Spiropyrazole compounds, pharmaceutical composition containing thereof, method for modulation of opioid receptor and method for treatment using such compounds

FIELD: chemical industry, organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel spiropyrazole compounds of the general formula (I): wherein W means hydrogen atom, (C1-C10)-alkyl, (C3-C7)-cycloalkyl, cyano-(C1-C10)-alkyl, -(C1-C4)-alkyl-COOV1 wherein V1 means hydrogen atom (H) or (C1-C6)-alkyl, -(C1-C5)-alkyl-C(=O)-W1 wherein W1 means amino-group, or -(C1-C5)-alkyl-NHS(=O)2-W1 wherein W1 means -(C1-C10)-alkyl; Q means phenyl; n mean a whole number 0 or 1; A, B and C mean hydrogen atom; Z means a simple bond, methylene or ethylene group; R1 means (C3-C12)-cycloalkyl substituted optionally with (C1-C10)-alkyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, indenyl, norbornyl, dibenzocycloheptyl, 9-acenaphthyl, phenyl substituted optionally with benzyloxy-group, biphenyl or (C1-C10)-alkyl substituted optionally with 1-3 substitutes chosen from phenyl, cyano-group, -COOV1 wherein V1 means (C1-C6)-alkyl and -(C1-C5)-alkyl-C(=O)-W1 wherein W1 means amino-, (C1-C4)-alkylamino- or di-(C1-C4)-alkylamino-group; R2 means (C1-C10)-alkyl, (C3-C7)-cycloalkyl or halogen atom. Also, invention to their pharmaceutically acceptable salts, solvates, pharmaceutical composition containing thereof, a method for treatment of pain and a method for modulation of pharmacological response of described ORL-1- or μ-receptors. Invention can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 3 tbl, 5 ex

 

This application claims the priority of provisional patent application U.S. No. 60/284675 filed April 18, 2001, the description of which is included here for information.

Prior art

Chronic pain is one of the main factors contributing to the disability, and cause unbearable suffering. Successful treatment of severe and chronic pain is the main task of the doctor is preferred drugs are opioid analgesics.

Until recently, there were reports of the existence in the Central nervous system (CNS) of the three major classes of opioid receptors, and each class has its own receptor subtypes. These classes of receptors have been identified as μ, δ and κ. Because opiates (opium preparations) had a high affinity for these receptors, without being endogenous to the body, in the future, followed by a study identification and selection of endogenous ligands in relation to the above receptors. These ligands were identified as enkephalins, endorphins and dynorphin.

Recently experiments have led to the identification of a cDNA that encodes a receptor (ORL1), similar to the opioid receptor, with a high degree of homology in relation to known classes of receptors. The recently identified receptor was classy econovan as opioid receptor, from purely structural grounds, because the receptor showed no pharmacological homology. Initially it was shown that non-selective ligands with high affinity to receptors μ, δ and κhave a low affinity for ORL1. This characteristic, along with the fact that the endogenous ligand has not yet been discovered, led to the term "orphan receptor" ("not related to anything that does not belong to the receptor").

Subsequent research led to the selection and interpretation patterns of the endogenous ligand of the ORL1 receptor. The above ligand is a peptide of seventeen amino acids, structurally similar members of the family of opioid peptides.

The opening of the ORL1 receptor is able to create drugs based on new compounds that could be used to alleviate pain or other symptoms, the above-mentioned modulated receptor.

All documents cited here, including those mentioned above, are an integral part of the present description by reference.

The purpose and essence of the invention

Accordingly, the aim of some embodiments of the present invention to provide new compounds which exhibit affinity for the ORL1 receptor.

The aim of some embodiments of the present izobreteniyami for new connections who demonstrate an affinity for the ORL1 receptor and one or more receptors μ, δ or κ.

The aim of some embodiments of the present invention is to provide new compounds for the treatment of a patient suffering from chronic or acute pain, by introducing compounds having affinity for the ORL1 receptor.

The purpose of some variants of the embodiment of the present invention is to offer new compounds that have agonist activity of receptor μ, δ and κwhich by its magnitude higher than currently available compounds, such as morphine.

The aim of some embodiments of the present invention is to provide methods of treating chronic and acute pain by introducing compounds that have the activity of the agonist-receptor μ, δ and κwhich by its magnitude higher than currently available compounds.

The aim of some embodiments of the present invention is to offer ways to treat chronic and acute pain by introducing non-compounds that have the activity of the agonist-receptor μ, δ and κ and which would have caused fewer side effects than currently available connection.

p> The aim of some embodiments of the present invention is to provide compounds useful as analgesics, anti-inflammatory drugs, diuretics, anesthetics and neuroprotective tools, anti-hypertensive funds protivoastmaticheskih means; means for regulating appetite; regulators hearing; antitussive funds, Antiasthmatic agents, modulators of locomotor activity, modulators of learning and memory, controls the release of neurotransmitters and hormones, modulators of renal function, anti-depressants, for the treatment of memory loss due to Alzheimer's disease or other dementia; anti-epileptics, anticonvulsants, funds for the treatment of chronic alcoholism and addiction to the excessive use of drugs (drug abuse), means for regulating water balance, means for regulating the excretion of sodium and tools for regulation violations arterial blood pressure, and means for the introduction of these compounds.

