Nociceptin analogues

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof , where D denotes phenyl; n equals 0; A, B and Q denote hydrogen; Z is selected from a group comprising a bond, straight C1-3alkylene; R1 is selected from a group comprising hydrogen, C1-10alkyl, C3-8cycloalkyl, benzyl, a 6-member monocyclic, 9-10-member bicyclic aromatic carbon-containing ring system and a spiro-ring system of formula (V): where X1 and X3 denote O; and where the said alkyl, cycloalkyl or benzyl from the R1 group is optionally substituted with 1-3 substitutes selected from a group comprising C1-3alkyl, cyano, phenyl, wherein the said phenyl is optionally substituted with 1-3 substitutes selected from halogen. The invention also relates to compounds of formulae .

Values of radicals of the said compounds are given in the claim. The invention also relates to a pharmaceutical composition having ORL1 receptor or µ opioid receptor inhibiting properties, containing an effective amount of the disclosed compound, a method of curing pain and a method of modulating pharmacological response from the opioid receptor, including the ORL1 or µ opioid receptor.

EFFECT: improved method.

41 cl, 5 tbl, 16 ex

 

Background of the invention

Chronic pain is the main reason that is causing the impotence and causes great suffering. Successful treatment of sharp and chronic pain is the primary goal of the doctor, using as the preferred drug of the opioid analgesic means.

Until recently it was obvious existence in the Central nervous system (CNS) of the three major classes of opioid receptors, while each class has subtypes of receptors. These classes of receptors have been identified as µ, δ and κ. Because opiates have a high affinity for these receptors, while not being endogenous to the body, conducted a subsequent study aimed at identification and isolation of endogenous ligands for these receptors. These ligands are identified as enkephalins, endorphins and dynorphin.

Recent experiments have led to the identification of a cDNA that encodes a receptor that is similar to the opioid receptor (ORL1), with a high degree of homology with known classes of receptors. This newly discovered receptor was classified as an opioid receptor only on the basis of its structure, as the receptor showed no pharmacological homology. Initially it was shown that non-selective ligands with you will fetter the affinity respect to µ, δ and κ receptors have a low affinity in relation to the ORL1. This characteristic, along with the fact that the endogenous ligand has not yet been opened, led to the term "ivanovii receptor".

Subsequent investigation led to the isolation and structural determination of endogenous ligand of the ORL1 receptor. This ligand is a peptide of seventeen amino acids, structurally similar to members of the opioid peptide family.

The opening of the ORL1 receptor provides the opportunity for discovering new compounds for drug development that can be entered to control pain or other symptoms, modelirovaniya this receptor.

All documents cited herein, are incorporated in their entirety by reference for all purposes.

Objectives and summary of invention

Accordingly, the purpose of some variants of the embodiment of this invention is to provide new compounds which have affinity in relation to the ORL1 receptor.

The goal of some variants of the embodiment of this invention is to provide new compounds which exhibit affinity in relation to the ORL1 receptor and one or more of the receptors μ, δ or κ.

The goal of some variants of the embodiment of this invention is the provision of new compounds cured for who I am patient, suffering from chronic or acute pain, by introducing compounds having affinity towards the receptor ORL1.

The goal of some variants of the embodiment of this invention is the provision of new compounds with agonistic activity against µ, δ and κ receptors, which is greater than the currently available compounds, such as morphine.

The goal of some variants of the embodiment of this invention is the provision of methods for treating chronic or acute pain by introducing compounds with agonistic activity against µ, δ and κ receptors, which is greater than the currently available compounds.

The goal of some variants of the embodiment of this invention is the provision of methods for treating chronic or acute pain by introducing non-compounds with agonistic activity against µ, δ and κ receptors and cause fewer side effects than currently available connection.

The goal of some variants of the embodiment of the present invention is to provide compounds which are useful as analgesic means, anti-inflammatory drugs, diuretics, anesthetics and neuroprotective funds, antihypertensive agents, demulcents; means for responding the Oia appetite; regulators hearing; funds cough, Antiasthmatic agents, modulators of motor activity, modulators of cognitive ability and memory, controls the release of neurotransmitter and hormone release, modulators of renal function, antidepressants for the treatment of memory loss as a result of Alzheimer's or other dementias, anti-epilepsy, anticonvulsant drugs, remedies for the treatment of alcohol and drug abstinencia, means for regulating water balance, means for regulating the excretion of sodium and tools for regulation violations arterial blood pressure and methods for such compounds.

The compounds of this invention are useful for modulating pharmacodynamic response from one or more opioid receptor (ORL1, µ, δ and κ) of the Central and/or peripheral nervous system. The answer can be attributed to compounds stimulating (agonist) or inhibitory (antagonist) one or more receptors. Some compounds can stimulate one receptor (e.g., µ agonist) and to inhibit other receptor (e.g., ORL1 antagonist).

Other objectives and advantages of this invention will become apparent from the following detailed description of the invention. The invention in some embodiments, the GP is osenia includes connection, having the General formula (I):

(I)

where

D represents a 5-8-membered cycloalkyl, 5-8-membered heterocyclic or 6-membered aromatic or heteroaromatic group;

n represents an integer from 0 to 3;

A, B and Q represent, independently, hydrogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkane, -CH2OH, -NHSO2hydraxis1-10alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, dis1-4alkylaminocarbonyl, acylamino, acylaminoalkyl-, amide, sulfonylamino1-10alkyl-, or A-B can together form a bridge of C2-6or B-Q together may form a bridge of C3-7or A-Q can together form a bridge of C1-5;

Z is selected from the group consisting of communication, direct or branched C1-6alkylene, -NH-, -CH2O-, -CH2NH-, -CH2N(CH3)-, -NHCH2-, -CH2CONH-, -NHCH2CO-, -CH2CO-, -COCH2-, -CH2COCH2-, -CH(CH3)-, -CH=, -O - and-HC=CH-, in which the carbon atoms and/or nitrogen is unsubstituted or substituted by one or more groups of lower alkyl, hydroxy, halogen or alkoxy;

R1selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino-, C3-12cyclooctylamino-, -COOV1, -C1-4COV 1, cyano, tsianos1-10the alkyl-, tsianos3-10cycloalkyl-, NH2SO2-, NH2SO2C1-4the alkyl-, NH2SOC1-4the alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, dis1-4alkylaminocarbonyl-benzyl, C3-12cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heterophilically ring, heterobicyclic ring system, and a Spiro ring system of the formula (V):

(V)

where X1and X2independently selected from the group consisting of NH, O, S, and CH2; and in which the specified alkyl, cycloalkyl, alkenyl, C1-10alkylamino-, C3-12cyclooctylamino or benzyl group, R1optionally substituted by 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl-, cyano, -COOV1, -C1-4COOV1tsianos1-10the alkyl-, -C1-5(=O)W1, -C1-5NHS(=O)2W1, -C1-5NHS(=O)W1A 5-membered heteroaryl0-4the alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy and cyano; and where the specified C3-12cycloalkyl, C3-12qi is alkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heterophilically ring, heterobicyclic ring system, or Spiro ring system of the formula (V) optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, where mentioned phenyl, benzyl, phenyloxy or benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy and cyano;

W1represents hydrogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkane, -CH2OH, amino, C1-4alkylamino-, dis1-4alkylamino - or 5-membered heteroaromatic ring, optionally substituted by 1-3 lower alkilani;

V1represents H, C1-6alkyl, C3-6cycloalkyl, benzyl or phenyl;

R2selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl and halogen, with the specified alkyl or cycloalkyl optionally substituted by oxo, amino, alkylamino or dialkylamino;

and their pharmaceutically acceptable salt and solvate.

The invention in some embodiments embodiment includes compounds having the following General formula (IA):

p>

(IA)

where

n represents an integer from 0 to 3;

Z is selected from the group consisting of-CH2-, -NH-, -CH2O-, -CH2CH2-, -CH2NH-, -CH2N(CH3)-, -NHCH2-, -CH2CONH-, -NHCH2CO-, -CH2CO-, -COCH2-, -CH2COCH2-, -CH(CH3)-, -CH= and-HC=CH-, in which the carbon atoms and/or nitrogen is unsubstituted or substituted by lower alkyl, halogen, hydroxy or alkoxygroup;

R1selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino, C3-12cyclooctylamino, benzyl, C3-12cycloalkenyl, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heterophilically ring, heterobicyclic ring system, and a Spiro ring system of the formula (V):

(V)

where X1and X2independently selected from the group consisting of NH, O, S, and CH2;

in which the specified monocyclic aryl preferably represents phenyl;

in which the specified bicyclic aryl is preferably naphthyl;

in which the specified alkyl, cycloalkyl, alkenyl, C1-10alkylamino, C3-12cyclooctylamino or benzyl optionally substituted by 1-3 substituents, wybran the mi group, consisting of halogen, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy and cyano;

in which the specified C3-12cycloalkyl, C3-12cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heterophilically ring, heterobicyclic ring system, and a Spiro ring system of the formula (V) optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl, phenyl, benzyl, phenyloxy and benzyloxy, where mentioned phenyl, benzyl, phenyloxy and benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy and cyano;

R2selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl and halogen, with the specified alkyl optionally substituted by oxopropoxy;

and their pharmaceutically acceptable salt and solvate.

In some preferred embodiments, the embodiments of formula (I) D is phenyl or 6-membered heteroaromatic group containing 1-3 nitrogen atom.

N what are the preferred embodiments embodiment of formula (I) or (IA) R 1alkyl represents methyl, ethyl, propyl, butyl, pentyl or hexyl.

In some preferred embodiments, the embodiments of formula (I) or (IA) R1cycloalkyl represents cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl or norbornyl.

In other preferred embodiments, the embodiments of formula (I) or (IA) a bicyclic ring system R1represents naphthyl. In other preferred embodiments, the embodiments of formula (I) or (IA) a bicyclic ring system R1represents tetrahydronaphthyl or decahydronaphthalene and tricyclic ring system R1represents dibenzocycloheptadiene. In other preferred embodiments of embodiment R1represents phenyl or benzyl.

In other preferred embodiments, the embodiments of formula (I) or (IA) bicyclic aromatic ring, R1is a 10-membered ring, preferably a quinoline or naphthyl.

In other preferred embodiments, the embodiments of formula (I) or (IA) bicyclic aromatic ring, R1is a 9-membered ring, preferably indenyl.

In some embodiments of the embodiments of formula (I) or (IA), Z is a bond, methyl or ethyl.

In some embodiments of the embodiments of formula (I) or (IA), the group Z is the maximum substituted, so that on the main Z group does not have any hydrogen substitution. For example, if the main group Z is-CH2-when the substitution of two methyl groups are removed hydrogens main-CH2group Z.

In other preferred embodiments, the embodiments of formula (I) or (IA) n is 0.

In some embodiments of the embodiments of formula (I) or (IA) X1and X2both represent O.

In some embodiments of the embodiments of formula (I) ZR1is cyclohexylethyl, cyclohexylmethyl, cyclopentylmethyl, dimethylcyclohexylamine-, phenylethyl-, proliteracy, tinytitties, pyridylethyl, cyclopentyl-, cyclohexyl-, methoxycyclohexyl, tetrahydropyranyl, propylpiperidine, indoleacetic-, pyrazolidine, triazolylmethyl, denitrifier, hydroxyhexyl, methoxyacetyl, isopropoxy-, hexyl - or exokernel-.

In some embodiments of the embodiments of formula (I) ZR1represents-CH2COOV1tetrazolyl, cyanomethyl-, NH2SO2methyl-, NH2SO, aminocarbonylmethyl-, C1-4alkylaminocarbonyl - or dis1-4alkylaminocarbonyl-.

In some embodiments of the embodiments of formula (I) ZR1is 3,3-diphenylpropyl, optionally substituted at the 3 carbon atom propyl group COOV1tetrazolyl0-4the alkyl-, cyano-, aminocarbonyl-, C1-4alkylaminocarbonyl - or dis1-4-alkyl what aminocarbonyl-.

The invention in some embodiments embodiment includes compounds having the General formula (II):

(II)

where

the dotted line represents an optional double bond;

R represents hydrogen, C1-10alkyl, C3-12cycloalkyl, C3-12cycloalkyl1-4alkyl, C1-10alkoxy, C3-12cycloalkane-, C1-10alkenyl, C1-10alkylidene, oxo, C1-10alkyl substituted with 1-3 Halogens, (C3-12cycloalkyl substituted by 1-3 Halogens, (C3-12cycloalkyl1-4alkyl-substituted by 1-3 Halogens, (C1-10alkoxy substituted by 1-3 Halogens, (C3-12cycloalkane-substituted by 1-3 Halogens, -COOV1, -C1-4COOV1, -CH2OH, -SO2N(V1)2hydraxis1-10alkyl-, hydroxys3-10cycloalkyl, tsianos1-10alkyl-, tsianos3-10cycloalkyl-, -CON(V1)2, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, sulfonylamino1-10alkyl-, diaminoalkyl-, -sulfonyl1-4alkyl, 6-membered heterocyclic ring, 6-membered heteroaromatic ring, 6-membered heterocyclic1-4alkyl-, 6-membered heteroaryl1-4alkyl-, 6-membered aromatic ring, 6-membered aryls1-4alkyl, 5-membered heterocyclic ring, optionally substituted by an oxo or thio, a 5-membered heteroaromatic for lzo, 5-membered heterocyclic1-4alkyl-, optionally substituted by an oxo or thio, a 5-membered heteroaryl1-4alkyl-, -C1-5(=O)W1, -C1-5(=NH)W1, -C1-5NHC(=O)Wl, -C1-5NHS(=O)2W1, -C1-5NHS(=O)W1where W1represents hydrogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkane, -CH2OH, amino, C1-4alkylamino-, dis1-4alkylamino - or 5-membered heteroaromatic ring, optionally substituted by 1-3 lower alkilani;

where each V1independently selected from H, C1-6of alkyl, C3-6cycloalkyl, benzyl and phenyl;

n represents an integer from 0 to 3;

D represents a 5-8-membered cycloalkyl, 5-8-membered heterocyclic or 6-membered aromatic or heteroaromatic group;

A, B and Q represent, independently, hydrogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkane, C1-10alkenyl, C1-10alkylidene, oxo, -CH2OH, -NHSO2hydraxis1-10alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, dis1-4alkylaminocarbonyl, acylamino, acylaminoalkyl-, amide, sulfonylamino1-10alkyl-, or A-B can together form a bridge of C2-6or B-Q together may form a bridge of C3-7or A-Q can together form a bridge of C1-5;

Z is selected and the group, consisting of communication, direct or branched C1-6alkylene, -NH-, -CH2O-, -CH2NH-, -CH2N(CH3)-, -NHCH2-, -CH2CONH-, -NHCH2CO-, -CH2CO-, -COCH2-, -CH2COCH2-, -CH(CH3)-, -CH=, -O - and-HC=CH-, in which the carbon atoms and/or nitrogen is unsubstituted or substituted by one or more groups of lower alkyl, hydroxy, halogen or alkoxy;

R1selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino-, C3-12cyclooctylamino-, -COOV1, -C1-4COOV1, cyano, tsianos1-10the alkyl-, tsianos3-10cycloalkyl-, NH2SO2-, NH2SO2C1-4the alkyl-, NH2SOC1-4the alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, dis1-4alkylaminocarbonyl-benzyl, C3-12cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heterophilically ring, heterobicyclic ring system, and a Spiro ring system of the formula (V):

(V)

where X1and X2independently selected from the group consisting of NH, O, S, and CH2; and in which the specified alkyl, cycloalkyl, alkenyl, C1-10alkylamino-, C3-12cyclooctylamino or benzyl group, R1not necessarily amesen 1-3 substituents, selected from the group consisting of halogen, hydroxy, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl-, cyano, -COOV1, -C1-4COOV1tsianos1-10the alkyl-, -C1-5(=O)W1, -C1-5NHS(=O)2W1, -C1-5NHS(=O)W1A 5-membered heteroaryl0-4the alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy and cyano; and in which the specified C3-12cycloalkyl, C3-12cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heterophilically ring, heterobicyclic ring system, or Spiro ring system of the formula (V) optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, where mentioned phenyl, benzyl, phenyloxy or benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy and cyano;

R2selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl and halogen, with the specified alkyl or cycloalkyl optionally substituted by oxo, AMI is about, alkylamino or dialkylamino;

and their pharmaceutically acceptable salt and solvate.

The invention in some embodiments embodiment includes compounds having the General formula (IIA):

(IIA)

where

the dotted line represents an optional double bond;

Z is selected from the group consisting of-CH2-, -NH-, -CH2O-, -CH2CH2-, -CH2NH-, -CH2N(CH3)-, -NHCH2-, -CH2CONH-, -NHCH2CO-, -CH2CO-, -COCH2-, -CH2COCH2-, -CH(CH3)-, -CH= and-HC=CH-, where the carbon atoms and/or nitrogen is unsubstituted or substituted by lower alkyl, halogen, hydroxy or alkoxygroup;

R and Q are the same or different and each is selected from the group consisting of hydrogen, halogen, C1-10of alkyl, C1-10alkenyl, C1-10alkylidene, C3-12cycloalkyl, C1-10alkoxy and oxo;

R1selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino-, C3-12cyclooctylamino-benzyl, C3-12cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heterophilically ring, bicyclic ring system, and a Spiro ring system of the formula (V):

(V)

in which X1and X2independently selected from the group consisting of NH, O, S, and CH2;

in which the specified monocyclic aryl preferably represents phenyl;

in which the specified bicyclic aryl is preferably naphthyl;

in which the specified alkyl, cycloalkyl, alkenyl, C1-10alkylamino, C3-12cyclooctylamino or benzyl optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy and cyano;

in which the specified C3-12cycloalkyl, C3-12cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heterophilically ring, heterobicyclic ring system, and a Spiro ring system of the formula (V) optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl, phenyl, benzyl, phenyloxy and benzyloxy, where mentioned phenyl, benzyl, phenyloxy and benzyloxy optionally substituted by 1-3 substituents selected from the group status is the present from halogen, C1-10of alkyl, C1-10alkoxy and cyano;

R2selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl and halogen, with the specified alkyl optionally substituted by oxopropoxy;

and their pharmaceutically acceptable salts.

In some preferred embodiments, embodiments, Q in formula (II) or (IIA) represents hydrogen or methyl.

In some preferred embodiments of embodiment R in formulas (II) or (IIA) represents hydrogen, methyl, ethyl or ethylidene.

In some preferred embodiments embodiment of formula (II) D is phenyl or 6-membered heteroaromatic group containing 1-3 nitrogen atom.

In some preferred embodiments embodiment of formula (II) or (IIA) R1alkyl represents methyl, ethyl, propyl, butyl, pentyl or hexyl.

In some preferred embodiments embodiment of formula (II) or (IIA) R1cycloalkyl represents cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl or norbornyl.

In other preferred embodiments embodiment of formula (II) or (II-A) R1bicyclic ring system is a naphthyl. In other preferred embodiments embodiment of formula (II) or (IIA) R1bicyclic ring system is tetrahydronaphthyl or decahydronaphthalene and R1tricyclic the Skye ring system is dibenzocycloheptadiene. In other preferred embodiments of embodiment R1represents phenyl or benzyl.

In other preferred embodiments embodiment of formula (II) or (IIA) R1bicyclic aromatic ring is a 10-membered ring, preferably a quinoline or naphthyl.

In other preferred embodiments embodiment of formula (II) or (IIA) R1bicyclic aromatic ring is a 9-membered ring, preferably indenyl.

In some embodiments of the embodiments of formula (II) or (IIA) Z represents a bond, methyl or ethyl.

In some embodiments of the embodiments of formula (II) or (IIA), the group Z is the maximum substituted, so that the main Z group does not have any hydrogen substitution. For example, if the main group Z is-CH2-when the substitution of two methyl groups are removed hydrogens main-CH2group Z.

In other preferred embodiments embodiment of formula (II) or (IIA) n is 0.

In some embodiments of the embodiments of formula (II) or (IIA) X1and X2both represent O.

In other preferred embodiments the embodiment of the dotted line represents a double bond.

In some embodiments of the embodiments of formula (II) R is-CH2C(=O)NH2, -C(NH)NH2pyridylmethyl, cyclopentyl, cyclohexyl, furylmethyl, -C(=O)CH3, -CH CH2NHC(=O)CH3, -SO2CH3CH2CH2NHS2CH3fornicator, methylpyrrolidinyl, diazocarbonyl, asamati, triptorelin-, hydroxyethyl-, cyanomethyl, accountability or diazomethyl-.

In some embodiments of the embodiments of formula (II) ZR1is cyclohexylethyl, cyclohexylmethyl, cyclopentylmethyl, dimethylcyclohexylamine-, phenylethyl-, proliteracy, tinytitties, pyridylethyl, cyclopentyl-, cyclohexyl-, methoxycyclohexyl, tetrahydropyranyl, propylpiperidine, indoleacetic-, pyrazolidine, triazolylmethyl, denitrifier, hydroxyhexyl, methoxyacetyl, isopropoxy-, hexyl - or exokernel-.

In some embodiments of the embodiments of formula (II) at least one of ZR1and R is-CH2COOV1tetrazolyl, cyanomethyl-, NH2SO2methyl-, NH2SO, aminocarbonylmethyl-, C1-4alkylaminocarbonyl - or dis1-4alkylaminocarbonyl-.

In some embodiments of the embodiments of formula (II) ZR1is 3,3-diphenylpropyl, optionally substituted at the 3 carbon atom propyl group COOV1tetrazolyl0-4the alkyl-, cyano-, aminocarbonyl-, C1-4alkylaminocarbonyl - or dis1-4alkylaminocarbonyl-.

