 50 ° C for another 24 h, the reaction mixture was cooled to temperature

ES 2 322 158 T3 room and subjected to rapid cooling with water. The layers were separated and the aqueous layer was extracted with ethyl acetate (1 time). The combined organic extracts were washed with aqueous sodium bicarbonate solution (1 time) and dried over MgSO.₄ and the solvent was evaporated to obtain the crude product as a yellow solid. By trituration with diethyl ether, pure 2 was obtained 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).

To a solution of 2 (3.60 g, 9.74 mmol) in 100 ml of ethyl acetate was added 25 ml of a 1: 1 mixture of ethyl acetate and concentrated HCl. The mixture was vigorously stirred at room temperature for 2 h and evaporated to dryness. The residue was neutralized with 50 ml of 10: 1 methanolic ammonia and evaporated again to dryness. The residue was resuspended in 100 ml of a 1: 1 mixture of MeOH and CH2Cl2 and filtered and the filtrate was evaporated to dryness leaving an off-white solid. By flash chromatography (flash chromatography) on silica gel eluting with CH₂Cl₂: MeOH: NH₃ (300: 10: 1) was obtained pure 3 in the form of 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

Union of the tail groups

The tail groups were joined to the head groups according to the following procedures:

<img file="ES2322158T3_D0019.tif" />

General procedure for alkylation

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

General procedure for reductive amination

To a mixture of ketone or aldehyde (1 eq), amine (1 eq) and acetic acid (1 eq) in methanol was added in one portion sodium cyanoborohydride (1.4 eq). The mixture was stirred overnight at room temperature. TLC indicated that the reaction was complete. The reaction was quenched by the addition of water followed by 1N NaOH until pH 10. The mixture was extracted 2 times with Et2O. Organic extracts com

ES 2 322 158 T3 were dried with potassium carbonate and the solvent was evaporated, after which chromatography was carried out to obtain the pure product.

The following reference compounds were prepared by linking the tail groups using the general procedures described:

2-cyanoimino-3-ethyl-1- [1- (p-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, 1H).

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).

2-cyanoimino-3-ethyl-1- [1- (naphth-2-yl-methyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 93.9%

MS: m / z ¹H NMR (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).

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).

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).

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).

2-cyanoimino-3-ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 100%

MS: m / z 380.3 (M + 1) ¹H NMR (CDCl₃): d 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).

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)

ES 2 322 158 T3'H 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).

2-cyanoimino-3-ethyl-1- [1- (3,3-bis (phenyl) propyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

MS: m / z 462.2 (M + 1) 'H 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) .

2-cyanoimino-3-ethyl-1- [1- (1,2,3,4-tetrahydronaphthyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 94.0%

MS: mlz 400.2 (M + 1) 'H 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).

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) 'H 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, 1 HOUR).

2-cyanoimino-3-ethyl-1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 99.2%

MS: m / z 364.7 (M + 1) 'H 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).

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) 'H 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).

2-cyanoimino-3-ethyl-1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 100%

MS: m / z 394.7 (M + 1) 'H 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) .

2-cyanoimino-3- (2-hydroxy) ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 100%

MS: m / z 396.3 (M + 1) 'H 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).

2-cyanoimino-3-methoxycarbonylmethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 98.3%

ES 2 322 158 T3

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).

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 (m, 1H), 3.33 (d, 2H) , 2.88 (m, 2H), 2.62 (bt, 1H), 2.33 (m, 4H), 1.86-1.37 (m, 16H).

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).

2-cyanoimino-3- (2-methanesulfonamido) ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 100%

MS: m / z 473.2 (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).

2-cyanoimino-3-acetomido-1- [1- (cyclooctyl) -4-piperidinyl] -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).

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).

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).