Compounds of the present invention are used to modulate the pharmacodynamic response from one or more opioid receptor (ORL1, μ, δ and κ) the Central or peripheral origin. Off the it can be attributed to the stimulating (agonist) or inhibitory (antagonist) one or more receptors to the action of the connection. Some compounds can stimulate one receptor (e.g., agonist μ) and to inhibit other receptor (e.g., the ORL1 antagonist).

Other objectives and advantages of the present invention become apparent from the following detailed description. The present invention in some embodiments, the implementation includes compounds having General formula (I):

where W represents hydrogen, C1-10-alkyl, C3-12-cycloalkyl, C3-12-cycloalkyl-C1-4-alkyl, C1-10-alkoxy,C3-12-cycloalkane-, C1-10-alkyl substituted with 1-3 Halogens, (C3-l2-cycloalkyl substituted by 1-3 Halogens, (C3-12-cycloalkyl-C1-4-alkyl substituted with 1-3 Halogens, (C1-10-alkoxy substituted by 1-3 Halogens, (C3-12-cycloalkane substituted by 1-3 Halogens, -COOV1, -C1-4COOV1, -CH2OH, -SO2N(V1)2, hydroxy-C1-10-alkyl-, hydroxy-C3-10-cycloalkyl-, cyano-C1-10-alkyl-, cyano-C3-10-cycloalkyl-, -CON(V1)2, NH2SO2C1-4-alkyl-, NH2SOC1-4-alkyl-, sulfonylamino-C1-10-alkyl-, diaminoalkyl-, -sulfonyl-C1-4-alkyl, 6-membered heterocyclic ring, 6-membered heteroaromatic ring, 6-membered heterocyclyl-C1-4-alkyl-, (6-membered heteroaromatic cycle)-the 1-4-alkyl-, 6-membered aromatic ring, (6-membered aromatic cycle)-C1-4alkyl, 5-membered heterocyclic ring, optionally substituted by an oxo or thio, a 5-membered heteroaromatic ring, a 5-membered heterocyclyl-C1-4alkyl-, optionally substituted by an oxo or thio, (5-membered heteroaromatic cycle)-C1-4alkyl-, -C1-5(=O)W1, -C1-5(=NH)W1, -C1-5NHC(=O)W1, -C1-5NHS(=O)2W1, -C1-5NHS(=O)W1where W1represents hydrogen, C1-10-alkyl, C3-12-cycloalkyl, C1-10-alkoxy, C3-12-cycloalkane, -CH2OH, amino, C1-4-alkylamino-, di-C1-4-alkylamino - or 5-membered heteroaromatic ring, optionally substituted by 1-3 lower alkilani;

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

Q represents C1-8-alkyl, (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 C represent independently hydrogen, C1-10-alkyl, C3-12-cycloalkyl,1-10-alkoxy, C3-12-cycloalkane, -CH2OH, -NHSO2, hydroxy-C1-10-alkyl-, aminocarbonyl-, C1-4-alkylaminocarbonyl-, di-C1-4-alkylaminocarbonyl, acylamino, acylamino lcil-, amide, sulfonylamino-C1-10-alkyl-, or A-B can together form With2-6-bridge, or B-C may together form a3-7-bridge, or A-C may together form a C1-5-bridge;

Z is selected from the group consisting of communication, direct or branched C1-6-alkylene, -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 not substituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups;

R1selected from the group consisting of hydrogen, C1-10-alkyl, C3-12-cycloalkyl,2-10-alkenyl, amino, C1-10-alkylamino,3-12-cyclooctylamino-, -COOV1, -C1-4COOV1, cyano, cyano-C1-10-alkyl-, cyano-C3-10-cycloalkyl-, NH2SO2-, NH2SO2C1-4-alkyl-, NH2SOC1-4-alkyl-, aminocarbonyl-From1-4-alkylaminocarbonyl-, di-C1-4-alkylaminocarbonyl-benzyl, C3-12-cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl structure, hetero-monocyclic ring, hetero-bicyclic structure and spiritlessly structure of formula (II):

where X1and X independently selected from the group consisting of NH, O, S, and CH2; and where the specified alkyl, cycloalkyl, alkenyl, C1-10-alkylamino-From3-12-cyclooctylamino or benzyl, representing R1, optionally substituted by 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-10-alkyl, C1-10-alkoxy, nitro, trifloromethyl-, cyano, -COOV1, -C1-4COOV1, cyano-C1-10-alkyl-, -C1-5(=O)W1, -C1-5NHS(=O)2W1, -C1-5NHS(=O)W1, (5-membered heteroaromatic cycle)-C0-4-alkyl-, phenyl, benzyl, benzyloxy, and the specified phenyl, benzyl, and benzyloxy optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10-alkyl, C1-10-alkoxy and cyano; and where the3-12-cycloalkyl,3-12-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic structure or spiritlessly structure of formula (II) optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10-alkyl, C1-10-alkoxy, nitro, trifloromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, where the specified phenyl, benzyl, phenyloxy or benzyloxy optionally substituted by 1-3 substituents selected from the group consisting whom her from halogen, With1-10of alkyl, C1-10-alkoxy and cyano;

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

and their pharmaceutically acceptable salt and solvate.