The invention in some variant of the tenth embodiment includes compounds having the General formula (III):

(III)

where R is hydrogen, C1-10alkyl, C3-12cycloalkyl, C3-12cycloalkyl1-4alkyl, C1-10alkoxy, C3-12cycloalkane-, C1-10alkyl substituted with 1-3 Halogens, (C3-12cycloalkyl substituted by 1-3 Halogens, (C3-12cycloalkyl1-4alkyl-substituted by 1-3 Halogens, (C1-10alkoxy substituted by 1-3 Halogens, (C3-12cycloalkane-substituted by 1-3 Halogens, -COOV1, -C1-4COOV1, -CH2OH, -SO2N(V1)2hydraxis1-10alkyl-, hydroxys3-10cycloalkyl, tsianos1-10alkyl-, tsianos3-10cycloalkyl-, -CON(V1)2, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, sulfonylamino1-10alkyl-, diaminoalkyl-, -sulfonyl1-4alkyl, 6-membered heterocyclic ring, 6-membered heteroaromatic ring, 6-membered heterocyclic1-4alkyl-, 6-membered heteroaryl1-4alkyl-, 6-membered aromatic ring, 6-membered aryls1-4alkyl, 5-membered heterocyclic ring, optionally substituted by an oxo or thio, a 5-membered heteroaromatic ring, a 5-membered heterocyclic1-4alkyl-, optionally substituted by an oxo or thio, a 5-membered heteroaryl1-4alkyl-, -C1-5(=O)W1, -C1-5(=NH)W1, -C1-5NHC(=O)Wl, -C15 NHS(=O)2W1, -C1-5NHS(=O)W1where W1represents hydrogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkane, -CH2OH, amino, C1-4alkylamino-, dis1-4alkylamino - or 5-membered heteroaromatic ring, optionally substituted by 1-3 lower alkilani;

where each V1independently selected from H, C1-6of alkyl, C3-6cycloalkyl, benzyl and phenyl;

n represents an integer from 0 to 3;

D represents a 5-8-membered cycloalkyl, 5-8-membered heterocyclic or 6-membered aromatic or heteroaromatic group;

Z is selected from the group consisting of communication, direct or branched C1-6alkylene, -NH-, -CH2O-, -CH2NH-, -CH2N(CH3)-, -NHCH2-, -CH2CONH-, -NHCH2CO-, -CH2CO-, -COCH2-, -CH2COCH2-, -CH(CH3)-, -CH=, -O - and-HC=CH-, where the carbon atoms and/or nitrogen is unsubstituted or substituted by one or more groups of lower alkyl, hydroxy, halogen or alkoxy; or Z represents a system cyclooctylamino formula(VI):

(VI)

where A, B and Q represent, independently, hydrogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkane, -CH2OH, -NHSO2hydraxis1-10alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, dis14 alkylaminocarbonyl, acylamino, acylaminoalkyl-, amide, sulfonylamino1-10alkyl-, or A-B can together form a bridge of C2-6or B-Q together may form a bridge of C3-7or A-Q can together form a bridge of C1-5;

R1selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino-, C3-12cyclooctylamino-, -COOV1, -C1-4COOV1, cyano, tsianos1-10the alkyl-, tsianos3-10cycloalkyl-, NH2SO2-, NH2SO2C1-4the alkyl-, NH2SOC1-4the alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, dis1-4alkylaminocarbonyl-benzyl, C3-12cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heterophilically ring, heterobicyclic ring system, and a Spiro ring system of the formula (V):

(V)

where X1and X2independently selected from the group consisting of NH, O, S, and CH2; and where the specified alkyl, cycloalkyl, alkenyl, C1-10alkylamino-, C3-12cyclooctylamino or benzyl group, R1optionally substituted by 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl-, qi is but -COOV1, -C1-4COOV1tsianos1-10the alkyl-, -C1-5(=O)W1, -C1-5NHS(=O)2W1, -C1-5NHS(=O)W1A 5-membered heteroaryl0-4the alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy and cyano; and where the specified C3-12cycloalkyl, C3-12cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heterophilically ring, heterobicyclic ring system, and a Spiro ring system of the formula (V) optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, where mentioned phenyl, benzyl, phenyloxy or benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy and cyano;

R2selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl and halogen, with the specified alkyl or cycloalkyl optionally substituted by oxo, amino, alkylamino or dialkylamino;

and their pharmaceutically acceptable salt and solvate.

The invention in some the embodiments embodiment includes compounds having the General formula (IIIA):

(IIIA)

where

n represents an integer from 0 to 3;

Z is selected from the group consisting of-CH2-, -NH-, -CH2O-, -CH2CH2-, -CH2NH-, -CH2N(CH3)-, -NHCH2-, -CH2CONH-, -NHCH2CO-, -CH2CO-, -COCH2-, -CH2COCH2-, -CH(CH3)-, -CH=, -HC=CH -, and system cyclooctylamino formula (VI):

(VI)

where the carbon atoms and/or nitrogen is unsubstituted or substituted by lower alkyl, halogen, hydroxy, phenyl, benzyl or alkoxygroup;

R is selected from the group consisting of hydrogen, C1-10of alkyl, C1-10alkoxy and C3-12cycloalkyl;

R1selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino-, C3-12cyclooctylamino-benzyl, C3-12cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heterophilically ring, heterobicyclic ring system, and a Spiro ring system of the formula (V):

(V)

in which X1and X2independently selected from the group consisting of NH, O, S, and CH2;

in which the specified monocyclic aryl preferably represents phenyl

in which the specified bicyclic aryl is preferably naphthyl;

in which the specified alkyl, cycloalkyl, alkenyl, C1-10alkylamino, C3-12cyclooctylamino or benzyl optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy and cyano;

in which the specified C3-12cycloalkyl, C3-12cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heterophilically ring, heterobicyclic ring system, and a Spiro ring system of the formula (V) optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl, phenyl, benzyl, phenyloxy and benzyloxy, where mentioned phenyl, benzyl, phenyloxy and benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy and cyano;

R2selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl and halogen, with the specified alkyl is obazatelno replaced by oxopropoxy;

and their pharmaceutically acceptable salts.

In some preferred embodiments embodiment of formula (III) D is phenyl or 6-membered heteroaromatic group containing 1-3 nitrogen atom.

In some preferred embodiments embodiment of formula (III) or (IIIA) R1alkyl represents methyl, ethyl, propyl, butyl, pentyl or hexyl.

In some preferred embodiments embodiment of formula (III) or (IIIA) R1cycloalkyl represents cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl or norbornyl.

In other preferred embodiments embodiment of formula (III) or (IIIA) a bicyclic ring system R1represents naphthyl. In other preferred embodiments of formula (III) or (IIIA) a bicyclic ring system R1represents tetrahydronaphthyl or decahydronaphthalene and tricyclic ring system R1represents dibenzocycloheptadiene. In other preferred embodiments of embodiment R1represents phenyl or benzyl.

In other preferred embodiments embodiment of formula (III) or (IIIA) bicyclic aromatic ring, R1is a 10-membered ring, preferably a quinoline or naphthyl.

In other preferred embodiments embodiment of formula (III) or (IIIA) bicyclic aromatic the ring R 1is a 9-membered ring, preferably indenyl.

In some embodiments of the embodiments of formula (III) or (IIIA) Z represents a bond, methyl or ethyl.

In some embodiments of the embodiments of formula (III) or (IIIA), the group Z is the maximum substituted, so that the main Z group does not have any hydrogen substitution. For example, if the main group Z is-CH2-when the substitution of two methyl groups are removed hydrogens main-CH2group Z.

In some embodiments of the embodiments of formula (III) or (IIIA) Z represents the system cyclooctylamino formula (VI):

(VI)

where the nitrogen atom optionally substituted C1-3the alkyl, phenyl or benzyl.

In other preferred embodiments embodiment of formula (III) or (IIIA) n is 0.

In some embodiments of the embodiments of formula (III) or (IIIA) X1and X2both represent O.

In some embodiments of the embodiments of formula (III) R is-CH2C(=O)NH2, -C(NH)NH2pyridylmethyl, cyclopentyl, cyclohexyl, furylmethyl, -C(=O)CH3, -CH2CH2NHC(=O)CH3, -SO2CH3CH2CH2NHS2CH3fornicator, methylpyrrolidinyl, diazocarbonyl, asamati, triptorelin-, hydroxyethyl-, cyanomethyl, accountability or diazomethyl-.

In nektarinukiniai embodiment of formula (III) ZR 1is cyclohexylethyl, cyclohexylmethyl, cyclopentylmethyl, dimethylcyclohexylamine-, phenylethyl-, proliteracy, tinytitties, pyridylethyl, cyclopentyl-, cyclohexyl-, methoxycyclohexyl, tetrahydropyranyl, propylpiperidine, indoleacetic-, pyrazolidine, triazolylmethyl, denitrifier, hydroxyhexyl, methoxyacetyl, isopropoxy-, hexyl - or exokernel-.

In some embodiments of the embodiments of formula (III) at least one of ZR1and R is-CH2COOV1tetrazolyl, cyanomethyl-, NH2SO2methyl-, NH2SO, aminocarbonylmethyl-, C1-4alkylaminocarbonyl - or dis1-4alkylaminocarbonyl-.

In some embodiments of the embodiments of formula (III) ZR1is 3,3-diphenylpropyl, optionally substituted at the 3 carbon atom propyl group COOV1tetrazolyl0-4the alkyl-, cyano-, aminocarbonyl-, C1-4alkylaminocarbonyl - or dis1-4alkylaminocarbonyl-.

The invention in some embodiments embodiment includes compounds having the General formula (IV):

(IV)

where R is hydrogen, C1-10alkyl, C3-12cycloalkyl, C3-12cycloalkyl1-4alkyl, C1-10alkoxy, C3-12cycloalkane-, C1-10alkyl, samisen the th 1-3 Halogens, C3-12cycloalkyl substituted by 1-3 Halogens, (C3-12cycloalkyl1-4alkyl-substituted by 1-3 Halogens, (C1-10alkoxy substituted by 1-3 Halogens, (C3-12cycloalkane-substituted by 1-3 Halogens, -COOV1, -C1-4COOV1, -CH2OH, -SO2N(V1)2hydraxis1-10alkyl-, hydroxys3-10cycloalkyl, tsianos1-10alkyl-, tsianos3-10cycloalkyl-, -CON(V1)2, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, sulfonylamino1-10alkyl-, diaminoalkyl-, -sulfonyl1-4alkyl, 6-membered heterocyclic ring, 6-membered heteroaromatic ring, 6-membered heterocyclic1-4alkyl-, 6-membered heteroaryl1-4alkyl-, 6-membered aromatic ring, 6-membered aryls1-4alkyl, 5-membered heterocyclic ring, optionally substituted by an oxo or thio, a 5-membered heteroaromatic ring, a 5-membered heterocyclic1-4alkyl-, optionally substituted by an oxo or thio, a 5-membered heteroaryl1-4alkyl-, -C1-5(=O)W1, -C1-5(=NH)W1, -C1-5NHC(=O)Wl, -C1-5NHS(=O)2W1, -C1-5NHS(=O)W1where W1represents hydrogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkane, -CH2OH, amino, C1-4alkylamino-, dis1-4alkylamino - or 5-membered heteroaromatic for lzo, optionally substituted by 1-3 lower alkilani;

where each V1independently selected from H, C1-6of alkyl, C3-6cycloalkyl, benzyl and phenyl;

D represents a 5-8-membered cycloalkyl, 5-8-membered heterocyclic or 6-membered aromatic or heteroaromatic group;

n represents an integer from 0 to 3;

A, B and Q represent, independently, hydrogen, C1-10alkyl, C3-12cycloalkyl, C1-10alkoxy, C3-12cycloalkane, -CH2OH, -NHSO2hydraxis1-10alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, dis1-4alkylaminocarbonyl, acylamino, acylaminoalkyl-, amide, sulfonylamino1-10alkyl-, or A-B can together form a bridge of C2-6or B-Q together may form a bridge of C3-7or A-Q can together form a bridge of C1-5;

Z is selected from the group consisting of communication, direct or branched C1-6alkylene, -NH-, -CH2O-, -CH2NH-, -CH2N(CH3)-, -NHCH2-, -CH2CONH-, -NHCH2CO-, -CH2CO-, -COCH2-, -CH2COCH2-, -CH(CH3)-, -CH=, -O - and-HC=CH-, where the carbon atoms and/or nitrogen is unsubstituted or substituted by one or more groups of lower alkyl, hydroxy, halogen or alkoxy;

R1selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-0 alkylamino-, C3-12cyclooctylamino-, -COOV1, -C1-4COOV1, cyano, tsianos1-10the alkyl-, tsianos3-10cycloalkyl-, NH2SO2-, NH2SO2C1-4the alkyl-, NH2SOC1-4the alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, dis1-4alkylaminocarbonyl-benzyl, C3-12cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heterophilically ring, heterobicyclic ring system, and a Spiro ring system of the formula (V):

(V)

where X1and X2independently selected from the group consisting of NH, O, S, and CH2; and where the specified alkyl, cycloalkyl, alkenyl, C1-10alkylamino-, C3-12cyclooctylamino or benzyl group, R1optionally substituted by 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl-, cyano, -COOV1, -C1-4COOV1tsianos1-10the alkyl-, -C1-5(=O)W1, -C1-5NHS(=O)2W1, -C1-5NHS(=O)W1A 5-membered heteroaryl0-4the alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alcox is - and cyano; and where specified C3-12cycloalkyl, C3-12cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heterophilically ring, heterobicyclic ring system, and a Spiro ring system of the formula (V) optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, where mentioned phenyl, benzyl, phenyloxy or benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy and cyano;

R2selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl and halogen, with the specified alkyl or cycloalkyl optionally substituted by oxo, amino, alkylamino or dialkylamino;

and their pharmaceutically acceptable salt and solvate.

The invention in some embodiments embodiment includes compounds having the General formula (IVA):

where

n represents an integer from 0 to 3;

Z is selected from the group consisting of-CH2-, -NH-, -CH2O-, -CH2CH2-, -CH2NH-, -CH2N(CH3)-, -NHCH2-, -CH2CONH-, -NHCH2CO-, -CH2CO-, -COCH2-, -CH2COCH2-, -CH(CH3)-, -CH= THE-HC=CH-, where the carbon atoms and/or nitrogen is unsubstituted or substituted by lower alkyl, halogen, hydroxy or alkoxygroup;

R is selected from the group consisting of hydrogen, C1-10of alkyl, C1-10alkoxy and C3-12cycloalkyl;

R1selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino-, C3-12cyclooctylamino-benzyl, C3-12cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heterophilically ring, heterobicyclic ring system, and a Spiro ring system of the formula (V):

(V)

in which X1and X2independently selected from the group consisting of NH, O, S, and CH2;

in which the specified monocyclic aryl preferably represents phenyl;

in which the specified bicyclic aryl is preferably naphthyl;

in which the specified alkyl, cycloalkyl, alkenyl, C1-10alkylamino, C3-12cyclooctylamino or benzyl optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally substituted by 1-3 cover the firs, selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy and cyano;

in which the specified C3-12cycloalkyl, C3-12cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heterophilically ring, heterobicyclic ring system, and a Spiro ring system of the formula (V) optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy, nitro, trifloromethyl, phenyl, benzyl, phenyloxy and benzyloxy, where mentioned phenyl, benzyl, phenyloxy and benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10of alkyl, C1-10alkoxy and cyano;

R2selected from the group consisting of hydrogen, C1-10of alkyl, C3-12cycloalkyl and halogen, with the specified alkyl optionally substituted by oxopropoxy;

and their pharmaceutically acceptable salts.

In some preferred embodiments embodiment of formula (IV) D is phenyl or 6-membered heteroaromatic group containing 1-3 nitrogen atom.

In some preferred embodiments embodiment of formula (IV) or (IVA) alkyl, R1represents methyl, ethyl, propyl, butyl, pentyl or hexyl.

In some preferred embodiments embodiment of formula (IV) and the and (IVA) cycloalkyl R 1represents cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl or norbornyl.

In other preferred embodiments embodiment of formula (IV) or (IVA) bicyclic ring system R1represents naphthyl. In other preferred embodiments embodiment of formula (IV) or (IVA) bicyclic ring system R1represents tetrahydronaphthyl or decahydronaphthalene and tricyclic ring system R1represents dibenzocycloheptadiene. In other preferred embodiments of embodiment R1represents phenyl or benzyl.

In other preferred embodiments embodiment of formula (IV) or (IVA) bicyclic aromatic ring, R1is a 10-membered ring, preferably a quinoline or naphthyl.

In other preferred embodiments embodiment of formula (IV) or (IVA) bicyclic aromatic ring, R1is a 9-membered ring, preferably indenyl.

In some embodiments of the embodiments of formula (IV) or (IVA) Z represents a bond, methyl or ethyl.

In some embodiments of the embodiments of formula (IV) or (IVA) group Z is maximum substituted, so that the main Z group does not have any hydrogen substitution. For example, if the main group Z is-CH2-when the substitution of two methyl groups is removed hydrogens main-CH 2group Z.

In other preferred embodiments embodiment of formula (IV) or (IVA) n is 0.

In some embodiments of the embodiments of formula (IV) or (IVA) X1and X2both represent O.

In some embodiments of the embodiments of formula (IV) R is-CH2C(=O)NH2, -C(NH)NH2pyridylmethyl, cyclopentyl, cyclohexyl, furylmethyl, -C(=O)CH3, -CH2CH2NHC(=O)CH3, -SO2CH3CH2CH2NHS2CH3fornicator, methylpyrrolidinyl, diazocarbonyl, asamati, triptorelin-, hydroxyethyl-, cyanomethyl, accountability or diazomethyl-.

In some embodiments of the embodiments of formula (IV) ZR1is cyclohexylethyl, cyclohexylmethyl, cyclopentylmethyl, dimethylcyclohexylamine-, phenylethyl-, proliteracy, tinytitties, pyridylethyl, cyclopentyl-, cyclohexyl-, methoxycyclohexyl, tetrahydropyranyl, propylpiperidine, indoleacetic-, pyrazolidine, triazolylmethyl, denitrifier, hydroxyhexyl, methoxyacetyl, isopropoxy-, hexyl - or exokernel-.

In some embodiments of the embodiments of formula (IV) at least one of ZR1and R is-CH2COOV1tetrazolyl, cyanomethyl-, NH2SO2methyl-, NH2SO, aminocarbonylmethyl-, C1-4alkylaminocarbonyl - or dis1-4/sub> alkylaminocarbonyl-.

In some embodiments of the embodiments of formula (IV) ZR1is 3,3-diphenylpropyl, optionally substituted at the 3 carbon atom propyl group COOV1tetrazolyl0-4the alkyl-, cyano-, aminocarbonyl-, C1-4alkylaminocarbonyl - or dis1-4alkylaminocarbonyl-.

In alternative embodiments of formulas (I), (IA), (II), (IIA), (III), (IIIA), (IV) and (IVA) ZR1can be :

where

Y1is R3-(C1-C12)alkyl, R4-aryl, R5-heteroaryl, R6-(C3-C12)cycloalkyl, R7-(C3-C7)heteroseksualci, -CO2(C1-C6)alkyl, CN or-C(O)NR8R9; Y2represents hydrogen or Y1; Y3represents hydrogen or(C1-C6)alkyl; or Y1, Y2and Y3together with the carbon atom to which they are attached, form one of the following structures:

,

or

where r is 0-3; w and u are each equal to 0 to 3, provided that the sum of w and u is 1-3; c and d each independently is 1 or 2; s is 1 to 5; and ring E is a condensed R4is phenyl, or R5-heteroaryl ring;

R10is 1-3 substituent, independently selected the data from the group consisting of H, (C1-C6)alkyl, -OR8, -(C1-C6)alkyl-OR8, -NR8R9and -(C1-C6)alkyl-NR8R9;

R11is 1-3 substituent, independently selected from the group consisting of R10, -CF3, -OCF3, NO2and halogen, or R11the substituents on adjacent ring carbon atoms together may form a ring methylendioxy or Ethylenedioxy;

R8and R9independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C3-C12)cycloalkyl, aryl and aryl(C1-C6)alkyl;

R3is 1-3 substituent, independently selected from the group consisting of H, R4-aryl, R6-(C3-C12)cycloalkyl, R5-heteroaryl, R7-(C3-C7)geterotsiklicheskie, -NR8R9, -OR12and-S(O)0-2R12;

R6is 1-3 substituent, independently selected from the group consisting of H, (C1-C6)alkyl, R4-aryl, -NR8R9, -OR12and-SR12;

R4is 1-3 substituent, independently selected from the group consisting of hydrogen, halogen, (C1-C6)alkyl, R13-aryl, (C3-C12)cycloalkyl, -CN, -CF3, -OR8, -(C1-C6)alkyl-OR8, -OCF3, -NR8R9, -(C1-C6alkyl-NR 8R9, -NHSO2R8, -SO2N(R14)2, -SO2R8, -SOR8, -SR8, -NO2, -CONR8R9, -NR9R8, -COR8, -COCF3, -OCOR8, -OCO2R8, -COOR8, -(C1-C6)alkyl-NHCOOC(CH3)3, -(C1-C6)alkyl-NHCOCF3, -(C1-C6)alkyl-NHSO2-(C1-C6)alkyl, -(C1-C6)alkyl-NHCONH-(C1-C6)-alkyl and

where f is 0-6; or R4the substituents on adjacent ring carbon atoms together may form a ring methylendioxy or Ethylenedioxy;

R5is 1-3 substituent, independently selected from the group consisting of hydrogen, halogen, (C1-C6)alkyl, R13-aryl, (C3-C12)cycloalkyl, -CN, -CF3, -OR8, -(C1-C6)alkyl-OR8, -OCF3, -NR8R9, -(C1-C6)alkyl-NR8R9, -NHSO2R8, -SO2N(R14)2, -NO2, -CONR8R9, -NR9R8, -COR8, -OCOR8, -OCO2R8and-COOR8;

R7is H, (C1-C6)alkyl, -OR8, -(C1-C6)alkyl-OR8, -NR8R9or -(C1-C6)alkyl-NR8R9;

R12is H, (C1-C6)alkyl, R4-aryl, -(C1-C6)Alki is-OR 8, -(C1-C6)alkyl-NR8R9, -(C1-C6)alkyl-SR8or aryl(C1-C6)alkyl;

R13is 1-3 substituent, independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy and halogen;

R14independently selected from the group consisting of H, (C1-C6)alkyl and R13-C6H4-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 methyl, propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl. Branched alkyl means that one or more alkyl groups such as methyl, ethyl or propyl, replaces one or both of the hydrogen in the group-CH2linear alkyl chain. The term "lower alkyl" means alkyl, consisting of 1-3 carbon atoms.

The term "alkoxy" means an alkyl, as defined above, associated with an oxygen radical.

The term "cycloalkyl" means a non-aromatic mono - or polycyclic hydrocarbon ring system having a single radical and 3-12 carbon atoms. Examples of monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl and cyclohexyl. Examples of polycyclic CEC is alkiline rings include substituted and norbornyl.

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

"Branched alkenyl" means that one or more alkyl groups such as methyl, ethyl or propyl, replaces one or both of the hydrogen in the group-CH2- or-CH= linear alkenylphenol chain. Examples alkenyl groups include ethynyl, 1 - and 2-propenyl, 1-, 2 - and 3-butenyl, 3-methylbut-2-enyl, 2-propenyl, heptenyl, octenyl and decenyl.

The term "cycloalkenyl" means a non-aromatic monocyclic or polycyclic hydrocarbon ring system containing a double bond of carbon-carbon, having a single radical and 3-12 carbon atoms. Examples of monocyclic cycloalkenyl rings include cyclopropyl, cyclopentyl, cyclohexenyl or cycloheptenyl. Examples of polycyclic cycloalkenyl rings include norbornene.

The term "aryl" means a carbocyclic aromatic ring system containing one, two or three rings that can be attached to each other or condensed, and containing a single radical. Examples of aryl groups include phenyl, naphthyl and acenaphthyl.