2-cyanoimino-1- [1- (cyclooctyl) -3-hydroxymethyl-4-piperidinyl] -1,3-dihydro-2H-benzimidazole

2-cyanoimino-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-7-azabenzimidazole;

2-cyanoimino-1- [1- (cyclooctyl) -2,6-ethane-4-one-4-piperidinyl] -1,3-dihydro-2H-benzimidazole

ES 2 322 158 T3

Reference Example 15

The nociceptin affinity at the ORL-1 receptor for preferred compounds was obtained using the following assay:

Membranes of recombinant HEK-293 cells expressing the human opioid-like receptor (ORL1) (Receptor-Biology) were prepared by lysing cells in ice-cold hypotonic buffer (MgCl₂ 2.5 mM, 50 mM HEPES, pH 7.4) (10 ml / 10 cm plate) followed by homogenization with a Teflon tissue grinder / pestle. The membranes were harvested by centrifugation at 30,000 xg for 15 min. at 4 ° C, and the pellets were 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 Albumin as a standard. Aliquots of the ORL-1 receptor membranes were stored at -80 ° C.

Functional SGTPgS binding assays were carried out 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 [³⁵S] 0.20 nM 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 shallow 96-well polypropylene plates containing 10 ml of 20x concentrated solutions of agonist prepared in DMSO. The plates were incubated for 30 min. at room temperature with shaking. Reactions were terminated by rapid filtration on Unifilter GF / B 96-well filter plates (Packard) using a 96-well tissue harvester (Brandel) followed by three filter washes with 200 ml of ice-cold binding buffer. (NaH₂PO₄ 10 mM, Na₂HPO₄ 10 mM, pH 7.4). The 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 on a Packard TopCount for 1 min / well.

The data were analyzed using the curve fitting functions in GraphPad PRISMO, v. 3.0, and the results are indicated in the following table 4:

(Table goes to next page)

ES 2 322 158 T3

<td colspan="2">TABLE 4</td>

<td colspan="2">Nociceptin Affinity</td>

<td>REFERENCE compound</td><td>Κι (ηΜ) cale</td>

<td>2-cyanoimino-3-ethyl-1 - [1 - (p-phenylbenzyl) -4-pi peridinyl] -1,3-d ih¡dr-2Hbenzimidazole</td><td> 5558</td>

<td>2-cyanoim¡no-3-ethyl-1 - [1 - (p-benzyloxybenzyl) -4-p¡perid¡n¡l] -1,3-dihhydro-2Hbenzimidazole</td><td> 1660</td>

<td>2-cyanoimino-3-ethyl-1- [1- (naphth-2-¡l-methyl) -4-piperidinyl] -1,3-dihydro-2Hbenzimidazole</td><td> 882</td>

<td>2-cyanoimino-3-ethyl-1 - [1 - (4-propi Icyclohexy l) -4-p, peridin i I] -1,3-dihhydro-2Hbenzimidazole</td><td> 241</td>

<td>2-cyanoimino-3-ethyl-1 - [1 - [4- (2-propyl) -c¡ clohexy l] -4-pi peridin i I] -1,3-dihhydro-2 Hbenzimidazole</td><td> 6,9</td>

<td>2-cyanoimino-3-ethyl-1 - [1 - (decah idro-2-naphthy l) -4-pi pe rid ini I] -1,3-d ih id ro-2Hbenzimidazole</td><td> 6,6</td>

<td>2-cyanoimino-3-ethyl-1 - [1 - (cyclooctyl) -4-pipe rid ini I] -1,3-dih id ro-2 Hbenzimidazole</td><td> 5,57</td>

<td>2-cyanoimino-3-ethyl-1 - [1 - (10, 11 -dihydro-5H-dibenzo [a, d] -cyclohepten-5-¡l) -4piperidinyl] -1,3-dihydro- 2H-benzimdazole</td><td> &gt;10000</td>

<td>2-cyanoimino-3-ethyl-1 - [1 - (3,3-bis (phen i I) propyl) -4-pi pe rid ini IJ-1,3-dih id ro-2Hbenzimidazole</td><td> 80</td>

<td>2-cyanoimino-3-ethyl-1 - (1 - (1,2,3,4-tetrahydro naphthyl) -4-piperidini I) -1,3-dihydro2H-benzimidazole</td><td> 157</td>