The term "heterocyclic" refers to cyclic compounds having one or more heteroatoms (atoms other than the carbon is in the ring and having one radical. The ring may be saturated, partially saturated or unsaturated, and the heteroatoms may be selected from the group consisting of nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3-6 membered heterogenities group containing 1-4 nitrogen atom, such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinil; saturated 3-6 membered heterogenities group containing 1-2 oxygen atoms and 1-3 nitrogen atom, such as morpholinyl; saturated 3-6 membered heterogenities group containing 1-2 sulfur atom and 1 to 3 nitrogen atom, such as diazolidinyl. Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran and dihydrofuran. Other heterocyclic groups can be rings, consisting of 7-10 carbon atoms, substituted by heteroatoms, such as axokine and ciocanel. If the heteroatom represents sulfur, the sulfur may be sulfur dioxide, such as tiaanidine.

The term "heteroaryl" means unsaturated heterocyclic radicals, where the term "heterocyclic" is the same as defined above. Examples of heteroaryl groups include unsaturated 3-6 membered heterogenities group containing 1-4 nitrogen atom, such as pyrrolyl, pyridyl, pyrimidyl and pyrazinyl; unsaturated condensed hetero is ilycheskie group, containing 1 to 5 nitrogen atoms, such as indolyl, chinosol and ethanolic; unsaturated 3-6 membered heterogenities group containing an oxygen atom, such as furyl; unsaturated 3-6 membered heterogenities group containing a sulfur atom, such as thienyl;

unsaturated 3-6 membered heterogenities group containing 1-2 oxygen atoms and 1-3 nitrogen atom, such as oxazolyl; unsaturated condensed heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atom, such as benzoxazolyl; unsaturated 3-6 membered heterogenities group containing 1-2 sulfur atom and 1 to 3 nitrogen atom, such as thiazolyl; and unsaturated condensed heterocyclic group containing 1-2 sulfur atom and 1 to 3 nitrogen atom, such as benzothiazolyl. The term "heteroaryl also includes unsaturated heterocyclic radicals, where the term "heterocyclic" is the same as defined above, in which the heterocyclic group is condensed with an aryl group, in which aryl is as defined above. Examples of the condensed radicals include benzofuran, benzodioxan and benzothiophen.

As used herein, the term "heterocyclic1-4alkyl, heteroaryl1-4alkyl" and the like refers to a ring structure associated with1-4alkyl radical.

All cyclic ring structure disclosed herein, may be attached in any position where such connection is possible, as is obvious to a person skilled in the field.

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

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

The invention disclosed in this specification, is intended to include all pharmaceutically acceptable salts of the disclosed compounds. Pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; salts of alkaline earth metals such as calcium salt, magnesium salt and the like; salts of organic amine, such as salt, triethylamine salt of pyridine, picoline salt, ethanolamine salt, triethanolamine salt, salt dicyclohexylamine, salt N,N'-dibenziletilendiaminom and the like; inorganic salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, triptorelin, maleate, fumarate, tartrate and the like; sulfonates such as methanesulfonate, bansilalpet, p-toluensulfonate and the like; salts of amino acids such as arginate, Asparaginate, glutamate, etc.

The image is the group of disclosed in this specification also covers all prodrugs of the disclosed compounds. Prodrugs are any covalently linked carriers that release the active source drugin vivo.

The invention disclosed in this specification also covers productsin vivometabolism of disclosed compounds. Such products can be formed, for example, oxidation, recovery, hydrolysis, amidation, esterification and the like of the input connections, primarily due to enzymatic processes. Accordingly, the invention includes compounds obtained by the process comprising contacting compounds of the present invention with a mammal for a period of time sufficient to obtain its metabolic product. Such products are usually identified by obtaining radioactively labeled compounds of the invention, the introduction of it parenterally in a detectable dose to an animal such as rat, mouse, Guinea pig, monkey, or to man, after a period of time sufficient to complete the metabolism and excretion of its conversion products from the urine, blood or other biological samples.

The invention disclosed herein, also encompasses the disclosed compounds, which are isotope-sword is nymi, by replacing one or more atoms of an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as2H,3H,13C,14C,15N18Oh,17Oh,31P,32R35S18F and36Cl, respectively. Some compounds disclosed herein may contain one or more asymmetric centers, which leads to the formation of enantiomers, diastereomers, and other stereoisomeric forms. This invention also includes all such possible forms as well as their racemic and separated forms and their mixtures. If the compounds described in this invention contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, refers to that included both E and Z geometric isomers. Also have in mind that all tautomers are encompassed by this invention.

As used herein, the term "stereoisomers" is a General term for all isomers of individual molecules that differ only in the spatial orientation of their atoms. It includes enantiomers and isomers of compounds with more than one chiral center, and which are not is zerkalnimi images of each other (diastereomers).

The term "chiral center" refers to the carbon atom is attached to four different groups.

The term "enantiomer" or "enantiomeric" refers to a molecule on which it is impossible to impose its mirror image and hence optically active, in which the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.

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

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

The term "modulate", as used herein, in relation to the ORL1 receptor means mediating pharmacodynamic response (e.g., analgesia) in the subject (i) due to inhibition or activation of the receptor, or (ii) directly or indirectly, due to the impact on the normal regulation of the activity of the receptor. Compounds that modulate the activity of the receptor, include agonists, antagonists, mixed agonists/antagonists and compounds that directly or indirectly affect the regulation of the activity of the receptor.

Specific preferred compounds of formula (I) and (IA) include:

3-[1-(naphthas-2-yl is ethyl)-4-piperidinyl]-2H-benzoxazol-2-he;

3-[1-(naphthas-1-ylmethyl)-4-piperidinyl]-2H-benzoxazol-2-he;

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

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

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

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

3-[1-[4,4-bis-(4-forfinal)butyl]-4-piperidinyl]-2H-benzoxazol-2-he;

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

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

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

3-[1-(5-metrex-2-yl)-4-piperidinyl]-2H-benzoxazol-2-he;

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

3-[1-(4-propylcyclohexyl)-4-piperidinyl]-2H-benzoxazol-2-he;

3-[1-(norbornane-2-yl)-4-piperidinyl]-2H-benzoxazol-2-he;

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

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

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

3-[1-(1,3-dihydroindol-2-yl)-4-piperidinyl]-2H-benzoxazol-2-he;

3-[1-(cyclooctyl)-4-piperidinyl]-2H-benzoxazol-2-he; and

their pharmaceutically acceptable salt and solvate.

Specific preferred compounds of formula (II) and (IIA) include:

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

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

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

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

3-ethylidene-1-[1-(naphthas-2-ylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

1-[1-(naphthas-1-ylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he;

1-[1-(naphthas-2-ylmethyl)-4-piperidinyl]-1,3-dihydro-H-indole-2-he;

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

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

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

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

1-[1-(1,2,3,4-tetrahydronaphtyl-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he;

1-[1-(5-metrex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he;

1-[1-(norbornane-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he;

1-[1-(1,3-dihydroindol-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he;

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

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

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

1-[1-(5-metrex-2-yl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he;

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

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

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

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

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

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

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

3-ethyl-1-[1-[4-(1-mutilat the l)cyclohexyl]-3-methyl-4-piperidinyl]-1,3-dihydro-2H-indol-2-he;

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

their pharmaceutically acceptable salt and solvate.

Specific preferred compounds of formula (III) and (IIIA) include:

3-ethyl-1-(p-vinylbenzyl)-1,3-dihydro-2H-benzimidazole-2-he;

3-ethyl-1-(5-metrex-2-yl)-1,3-dihydro-2H-benzimidazole-2-he;

3-ethyl-1-(4-propylcyclohexyl)-1,3-dihydro-2H-benzimidazole-2-he;

3-ethyl-1-(decahydro-2-naphthyl)-1,3-dihydro-2H-benzimidazole-2-he;

3-ethyl-1-(naphthas-2-ylmethyl)-1,3-dihydro-2H-benzimidazole-2-he;

1-(p-benzyloxybenzyl)-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he;

1-benzyl-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-(benzylamino)cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he;

3-ethyl-1-(naphthylmethyl)-1,3-dihydro-2H-benzimidazole-2-he;

3-ethyl-1-[5-(3-forfinal)-5-(4-forfinal)hexyl]-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(naphthas-2-ylmethyl)ethylamino]cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-(norbornane-2-ylamino)cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[[4-(1-methylethyl)cyclohexyl]amino]cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(decahydro-2-naphthyl)amino]cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-(ethylamino)cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-(benzylamino)cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(indan-2-yl)benzoylamino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzoni the azole-2-he;

1-[4-[(cyclooctylmethyl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(naphthas-2-yl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(p-benzyloxybenzyl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(cyclooctylmethyl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(decahydro-2-naphthyl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-(benzylamino)cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-(dibenzylamino)cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(p-phenylbenzyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(1,2,3,4-tetrahydronaphthyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(4-propylcyclohexyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(5-metrex-2-yl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(decahydro-2-naphthyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-(cyclooctylamino)cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(indan-2-yl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(4-phenylcyclohexyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he;

1-[4-[(5-metrex-2-yl)amino]cyclohexyl]-7-carbarnoyl-1,3-dihydro-2H-benzimidazole-2He; and

their pharmaceutically acceptable salt and solvate.

Other preferred compounds of formula (IV) and (IVA) include:

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

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

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

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

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

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

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

2 cyanoimino-3-ethyl-1-[1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;

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

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

2 cyanoimino-3-ethyl-1-[1-(5-metrex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;

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

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

2 cyanoimino-3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihyd the on-2H-benzimidazole; and

their pharmaceutically acceptable salt and solvate.

Other preferred compounds of formula (IV) include:

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

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

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

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

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

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

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

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

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-azobenzenes;

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

and their pharmaceutically acceptable salt and solvate.

This invention also provides the use of any of the disclosed compounds when getting medicines for the treatment of pain and other painful status is I, modulating opioid receptor, for example, receptor ORL-1.

Detailed description of the invention

The compounds of this invention can be introduced to any subject in need of modulation of opioid and ORL1 receptors. The introduction can be done orally, topically, by means of a suppository, inhalation, or parenteral.

This invention also encompasses all pharmaceutically acceptable salts of the compounds above. The person skilled in the art will understand that the acid additive salts of the compounds according to this invention can be obtained by the interaction of the compounds with the appropriate acid using a variety of known methods.

Can be used in various dosage forms for oral administration, including such solid forms as tablets, gel capsules, capsules, caplet, granules, pellet and granular powders, and liquid forms such as emulsions, solutions or suspensions. The compounds of this invention can be introduced separately or can be combined with various pharmaceutically acceptable carriers and excipients known to the person skilled in the art, including, but not limited to, diluents, suspendresume funds soljubilizatory, binders, disintegrators, preservatives, dyes, lubricants, etc.

If the connection is given the CSOs of the invention include tablets for oral administration, such tablets can be compressed, processed on the machine for tabletting, covered intersolubility shell, covered with sugar, covered with foil, repeatedly compacted or covered with several layers. Liquid dosage forms for oral administration include aqueous and non-aqueous solutions, emulsions, suspensions and solutions and/or suspensions recovered from nishiuchi granules, containing suitable solvents, preservatives, emulsifiers funds suspendresume tools, diluents, sweeteners, dyes and fragrances. If the compounds of this invention administered parenterally, they may be, for example, in the form of an isotonic sterile solution. Alternatively, if the compounds of this invention provide a means for inhalation, they can be prepared in a dry aerosol or can be prepared in aqueous or partially aqueous solution.

In addition, if the compounds of this invention administered in dosage forms for oral administration, it is meant that such dosage forms can provide immediate release of the compound in the gastrointestinal tract or, alternatively, can provide controlled and/or delayed release throughout the gastrointestinal tract. The person skilled in the art well known to the th range of compositions controlled and/or sustained release, which can be used in connection with the compositions according to this invention. Controlled and/or delayed release can be achieved, for example, by coating on the dosage form for oral administration, or administration of the compound(s) according to the invention in a matrix controlled and/or sustained release.

Specific examples of pharmaceutically acceptable carriers and excipients that may be used to produce dosage forms for oral administration, as described inHandbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986). Technology and composition for producing solid dosage forms for oral administration are described inPharmaceutical Dosage Forms: Tablets(Lieberman, Lachman and Schwartz, editors) 2nd edition, published by Marcel Dekker, Inc. Technology and composition to obtain tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described inRemington,'s Pharmaceutical Sciences(Arthur Osol, editor), V (1980). Technology and composition to obtain a liquid dosage forms for oral administration are described inPharmaceutical Dosage Forms: Disperse Systems, (Lieberman, Rieger and Banker, editors), published by Marcel Dekker, Inc.

If the compounds of this invention include a composition for parenteral administration by injection (e.g., continuous infusion or bolus injection), the composition is for parenteral administration may be in the form of suspensions, solutions, emulsions in oily or aqueous carriers, and such compositions may contain pharmaceutically necessary additives such as stabilizers, suspendresume means, dispersing funds, etc. Compounds according to the invention can also be in powder form, subject to recovery in the composition for injection.

In specific embodiments of the compounds of this invention can be used in combination with at least one other therapeutic agent. Therapeutic agents include, but are not limited to, the µ-opioid agonists; non-analgesic funds; non-steroidal anti-inflammatory agents; inhibitors SOH-II; anti-emetics; β-adrenergic blockers; anticonvulsants; antidepressants; blockers of Ca2+channels; antineoplastic agents, and mixtures thereof.

In specific embodiments, the embodiment of the compounds of this invention can be prepared in pharmaceutical dosage form in combination with µ-opioid agonist. µ-Opioid agonists that can be included in the compositions of this invention include, but are not limited to, Alfentanil, allylprodine, Alphaprodine, Anileridine, benzylmorphine, Bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamor is he, Dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl, Dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, Ethylmorphine, etonitazene, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, Ketobemidone, Levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, mirfin, nalbuphine, narceine, Nicomorphine, norlevorphanol, Normethadone, nalorfin, normorphine, norpipanone, opium, oxycodone, Oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, Phenoperidine, piminodine, Piritramide, proheptazine, promedol, properidine, propiram, propoksifen, Sufentanil, Tilidine, tramadol, pharmaceutically acceptable salts and mixtures.

In specific preferred embodiments the embodiment of the µ-opioid agonists are selected from codeine, hydromorphone, hydrocodone, oxycodone, Dihydrocodeine, dihydromorphine, morphine, tramadol, Oxymorphone, their pharmaceutically acceptable salts and mixtures.

In another variant embodiment of the invention, the drug includes a mixture of inhibitor SOH-II and an inhibitor of 5-lipoxygenase for the treatment of pain and/or inflammation. Suitable inhibitors SOH-II inhibitors, 5-lipoxygenase, as well as combinations thereof, are described in U.S. patent No. 6136839, which is included in its entirety in this description pore the STV links. Inhibitors SOH-II include, but are not limited to, rofecoksib (Vioxx), celecoxib (Celebrex), DUP-697, flosulide, meloxicam, 6-MNA, L-745337, nabumetone, nimesulide, NS-398, SC-5766, T-614, L-768277, GR-253035, JTE-522, RS-57067-000, SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367, SC-5766, PD-164387, etoricoxib valdecoxib, parecoxib or their pharmaceutically acceptable salts, enantiomers or tautomers.

The compounds of this invention can also be combined in a dosage form with a non-analgesics, for example, non-steroidal anti-inflammatory drugs, including aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, Louboutin, Ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bullocksandra acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, exping, mefenamico acid, meclofenamic acid, flufenamic acid, niflumova acid, tolfenamic acid diflunisal, flufenisal, piroxicam, sudoxicam or isoxicam, their pharmaceutically acceptable salts and mixtures. Other suitable non-opioids, which can be included in the dosage forms of the present invention include, without limitation, chemical is lossy analgesic, antipyretics, nonsteroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, holinomimeticalkie, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine and olsalazine; derivatives of para-aminophenol, including acetaminophen; indologie and indene acetic acids, including indomethacin, sulindac and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and Ketorolac; Anthranilic acid (fenamate), including mefenamico acid and meclofenamic acid; enol acids, including oxicam (piroxicam, tenoxicam), and pyrazolidinone (phenylbutazone, exifinterface); and alkenone, including nabumetone. For a more detailed description NSPs that can be included in a medicinal product used in accordance with this invention, see Paul A. Insel Analgesic-Antipyretic and Anti-Inflammatory Agents and Drugs Employed in the treatment of Gout in Goodman & Gilman''s The Pharmacological Basis of Therapeutics, 617-57 (Perry B. Molinhoffand Raymond W. Ruddon, Eds., Ninth Edition, 1996), and Glen R. Hanson Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol II, 1196-1221 (A. R. Gennaro, Ed. 19th Ed. 1995), which are included in this description in their entirety by reference.

In some embodiments the embodiment of the compounds of this invention can be prepared in pharmaceutical dosage form in combination with drug what Redstone against migraines. Drugs against migraine include, but are not limited to, aspirated, digidroergotamin, dolasetron, ergocornine, ergocornine, ergocryptine, ergot, ergotamine, flumetasone acetate, fonadin, lisuride, lomerizine, methysergide oximoron, pizotyline and mixtures thereof.

The other therapeutic agent can also be adjuvant to reduce potential side effects, such as an antiemetic. Suitable anti-emetics include, but are not limited to, metoclopramide, domperidone, prochlorperazine, promethazine, chlorpromazine, timeoriented, ondansetron, granisetron, hydroxyzine, acetylacetonates, alizapride, azasetron, benchenane, batanouny, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, difenidol, dolasetron, meclizine, metallical, metopimazine, nabilone, oxybenzyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.

In some embodiments the embodiment of the compounds of this invention can be prepared in pharmaceutical dosage form in combination with β-adrenergic blockers. Suitable β-adrenergic blockers include, but are not limited to, acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, Bogomolov, buretrol, bufuralol, bunitrolol, bupranolol, baterina hydrochlorid, butoverall, carazolol, carteolol, carvedilol, celiprolol, atemolol, carnosol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, ngoxolo, nebivolol, neftaly, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sulfinol, talinolol, tertatolol, tilisolol, timolol, celiprolol and xianya.

In some embodiments the embodiment of the compounds of this invention can be prepared in pharmaceutical dosage form in combination with anticonvulsant drugs. Suitable anti-convulsants include, but are not limited to, acetylphenyl, albutein, aloxide, aminoglutetimid, 4-amino-3-hydroxybutiric acid, atrracted, reclamed, burlat, calcium bromide, carbamazepine, cinnamic, clomethiazole, clonazepam, decimated, dietition, limitation, doccentral, aerobars, Acadian, ethosuximide, ethotoin, felbamate, fluoresant, gabapentin, 5-hydroxy-tryptophane, lamotrigine, magnesium bromide, magnesium sulfate, mephenytoin, mephobarbital, metharbital, Meteon, methsuximide, 5-methyl-5-(3-phenanthrol)as, 3-methyl-5-phenylhydantoin, nachobarbero, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide, penetrometer, featured, phenobarbital, phensuximide, phenylmethylsulfonyl acid, phenytoin, sodium, patenet, potassium bromide, pregabalin, primidone, progabid, sodium bromide, Solanum, strontium bromide, with clopine, sultam, atlantain, tiagabine, topiramate, trimethadione, valproate acid, valpromide, vigabatrin and zonisamide.

In some embodiments the embodiment of the compounds of this invention can be prepared in pharmaceutical dosage form in combination with antidepressanta. Suitable antidepressant include, but are not limited to, bendalin, Caracazo, citalopram, deltason, fenomen, indalpine, indeloxazine hydrochloride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, tiazesim, trazodone, benmoxin, preclosed, iproniazid, isocarboxazid, nialamide, actimoxi, phenelzine, cotinine, railpen, rolipram, maprotiline, metralindol, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptyline, amoxapine, butriptyline, clomipramine, deoxidation, desipramine, dibenzepin, timetaken, dothiepin, doxepin, placesin, imipramine, imipramine N-oxide iprindole, lofepramine, melitracen, metabromine, nortriptyline, noxiptiline, opipramol, pizotyline, proposedin, protriptyline, minupren, tianeptine, trimipramine, adrafinil, benactyzine, bupropion, buttetin, dixital, DULOXETINE, etoperidone, debarbat, femoxetine, fenbendazol, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, levorotatory, modificatin, milnacipran, minupren, moclobemide, nefazodone, oxaprozin, piperalin, prolintane, perinuclear, ritanserin, roxindole, rubidium chloride, sulpirid, tandospirone, totaline, ciencin, tolocate is, tranilcipromin, L-tryptophan, venlafaxine, viloxazine and zimeldine.

In some embodiments the embodiment of the compounds of this invention can be prepared in pharmaceutical dosage form in combination with blockers of Ca2+channels. Suitable blockers of Ca2+channels include, but are not limited to, bepridil, clentiazem, diltiazem, fendilin, gallopamil, mibefradil, prenilamin, remotedir, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elhadidy, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipin, Cinnarizine, flunarizin, lidoflazine, lomerizine, bencyclane, athenon, fanfaron and perhexiline.

In some embodiments the embodiment of the compounds of this invention can be prepared in pharmaceutical dosage form in combination with anticancer agents. Suitable anti-cancer agents include, but are not limited to, acivicin; aclarubicin; Hakodate hydrochloride; Acronis; adozelesin; aldesleukin; altretamin; ambomycin; ametantrone acetate; aminoglutetimid; amsacrine; anastrozole; astromicin; asparaginase; aspirin; azacytidine; asettaa; azotomycin; batimastat; benzodepa; bikalutamid; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide;carbetimer; carboplatin; carmustine; karubitina hydrochloride; carzelesin; Cedeira; chlorambucil; cirolemycin; cisplatin; cladribine; Kristol mesilate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; decompletion; deazaguanine; deazaguanine mesilate; diazinon; docetaxel; doxorubicin, doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; deatomizer; edatrexate; eflornithine hydrochloride; elsamitrucin; anoplate; enpromate; epirubicin; epirubicin hydrochloride; arbolada; azorubine hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; atopen; fadrozole hydrochloride; fazarabine; phenetidine; floxuridine; fludarabine phosphate; fluorouracil; fluorocytosine; fashion; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubitsina hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II or rIL2), interferon alpha-2a; interferon Alfa-2b; interferon Alfa-n1; interferon Alfa-n3; interferon beta-Ia; interferon gamma-Ib; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustin; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; Matorin; matureup; maintain; metacart is n; mitotropin; mitogillin; mitomycin; mitomycin; mitosis; mitotane; mitoxantrone hydrochloride; mycophenolate acid; nocodazole; nogalamycin; ormaplatin; oxysure; paclitaxel; pegaspargase; polymycin; pentamycin; peplomycin sulfate; perforated; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomelin; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; ibuprin; reglated; safingol; safingol hydrochloride; semustine; contrast; sodium spartacat; sparsomycin; spirogermanium hydrochloride; spiramycin; spiroplatin; streptonigrin; streptozocin; alienor; talisayan; tecogen sodium; tegafur; Alexandrina hydrochloride; ]; teniposide; teraxion; testolactone; timipre; tioguanin; thiotepa; teatterin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulosa hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; wikpedia sulfate; singleseat sulfate; winnersin sulfate; vinorelbine tartrate; Vinpocetine sulfate; ventricina sulfate; vorozole; senility; zinostatin; zorubicin hydrochloride. Other antitumor agents include, but are not limited to: 20-EPI-1,25 dihydroxyvitamin D3; 5-itinerarary; abiraterone; aclarubicin; allpole; decibel; adozelesin; aldesleukin; antagonists ALL-TK; altretamin; ambamustine; amidax; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; Andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; entrelacs; anti-dorkalicious morphogenetic protein-1; antiandrogen, an anti-prostate carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; genetic modulators of apoptosis; regulators of apoptosis; apurinovaya acid; ara-CDP-DL-PTBA; argininosuccinate; Bulacan; atamestane; attemptin; achinstein 1; achinstein 2; 3 achinstein; azasetron; anatoxin; asteroid; derivatives baccatin III; balana; batimastat; BCR/ABL antagonists; benzocaine; benzoyltartaric; derivatives of beta-lactam beta-alamin; butaclamol In; Betulinol acid; an inhibitor of bFGF; bikalutamid; bisantrene; besuseradminclient; bisnafide; bitraten A; bizelesin; Brevet; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin; derivatives camptothecin; canarypox IL-2; capecitabine; carboxamidine; carboxamidates; Rest M3; CARN 700; inhibitor derived from cartilage; carzelesin; inhibitors caseinline (ICOS); castanospermine; cecropin; cetrorelix; chlorins; chloroquinoxaline the sulfonamide; cicaprost; CIS-porphyrin; cladribine; analogues clomiphene; clotrimazole; colimycin a; colimycin; combretastatin A4; analogues of combretastatin; convenin; kambezidis 816; Kristol; cryptophycin 8; produced by the water cryptophycin A; curacin a; cyclopentadecanone; cyclopean; cephamycin; tsitarabina ocfosfate; cytolytic factor; cytostatin; daclizumab; decitabine; dehydrodidemnin; deslorelin; dexamethasone; Taxifolin; dexrazoxane; dexverapamil; dietician; didemnin; detox; diethylnitrosamine; dihydro-5-azacytidine; dihydroxy, 9-; dioxazine; diphenylpyraline; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; elastin; edelfosine; edrecolomab; eflornithine; elements; Amateur; epirubicin; epristeride; similar estramustine; agonists of estrogen; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; phenetidine; filgrastim; finasteride; flavopiridol; fileselection; fluasterone; fludarabine; fluoroguanosine hydrochloride; forenames; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; Galitsin; ganirelix; inhibitors gelatinase; gemcitabine; inhibitors of glutathione; HaSulam; heregulin; hexamethylene biocetamol; hypericin; ibandronate acid; idarubitsin; idoxifene; Idamante; ilmofosine; ilomastat; imidazolidone; imagined; immunostimulating peptides; inhibitor of a receptor of insulin-like factor-1; interferon agonists; interferons; interleukins; iobenguane; iododeoxyuridine; ipomeanol, 4-; ireplace; irsogladine; isomerases; isohemagglutinins; fusetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; lanemile; lenograstim; tape is Nana sulfate; leptostachys; letrozole; factor, leukemia inhibitory; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leiprorelina; levamisole; lioresal; linear analogue polyamine; lipophilic disaccharide glycosides peptide; lipophilic platinum compounds; lissoclinum 7; lobaplatin; lubricin; lometrexol; lonidamine; losoxantrone; lovastatin; doxorubin; lurtotecan; Lutetia texaphyrin; lisofylline; lytic peptides; maytansine; sandostatin a; marimastat; masoprocol; maspin; inhibitors matrilysin; matrix inhibitors of metalloproteinases; menogaril; merbanan; peterlin; methionine; metoclopramide; inhibitor of MIF; mifepristone; miltefosine; Miramistin; mismatched double-stranded RNA; mitoguazone; mitolactol; analogues of mitomycin; mitonafide; mycotoxicosis the fibroblast growth factor-saporin; mitoxantrone; Maarten; molgramostim; monoclonal antibody, human chorionic of gonadotropin person; monophosphoryl lipid A+ myobacterial cell membrane preparation sk; mopidamol; inhibitor of gene resistance to many drugs; therapeutic tool of suppression of multiple tumors-1; mustard anticancer agent; megaproxy; extract mycobacterial cell membranes; mylapore; N-azetidinone; N-substituted benzamide; nafarelin; Agresti; naloxone+pentazocine; nipawin; Natterer; nartograstim; nedaplatin; nemorubicin; Nejdanov acid; neutral endopeptidase; nilutamide; Nizami is n; modulators of nitric oxide; nitroxide antioxidant; nitrolon; O6-benzylguanine; octreotide; okizeme; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral inducer of cytokines; ormaplatin; asteron; oxaliplatin; axiomized; paclitaxel; analogues of paclitaxel, derivatives of paclitaxel; palyulin; palmitoylation; pamidronate acid; panaxytriol; promife; pyrabactin; panelitem; pegaspargase; peltatin; pentosan polysulfate sodium; pentostatin; petrosal; perflubron; perforated; parallelly alcohol; fansinating; phenylacetate; inhibitors of phosphatase; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placedin A; placein; inhibitor of plasminogen activator; a complex of platinum; platinum compounds; complex platinum-triamine; sodium porfimer; porfiromycin; prednisone; propylbis-acridan; prostaglandin J2; proteasome inhibitors; immune modulator based on A protein; inhibitor of protein kinase C, inhibitors of protein kinase C, microalgal; inhibitors patientinitiated; inhibitors polynucleotides; purpurin; pyrazoloacridine; paradoxrecovery conjugate of hemoglobin-polyoxyethylene; antagonists raf; raltitrexed; ramosetron; inhibitors farnesyltransferase ras; ras inhibitors; inhibitors of ras-GAP; demetilirovanny reality; etidronate rhenium Re 186; rhizoxin; ribozymes; RII retinamide; reglated; rohitukine; romantic; rainmax; rubiginosa B1; robaxin; safingol; Shinto is in; SarCNU; sarcophyton A; sargramostim; mimetics Sdi 1; semustine; derived inhibitor 1 aging; sense oligonucleotides; inhibitors of signal transduction; modulators of signal transduction; single-chain protein binding antigen; sizofiran; sobuzoxane; borocaptate sodium; sodium phenylacetate; solvera; protein binding of somatomedin; sonarmen; sportsinfo acid; spicamycin D; spiramycin; splenopathy; spongistatin 1; shyalaman; inhibitor of stem cells; inhibitors of dividing stem cells; stipend; inhibitors stromelysin; sulfonation; super active vasoactive intestinal peptide antagonist; coralista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen-methodid; terramycin; tazarotene; ecogarantie; tegafur; tolerability; telomerase inhibitors; ]; temozolomide; teniposide; tetrachlorodecaoxide; tetrasomy; teleblaster; thiocoraline; thrombopoietin; mimetics thrombopoietin; thymalfasin; agonist receptor thymopoietin; timorian; thyroid stimulating hormone; atilola adipocere; tirapazamine; titanocene bichloride; topsentin; toremifene; prepotentials factor stem cells; inhibitors broadcast; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostin; inhibitors UBC; ubenimex; inhibitor urogenital sinus-growth factor; receptor antagonists urokinase; Vaprio the ID; variolin; vector system, erythrozyten therapy; valarezo; vermin; verdini; verteporfin; vinorelbine; Wincanton; vitaxin; vorozole; sonotron; senility; salaskar and zinostatin stimulater.

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

In the case of the introduction of the compounds of this invention is a mammal, for example, oral, parenteral or local path, you can use a dosage in the range from about 0.01 mg/kg to about 3000 mg/kg body weight of the patient per day, preferably from about 0.01 mg/kg to about 1000 mg/kg body weight per day, which is administered once or divided doses. However, the dosage must be changed depending on the weight and physical condition (e.g., liver and kidney) of the subject undergoing treatment, sufferings, severity of symptoms, the JV is soba introduction, frequency of dosing, the presence of any harmful side effects and, among other things, the specific connection.

The compounds of this invention preferably have a binding affinity of Kiin respect of the 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. The binding affinity of Kican be measured by the person skilled in the art by means of analysis using membranes from recombinant cells SOME 293 expressing the receptor, similar to the opioid receptors of the man, (ORL1), as described below.

The following examples illustrate various aspects of the present invention and in no way claim to be his limit.

Example 1

Synthesis of head groups benzoxazolone

Head of the group in accordance with this invention synthesized in accordance with the following method:

Method

To a mixture of compounds1(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 triacetoxyborohydride sodium (2,97 g, 14 mmol). The mixture was stirred at room temperature overnight. The mixture was filtered through celite and was added 1N NaOH (50 ml)to quench the reaction. The organic layer was separated and the aq is th layer was extracted with EtOAc (2 x 30 ml). The combined organic layers were dried over K2CO3, filtered and evaporated in vacuum to obtain compound3in a solid brown color (2,75 g, yield: 94%).

1H-NMR (CDCl3):d 1,20-1,60 (m, 11H), 2,00 (DD, 2H), 2,9 (m, 2H), 3,40 (m, 1H), 4.00 points (m, 2H), 6,60-6,85 (m, 4H).

It chilled with ice to a solution of the crude compound3(12.0 g, 40 mmol) and DIEA (20,8 ml, 120 mmol) in 200 ml THF solution was added triphosgene (4,32 g, 14.4 mmol) in 200 ml THF. After complete addition, the ice bath was removed and the mixture was stirred at room temperature overnight. The solids were filtered off and the filtrate evaporated in vacuum. The remaining brown oil was dissolved in EtOAc and washed with saturated aqueous K2CO3. The organic phase was dried over K2CO3, filtered and evaporated in vacuum to obtain a red oil which was filtered through a column of silica gel, elwira a mixture of 5% Et3N, 25% EtOAc and 70% hexane. Selected fractions were combined and the solvent evaporated in vacuum to obtain a brown solid, which was led from EtOAc to obtain pure compounds4(10.0 g, yield: 78%).

1H-NMR (CDCl3):d of 1.50 (s, 9H), of 1.85 (d, 2H, in), 2.25 (m, 2H), 2,85 (m, 2H), 4,20 is 4.45 (m, 3H), 7,00-7,25 (m, 4H).

A solution of compound4(4.0 g, and 17.2 mmol) in a mixture of 30% TFU/dichloromethane (25 ml) was stirred at room te is the temperature for 3 hours. The solvent is evaporated in vacuum and the oily residue was added a saturated aqueous solution of K2CO3. 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. Chromatography on silica gel with elution with a mixture of 10% Et3N, 60% EtOAc and 30% hexane gave compound5in a solid yellow color (1,82 g, yield: 66%).

MS: m/z 450

1H-NMR (CDCl3):d 1,75-2,10 (m, 3H), 2,30 (d, 2H), 2,80 (m, 2H), 3,20 (m, 2H), 4,25 (m, 1H), 7,00-7,25 (m, 4H).

Example 2

The accession of end groups

End groups attached to the head groups in accordance with the following methods:

The main method for alkylation:

To a solution of amine (1 EQ.) triethylamine (1 EQ.) in dimethylformamide one portion was added 1 EQ. allylbromide or chloride. The mixture was stirred and heated at 80°C during the night. TLC showed completion of reaction. The reaction was suppressed by the addition of water and then bringing the pH to 10 with 1N NaOH. The mixture was twice extracted with Et2O. the combined organic extracts were dried over potassium carbonate and the solvent is evaporated, followed by chromatography was obtained pure product.

The main method on the I reductive amination:

To a mixture of ketone or aldehyde (1 EQ.), amine (1 EQ.) and acetic acid (1 EQ.) in methanol to one portion was added cyanoborohydride sodium (1.4 EQ.). The mixture was stirred at room temperature overnight. TLC showed completion of reaction. The reaction was suppressed by the addition of water and then bringing the pH to 10 with 1N NaOH. The mixture was twice extracted with Et2O. the combined organic extracts were dried over potassium carbonate and the solvent is evaporated, followed by chromatography was obtained pure product.

The following compounds were obtained by the joining of end groups, using the described basic methods:

3-[1-(naphthas-2-ylmethyl)-4-piperidinyl]-2H-benzoxazol-2-he

3-[1-(naphthas-1-ylmethyl)-4-piperidinyl]-2H-benzoxazol-2-he

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

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

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

MS: m/z 334,4 (M+1)

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

3-[1-[4,4-bis-(4-forfinal)butyl]-4-piperidinyl]-2H-benzoxazol-2-he

MS: m/z 463,6 (M+1)

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

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

LC: 100%

MS: m/z 343,6 (M+1)

1H-NMR (CDCl3):d 1,25 (m, 2H), 1,40-1,7 (m, 17H), 2,10 (m, 4H), 3,10 (m, 2H), 4,20 (m, 1H), 7,10-7,20 (4H).

13C-NMR (CDCl3):d to 26.02, 26,87, 27,55, 9,27, 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-he

LC: 100%

MS: m/z 349,6 (M+1)

1H-NMR (CDCl3):d to 1.70 (m, 1H), 2,00 (width, 2H), 2,10 (width, 1H), 2.40 a (m, 4H), 2,90 (m, 5H), 3,10 (m, 2H), 4,20 (m, 1H), 7,10-7,30 (m, 8H).

3-[1-(5-metrex-2-yl)-4-piperidinyl]-2H-benzoxazol-2-he

LC: 100%

MS: m/z 317,4 (M+1)

1H-NMR (CDCl3):d of 0.90 (d, 6H), and 1.00 (d, 3H), of 1.20 (m, 3H), 1,50-1,60 (m, 4H), of 1.80 (m, 2H), 2,20-2,60 (m, 5H), 2,90 (width, 2H), 4,2 (m, 1H), 6.90 to-7,30 (m, 4H).

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

LC: 96,4%

1H-NMR (CDCl3):d of 1.80 (DD, 2H), 2,00 (dt, 2H), 2,30 (DQC, 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-propylcyclohexyl)-4-piperidinyl]-2H-benzoxazol-2-he

MS: m/z 343,0

3-[1-(norbornane-2-yl)-4-piperidinyl]-2H-benzoxazol-2-he

LC: 97%

MS: m/z 313,41 (M+1)

1H-NMR (CDCl3):d 0,90 (m, 1H), 1.30 and of 2.50 (m, 17H), 3,20 (m, 2H), 4,3 (m, 1H), 6.90 to-7,30 (m, 4H).

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

MS: m/z 355,4

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

MS: m/z 401,3

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

MS: m/z 343,0

3-[1-(1,3-dihydroindol-2-yl)-4-piperidinyl]-2H-benzoxazol-2-he

LC: 100%

MS: m/z 335,4 (M+1)

1H-NMR (CDCl3):d 1,90 (m, 1H), 2.40 a (m, 2H), 2,50 (m, 2H), 2,90 (m, 2H), 3,10 is 3.40 (m, 6H), 4,20 (m, 1H), 7,10-7,30 (m, 8H).

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

LC: 100%

MS: m/z 329,2 (M+1)

1H-NMR (CDCl3):d 1,40-2,00 (m, 16H), 2,40-to 2.65 (m, 4H), 2,80 (m, 1H), 3,05 (m, 2H), 4,25 (m, 1H), 7,10-7,40 (m, 4H).

Other compounds covered by formula (I) or (IA) of this invention can be synthesized by similar methods.

Example 3

The affinity against nociceptin on the ORL1 receptor for the preferred compounds was determined using the following analysis:

Membranes of recombinant cells SOME 293 expressing the receptor, similar to the opioid receptors of the man, (ORL1), (Receptor Biology), was obtained by lizirovania cells in ice hypotonic buffer (2.5 mm MgCl2, 50 mm HEPES, pH 7.4) (10 ml/10 cm Petri dish) followed by homogenization using a homogenizer fabric/Teflon pestle. Membranes were collected by centrifugation at 30,000 x g for 15 min at 4°C and the precipitate after centrifugation resuspendable in hypotonic buffer to a final concentration of 1-3 mg/ml protein Concentration was determined using the reagent for analysis BioRad protein with bovine serum albumin as standard. Aliquots of membrane receptor ORL1 kept at -80°C.

Analyses of functional binding SGTPgS was carried out as follows. The solution membranes ORL1 received sequential addition of final concentration of 0.066 mg/ml membrane protein ORL1, 10 mg/ml saponin, 3 mm GDP and 20 nm [ 35S]GTPgS to binding buffer (100 mm NaCl, 10 mm MgCl2, 20 mm HEPES, pH 7.4) on ice. These membrane solution (190 ml/well) was transferred into a 96-well polypropylene tablets containing 10 ml of 20x concentrated source solutions agonist obtained in DMSO. The plates were incubated for 30 min at room temperature with shaking. The reaction was interrupted by rapid filtration onto 96-well filter tablets Unifilter GF/B, Packard) using a 96-well harvester tissue (Brandel), followed by three filtration washes with 200 ml chilled on ice binding buffer (10 mm NaH2PO4, 10 mm Na2HPO4, pH 7.4). Filter plates were then dried at 50°C for 2-3 hours. Added fifty ml/well scintillation cocktail account (BetaScint; Wallac) and tablets read in a Packard Top-Count for 1 min/well.

Data were analyzed using a curve approximation of functional dependence in GraphPad PRISMO, v.3.0, and the results are presented in table 1 below:

TABLE 1
The affinity against nociceptin
Connectionwyciski(nm)
3-[1-(naphthas-2-ylmethyl)-4-piperidinyl]-2H-benzox the evils-2-he 3030
3-[1-(naphthas-1-ylmethyl)-4-piperidinyl]-2H-benzoxazol-2-he370
3-[1-(p-phenylbenzyl)-4-piperidinyl]-2H-benzoxazol-2-he>10000
3-[1-(p-benzyloxybenzyl)-4-piperidinyl]-2H-benzoxazol-2-he2173
3-[1-(p-cyanobenzyl)-4-piperidinyl]-2H-benzoxazol-2-he>10000
3-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2H-benzoxazol-2-he726
3-[1-[4,4-bis-(4-forfinal)butyl]-4-piperidinyl]-2H-benzoxazol-2-he3070
3-[1-(2-phenylethyl)-4-piperidinyl]-2H-benzoxazol-2-he7087
3-[1-(cyclooctylmethyl)-4-piperidinyl]-2H-benzoxazol-2-he64
3-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-2H-benzoxazol-2-he93
3-[1-(5-metrex-2-yl)-4-piperidinyl]-2H-benzoxazol-2-he60
3-[1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-4-piperidinyl]-2H-benzoxazol-2-he >10000
3-[1-(3,3-dimethyl-1,5-dioxaspiro[5,5]undeca-9-yl)-4-piperidinyl]-2H-benzoxazol-2-he>10000
3-[1-(1,3-dihydroindol-2-yl)-4-piperidinyl]-2H-benzoxazol-2-he512
3-[1-(cyclooctyl)-4-piperidinyl]-2H-benzoxazol-2-he16

Example 4

The SYNTHESIS of SUBSTITUTED INDOLE HEAD GROUPS

Method

To a mixture of compounds2(23.3 g, 0.25 mol),1(43,7 g, 0.25 mol), acetic acid (15 g, 0.25 mol) and molecular sieves (15 g) in 500 ml of dichloroethane was added to one portion of triacetoxyborohydride sodium (74,2 g, 0.35 mol) and the mixture was stirred over night. The molecular sieve was filtered and was added 1N NaOH (500 ml)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 K2CO3was filtered and the solvent evaporated in vacuum to obtain crude compound3in a solid brown color, which is directly used in the next stage.

Connection 3

1H-NMR (CDCl3):d 1,50 (m, 2H), 2.05 is (m, 2H), 2,20 (shirt, 2H), 285 (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).

It chilled with ice to a solution of the crude compound3(0.25 mol, estimated yield 100%) and DIEA (48,4 g, 0.38 mol) in 500 ml of dichloromethane was added dropwise a solution of chloroacetaldehyde (42,4 g, the 0.375 mol). After complete addition, the ice bath was removed and the reaction mixture was stirred over night. The solvent was removed in vacuum and the residue was dissolved in dichloromethane. The organic phase was washed with saturated aqueous K2CO3, dried over2CO3was filtered and the solvent was removed in vacuum to obtain a brown resin, which was filtered through a column of silica gel, elwira a mixture of 10% Et3N, 40% EtOAc and 50% hexane. Selected fractions were combined and the solvent evaporated in vacuum to obtain a brown solid, which was led from EtOAc with getting to 42.2 g of compound4(49,2%, stage 2).

Connection 4

1H-NMR (DMSO): d 1,22 (m, 2H), 1.70 to (width, 2H), 2.00 in (t, 2H), 2,80 (width, 2H), 3,40 (s, 2H), 3,80 (s, 2H), and 4.40 (m, 1H), 7,15-7,30 (m, 7H), was 7.45 (m, 3H).

A mixture of compound4(42.2 g, 0.12 mol) and AlCl3(49.2 g, 0,369 mol) were mixed in the flask with rapid stirring. The mixture then was heated on an oil bath at 130°C. for several minutes, the solids were melted and became a dark liquid, which was accompanied by evolution of gas. After on the rewane for 1 hour, the reaction mixture was slightly cooled and, while she was still mobile, poured in chemical beaker containing 500 ml of ice water. The solution was podslushivaet and was extracted with dichloromethane. The organic layer was dried over Na2SO4was filtered and the solvent evaporated in vacuum to obtain a dark oil which was filtered through a column of silica gel, elwira a mixture of 10% Et3N, 40% EtOAc and 50% hexane. Selected fractions were combined and the solvent evaporated in vacuum to obtain compound5in the form of a red oil, which when cured has turned into a solid pale color (22,0 g, 58.5 per cent).

Connection 5

1H-NMR (CDCl3):d to 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 compound5(16.0 g, 0,052 mol) in 35 ml of methanol was added Pd(OH)2(4.0 g). The resulting suspension was first made at 50 psi for 12 hours at room temperature. The solution was filtered through a layer of celite and layer washed with methanol (2 x 20 ml). Evaporation of the solvent in vacuo gave compound6in a solid pale color (11.2 g, 100%).

Connection 6

LC: 100%

MS: m/z 217 (M+1).

1H-NMR (CDCl3):d to 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 compound6(8.0 g, 37,0 mmol) in 50 ml dichloromethane was added Et3N (4,07 g of 40.7 mmol) and BOC anger is d (8,87 g, 40,7 mmol). After stirring for 3 hours was added saturated aqueous K2CO3and 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 vacuum to obtain a brown oil, which was filtered through a column of silica gel, elwira a mixture of 10% Et3N, 40% EtOAc and 50% hexane. Selected fractions were combined and the solvent evaporated in vacuum to obtain compound7as not quite white solid (8,50 g, 73%).