<td>2-cyanoimino-3-ethyl-1 - [1 - (5-methi I hex-2-yl) -4-piperid-yl] -1,3-dih id ro-2Hbenzimidazole</td><td> 76</td>

<td>2-cyanoimino-3-ethyl-1- [1 - (norbornan-2-yl) -4-piperidinl] -1,3-dihydro-2Hbenzimidazole</td><td> 323</td>

<td>2-cyanoimino-3-ethyl-1 - [1 - (1,3-d¡h id roinden-2-yl) -4-p¡peridynyl] -1,3-dihid ro-2 Hbenzimidazole</td><td> 89</td>

<td>2-cyanoimino-3-ethyl-1 - [1 - (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2Hbenzimidazole</td><td> 7,1</td>

<td>2-cyan oí mi no-3- (2-h¡droxy) ethyl-1 - [1 - (cyclooctyl) -4-p¡perid in ¡I] -1,3-dih¡dr-2Hbenzimidazole</td><td> 6,4</td>

<td>2-cyanoimine-3-methoxycarbonylmethyl-1- [1- (cyclooctyl) -4-pyridinyl] -1,3-dihydro-2H-benzimidazole</td><td> 3,3</td>

<td>2-cyanoimno-3-cyanomethyl-1 - [1 - (cyclooctyl) -4-piperidine I] -1,3-dihydro-2Hbenzimidazole</td><td> 0,97</td>

<td>2-cyanomino-3-butyl-1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimdazole</td><td> 1,36</td>

ES 2 322 158 T3

<td>2-cyanoimino-3- (2-methanesulfonamide) ethyl-1- [1- (cyclooctyl) -4-piperidinl] -1,3- dihydro-2H-benzimidazole</td><td> 78</td>

<td>2-kano¡m¡no-3-acetomido-1- [1- (cyclooctyl) -4-piperidin¡l] -1,3-d¡hydro-2H- benzimidazole</td><td> 11</td>

<td>2-cyanoimino-3-carboxymethyl-1- [1- (cyclooct¡l) -4-piper¡d¡n¡l] -1,3-dihydro-2Hbenzimidazole</td><td> 201</td>

<td>2-cyano amino-3- (2-dimethylamine) ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro- 2H-benzimidazole</td><td> 18</td>

<td>2-cyanoimino-1 - [1 - (cyclooctyl) -3-hydroxy methyl-4-piperid in i I] -1,3-dihydro-2Hbenzimidazole</td><td> 473</td>

<td>2-cyanoimino-1 - [1 - (cyclooctyl) -4-pi peridynyl] -1,3-dihydro-2H-benzimidazole</td><td> 3743</td>

<td>2-cyanoimino-1- [1- (cyclooctyl) -2,6-ethane-4-one-4-piperidinyl] -1,3-dihydro-2H- benzimidazole</td><td> 19</td>

Example 16

The μ receptor affinity for the compounds was obtained according to the following test: Mu opioid receptor membrane solution was prepared by sequentially adding final concentrations of 0.075 μg / μl of the desired membrane protein, 10 μg / l saponin, GDP 3 μM and [³⁵S] GTPyS 0.20 nM to binding buffer (100 mM NaCl, MgCl₂ 10 mM, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 µl / well) was transferred to shallow 96-well polypropylene plates containing 10 µl of 20x concentrated agonist solutions prepared in DMSO (DMSO = dimethyl sulfate). The plates were incubated for 30 min. at room temperature with shaking. Reactions were terminated by rapid filtration on Unifilter GF / B 96-well filter plates (Packard) using a 96-well tissue harvester (Brandel), followed by three filter washes with 200 µl of ice-cold binding buffer. (NaH₂PO₄ 10 mM, Na₂HPO₄ 10 mM, pH 7.4). The 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.