Connection 7

1H-NMR (CDCl3):d 1,50 (m, 9H), to 1.70 (m, 2H), 2,20-of 2.50 (m, 2H), 2,80-3,00 (m, 2H), 3,50 (s, 2H), 4,20-4,50 (m, 3H), 6.90 to-7,60 (m, 5H).

To a mixture of compound7(6.0 g, 19.0 mmol) and sodium acetate (2.58 g, 19.0 mmol) in 150 ml of methanol was added acetaldehyde (1,67 g, 38 mmol). The mixture was boiled under reflux for 2 hours. The solvent is evaporated in vacuum to obtain a dark oil which was filtered through a column of silica gel, elwira a mixture of 10% Et3N, 40% EtOAc and 50% hexane. Selected fractions were combined and the solvent evaporated in vacuum to obtain compound8as a red oil (5,90 g, 91%).

Compound 8

LC: 2 isomers in a 2:1 ratio.

1H-NMR (CDCl3): (mixture of 2 isomers) d 1,50 (m, 9H), to 1.70 (m, 2H), 2,20-of 2.50 (m, 6H), 2,60-3,00 (m, 2H), 4,20-4,50 (m, 3H), 6.90 to-7,60 (m, 5H).

The solution is unity 8(5,90 g, and 17.2 mmol) in a mixture of 30% TFU/dichloromethane (100 ml) was stirred at room temperature for 3 hours. The solvent is evaporated in vacuum and the oily residue was added saturated aqueous K2CO3. The resulting mixture was extracted with dichloromethane (3 x 150 ml). The combined organic extracts were dried over K2CO3, filtered and evaporated in vacuo to obtain the crude product. Chromatography on silica gel with elution with a mixture of 10% Et3N, 50% EtOAc and 40% hexane gave compound9(E/Z isomers) as a yellow foam (of 3.60 g, 82%).

Connection 9

LC: 2 isomers in a 2:1 ratio.

MS: m/z 243,1 (M+1).

1H-NMR (CDCl3): (mixture of 2 isomers) d of 0.85 (m, 1H), 1,50-2,00 (m, 4H), 2,20-of 2.50 (m, 5H), 2,60 (m, 1H), 3,10-to 3.50 (m, 2H), 4,30 (m, 1H), 6.90 to-7,60 (m, 5H).

Example 5

To a mixture of compound5(5.50 g, 18 mmol) and sodium acetate (2,45 g, 18 mmol) in 150 ml of methanol was added acetaldehyde (1,58 g, 36 mmol). The mixture was boiled under reflux for 2 hours. The solvent is evaporated in vacuum to obtain a dark oil which was filtered through a column of silica gel, elwira a mixture of 10% Et3N, 40% EtOAc and 50% hexane. Selected fractions were combined and the solvent evaporated in vacuum to obtain compound10as a red oil (5,90 g, 98%).

Connection 10

LC: 2 isomers a 2:1 ratio.

MS: m/z 333,2 (M+1)

1H-NMR (CDCl3):d to 1.70 (m, 2H), 2,17 (m, 2H), 2,30 (d, 3H), of 2.50 (m, 2H), 3,05 (m, 2H), 3,55 (s, 2H), 4,33 (m, 1H), 7,00-7,40 (m, 9H), and 7.6 (d, 1H).

To a solution of compound10(5,90 g of 17.7 mmol) in 30 ml of methanol was added Pd(OH)2(3.0 g). The resulting suspension was first made at 50 psi for 12 hours at room temperature. The solution was filtered through a layer of celite and layer washed with methanol (2 x 20 ml). Evaporation of the solvent in vacuo gave a solid pale color, which was purified by chromatography on silica gel, elwira a mixture of 10% methanol and 90% EtOAc, to obtain the connection11as not quite white solid (2,02 g, 50%).

Connection 11

LC: 97%

MS: m/z 245,2 (M+1)

1H-NMR (CDCl3):d of 0.85 (t, 3H), 1.26 in (m, 2H), 2,00 (m, 2H), 2,43 (m, 2H), 2,90 (m, 2H), 3,3 (m, 2H), 3,4 (m, 1H), 4,4 (m, 1H), 7,05 (m, 1H), 7,15-7,30 (m, 3H).

Example 6

Method

Connection16was obtained in a manner analogous to the connection6.

Connection 13

LC: 89,4%

MS: m/z 281,2 (M+1)

1H-NMR (mixture of TRANS and CIS)(CDCl3):d of 0.95 (m, 3H), 1,50 is 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-to 6.80 (m, 2H), 7,05 was 7.45 (m, 8H).

The connection 14

MS: m/z 357,2 (M+1)

1H-NMR (mixture of TRANS and CIS)(CDCl3):d of 1.10 (m, 3H), 1,40-4,20 (m, 11H), and 4.40 (m, 1H), 7,05 is 7.50 (m, 10H).

The connection 15

LC: 90,0%

What: m/z 321,2 (M+1)

1H-NMR (CDCl3):d of 1.20 (d, 3H), of 1.75 (m, 1H), 2,10 (dt, 1H), 2,25 (width, 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 percent (m, 3H), 7,37 (m, 4H).

The connection 16

LC: 92,5%

MS: m/z 231,2 (M+1)

1H-NMR (CDCl3):d d of 1.20 (d, 3H), of 1.75 (m, 1H), 2,10 (dt, 1H), 2,25 (width, 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 percent (m, 3H), 7,37 (m, 4H).

Example 7

Method

Connection18was obtained in a manner analogous to the connection11.

Connection 17

MS: m/z 347,3 (M+1)

The connection 18

LC: 82,6%

MS: m/z 259,3 (M+1)

1H-NMR (CDCl3):d of 0.80 (t, 3H), of 1.20 (d, 3H), 2,00 (m, 2H), 2,30 (m, 1H), 2,65 (m, 1H), 2,82 (m, 1H), 3.15 and is 3.25 (m, 1H), 3,32 (m, 1H), of 3.45 (m, 1H), 3,65 (m, 1H, in), 3.75 (m, 1H), 4,25 (m, 1H), 6.90 to (d, 1H), 7,05 (t, 1H), 7,25 (m, 2H).

Example 8

The accession of end groups

End groups attached to the head groups in accordance with the following methods:

The main method for alkylation:

To a solution of amine (1 EQ.) triethylamine (1 EQ.) in dimethylformamide one portion was added 1 EQ. allylbromide or chloride. The mixture was stirred and heated at 80°C during the night. TLC showed completion of reaction. The reaction was suppressed by the addition of water and then bringing the pH to 10 with 1N NaOH. The mixture was twice extracted with Et2Acting United the content of inorganic fillers extracts were dried over potassium carbonate and the solvent is evaporated, subsequent chromatography was obtained pure product.

The main method for reductive amination:

To a mixture of ketone or aldehyde (1 EQ.), amine (1 EQ.) and acetic acid (1 EQ.) in methanol to one portion was added cyanoborohydride sodium (1.4 EQ.). The mixture was stirred at room temperature overnight. TLC showed completion of reaction. The reaction was suppressed by the addition of water and then bringing the pH to 10 with 1N NaOH. The mixture was twice extracted with Et2O. the combined organic extracts were dried over potassium carbonate and the solvent is evaporated, followed by chromatography was obtained pure product.

The following compounds were obtained by the joining of end groups, using the described basic methods:

1-[1-(naphthas-1-ylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he

MS: m/z 357,2 (M+1)

1-[1-(naphthas-2-ylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he

MS: m/z 357,3 (M+1)

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

MS: m/z 383,2 (M+1)

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

LC: 98,7%

MS: m/z 411,2 (M+1)

1H-NMR (CDCl3):d 1,65 (shirt, 2H), 2.05 is (shirt, 2H), 2,30 (m, 4H), of 2.45 (m, 2H), 3,02 (shirt, 2H), 3,50 (s, 2H), 4,01 (t, 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-he

MS: m/z 332,2 (M+1)

1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-1,3-dihydro-2H-in the ol-2-he

MS: m/z 413,3 (M+1)

1-[1-(1,2,3,4-tetrahydronaphtyl-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he

LC: 100%

MS: m/z to 347.5 (M+1).

1H-NMR (CDCl3):d to 1.70 (m, 3H), 2,10 (m, 1H), 2.40 a (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-metrex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he

LC: 100%

MS: m/z 315,4 (M+1).

1H-NMR (CDCl3):d of 0.90 (m, 6H), and 1.00 (m, 3H), of 1.20 (m, 3H), 1.5 and 1.8 (m, 2H), 2,2-2,6 (m, 5H), 2,90 (m, 2H), 3,60 (s, 2H), 4,2 (m, 1H), 6.90 to-7,30 (m, 4H).

1-[1-(norbornane-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he

LC: 97%

MS: m/z 311,41 (M+1).

1H-NMR (CDCl3):d 0,90 (m, 1H), 1.30 and a 2.00 (m, 7H), 2,10-of 2.30 (m, 5H), 3,20 (m, 2H), 3,60 (s, 2H), 4,3 (m, 1H), 6.90 to-7,30 (m, 4H).

1-[1-(1,3-dihydroindol-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he

LC: 100%

MS: m/z 332,4 (M+1).

1H-NMR (CDCl3):1,80 d (m, 2H), 2.40 a (m, 2H), 2,50 (m, 2H), 2,90 (m, 2H), 3,10 is 3.40 (m, 5H), of 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-he

LC: 97%

MS: m/z 341,50 (M+1).

1H-NMR (CDCl3):d 1,25 (m, 3H), 1,4-1,7 (m, 14H), 2,10 (m, 4H), of 2.50 (m, 2H), 3,10 (m, 2H), 3,60 (s, 2H), 4,3 (m, 1H), 7,10-7,20 (m, 4H).

13C-NMR (CDCl3):d 23,07, 26,04, 26,89, 27,56, 28,63, 31,27, 32,00, 35,30, 36,33, 46,63, 50,65, 54,06, 66,47, 110,90, 122,17, 124,90, 125,26, 127,94, 144,25, 175,31.

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

MS: m/z 375,3 (M+1).

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

MS: m/z 369,2 (M+1).

3-ethyl-1-[1-(5-metrex-2-yl)-4-piperidinyl]-1,3-dig the DRO-2H-indol-2-he

LC: 100%

MS: m/z 342,4 (M+1).

1H-NMR (CDCl3):d of 0.80 (t, 3H), of 0.90 (m, 6H), and 1.00 (m, 3H), of 1.20 (m, 3H), 1.5 and 1.8 (m, 2H), 2,2-2,6 (m, 5H), 2,90 (m, 2H), 3,40 (m, 1H), 4,3 (m, 1H), 6.90 to-7,30 (m, 4H).

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

LC: 100%

MS: m/z 339,41 (M+1).

1H-NMR (CDCl3):d 0,80 (m, 3H), of 0.90 (m, 1H), 1,30-1,45 (m, 5H), 1,50-2,05 (m, 8H), 2,10 (m, 1H), measuring 2.20 (m, 2H), 2,50 (m, 2H), 3,10 (m, 2H), 3,40 (m, 1H), 4,3 (m, 1H), 6.90 to-7,30 (m, 4H).

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

MS: m/z 381,3 (M+1).

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

MS: m/z 369,3 (M+1)

1H-NMR (CDCl3):d to 0.88 (t, 3H), of 0.92 (d, 6H), 1,17 (m, 1H), 1,40 (m, 2H), 1,50-1,70 (m, 9H), was 2.05 (m, 2H, in), 2.25 (m, 2H), 2,32 is 2.55 (m, 3H), 3.15 in (lat., 2H), 3.43 points (t, 1H), 4,35 (m, 1H), 7,05 (t, 1H), 7,22 (d, 1H), 7,28 (m, 2H).

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

MS: m/z 361,2 (M+1)

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

LC: 97%

MS: m/z 369,50 (M+1)

1H-NMR (CDCl3):d of 0.80 (t, 3H), 1,25 (m, 3H), 1,4-1,7 (m, 14H), 2,10 (m, 6H), of 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-he

MS: m/z 333,2 (M+1)

1H-NMR (CDCl3):d to 1.70 (m, 2H), 2,15 (dt, 2H), 2,28 (d, 3H), 2,47 (m, 2H), 3,05 (width, 2H), only 3.57 (s, 2H), 4,34 (m, 1H), 7,02 (t, 1H), 7,08-7,40 (m, 8H), 7,58 (d, 1H).

3-ethylidene-1-[1-(naphthas-2-ylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he

MS: m/z 405,2

3-ethylidene-1-[1-(3,3-diphenylpropyl)-4-piperidin the yl]-1,3-dihydro-2H-indol-2-he

LC: >97% (2 isomers together)

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-he

LC: >97% (2 isomers together)

MS: m/z 358,5 (M+1)

1H-NMR (CDCl3):1,80 d (m, 4H), 2,10-2,60 (m, 5H), 3,10 (m, 2H), 3,70 (s, 2H), 4,3 (m, 1H), 6.90 to-7,60 (m, 8H).

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

MS: m/z 405,2

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

LC: >97% (2 isomers together)

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-he

LC: >97% (2 isomers together)

MS: m/z 367,5 (M+1)

1H-NMR (CDCl3):d 0,90 (m, 1H), 1.30 and a 2.00 (m, 7H), 2,10-of 2.30 (m, 5H), 3,20 (m, 2H), 3,60 (s, 2H), 4,3 (m, 1H), 6.90 to-7,30 (m, 5H).

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

LC: >97% (2 isomers together)

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 to-7,30 (m, 5H).

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

LC: >97% (2 isomers together)

MS: m/z 337,41 (M+1)

1H-NMR (CDCl3):d 0,90 (m, 1H), 1.30 and of 2.50 (m, 17H), 3,10 (m, 2H), 4,3 (m, 1H), 6.90 to-7,30 (m, 5H).

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

LC: >97% (2 isomers together)

p> MS: m/z 359,4 (M+1)

1H-NMR (CDCl3):1,80 d-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-he

LC: >97% (2 isomers together)

MS: m/z 367,50 (M+1)

1H-NMR (CDCl3):d 1,25 (m, 3H), 1,4-1,7 (m, 21H), 2,10-of 2.50 (m, 2H), 3,10 (m, 2H), 4,3 (m, 1H), 6.90 to-7,60 (m, 5H).

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

LC: 100%

MS: m/z 425,3 (M+1)

1H-NMR (CDCl3):d of 1.20 (d, 3H), 1.69 in (shirt, 1H), 1,95 (dt, 1H), 2,13-of 2.30 (m, 5H), 2,72 (shirt, 1H), 2,98 (shirt, 1H), 3.15 in (DQC, 1H), 3,50 (s, 2H), a 4.03 (dt, 1H), 4,12 (t, 1H), 6,94 (d, 1H), 7,00 (t, 1H), 7,10-7,30 (m, 12H).

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

LC: 100%

MS: m/z 321,2 (M+1)

1H-NMR (CDCl3):d of 1.20 (d, 3H), of 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 (DQC, 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-he

LC: 96,2%

MS: m/z 355,2 (M+1)

1H-NMR (CDCl3):d of 0.85 (m, 3H)and 1.15 (m, 3H), 1,22-of 1.85 (m, 13H), 2,05-2,90 (m, 6H), 2.95 and-3,20 (m, 2H), 3,50 (s, 2H), of 4.05 (m, 1H), 7,00 (m, 2H), 7,22 (m, 2H).

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

LC: 100%

MS: m/z 329,2 (M+1)

1H-NMR (CDCl3):d of 0.85 (m, 9H)and 1.15 (m, 3H), 1,20-of 1.75 (m, 6H), of 2.25 (m, 1H), 2,45 is 2.75 (m, 4H), 2,88 (m, 1H), 3,10 (m, 1H), 3,50 (s, 2H), of 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-he

LC: 95.3%of the

MS: m/z 367,2 (M+1)

1N the Mrs (CDCl 3):d is 1.11 (d, 3H), 1,16-of 1.85 (m, 16H), of 2.20 (m, 1H), 2,35 (m, 2H), 2,52 (m, 2H), 2,75 (m, 1H), to 3.02 (m, 2H), 3,50 (s, 2H), of 4.05 (m, 1H), of 6.96 (m, 2H), 7,20 (m, 2H).

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

LC: 96,1%

MS: m/z 355,2 (M+1)

1H-NMR (CDCl3):d of 0.80 (m, 6H)and 1.15 (m, 3H), 1,22 is 1.48 (m, 3H), 1,50-1,90 (m, 6H), 2,15-2,90 (m, 4H), 2.95 and is 3.25 (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-he

LC: 100%

MS: m/z 355,2 (M+1)

1H-NMR (CDCl3):d of 1.12 (d, 3H), 1,15-of 1.75 (m, 16H), 1,92 is 2.10 (m, 3H), of 2.20 (m, 2H), 2,73 (m, 1H), 3,00 (m, 1H), 3,12 (DQC, 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-he

LC: 96,3%

MS: m/z 453,3 (M+1)

1H-NMR (CDCl3):d (two t, 3H), of 1.18 (d, 3H), of 1.70 (m, 1H), 1,90-2,05 (m, 3H), 2,12-of 2.30 (m, 5H), 7,73 (m, 1H), 2,97 (shirt, 1H), 3,10-3,30 (m, 1H), 3,38 (t, 1H), 3,90-of 4.05 (m, 1H), 4,12 (kV, 1H), 6.90 to-7,00 (two d, 1H), 7,02 (t, 1H), 7,12-to 7.32 (m, 12H).

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

LC: 93,2%

MS: m/z 383,3 (M+1)

1H-NMR (CDCl3):d 0,75-0,95 (m, 6H), 1,05-1,20 (m, 5H), of 1.20 and 1.35 (m, 4H), of 1.35 and 1.75 (m, 6H), 1,75-1,90 (m, 2H), 1,95-2,05 (m, 2H), of 2.15-2.45 (m, 3H), by 2.55 (d, 0,5H), 2,75 (d, 0,5H), 2.95 and is 3.15 (m, 2H), 3,38 (t, 1H), 3,90-4,10 (m, 1H), 6.90 to-7,05 (2H), 7,20-7,25 (m, 2H).

3-ethyl-1-[1-(5-metrex-2-yl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he

LC: 92,3%

MS: m/z 357,4 (M+1)

1H-NMR (CDCl3):d 0,75-0,95 (m, 10H), 1,10 (d, 3H), 1,15-of 1.40 (m, 3H), 1,40 is 1.75 (m, 4H), 1,97 is 2.10 (m, 2H), measuring 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 to-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-he

LC: 94,7%

MS: m/z 383,4 (M+1)

1H-NMR (CDCl3):d of 0.75 to 1.05 (m, 8H), 1,10-1,50 (m, 7H), 1,50-1,90 (m, 7H), 1,90-2,10 (m, 2H), 2,15 is 2.43 (m, 3H), by 2.55 (d, 0,5H), 2,75 (d, 0,5H), 2,90-of 3.25 (m, 3H), 3,40 (t, 1H), 3,90-4,10 (m, 1H), 6.90 to-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-he

LC: 94,3%

MS: m/z 395,3 (M+1)

1H-NMR (CDCl3):d 1,75-1,90 (two t, 3H), 1,10 (d, 3H), 1,15-1,90 (m, 15H), from 2.00 (m, 2H), 2,20 (Sirs, 1H), 2.40 a (m, 2H), 2,45-2,60 (m, 2H), 2,75 (m, 1H), 2,90-3,20 (m, 2H), 3,40 (Sirs, 1H), 3,90-to 4.15 (m, 1H), 6.90 to-7,05 (m, 2H), 7,25 (m, 2H).

Other compounds covered by formula (II) or (IIA) of the present invention, can be synthesized by similar methods.

Example 9

The affinity against nociceptin on the ORL1 receptor for the preferred compounds was determined using the following analysis:

Membranes of recombinant cells SOME 293 expressing the receptor, similar to the opioid receptors of the man, (ORL1), (Receptor Biology), was obtained by lizirovania cells in ice hypotonic buffer (2.5 mm MgCl2, 50 mm HEPES, pH 7.4) (10 ml/10 cm Cup) followed by homogenization using a homogenizer fabric/Teflon pestle. Membranes were collected by centrifugation at 30,000 x g for 15 min at 4°C and the precipitate after centrifuge the Finance resuspendable in hypotonic buffer to a final concentration of 1-3 mg/ml Protein concentration was determined using the reagent for analysis BioRad protein with bovine serum albumin as standard. Aliquots of membrane receptor ORL1 kept at -80°C.

Analyses of functional binding SGTPgS was carried out as follows. Membrane solution ORL1 received sequential addition of final concentration of 0.066 mg/ml membrane protein ORL1, 10 mg/ml saponin, 3 mm GDP and 0.20 nm [35S]GTPgS to binding buffer (100 mm NaCl, 10 mm MgCl2, 20 mm HEPES, pH 7.4) on ice. These membrane solution (190 ml/well) was transferred into a 96-well polypropylene tablets containing 10 ml of 20x concentrated source solutions agonist obtained in DMSO. The plates were incubated for 30 min at room temperature with shaking. The reaction was interrupted by rapid filtration onto 96-well filter tablets Unifilter GF/B, Packard) using a 96-well harvester tissue (Brandel), followed by three filtration washes with 200 ml chilled on ice binding buffer (10 mm NaH2PO4, 10 mm Na2HPO4, pH 7.4). Filter plates successively dried at 50°C for 2-3 hours. Added fifty ml/well scintillation cocktail account (BetaScint; Wallac) and tablets read in a Packard Top-Count for 1 min/well.

Data were analyzed using approximatively functional dependencies in GraphPad PRISMO, v.3.0, and the results are presented in table 2 below:

TABLE 2
The affinity against nociceptin
Connectionwyciski(nm)
3-ethylidene-1-[1-(5-metrex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he11,1
3-ethylidene-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he19
3-ethylidene-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he16,7
3-ethylidene-1-[1-(1,3-dihydroindol-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he20,7
3-ethylidene-1-[1-(naphthas-2-ylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he630
3-ethylidene-1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he516
3-ethylidene-1-[1-(benzyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he1854
3-ethylidene-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he 22,3
3-ethylidene-1-[1-(3,3-diphenylpropyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he100,7
3-ethylidene-1-[1-(norbornane-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he922
3-ethylidene-1-[1-(p-cyanobenzyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he7652
3-ethyl-1-[1-(5-metrex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he4
3-ethyl-1-[1-[4-(1-methylethyl)cyclohexyl]-4-piperidinyl]-1,3-dihydro-2H-indol-2-he0,86
3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he40
3-ethyl-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he124
3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he3,6
3-ethyl-1-[1-(1,3-dihydroindol-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he43
3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he
3-ethyl-1-[1-(norbornane-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he82,7
1-[1-(naphthas-1-ylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he92
1-[1-(naphthas-2-ylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he107
1-[1-(p-phenylbenzyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he1362
1-[1-(3,3-bis(phenyl)propyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he12,5
1-[1-(p-cyanobenzyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he1267
1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he32
1-[1-(1,2,3,4-tetrahydronaphtyl-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he28,7
1-[1-(5-metrex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he7,4
1-[1-(norbornane-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he215
1-[1-(1,3-dihydroindol-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he 18,7
1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he54,3
1-[1-(benzyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he>10000
1-[1-(4-propylcyclohexyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he2435
1-[1-(5-metrex-2-yl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he4335
1-[1-(decahydro-2-naphthyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he366
1-[1-(4-(1-methylethyl)cyclohexyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he167
1-[1-(cyclooctylmethyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he189

Example 10

Synthesis of some head groups

Scheme 1:

Method

To a mixture of compound4(to 21.6 g, 0.2 mol), compound5(15.6 g, 0.1 mol), acetic acid (6 g, 0.1 mol) in 500 ml of dichloromethane to one portion was added to 29.7 g triacetoxyborohydride sodium (0.14 mol, 1.4 EQ.). The evolution of gas occurred in the interval between 30 minutes and 1 hour. A mixture of AC is stirred over night. TLC showed completion of reaction. Added 1N NaOH (500 ml)to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (300 ml x 2). The combined organic substance is dried over potassium carbonate and the solvent evaporated to obtain a red oil which was filtered through a column (5% Et3N, 25% EtOAc and 70% hexane) to give 14 g of the product6in the form of a white solid (54%).

Connection 6

MS: m/z 249,3 (M+1)

1H-NMR (CDCl3):d 1,50-1,90 (m, 6H), was 2.05 (m, 2H), 3,30 (m, 4H), of 3.95 (s, 4H), 6,60-to 6.80 (m, 4H).

To a solution of 13.5 g of compound6(54,4 mmol) in 50 ml of acetonitrile to one portion was added 11,02 g carbonyldiimidazole. The mixture was stirred over night. The solid precipitated from the solution, which was filtered and washed with N2Oh and TBME, gave 7.5 g of product. The filtrate is evaporated and the crude substance was dissolved in EtOAc, washed with water and saturated solution of potassium carbonate. Organic matter was dried over potassium carbonate. The solvent is evaporated to obtain a second batch of solid pink color, which was filtered through a column (10% Et3N, 40% EtOAc and 50% hexane) to give 4,5 g of the product7(81%combined).

Connection 7

MS: m/z 274,7 (M+1)

1H-NMR (CDCl3):d 1,50-1,90 (m, 7H), of 2.50 (m, 2H), 4.00 points (m, 4H), 4,50 (m, 1H), 7,10 (m, 3H), 7,25 (m, 1H).

A mixture of compound7(7.5 g a 27.4 mmol) and compared to 8.26 g of PPTS in 50 ml of acetone and N 2About (10:1) was stirred while boiling under reflux overnight. The mixture was cooled to room temperature and the acetone evaporated. Adding water to the mixture initiated crystallization to obtain 3 g of the product8(47,4%).

Compound 8

MS: m/z 231 (M+1)

1H-NMR (CDCl3):d of 2.20 (m, 2H), 2,60 (m, 2H), 4,50 (m, 1H), 7,10 (m, 4H), 9.5cm (width, 1H).

To a mixture of compound8(of 7.75 g, 33,65 mmol), benzylamine (3,61 g, 33,65 mmol), acetic acid (2.0 g, 33,65 mmol) in 150 ml of dichloromethane to one portion was added 10.3 g of triacetoxyborohydride sodium (47,1 mmol, 1.4 EQ.). The gas released between 30 minutes and 1 hour. The mixture was stirred over night. TLC indicated completion of reaction. Added 1N NaOH (500 ml)to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (300 ml x 2). The combined organic substance is dried over potassium carbonate and the solvent evaporated to obtain solid brown color, which was filtered through a column (5% Et3N, 25% EtOAc and 70% hexane to 10% Et3N, 40% EtOAc and 50% hexane) to give 4.7 g of product10in the form of a white solid (53,4%) and a 3.01 g of the product9in the form of a white solid (34.2 per cent).

Connection 9

MS: m/z 322 (M+1)

1H-NMR (CDCl3):d of 1.40 (m, 2H), 1,80 to 2.35 (m, 6H), 2,70 (m, 1H), 3,86 (s, 2H), 4,30 (m, 1H), 7,10-to 7.50 (m, 9H), 9,6 (width, 1H).

Connection 10

MS: m/z 322 (M+1)

1 H-NMR (CDCl3):d to 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-to 7.50 (m, 9H), 9,6 (width, 1H).

In a solution of 30 ml of methanol containing 4.7 g of the compound10added 2 g of Pd(OH)2. The resulting suspension was first made at 50 psi for 12 hours at room temperature. TLC indicated completion of reaction. The solution was filtered through a layer of celite to remove the catalyst. Celite was twice washed with methanol (20 ml). Organic substances were combined and the solvent was removed, getting a solid pale color, which was purified by chromatography (10% Meon, 90% EtOAc) to give the not quite white product11(1,79 g, 50.7 per cent).

Connection 11

MS: m/z 232 (M+1)

1H-NMR (CDCl3):d 1,50-of 1.85 (m, 8H), 2,60 (m, 2H), 4,30 (m, 1H), 7,10 (m, 3H), 7,30 (m, 1H).

To a mixture of compound11(1.7 g, 7.4 mmol), acetaldehyde (0.33 g, 7.4 mmol) in 50 ml of dichloroethane one portion was added 2.2 g of triacetoxyborohydride sodium (10,36 mmol, 1.4 EQ.). The evolution of gas occurred in the interval between 30 minutes and 1 hour. The mixture was stirred over night. TLC indicated completion of reaction. Added 1N NaOH (500 ml)to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (300 ml x 2). The combined organic substance is dried over potassium carbonate and the solvent evaporated to obtain a brown oil, which was chromatographically (10% Et3N, 40% EtOAc and 50% of Aksana) to obtain 1.5 g of the product 2as a sticky oil which was recrystallized from TWO with obtaining a white solid (78%).

Connection 2

MS: m/z 259,7 (M+1)

1H-NMR (CDCl3):d of 1.15 (t, 3H), 1,50-of 1.95 (m, 6H), 2.40 a is 2.75 (m, 4H), 2.95 and (m, 1H), 4,35 (m, 1H), 7,10 (m, 3H), 7,35 (m, 1H).

In a solution of 30 ml of methanol containing a 3.01 g of compound9added 1.5 g of Pd(OH)2. The resulting suspension was first made at 50 psi for 12 hours at room temperature. TLC indicated completion of the reaction during the night. The solution was filtered through a layer of celite to remove the catalyst. Celite was twice washed with methanol (20 ml). Organic substances were combined and the solvent was removed, getting a solid pale color, which was purified by chromatography (10% Meon, 90% EtOAc) to give the not quite white product1(1.68 g, 77.4 percent).

Connection 1

MS: m/z 232 (M+1)

1H-NMR (CDCl3):d 1,50 (m, 2H), 1,90 to 2.35 (m, 6H), to 3.00 (m, 1H), 4,30 (m, 1H), 7,10-7,30 (m, 4H).

Scheme 2:

Method

About 2.5 g of NaH was washed twice THF, suspended in 100 ml of DMF, and then to the mixture was added 8,15 g connection7(38 mmol). Was the gas, and after 5 minutes was added 7,13 g ethyliodide (of 45.7 mmol). The mixture was stirred over night. LC/MS indicated that starting material was completely consumed. The reaction mixture was cooled and the mixture is added N 2O. the Product began to precipitate from solution. The crystals were collected by filtration to obtain 9.7 g of the compound12(84,7%).

Connection 12

MS: m/z 303,3 (M+1)

1H-NMR (CDCl3):d of 1.30 (t, 3H), 1,70-1,90 (m, 6H), of 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 compound12(9.7 g, to 32.2 mmol) and 9,72 g of PPTS in 50 ml of acetone and N2About (10:1) was heated under reflux overnight. The mixture was cooled to room temperature and the acetone evaporated. Adding water to the mixture initiated crystallization with getting 6.85 g of product13(82,3%).

Connection 13

MS: m/z 259 (M+1)

1H-NMR (CDCl3):d is 1.35 (t, 3H), of 2.20 (m, 2H), 2,60 (m, 6H), of 3.95 (q, 2H), around 4.85 (m, 1H), 7,10 (m, 4H).

To a mixture of compound13(6.85 g, of 26.5 mmol), benzylamine (2,84 g of 26.5 mmol), acetic acid (1,59 g of 26.5 mmol) in 150 ml of dichloroethane one portion was added 7,86 g triacetoxyborohydride sodium (37,1 mmol, 1.4 EQ.). The evolution of gas occurred in the interval between 30 minutes and 1 hour. The mixture was stirred over night. TLC indicated completion of reaction. Added 1N NaOH (500 ml)to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (300 ml x 2). The combined organic substance is dried over potassium carbonate and the solvent evaporated to obtain solid brown color, which was filtered through a column (5% Et3N, 25% EtOAc and 70% hexane is up to 10% Et 3N, 40% EtOAc and 50% hexane) to give 1.52 g of product14in the form of a white solid and 1.08 g of the product15in the form of a white solid.

The connection 14

MS: m/z 350 (M+1)

1H-NMR (CDCl3):d is 1.35 (t, 3H), 1,50 (m, 2H), of 1.65 (m, 4H), of 1.95 (m, 2H), 2,60 (m, 2H), to 3.02 (m, 1H), 3,83 (s, 2H), 3,95 (DDD, 2H), of 4.45 (m, 1H), 7,00-to 7.50 (m, 9H).

The connection 15

MS: m/z 350 (M+1)

1H-NMR (CDCl3):d is 1.35 (m, 5H), 1,90 (m, 2H), 2,10 to 2.35 (m, 4H), 2,70 (m, 1H), 3,83 (s, 2H), 3,95 (DDD, 2H), and 4.40 (m, 1H), 7,00-to 7.50 (m, 9H).

In a solution of 20 ml of methanol containing 0.5 g of compound14was added 0.3 g of Pd(OH)2. The resulting suspension was first made at 50 psi for 12 hours at room temperature. TLC indicated completion of the reaction during the night. The solution was filtered through a layer of celite to remove the catalyst. Celite was twice washed with methanol (20 ml). Organic substances were combined and the solvent was removed, getting a solid pale color, which was purified by chromatography (10% Meon, 90% EtOAc) to give the not quite white product3(300 mg, 50%).

Connection 3

MS: m/z 232 (M+1)

1H-NMR (CDCl3):d is 1.35 (t, 3H), 1,50-of 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).

Example 11

The accession of end groups

End groups attached to the head groups in accordance with the following methods:

Cos the main method for alkylation:

To a solution of amine (1 EQ.) triethylamine (1 EQ.) in dimethylformamide one portion was added 1 EQ. allylbromide or chloride. The mixture was stirred and heated at 80°C during the night. TLC indicated completion of reaction. The reaction was suppressed by the addition of water and then bringing the pH to 10 with 1N NaOH. The mixture was twice extracted with Et2O. the combined organic extracts were dried over potassium carbonate and the solvent is evaporated, followed by chromatography was obtained pure product.

The main method for reductive amination:

To a mixture of ketone or aldehyde (1 EQ.), amine (1 EQ.) and acetic acid (1 EQ.) in methanol to one portion was added cyanoborohydride sodium (1.4 EQ.). The mixture was stirred at room temperature overnight. TLC indicated completion of reaction. The reaction was suppressed by the addition of water and then bringing the pH to 10 with 1N NaOH. The mixture was twice extracted with Et2O. the combined organic extracts were dried over potassium carbonate and the solvent is evaporated, followed by chromatography was obtained pure product.

The following compounds were obtained by the joining of end groups, using the described General procedures:

1-[4-(benzylamino)cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he

1-[4-[(naphthas-2-ylmethyl)ethylamino]cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he

MS: m/z 400,2 (M+1)

1-[4-(norbornane-2-ylamino)cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he

MS: m/z 326,3 (M+1)

1-[4-[[4-(1-methylethyl)cyclohexyl]amino]cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he

MS: m/z 356,4 (M+1)

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

MS: m/z 368,2 (M+1)

1-[4-(ethylamino)cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he

1-[4-(benzylamino)cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he

1-[4-[(indan-2-yl)benzoylamino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he

MS: m/z 466,3 (M+1)

1H-NMR (CDCl3):d of 1.30 (t, 3H), 1,50-1,75 (m, 2H), 1,90 (width, 2H), 2,02 (width, 2H), measuring 2.20 (m, 2H), 2,80 (m, 1H), 2,99 (m, 4H), of 3.75 (s, 2H), 3,90 (m, 3H), 4,25 (m, 1H), 6,95 was 7.45 (m, 13H).

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

LC: 99%

MS: m/z 384,5

1H-NMR (CDCl3):d 1,40-1,90 (m, 24H), is 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-[(naphthas-2-yl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he

LC: 97%

MS: m/z 399

1H-NMR (CDCl3):d 1,50 (t, 3H), of 1.80 (m, 5H), 2.0 (m, 2H), 2,70 (m, 2H), 3,10 (m, 1H), 3,90 (m, 2H), 4,0 (m, 2H), and 4.40 (m, 1H), 7,10 (m, 3H), 7,50 (m, 4H), of 7.90 (m, 4H).

1-[4-[(p-benzyloxybenzyl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he

LC: 97%

MS: m/z 455

1H-NMR (CDCl3):d of 1.40 (t, 3H), of 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), to 7.50 (m, 6H), of 7.90 (m, 1H).

1-[4-[(cyclooctylmethyl)amino]CEC shall hexil]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he

LC: 99%

MS: m/z 369

1H-NMR (CDCl3):d of 1.40 (t, 3H), of 1.70 (m, 5H), 1,90 (m, 12H), 2,10 (m, 3H), 2.40 a (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-benzimidazole-2-he

LC: 99%

MS: m/z 395

1H-NMR (CDCl3):d of 1.40 (t, 3H), of 1.70 (m, 3H), of 1.80 (m, 3H), 1,90 (m, 12H), of 2.20 (m, 2H), 2,30 (m, 3H), of 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-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he

LC: 100%

MS: m/z 440,8 (M+1)

1H-NMR (MeOH-d4):d to 1.75 (m, 2H), 2,00 (m, 2H), 2.40 a is 2.55 (m, 4H), 3,35-to 3.52 (m, 2H), 4,35 (s, 2H), 7,40 (m, 2H), to 7.59 (t, 2H), 7,60-7,72 (m, 6H), 7,78 (d, 2H).

1-[4-[(1,2,3,4-tetrahydronaphthyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he

LC: 93,9%

MS: m/z 405,7 (M+1)

1H-NMR (MeOH-d4):d to 1.70 (m, 2H), of 1.85 (m, 1H), 2,02 (m, 2H), 2,39 (width, 3H), of 2.50 (m, 2H), 2,90 (m, 1H), 3.00 and (width, 2H), the 3.35 (m, 1H), 3,60 (m, 1H), 3.72 points Shir., 1H), 4,35 (m, 1H), 7,15 (width, 4H), 7,40 (d, 1H), 7,60 (s, 1H), 7,65 (d, 1H).

1-[4-[(4-propylcyclohexyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he

LC: 100%

MS: m/z 399,6 (M+1)

1H-NMR (MeOH-d4):d of 0.95 (t, 3H), 1,10 (m, 1H), 1,20-1,60 (m, 6H), 1.70 to (width, 5H), 1,80-2,00 (m, 4H), 2,10 (m, 1H), 2,30 (width, 2H), a 2.45 (m, 2H), 3,25 (m, 1H), 3,50 (m, 1H), and 4.40 (m, 1H), 7,40 (d, 1H), 7,60 (s, 1H), 7,65 (d, 1H).

1-[4-[(5-metrex-2-yl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he

LC: 100%

MS: m/z 373,5 (M+1)

1H-NMR (MeOH-d4):d of 0.95 (d, 6H), ,25-1,40 (m, 5H), 1,50-1,75 (m, 4H), of 1.85 (m, 1H), 1,95 (width, 2H), 2,30 (m, 2H), 2.40 a is 2.55 (m, 2H), 3,35-3,55 (m, 2H), to 4.38 (m, 1H), 7,40 (d, 1H), 7,60 (s, 1H), of 7.70 (d, 1H).

1-[4-[(decahydro-2-naphthyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he

LC: 100%

MS: m/z 411,7 (M+1)

1H-NMR (MeOH-d4):d 0,90 is 2.10 (m, 18H), 2,10-of 2.50 (m, 5H), 2,82 (m, 1H), 3,50 (m, 2H), 4,35 (m, 1H), 7,42 (d, 1H), 7,60 (s, 1H), of 7.70 (d, 1H).

1-[4-(cyclooctylamino)cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he

LC: 95,4%

MS: m/z 385,7 (M+1)

1H-NMR (MeOH-d4):d 1,50 is 2.10 (m, 13H), is 2.30 (m, 2H), 2.40 a-2,52 (m, 3H), 2,80-2,95 (m, 3H), of 3.45 (m, 2H), 3,70 (m, 1H), to 4.38 (m, 1H), 7,40 (d, 1H), 7,63 (s, 1H), of 7.70 (d, 1H).

1-[4-[(indan-2-yl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he

LC: 100%

MS: m/z 391,6 (M+1)

1H-NMR (MeOH-d4):d to 1.70 (m, 2H), 2,00 (m, 2H), 2,40-2,60 (m, 4H), of 3.10-3.20 (m, 2H), 3,50 (m, 3H), 4,30-4,45 (m, 2H), 7,25 (m, 2H), 7,35 (m, 2H), 7,42 (d, 1H), 7,60 (s, 1H), 7,72 (d, 1H).

1-[4-(benzylamino)cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he

LC: 100%

MS: m/z 399,5 (M+1)

1H-NMR (MeOH-d4):d 1,40-of 1.85 (m, 15H), from 2.00 (m, 4H), 2,25-2,50 (m, 4H), of 2.93 (d, 2H), 3,30 (m, 1H), 4,30 (m, 1H), was 7.36 (d, 1H), 7,60 (s, 1H), 7,65 (d, 1H).

1-[4-[(4-phenylcyclohexyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he

LC: 100%

MS: m/z 433,7 (M+1)

1H-NMR (MeOH-d4):d of 1.65 (m, 2H), 1.85 to of 2.20 (m, 8H), 2,25-2,50 (m, 5H), 3,90 (m, 1H), 3,50 (m, 2H), to 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-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he

LC: 100%

MS: m/z 455,6 (M+1)

1H-NMR (MeOH-d4):d 2,00-2,25 (m, 4H), 2.40 a (m, 4H), 3,52 (m, 2H), 4.25 in with 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-metrex-2-yl)amino]cyclohexyl]-7-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he

LC: 99,1%

MS: m/z 373,3 (M+1)

1H-NMR (MeOH-d4):d of 0.95 (d, 6H), of 1.30 (d, 3H), 1,45 by 1.68 (m, 5H), of 1.75 (m, 1H), 2,00 (m, 2H), 2,18 of-2.32 (m, 3H), 2,60 (m, 2H), 3,20-3,40 (m, 2H), 4,30 (m, 1H), 7,05-7,20 (m, 3H).

Other compounds covered by formula (III) or (IIIA) of the present invention, can be synthesized by similar methods.

Example 12

The affinity against nociceptin on the ORL1 receptor for the preferred compounds was determined using the following analysis:

Membranes of recombinant cells SOME 293 expressing the receptor, similar to the opioid receptors of the man, (ORL1), (Receptor Biology), was obtained by lizirovania cells in ice hypotonic buffer (2.5 mm MgCl2, 50 mm HEPES, pH 7.4) (10 ml/10 cm Cup) followed by homogenization using a homogenizer fabric/Teflon pestle. Membranes were collected by centrifugation at 30,000 x g for 15 min at 4°C and the precipitate after centrifugation resuspendable in hypotonic buffer to a final concentration of 1-3 mg/ml protein Concentration was determined using the reagent for analysis BioRad protein with bovine serum albumin as standard. Aliquots of the membrane, R is Ceptor ORL1 kept at -80°C.

Analyses of functional binding SGTPgS was carried out as follows. Membrane solution ORL1 received sequential addition of final concentration of 0.066 mg/ml membrane protein ORL1, 10 mg/ml saponin, 3 mm GDP and 0.20 nm [35S]GTPgS to binding buffer (100 mm NaCl, 10 mm MgCl2, 20 mm HEPES, pH 7.4) on ice. These membrane solution (190 ml/well) was transferred into a 96-well polypropylene tablets containing 10 ml of 20x concentrated source solutions agonist obtained in DMSO. The plates were incubated for 30 min at room temperature with shaking. The reaction was interrupted by rapid filtration onto 96-well filter tablets Unifilter GF/B, Packard) using a 96-well harvester tissue (Brandel), followed by three filtration washes with 200 ml chilled on ice binding buffer (10 mm NaH2PO4, 10 mm Na2HPO4, pH 7.4). Filter plates successively dried at 50°C for 2-3 hours. Added fifty ml/well scintillation cocktail account (BetaScint; Wallac) and tablets read in a Packard Top-Count for 1 min/well.