Data was analyzed using curve fitting functions in GraphPad PRISM^MF, v. 3.0 (MF = brand name), and the results for various compounds are shown in Table 5 below:

(Table goes to next page)

ES 2 322 158 T3

<td colspan="2">TABLE 5</td>

<td colspan="2">Affinity of Mu Receptors</td>

<td>Compound</td><td>Ki (nM) cale</td>

<td>3- [1 - (naphth-1 -yl-methyl) -4-piperidinl] -2H-benzoxazol-2-one *</td><td> 340</td>

<td>3- (1- (3,3-d¡phenylpropyl) -4-piperidinyl] -2H-benzoxazol-2-one *</td><td> 726</td>

<td>3- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinl] -2H-benzoxazol-2-one '</td><td> 343</td>

<td>3- [1- (4-propyl-cyclohexyl) -4-piperidinyl] -2H-benzoxazol-2-one '</td><td> 145</td>

<td>3-ethylidene-1- (1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro2H-indol-2-one</td><td> 23,3</td>

<td>3-ethylidene-1- [1- (naphth-2-yl-methyl) -4-piperidinyl] -1,3-dihydro-2H-indole-2- ona</td><td> 137</td>

<td>3-ethylidene-1- [1- (p-benzyloxybenzyl) -4-piperidinyl] -1,3-dihydro-2H-indole- 2-one</td><td> 1150</td>

<td>3-ethylidene-1- [1- (3,3-cliphenylpropyl) -4-pyridinyl] -1,3-dihydro-2H-indole-2- ona</td><td> 24</td>

<td>1- [4 - [(naphth-2-yl) amino] -cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2one *</td><td> 2,1</td>

<td>2-cyanoimino-3-ethyl-1- (1- (4-propylcyclohexyl) -4-piperıdinyl] -1,3-dihydro- 2H-benzimidazor</td><td> 46</td>

<td>2-cyanoimino-3-ethyl-1 - (1- (1,2,3,4-tetrahydronaphthyl) -4-piperidinyl] -1,3dihydro-2H-benzimidazole *</td><td> 458</td>

<td>2-cyanoimno-3-ethyl-1- [1- (5-methylhex-2-¡l) -4-piperidinyl] -1,3-dihydro-2H- benzimidazole *</td><td> 15</td>

<td>2-cyanoimino-3-ethyl-1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2Hbenzimidazole *</td><td> 1653</td>

<td colspan="2">REFERENCE COMPOUNDS</td>

References cited in description

This list of references cited by the applicant is provided only as information for the reader and is not part of the European patent document. Although great care has been taken in compiling the references, the possibility of errors or omissions cannot be excluded, and the EPO disclaims all liability in this regard.

Patent documents cited in the description • US 284666 P [0001] • US 60284667 P [0001] • US 60284668 P [0001] • US 60284669 P [0001] • WO 9932481 A [0007]

WO 9909984 A [0017]

WO 9613265 A [0018]

EP 0355663 A [0019]

US 5760054 A [0020]

WO 0160796 A [0021]

ES 2 322 158 T3 • US 5789402 A [0008]

WO 0170689 A [0022] • WO 9502405 A [0009]

WO 0214315 A [0023] • US 3325499 A [0010]

WO 0220011 A [0024] • WO 006157SA A [0015]

US 6136839 A [0080] • EP 0976732 A [0016]

EP 0029707 A [0169]

Non-patent literature cited in description • KLEIN et al. ARCHIV DER PHARMAZIE, VCH VERLAGSGESELLSCHAFT MBH, 1974, vol. 307, 360-366 [0011] • STN Database, 1974: 477786 [0012] • LOBBEZOO; SOUDIJN. J.MED.CHEM., 1981, vol. 24, 777-782 [0013] • KLEIN et al. ARCH. PHARMZ., 1976, vol. 398 (75), 910-916 [0014] • FORBES. TETRAHEDRON LETTERS, 2001, vol. 42, 6943-6945 [0025] • GOUT. Goodman &amp; Gilmans's The Pharmacological Basis of Therapeutics, 1996, 617-57 [0081] • GLEN R. HANSON. Analgesic, Anti-pyretic and Anit-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy, 1995, 1995, vol. II, 1196-1221 [0081]