Data were analyzed using a curve approximation of functional dependence in GraphPad PRISMO, v.3.0, and the results are presented in table 3 below:

THAT THE FACE 3
The affinity against nociceptin
Connectionwyciski(nm)
3-ethyl-1-(p-vinylbenzyl)-1,3-dihydro-2H-benzimidazole-2-he509
3-ethyl-1-(5-metrex-2-yl)-1,3-dihydro-2H-benzimidazole-2-he23
3-ethyl-1-(4-propylcyclohexyl)-1,3-dihydro-2H-benzimidazole-2-he68
3-ethyl-1-(decahydro-2-naphthyl)-1,3-dihydro-2H-benzimidazole-2-he1,6
3-ethyl-1-(naphthas-2-ylmethyl)-1,3-dihydro-2H-benzimidazole-2-he198
1-(p-benzyloxybenzyl)-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he438
1-benzyl-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he296
1-[4-(benzylamino)cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-heTRANS:112
CIS:>10000
3-ethyl-1-(naphthylmethyl)-1,3-dihydro-2H-benzimidazole-2-he39
3-ethyl-1-[5-(3-forfinal)-5-(4-forfinal)hexyl]-1,3-dihydro-2H-benzo is midazol-2-he 148
1-[4-[(naphthas-2-ylmethyl)ethylamino]cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he3598
1-[4-(norbornane-2-ylamino)cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he>10000
1-[4-[[4-(1-methylethyl)cyclohexyl]amino]cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he>10000
1-[4-[(decahydro-2-naphthyl)amino]cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he>10000
1-[4-(ethylamino)cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-he9179
1-[4-(benzylamino)cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-heTRANS:273
CIS:>10000
1-[4-[(indan-2-yl)benzoylamino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he>10000
1-[4-[(cyclooctylmethyl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he115
1-[4-[(naphthas-2-yl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he961
1-[4-[(p-benzyloxybenzyl)amino]cyclo is exyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he 2935
1-[4-[(cyclooctylmethyl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he286
1-[4-[(decahydro-2-naphthyl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he288
1-[4-(benzylamino)cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he>10000
1-[4-(dibenzylamino)cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he>10000
1-[4-[(p-phenylbenzyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he>10000
1-[4-[(1,2,3,4-tetrahydronaphthyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he>10000
1-[4-[(4-propylcyclohexyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he>10000
1-[4-[(5-metrex-2-yl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he>10000
1-[4-[(decahydro-2-naphthyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he >10000
1-[4-(cyclooctylamino)cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he>10000
1-[4-[(indan-2-yl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he>10000
1-[4-[(4-phenylcyclohexyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he>10000
1-[4-[(5-metrex-2-yl)amino]cyclohexyl]-7-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-he>10000

Example 13

The synthesis of substituted benzimidazole head groups

Method

60% Dispersion of sodium hydride in mineral oil (0,67 g, and 16.7 mmol) was washed with anhydrous pentane and then suspended in 80 ml of anhydrous THF in an atmosphere of N2. Added connection to1(European patent 0029707) (3.80 g, 11.1 mmol), the mixture was stirred at room temperature for 15 min and then was heated to 50°C. was Added ethylbromide (of 1.06 ml, 13.3 mmol) and the resulting mixture was stirred at 50°C for 18 hours. TLC (SiO2CH2Cl2:MeOH 96:4) showed that the reaction was completed by approximately 40%. Added an additional amount of sodium hydride (0,67 g) and ethylbromide (1.06 m is). After heating at 50°C for an additional 24 hours, the reaction mixture was cooled to room temperature and extinguished with water. The layers were separated and the aqueous layer was extracted with ethyl acetate (1x). The combined organic extracts were washed with an aqueous solution of sodium bicarbonate (1x), dried over MgSO4and the solvent evaporated to obtain the crude product as a yellow solid. Rubbing with diethyl ether gave the pure compound2in a solid white color (3,38 g, 82%).

1H-NMR (CDCl3):d 1,45-1,55 (m, 12H), 1,82 (Sirs, 2H), 2,30 (m, 2H), 2,87 (m, 2H), 4,30 (Sirs, 2H), to 4.41 (q, 2H), 4,82 (m, 1H), 7,10-7,30 (m, 4H).

To a solution of compound2(of 3.60 g, 9,74 mmol) in 100 ml of ethyl acetate was added 25 ml of a mixture of ethyl acetate and concentrated HCl (1:1). The mixture was thoroughly stirred for 2 hours at room temperature and evaporated to dryness. The residue was neutralized with 50 ml of methanolic ammonia solution 10:1 and again evaporated to dryness. The residue is suspended in 100 ml of a mixture of the Meon and CH2Cl21:1, filtered and the filtrate evaporated to dryness to obtain not quite white solid. Flash chromatography on silica gel with elution with a mixture of CH2Cl2:Meon:NH3(300:10:1) gave pure compound3in the form of a white crystalline solid (1.98 g, 76%).

1H-NMR (CDCl3):d of 1.45 (t, 3H), 1,82 (Shi is .c, 2H), 2,33 (m, 2H), 2,80 (m, 2H), and 4.40 (q, 2H), 4,80 (m, 1H), 7,10-7,30 (m, 3H), 7,45 (d, 1H).

Example 14

The accession of end groups

End groups attached to the head groups in accordance with the following methods:

The main method for alkylation:

To a solution of amine (1 EQ.) triethylamine (1 EQ.) in dimethylformamide one portion was added 1 EQ. allylbromide or chloride. The mixture was stirred and heated at 80°C during the night. TLC indicated completion of reaction. The reaction was suppressed by the addition of water and then bringing the pH to 10 with 1N NaOH. The mixture was twice extracted with Et2O. the combined organic extracts were dried over potassium carbonate and the solvent is evaporated, followed by chromatography was obtained pure product.

The main method for reductive amination:

To a mixture of ketone or aldehyde (1 EQ.), amine (1 EQ.) and acetic acid (1 EQ.) in methanol to one portion was added cyanoborohydride sodium (1.4 EQ.). The mixture was stirred at room temperature overnight. TLC indicated completion of reaction. The reaction was suppressed by the addition of water and then bringing the pH to 10 with 1N NaOH. The mixture was twice extracted with Et2O. the combined organic extracts were dried over potassium carbonate and the solvent is evaporated, followed by chromatogr is FIA received net product.

The following compounds were obtained by the joining of end groups, using the described basic methods:

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

1H-NMR (CDCl3):d 1,50 (t, 3H), of 1.88 (m, 2H), 2,28 (m ,2H), 2,62 (m, 2H), 3,12 (m, 2H), the 3.65 (s, 2H), 4,48 (kV, 2H), 4,80 (m, 1H), 7,15-of 7.70 (m, 13H).

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 of 1.55 (t, 3H), equal to 1.82 (m, 2H, in), 2.25 (m, 2H), 2,50 (m, 2H), 3,10 (m, 2H), 3,55 (s, 2H), 4,48 (kV, 2H), 4,78 (m, 1H), 5,20 (s, 2H), 7,00 (d, 2H), 7,15-the 7.65 (m, 11H).

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

LC: 93,9%

MS: m/z

1H-NMR (CDCl3):d of 1.55 (t, 3H), of 1.80 (m, 2H), 2,30 (t, 2H), 2,52 (m, 2H), 3,18 (shirt, 2H), of 3.78 (s, 2H), 4,50 (kV, 2H), 4,80 (m, 1H), 7,20-of 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-of 2.28 (m, 21H), 3,10 (m, 4H), 3,62 (m, 2H), 4,42 (kV, 2H), 5,15 (m, 1H), 7,20 (m, 1H), 7,30 (m, 1H), 7,50 (t, 1H), 7,80 (width, 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 of 0.90 (d, 3H), and 0.98 (d, 3H), of 1.15 to 2.35 (m, 14H), 3,10 (m, 5H), 3,70 (m, 2H), 3,92 (Sirs, 1H), and 4.40 (q, 2H), 5,20 (m, 1H), 7,20 (m, 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 of 1.25 to 2.35 (m, 24H)and 1.15 (m, 4H), of 3.60 (m, 2H), and 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), of 3.45 (m, 2H), 3,90 (m, 1H), 4,42 (kV, 2H), 5,15 (m, 1H), 7,20 (m, 1H), 7,35 (d, 1H), 7,50 (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)

1H-NMR (CDCl3):d of 1.40 (t, 3H), 1.70 to (Sirs, 2H), 2,01 (m, 2H), 2,28 (m, 2H), 2,80 (m, 4H), 3,95 (s, 1H), was 4.02 (m, 2H), 4,32 (kV, 2H)and 4.65 (m, 1H), 7,00-to 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 464,2 (M+1)

1H-NMR (CDCl3):d of 1.40 (t, 3H), 1,73 (Sirs, 2H), 2,09 (m, 2H), 2,18 at 2.45 (m, 6H), 2,98 (width, 2H), 3,93 (t, 1H), 4,35 (kV, 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: m/z 400,2 (M+1)

1H-NMR (CDCl3):d 1,30-1,70 (m, 6H), of 1.85 (m, 2H), 2.05 is (m, 1H), 2,45 (m, 3H), 2,85 (m, 4H), 3,10 (m, 2H), 4,35 (kV, 2H), 4,71 (m, 1H), 7,00-of 7.60 (m, 8H).

2 cyanoimino-3-ethyl-1-[1-(5-metrex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole

LC: 94,9%

MS: m/z 368,3 (M+1)

1H-NMR (CDCl3):d of 0.85 (d, 6H), of 0.95 (d, 3H), 1,12-of 1.65 (m, 8H), of 1.80 (m, 2H), 2,27-2,60 (m, 5H), 2,85 (m, 2H), to 4.38 (m, 2H), to 4.62 (m, 1H), 7,08-7,30 (m, 3H), 7,45 (m, 1H).

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

LC: 99,2%

MS: m/z 364,7 (M+1)

1H-NMR (CDCl3):d 1,10-2,10 (m, 13H), to 2.35 (m, 1H), 2,50-2,70 (m, 3H), 2,70-2,90 (m, 3H), 3,50 (m, 2H), 4,50 (kV, 2H), 4,80 (m, 1H), 7,35 (m, 2H), of 7.48 (m, 1H), to 7.75 (m, 1H).

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

LC: to 92.1%

MS: m/z 386,2 (M+1)

1H-NMR (CDCl3):d of 1.42 (t, 3H), equal to 1.82 (m, 2H), of 2.21 (m, 2H), 2,43 (m, 2H), 2,88 (m, 2H), 3,02-3,19 (m, 4H), 3,23 (m, 1H), to 4.38 (q, 2H), 4,80 (m, 1H), 7,08-7,30 (m, 7H), was 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)

1H-NMR (MeOH):d 1,35-2,00 (m, 20H), 2,60-to 2.85 (m, 6H), 3,40 (m, 2H), 2,52 (kV, 2H), 4,90 (m, 1H), 7,35 (m, 2H), of 7.48 (m, 1H), of 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)

1H-NMR (DMSO): 7,52 (dt, 1H), 7,45 (dt, 1H), 7,21 (m, 2H), equal to 4.97 (t, 1H), 4,55 (m, 1H), to 4.38 (t, 2H), 3,76 (kV, 2H), 2,88 (m, 2H), 2,61 (shirt, 1H), 2,33 (m, 4H), 1.76 staff to 1.37 (m, 16H).

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

LC: 98,3%

MS: m/z 424,2 (M+1)

1H-NMR (DMSO): 7,56 (DD, 1H), 7,51 (DD, 1H), 7,25 (m, 2H), 5,26 (s, 2H), 4,56 (m, 1H), and 3.72 (s, 3H), 3,34 (m, 2H), 2,78 (m, 2H), 2,62 (shirt, 1H), 2,32 (m, 4H), 1,80-of 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 and (d, 2H), 2,88 (m, 2H), 2,62 (shirt, 1H), 2,33 (m, 4H), 1,86 to 1.37 (m, 16H).

2-cyano the Mino-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), to 2.55 (m, 2H), of 2.38 (m, 2H), 1,80-of 1.30 (m, 18H), of 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 percent (m, 2H), 4,60 (m, 1H), 4,35 (t, 2H), 3,37 (t, 2H), 2,87 (m, 2H), 2,82 (s, 3H), 2,60 (shirt, 1H), 2,31 (m, 4H), 1.76 staff to 1.37 (m, 15H).

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

LC: 100%

MS: m/z 409,2 (M+1)

1H-NMR (DMSO): of 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 and (d, 2H), 2,88 (m, 2H), 2,62 (shirt, 1H), 2,30 (m, 4H), 1,80 to 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): was 7.45 (DD, 1H), 7,14 (m, 3H), of 4.57 (s, 2H), 4,50 (m, 1H), 2,87 (m, 2H), 2,61 (shirt, 1H), 2,33 (m, 4H), 1.75 is to 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-of 6.96 (m, 4H), is 6.54 (2H, s)and 4.65 (m, 1H), and 4.40 (t, 2H), 3,90 (m, 2H), 3,05 (m, 4H), 2,90 (m, 1H), 2.63 in (m, 3H), 2,56-is 2.37 (m, 4H), 1.85 to about 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-azobenzenes

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

Other compounds covered by formula (IV) or (IVA) of this invention can be synthesized by similar methods.

Example 15

The affinity against nociceptin on the ORL1 receptor for the preferred compounds was determined using the following analysis:

Membranes of recombinant cells SOME 293 expressing the receptor, similar to the opioid receptors of the man, (ORL1), (Receptor Biology), was obtained by lizirovania cells in ice hypotonic buffer (2.5 mm MgCl2, 50 mm HEPES, pH 7.4) (10 ml/10 cm Cup) followed by homogenization using a homogenizer fabric/Teflon pestle. Membranes were collected by centrifugation at 30,000 x g for 15 min at 4°C and the precipitate after centrifugation resuspendable in hypotonic buffer to a final concentration of 1-3 mg/ml protein Concentration was determined using the reagent for analysis BioRad protein with bovine serum albumin as standard. Aliquots of membrane receptor ORL1 kept at -80°C.

Analyses of functional binding SGTPgS was carried out as follows. Membrane solution ORL1 received sequential addition of final concentration of 0.066 mg/ml membrane protein ORL1, 10 mg/ml saponin, 3 mm GDP and 0.20 nm [35S]GTPgS to binding buffer (100 mm NaCl, 10 mm MgCl2, 20 mm HEPES, pH 7.4) on ice. These membrane process is (190 ml/well) was transferred into a 96-well polypropylene plates, containing 10 ml of 20x concentrated source solutions agonist obtained in DMSO. The plates were incubated for 30 min at room temperature with shaking. The reaction was interrupted by rapid filtration onto 96-well filter tablets Unifilter GF/B, Packard) using a 96-well harvester tissue (Brandel), followed by three filtration washes with 200 ml chilled on ice binding buffer (10 mm NaH2PO4, 10 mm Na2HPO4, pH 7.4). Filter plates successively dried at 50°C for 2-3 hours. Added fifty ml/well scintillation cocktail account (BetaScint; Wallac) and tablets read in a Packard Top-Count for 1 min/well.

Data were analyzed using a curve approximation of functional dependence in GraphPad PRISMO, v.3.0, and the results are presented in table 4 below:

TABLE 4
The affinity against nociceptin
Connectionwyciski(nm)
2 cyanoimino-3-ethyl-1-[1-(p-phenylbenzyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole5558
2 cyanoimino-3-ethyl-1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-1,3-dig the DRO-2H-benzimidazole 1660
2 cyanoimino-3-ethyl-1-[1-(naphthas-2-ylmethyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole882
2 cyanoimino-3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole241
2 cyanoimino-3-ethyl-1-[1-[4-(2-propyl)cyclohexyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazole6,9
2 cyanoimino-3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole6,6
2 cyanoimino-3-ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazoleto 5.57
2 cyanoimino-3-ethyl-1-[1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole>10000
2 cyanoimino-3-ethyl-1-[1-(3,3-bis(phenyl)propyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole80
2 cyanoimino-3-ethyl-1-[1-(1,2,3,4-tetrahydronaphthyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole157
2 cyanoimino-3-ethyl-1-[1-(5-metrex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole 76
2 cyanoimino-3-ethyl-1-[1-(norbornane-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole323
2 cyanoimino-3-ethyl-1-[1-(1,3-dihydroindol-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole89
2 cyanoimino-3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole7,1
2 cyanoimino-3-(2-hydroxy)ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole6,4
2 cyanoimino-3-methoxycarbonylmethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole3,3
2 cyanoimino-3-cyanomethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole0,97
2 cyanoimino-3-butyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole1,36
2 cyanoimino-3-(2-methanesulfonamido)ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole78
2 cyanoimino-3-acetamido-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole 11
2 cyanoimino-3-carboxymethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole201
2 cyanoimino-3-(2-dimethylamino)ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole18
2 cyanoimino-1-[1-(cyclooctyl)-3-hydroxymethyl-4-piperidinyl]-1,3-dihydro-2H-benzimidazole473
2 cyanoimino-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-7-azobenzenes3743
2 cyanoimino-1-[1-(cyclooctyl)-2,6-ethane-4-one-4-piperidinyl]-1,3-dihydro-2H-benzimidazole19

Example 16

The affinity in relation to the μ receptor for compounds were determined in accordance with the following analysis:

The solution of the membranes of µ opioid receptor has received consistent by adding a final concentration of 0.075 ág/ál of the desired membrane protein, 10 μg/ml saponin, 3 μm GDP and 0.20 nm [35S]GTPgS to binding buffer (100 mm NaCl, 10 mm MgCl2, 20 mm HEPES, pH 7.4) on ice. These membrane solution (190 ml/well) was transferred into a 96-well polypropylene tablets containing 10 ml of 20x concentrated source solutions agonist obtained in DMSO. Tablets in what was operovali for 30 min at room temperature with shaking. The reaction was interrupted by rapid filtration onto 96-well filter tablets Unifilter GF/B, Packard) using a 96-well harvester tissue (Brandel), followed by three filtration washes with 200 ál chilled on ice binding buffer (10 mm NaH2PO4, 10 mm Na2HPO4, pH 7.4). Filter plates successively dried at 50°C for 2-3 hours. Added fifty μl/well scintillation cocktail account (MicroScint20; Packard) and tablets read in a Packard Top-Count for 1 min/well.

Data were analyzed using a curve approximation of functional dependence in GraphPad PRISMO, v.3.0, and the results for some of the compounds are presented in table 5 below:

TABLE 5
The affinity in relation to the μ receptor
Connectionwyciski(nm)
3-[1-(naphthas-1-ylmethyl)-4-piperidinyl]-2H-benzoxazol-2-he340
3-[l-(3,3-diphenylpropyl)-4-piperidinyl]-2H-benzoxazol-2-he726
3-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-2H-benzoxazol-2-he343
3-[1-(4-propylcyclohexyl)-4-piperidinyl]-2H-benzoxazol-2-he145
3-ethylidene-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he23,3
3-ethylidene-1-[1-(naphthas-2-ylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he137
3-ethylidene-1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he1150
3-ethylidene-1-[1-(3,3-diphenylpropyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-he24
1-[4-[(naphthas-2-yl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-he2,1
2 cyanoimino-3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole46
2 cyanoimino-3-ethyl-1-[1-(1,2,3,4-tetrahydronaphthyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole458
2 cyanoimino-3-ethyl-1-[1-(5-metrex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole15
2 cyanoimino-3-ethyl-1-[1-(norbornane-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole1. The compound of formula (I)

where D represents phenyl;
n represents 0;
A, b and Q represent hydrogen;
Z is selected from the group consisting of communication, direct C1-3alkylene;
R1selected from the group consisting of hydrogen, C1-10of alkyl, C3-8cycloalkyl, benzyl, 6-membered monocyclic, 9-10-membered bicyclic aromatic carbon ring system and spericolata system of the formula (V):

where X1and X3present;
and where specified alkyl, cycloalkyl or benzyl group, R1optionally substituted by 1-3 substituents selected from the group consisting of C1-3of alkyl, cyano, phenyl, with the specified phenyl optionally substituted by 1-3 substituents selected from halogen;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which ZR1is cyclohexylethyl, cyclohexylmethyl, cyclopentylmethyl, dimethylcyclohexylamine-, phenylethyl-, cyclopentyl-, cyclohexyl - or hexyl-.

3. The compound according to claim 1, in which ZR1is cyanomethyl.

4. The compound according to claim 1, in which ZR1is 3,3-diphenylpropyl.

5. The compound of formula (IA):

where n represents 0;
Z is selected from the group consisting of-CH2-;
Rsub> 1selected from the group consisting of hydrogen, C1-10of alkyl, C3-8cycloalkyl, benzyl, 6-membered monocyclic, 9-10-membered bicyclic aromatic carbon ring system and spericolata system of the formula (V):

in which X1and X2present;
in which the specified alkyl, cycloalkyl or benzyl optionally substituted by 1-3 substituents selected from the group consisting of C1-3of alkyl, cyano, phenyl, with the specified phenyl optionally substituted by 1-3 substituents selected from halogen;
or its pharmaceutically acceptable salt.

6. The compound according to claim 5, in which R1is alkyl selected from the group consisting of methyl, ethyl, propyl, butyl, pentile and exile.

7. The compound according to claim 5, in which R1is cycloalkyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl or norbornyl.

8. The compound according to claim 5, in which R1is tetrahydronaphthyl, decahydronaphthalene or dibenzocycloheptadiene.

9. The compound according to claim 5, in which R1represents phenyl or benzyl.

10. The compound according to claim 5, in which R1is 9-10-membered bicyclic carbon-containing aromatic ring.

11. The connection of claim 10, in which the specified bicyclic aromatic ring
pre is is indenyl or naphthyl.

12. The compound according to claim 5, in which Z represents a bond.

13. A compound selected from the group consisting of:
3-[1-(p-cyanobenzyl)-4-piperidinyl]-2H-benzoxazol-2-it;
3-[1-[4,4-bis-(4-forfinal)butyl]-4-piperidinyl]-2H-benzoxazol-2-it;
3-[1-(2-phenylethyl)-4-piperidinyl]-2H-benzoxazol-2-it;
3-[1-(cyclooctylmethyl)-4-piperidinyl]-2H-benzoxazol-2-it;
3-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-2H-benzoxazol-2-it;
3-[1-(5-metrex-2-yl)-4-piperidinyl]-2H-benzoxazol-2-it;
3-[1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-4-piperidinyl]-2H-benzoxazol-2-it;
3-[1-(4-propylcyclohexyl)-4-piperidinyl]-2H-benzoxazol-2-it;
3-[1-(norbornane-2-yl)-4-piperidinyl]-2H-benzoxazol-2-it;
3-[1-(decahydro-2-naphthyl)-4-piperidinyl]-2H-benzoxazol-2-it;
3-[1-(3,3-dimethyl-1,5-dioxaspiro[5,5]undeca-9-yl)-4-piperidinyl]-2H-benzoxazol-2-it;
3-[1-[4-(1-methylethyl)cyclohexyl]-4-piperidinyl]-2H-benzoxazol-2-it;
3-[1-(1,3-dihydroindol-2-yl)-4-piperidinyl]-2H-benzoxazol-2-it;
3-[1-(cyclooctyl)-4-piperidinyl]-2H-benzoxazol-2-it;
and their pharmaceutically acceptable salts.

14. The compound of formula (II):

where the dotted line represents an optional double bond;
R represents a C1-3alkyl;
n represents 0;
D represents a 6-membered aromatic group;
A, b and Q are independently hydrogen, C1-3alkyl;
Z is chosen from the group consisting of communication, direct C1-3alkylene;
R1selected from the group consisting of C1-10of alkyl, C3-12cycloalkyl, benzyl, monocyclic 6-membered aryl ring system;
where the specified alkyl, cycloalkyl or benzyl group, R1optionally substituted by 1-3 substituents selected from the group consisting of cyano, phenyl, benzyloxy;
or its pharmaceutically acceptable salt.

15. The connection 14, in which D is phenyl.

16. The connection 14, in which ZR1selected from the group consisting of cyclohexylamine-cyclohexylmethyl-cyclopentylmethyl, phenylethyl-cyclopentyl-, cyclohexyl - or hexyl-.

17. The connection 14, in which ZR1is cyanomethyl.

18. The connection 14, in which ZR1is 3,3-diphenylpropyl.

19. The compound of formula (IIA):

where the dotted line represents an optional double bond;
Z is selected from the group consisting of-CH2-;
n represents 0;
R and Q are the same or different and each is selected from the group consisting of C1-3of alkyl;
R1selected from the group consisting of C1-10of alkyl, C3-12cycloalkyl, benzyl, monocyclic 6-membered aryl ring system;
where the specified alkyl, cycloalkyl, benzyl optionally substituted by 1-3 Zam is stitely, selected from the group consisting of cyano, phenyl, benzyloxy;
or its pharmaceutically acceptable salt.

20. The connection according to claim 19, in which Q is methyl.

21. The connection according to claim 19, in which R represents methyl, ethyl or ethylidene.

22. The connection according to claim 19, in which R1is alkyl selected from the group consisting of methyl, ethyl, propyl, butyl, pentile or exile.

23. The connection according to claim 19, in which R1is cycloalkyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, cyclonona, cyclodecyl and norbornyl.

24. The connection according to claim 19, in which R1represents phenyl or benzyl.

25. The connection according to claim 19, in which Z represents a bond.

26. The connection according to claim 19, in which the dotted line represents a double bond.

27. A compound selected from the group consisting of:
3-ethylidene-1-[1-(5-metrex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethylidene-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethylidene-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethylidene-1-[1-(1,3-dihydroindol-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethylidene-1-[1-(naphthas-2-ylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethylidene-1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethylidene-1-[1-(benzyl)-4-piperidine is]-1,3-dihydro-2H-indol-2-it;
3-ethylidene-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethylidene-1-[1-(norbornane-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethylidene-1-[1-(3,3-diphenylpropyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethylidene-1-[1-(p-cyanobenzyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethyl-1-[1-(5-metrex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethyl-1-[1-[4-(1-methylethyl)cyclohexyl]-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethyl-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethyl-1-[1-(norbornane-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(naphthas-1-ylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(naphthas-2-ylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(p-phenylbenzyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(3,3-bis(phenyl)propyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(p-cyanobenzyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(1,2,3,4-tetrahydronaphtyl-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(5-metrex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(norbornane-2-yl)-4-piperidinyl]-1,3-dihydr what-2H-indol-2-it;
1-[1-(1,3-dihydroindol-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(benzyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(4-propylcyclohexyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(5-metrex-2-yl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(decahydro-2-naphthyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(4-(1-methylethyl)cyclohexyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(cyclooctylmethyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
1-[1-(3,3-bis(phenyl)propyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethyl-1-[1-(3,3-bis(phenyl)propyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethyl-1-[1-(4-propylcyclohexyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethyl-1-[1-(5-metrex-2-yl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethyl-1-[1-[4-(1-methylethyl)cyclohexyl]-3-methyl-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
3-ethyl-1-[1-(decahydro-2-naphthyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-it;
and its pharmaceutically acceptable salts.

28. The compound of formula (III):

where R represents a C1-3alkyl;
n represents 0;
D represents a 6-membered aromatic group;
Z represents a system of cyclooctylamine formula (VI):

g is e a, And Q represent hydrogen;
R1selected from the group consisting of C1-3of alkyl, C3-12cycloalkyl, benzyl, 10-membered bicyclic aryl ring system;
where specified cycloalkyl or benzyl group, R1optionally substituted by 1-3 substituents selected from the group consisting of C1-10of alkyl, phenyl, benzyloxy;
or its pharmaceutically acceptable salt.

29. Connection p, in which D is phenyl.

30. The compound of formula (IIIA):

where n represents 0;
Z represents a system of cyclooctylamine formula (VI):

R represents a C1-3alkyl;
R1selected from the group consisting of C1-3of alkyl, C3-12cycloalkyl, benzyl, 10-membered bicyclic aryl ring system;
where specified cycloalkyl or benzyl optionally substituted by 1-3 substituents selected from the group consisting of C1-10of alkyl, phenyl, benzyloxy;
or its pharmaceutically acceptable salt.

31. Connection item 30, in which R1is alkyl selected from the group consisting of methyl, ethyl and propyl.

32. Connection item 30, in which R1is cycloalkyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, cyclonona, cyclodecyl and norbornyl.

33. Connection p, in which R1is tetrahydronaphthyl or decahydronaphthalene.

34. Connection item 30, in which R1represents benzyl.

35. Connection item 30, in which R1is 10-bicyclic aromatic ring.

36. Connection p in which the specified bicyclic aromatic ring is indenyl or naphthyl.

37. A compound selected from the group consisting of:
1-[4-(norbornane-2-ylamino)cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[[4-(1-methylethyl)cyclohexyl]amino]cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[(decahydro-2-naphthyl)amino]cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[(cyclooctylmethyl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[(naphthas-2-yl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[(p-benzyloxybenzyl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[(decahydro-2-naphthyl)amino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-(dibenzylamino)cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[(p-phenylbenzyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[(1,2,3,4-tetrahydronaphthyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[(4-propylcyclohexyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[(5-metrex-yl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[(decahydro-2-naphthyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-(cyclooctylamino)cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[(indan-2-yl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[(4-phenylcyclohexyl)amino]cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[(5-metrex-2-yl)amino]cyclohexyl]-7-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-it; and
its pharmaceutically acceptable salt.

38. A compound selected from
1-[4-[(naphthas-2-ylmethyl)ethylamino]cyclohexyl]-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-[(indan-2-yl)benzoylamino]cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-it;
1-[4-(benzylamino)cyclohexyl]-5-carbarnoyl-1,3-dihydro-2H-benzimidazole-2-it.

39. Pharmaceutical composition having the property of an inhibitor of receptor ORL1 or µ opioid receptor containing an effective amount of a compound according to any one of claims 1 to, 5, 13, 14, 19, 27, 28, 30, 37 or 38, and at least one pharmaceutically acceptable excipient.

40. A method of treating pain comprising the administration to a patient in need, an effective amount of an analgesic compound according to any one of claims 1 to, 5, 13, 14, 19, 27, 28, 30, 37 or 38.

41. The method of modulating a pharmacological response from the opioid receptor, including ORL1 receptor or the µ opioid receptor, including the introduction of a patient who, in need, an effective amount of a compound according to any one of claims 1 to, 5, 13, 14, 19, 27, 28, 30, 37 or 38.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula as well as separate enantiomers, diastereomers, racemic mixures and pharmaceutically acceptable salts thereof, having mitotic kinesin KSP inhibiting activity, as well as inhibitory action on tumour cells, use thereof in preparing a medicinal agent and a pharmaceutical composition based on said compounds. In said formula, R denotes Z-NR2R3, Z-OH, Ar1 and Ar2 independently denote a phenyl which, if needed, is substituted with one or more groups independently selected from: F, CI, Br, I, OH, Z denotes an alkylene having 1-6 carbon atoms which, if needed, is substituted with C1-6alkyl, and R1 assumes values given in the claim.

EFFECT: improved method.

16 cl, 3 dwg, 124 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

Heterocompound // 2425832

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to aryl-isoxazole-4-yl-imidazole derivatives of formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit GABA A α5 receptor binding site activity and selectivity. In general formula I

each of R1-R3 independently represents hydrogen atom or halogen atom; R4 represents hydrogen atom, lower alkyl, C3-C7cycloalkyl, -(CH2)n-O-lower alkyl or hydroxy substituted lowest alkyl; R5 represents -(CH2)m-phenyl or -(CH2)m-(5-6-members heteroaryl with 1-2 heteroatoms independently seected from N, O) which optionally substituted by one or more substitutes selected from a group consisting of halogen atom, cyano, nitro, lower alkyl, lower alkoxy, lower alkylsulphanyl, lower alkyl substituted by halogen atom, -C(O)-lower alkyl, -C(O)-O-lower alkyl, -NH-C(O)-O-lower alkyl or -C(O)-NH-R' where R' represents the lower alkynyl or hydroxy substituted lower alkyl, or represents -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(6-members heterocyclyl with 1-2 heteroatoms selected from N, O), -(CH2)n-(5-6-members heteroaryl with 1-2 heteroatoms selected from N, O) or -(CH2)n-phenyl optionally substituted by halogen atom; R6 represents hydrogen atom, -C(O)H, -(CH2)n-O-lower alkyl, -C(O)O-lower alkyl, lower alkyl substituted by hydroxy or halogen atom, or represents C3-C7-cycloalkyl, phenyl, or represents -(CH2)n-O-CH2-phenyl optionally substituted by halogen atom or lower alkyl, or represents -(CH2)n-O-CH2-(6-members heteroaryl with 1 heteroatom selected from N) optionally substituted by lower alkyl or lower alkyl substituted by halogen atoms, or represents -(CH2)n-NH-(CH2)o-(6-members heterocyclyl with 2 heteroatoms selected from N; n means 0, 1, 2 or 3; m means 0 or 1; o means 1, 2 or 3.

EFFECT: presented preparation of a drug containing one or more compound of formula I and application of the compounds for preparing the drug.

31 cl, 168 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxazole derivatives of general formula I. The disclosed compounds have affinity to the µ-opioid receptor. In general formula I

, n equals 0, 1 or 2, R1 denotes a phenyl residue bonded through a C1-C3alkyl chain, R2 denotes phenyl or thienyl, each of which is unsubstituted or mono-substituted with F or Cl, R3 and R4 independently denote a saturated, branched or straight C1-C6alkyl, phenyl or a phenyl residue bonded through a C1-C3akyl chain, or R3 and R4 together form an unsubstituted five-, six- or seven-member saturated ring which can optionally contain an extra heteroatom selected from a group comprising O or NR9, where R9 denotes phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which is unsubstituted or mono-substituted with a substitute selected from a group comprising F, Cl, Br, I and O-C1-C6alkyl, where the ring can be optionally condensed with a phenyl ring, R5 and R6 independently denote a saturated, branched or straight C1-C6alkyl, R7 and R8 independently denote a saturated, branched or straight unsubstituted C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, or R7 and R8 together form an unsubstituted or mono- or disubstituted five-, six- or seven-member saturated ring, where the substitutes are selected from a group comprising C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, where the ring can optionally contain an extra heteroatom selected from a group comprising S, O and NR10, where R10 denotes a phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which can be unsubstituted or mono-substituted with O-C1-C6alkyl. The invention also relates to methods of producing the disclosed compounds, a medicinal agent containing at least one substituted oxazole derivative of formula I, use of the compounds to prepare a medicinal agent.

EFFECT: improved properties.

13 cl, 1 tbl, 150 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I) in which A means a group of formula or in which * specifies a carbon atom binding site of a pyridinyl ring, and # specifies the a carbon atom binding site of a phenyl ring, R1 means an amino group or a methyl-carbonylamino group, R2 means hydrogen, R3 means hydrogen, R4 means hydrogen, R5 means hydrogen or halogen, R6 means hydrogen or halogen, R7 means hydrogen, R8 means hydrogen, or one of its salts, its solvate or solvate of its salts, to a method of preparing it, to an agent for treatment and/or prevention of viral infections, on the basis of this compound. Also, the invention refers to the application of the compound of formula I for preparing the agent and to the method of viral infection control.

EFFECT: new arylsulfonamides which can are effective as antiviral agents, preferentially for cytomegalovirus control are prepared and described.

9 cl, 5 ex, 2 tbl, 1 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula , where R1 represents aryl, heteroaryl or (C5-C6)-cycloalkyl, each of which has an optional substitute halogen or (C1-C6)-alkyl; R2 represents hydrogen or (C1-C4)-alkyl; R3 represents -P(=O)-(alkoxy)2 or Y1Y2N-SO2-, cycloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkenyl, each of which has an optional substitute: halogen, hydroxy, carboxy, Y1Y2N-, Y1Y2NC(=O)-, Y1Y2N-SO2, R7-SO2-NR6-, R7-C(=O)-NR6-, or alkyl, alkoxy, alkoxycarbonyl, each of which has an optional substitute halogen, -P(=O)-(alkoxy)2, Y1Y2NC(=O)-, Y1Y2N-SO2-, R7 -SO2-NR6 -, aryl or heteroaryl and when R3 is cycloalkyl, cycloalkenyl, heterocyclyl, it also optionally substituted by oxo; L1 represents a bond or (C1-C6)-alkylene, which is optionally substituted by -P(=O)-(alkoxy)2; R4, R5 and R6 are hydrogen, R7 represents alkyl; both Y1 and Y2 independently is hydrogen, alkyl which has an optional substitute: hydroxy, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, or Y1 and Y2 together with nitrogen atom whereto attached form heterocyclyl which optionally contains one more heteroatoms selected from oxygen, nitrogen or sulphur where heterocyclyl has an optional substitute alkyl or oxo; provided when L1 represents a bond, R3 is not optionally substituted by phenyl, optionally substituted by naphthyl, optionally substituted by benzoimidazolyl, optionally substituted by benzothiazolyl or optionally substituted by tetrazolyl; or to its pharmaceutically acceptable salt, and also to a pharmaceutical composition including a compound of formula I.

EFFECT: there are produced and described new compounds which can be effective in treating allergic or inflammatory disorders, particularly such disorders, as allergic rhinitis, asthma or chronic obstructive pulmonary disease.

25 cl, 118 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R1 is a 3-7-member carbocyclic ring and n is a number ranging from 1 to 8, and the rest of the radicals are described in the claim.

EFFECT: possibility of using such compounds and compositions in therapy as metabotropic glutamate receptor modulators.

33 cl, 367 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: chemistry.

SUBSTANCE: in formula (I) Cy1 is a 6-member heterocyclyl containing N as a heteroatom, a 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S and O, phenyl or phenyl condensed with a 5-member heterocycle containing O as a heteroatom, each optionally having 1-3 identical or different substituting Cy1 groups which are: (C1-C6)-acyl, cyano, carboxy, hydroxy, (C1-C6)alkylsulphonyl, (C3-C6)-cycloalkyl, a 6-member heterocyclyl containing 1-2 heteroatoms selected from O and N, phenyl, a 5-member heteroaryl containing 1-3 heteroatoms selected from N, S and O, Y1Y2N-, Y1Y2NC(=O)-, Y1Y2NSO2-, (C1-C6)-alkyl-SO2-N(R5)-C(=O)-, R6-C(=O)-N(R5)-, R7-NH-C(=O)-NH-; (C1-C6)-alkoxycarbonyl; (C1-C6)-alkyl, which optionally contains 1-3 identical or different substitutes which are halogen, carboxy, cyano, hydroxy, Y1Y2N-, Y1Y2N-C(=O)-, R6-C(=O)-N(R5)-, R8-SO2-N(R5)-C(=O)-, 5-member heterocyclyl, containing N as a heteroatom, 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; or (C1-C6)-alkoxycarbonyl; as well as (C1-C6)-alkoxy which optionally have 1-3 identical or different substitutes which are carboxy, (C1-C6)-alkoxycarbonyl, cyano, 3-member heterocyclyl containing O as a heteroatom, or 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; where phenyl or heteroaryl fragments in the substituting Cy1 groups optionally and independently have substitutes represented by hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6)-alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-; and where cycloalkyl fragments in the substituting Cy1 groups which optionally and independently have substitutes represented by (C1-C6)-alkoxy, carboxy; Cy2 is a 9-member cycloalkenyl, phenyl, 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteratoms selected from N, S and O, or phenyl condensed with a 5,6-member heterocycle containing 1-2 heteroatoms selected from N and O, each independently and optionally having 1-3 identical or different substitutes represented by (C1-C6)-alkoxy, (C1-C3)-alkyl, hydroxy, halogen, halogen-(C1-C6)-alkoxy, nitro, Y1Y2N-; L1 is an alkylene with a straight or branched chain containing 1-6 carbon atoms, optionally substituted carboxy; or L1 is -CH2-(C1-C5)halogenalkylene; L2 is a bond, -O- or -CH2-O-. Other values of radicals are given in the formula of invention.

EFFECT: novel compounds have prostaglandin D2 receptor antagonist properties, can be used in treating primarily allergic disorders such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy and other diseases.

39 cl, 1 tbl, 99 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula (I) or to their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity, and to a based pharmaceutical composition. (I) where P represents phenyl optionally substituted by 1 or 2 substitutes independently selected from halogen, C1-4alkyl, cyano, trifluoromethyl, C1-4alkoxy and trifluormethylthio, and R2 has the values specified in the patent claim.

EFFECT: preparation of new compounds of general formula (I) or their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity.

16 cl, 340 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula to its salt or hydrate where R1 represents hydrogen atom, alkyl group containing 1-6 carbon atoms or cycloalkyl group containing 3-6 carbon atoms; and alkyl group is optionally substituted by halogen atom; R2 represents hydrogen atom or alkyl group containing 1-6 carbon atoms; R3 represents alkyl group containing 1-6 carbon atoms or cycloalkyl group containing 3-6 carbon atoms; and alkyl group is optionally substituted by halogen atom; R4 and R5 independently represent hydrogen atom, halogen atom, alkyl group containing 1-6 carbon atoms, alkoxygroup containing 1-6 carbon atoms or alkenyl group containing 2-6 carbon atoms; and alkyl group is optionally substituted by halogen atom; and provided R4 and R5 are not hydrogen atoms simultaneously; or substitutes R4 and R5 together represent (a) 3-6-members cyclic compound including carbon atom, common for R4 and R5, with formation of a spirocyclic compound with a pyrrolidine ring; or (b) exomethylene group bound with the pyrrolidine ring by a double bond; R6 and R7 independently represent hydrogen atom or alkyl group containing 1-6 carbon atoms; R8 represents halogen-substituted alkyl group containing 1-6 carbon atoms or cycloalkyl group containing 3-6 carbon atoms; and cycloalkyl group can be substituted by halogen atom; R9 represents hydrogen atom; X1 represents hydrogen atom or halogen atom; and A represents nitrogen atom or a fragment presented by formula , where X2 represents hydrogen atom, alkyl group containing 1-6 carbon atoms or alkoxygroup containing 1-6 carbon atoms; or X2 together with R8 represents a cyclic compound containing a portion of a nucleus, and the ring formed thereby optionally contains oxygen atom and is substituted by alkyl group containing 1-6 carbon atoms. Besides, the invention refers to an antibacterial agent based on the compound of formula I, to a therapeutic agent for infections, to a method of treating an infectious disease and an application of said compounds for preparing an antibacterial drug.

EFFECT: there are produced and described new compounds showing strong antibacterial activity in relation to gram-positive and gram-negative bacteria.

30 cl, 112 ex, 10 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula , where R1 represents aryl, heteroaryl or (C5-C6)-cycloalkyl, each of which has an optional substitute halogen or (C1-C6)-alkyl; R2 represents hydrogen or (C1-C4)-alkyl; R3 represents -P(=O)-(alkoxy)2 or Y1Y2N-SO2-, cycloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkenyl, each of which has an optional substitute: halogen, hydroxy, carboxy, Y1Y2N-, Y1Y2NC(=O)-, Y1Y2N-SO2, R7-SO2-NR6-, R7-C(=O)-NR6-, or alkyl, alkoxy, alkoxycarbonyl, each of which has an optional substitute halogen, -P(=O)-(alkoxy)2, Y1Y2NC(=O)-, Y1Y2N-SO2-, R7 -SO2-NR6 -, aryl or heteroaryl and when R3 is cycloalkyl, cycloalkenyl, heterocyclyl, it also optionally substituted by oxo; L1 represents a bond or (C1-C6)-alkylene, which is optionally substituted by -P(=O)-(alkoxy)2; R4, R5 and R6 are hydrogen, R7 represents alkyl; both Y1 and Y2 independently is hydrogen, alkyl which has an optional substitute: hydroxy, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, or Y1 and Y2 together with nitrogen atom whereto attached form heterocyclyl which optionally contains one more heteroatoms selected from oxygen, nitrogen or sulphur where heterocyclyl has an optional substitute alkyl or oxo; provided when L1 represents a bond, R3 is not optionally substituted by phenyl, optionally substituted by naphthyl, optionally substituted by benzoimidazolyl, optionally substituted by benzothiazolyl or optionally substituted by tetrazolyl; or to its pharmaceutically acceptable salt, and also to a pharmaceutical composition including a compound of formula I.

EFFECT: there are produced and described new compounds which can be effective in treating allergic or inflammatory disorders, particularly such disorders, as allergic rhinitis, asthma or chronic obstructive pulmonary disease.

25 cl, 118 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R1 is a 3-7-member carbocyclic ring and n is a number ranging from 1 to 8, and the rest of the radicals are described in the claim.

EFFECT: possibility of using such compounds and compositions in therapy as metabotropic glutamate receptor modulators.

33 cl, 367 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (3S,5S)-7-[3-amino-5-methylpiperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-chinoline carboxylic acid malate salts and polymorphs.

EFFECT: invention refers to the pharmaceutical composition containing the described salts and polymorphs which can find application in medicine for treatment or prevention of infectious disorders.

16 cl, 13 dwg, 1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a pyridazine compound of formula (1), in which R1 is a chlorine atom, bromine atom, C1-C4 alkyl group of C1-C4 alkoxy group, R2 is a C1-C4 alkyl group, R3 is a halogen atom, m equals 0 or 1, Q is a 6-member aromatic heterocyclic group selected from a pyridyl group, pyridazinyl group, pyrimidinyl group or pyrazinyl group, wherein the said aromatic heterocyclic group is optionally substituted with at least one substitute selected from a group comprising halogen atoms, C1-C4 alkyl group optionally substituted with at least one halogen atom, and C1-C4 alkoxy group optionally substituted with at least one halogen atom. This compound has excellent plant disease suppression.

EFFECT: compound can be used plant disease control.

10 cl, 11 tbl, 56 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel benzimidazole and indole derivatives or pharmaceutically acceptable salts of general formula 1, where m assumes values from 0 to 2; n equals 1, X denotes: -NRa-; -CRbRc-; or -C(O)-; where: Ra is hydrogen or C1-6alkyl; Rb is hydrogen or C1-6alkyl; Rc is hydrogen, C1-6alkyl, hydroxy; or Ar denotes: phenyl, possibly substituted with 1-2 halogens; or isoxazole, possibly substituted with C1-6alkyl; R1 is a group of formula p assumes values from 1 to 3; Y denotes: -O-; -NRd-; or -CReRf-; where Rd, Re and Rf each independently denotes hydrogen or C1-6alkyl; each R2 independently denotes: halogen; C1-6alkyl; R3 and R4 each independently denotes hydrogen or C1-6alkyl; R5 and R6 each independently denotes; and R7 and R8 each independently denotes hydrogen or C1-6alkyl; or one of R7 and R8 and one of R5 and R6 together with atoms to which they are bonded can form a 4-6-member ring; or one of R7 and R8 together with Rd and atoms to which they are bonded can form a 6-7-member ring; or one of R7 and R8 and one of Re and Rf together with atoms to which they are bonded can form a 5-6-member ring. The invention also relates to a pharmaceutical composition based on compounds of formula I-VI and use of the compounds of formula I-VI.

EFFECT: obtaining novel benzimidazole and indole derivatives with selective 5-and/or 6-HT2A receptor antagonist properties.

27 cl, 1 tbl, 13 ex

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