The present invention in some embodiments embodiment includes compounds having the General formula (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-, where the carbon atoms and/or nitrogen, unsubstituted or substituted lower alkyl, halogen, hydroxy or alkoxy group;

R1selected from the group consisting of hydrogen, C1-10-alkyl, C3-12-cycloalkyl,2-10-alkenyl, amino, C1-10-alkylamino,3-12-cyclooctylamino, benzyl,3-12-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl or heteroaryl structure, hetero-monocyclic ring, hetero-bicyclic structure and spiritlessly structure of formula (II):

where X1and X 2independently selected from the group consisting of NH, O, S, and CH2;

where specified monocyclic aryl is preferably phenyl;

where specified bicyclic aryl is preferably naphthyl;

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

where specified3-12-cycloalkyl,3-12-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic structure and spiritlessly structure of formula (II) optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-10-alkyl, C1-10-alkoxy, 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, C1-10-alkyl, C1-10-alkoxy and cyano;

p> R2selected from the group consisting of hydrogen, C1-10-alkyl, C3-12-cycloalkyl 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) Q is phenyl or 6-membered heteroaromatic group containing 1-3 nitrogen atom.

In some preferred embodiments, the embodiments of formula (I) or (IA) alkyl in the value of R1represents methyl, ethyl, propyl, butyl, pentyl or hexyl.

In some preferred embodiments, the embodiments of formula (I) or (IA) cycloalkyl in the value of R1represents cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl or norbornyl.

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

In some preferred embodiments, the embodiments of formula (I) or (IA) bicyclic the Skye aromatic structure in the value of R 1is a 10-membered cyclic structure, preferably a quinoline or naphthyl.

In some preferred embodiments, the embodiments of formula (I) or (IA) bicyclic aromatic structure in the value of R1is a 9-membered cyclic structure, 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 no one unsubstituted hydrogen atom of carbon and/or nitrogen). For example, if the group Z is-CH2-the substitution of two methyl groups will lead to the destruction of both of the hydrogen atoms of-CH2-representing the group 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), W represents-CH2C=ONH2, -C(NH)NH2pyridylmethyl, cyclopentyl, cyclohexyl, furylmethyl, -C=OCH3, -CH2CH2NHC=OCH3,-SO2CH3CH2CH2NHSO2CH3fornicator, methylpyrrolidinyl, diazocarbonyl, asamati, triptorelin-, hydroxyethyl-, cyanomethyl-, oxo-oxazolidin - imidiatley-.

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

In some embodiments of the embodiments of formula (I), at least one of ZR1or W represents-CH2COOV1tetrazolyl, cyanomethyl-, NH2SO2-methyl-, NH2SO-methyl-, aminocarbonylmethyl-From1-4-alkylaminocarbonyl - or di-C1-4-alkylaminocarbonyl.

In some embodiments of the embodiments of formula (I) ZR1is 3,3-diphenylpropyl, optionally substituted at the 3 carbon of cut-COOV1, tetrazolyl-C0-4-alkyl, cyano-, aminocarbonyl,1-4-alkylaminocarbonyl or di-C1-4-alkylaminocarbonyl.

In alternative embodiments of formula (I) or (IA) ZR1can be

where

Y1is R3-(C1-C12)alkyl, R4-aryl, R5-heteroaryl, R6-(C3-C12)cycloalkyl, R7-(C3-C )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 to which they are attached, form one of the following structures:

or

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

R10is 1-3 substituent, independently selected 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 the substituents R11belonging to adjacent carbon atoms of the ring can join to form methylenedioxy or Ethylenedioxy ring;

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)0-2RI2;

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-C6)alkyl-NR8R9, -NHSO2R8, -SO2N(R14)2, -SO2R8, -SOR8, -SR8, -NO2, -CONR8R9, -NR9COR8, -COR8, -COCF3, -OCOR8, -OCO2R8, -COOR8, -(C1-C6)alkyl-NHCOOC(CH3)3,-(C1-C6)alkyl-NHCOCF3,-(C1-C6)alkyl-NHSO2-(C1-C6)alkyl, -(C1-C6)alkyl-NHCONH-(C1-C6)alkyl and

where f is from 0 to 6; or the substituents R4belonging to the neighboring and the Ohm carbon ring, may together form methylenedioxy or Ethylenedioxy ring;

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, -NR9COR8, -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)alkyl-OR8, -(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-.

Used herein, the term "alkyl" means a straight or branched saturated aliphatic hydrocarbon group, imoudu is one radical comprising from 1 to 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, replace one or both of the hydrogen in the group-CH2- straight alkyl chain. The term "lower alkyl" means alkyl with 1-3 carbon atoms.

The term "alkoxy" means the above-defined "alkyl"related to oxygen radical.

The term "cycloalkyl" means a non-aromatic mono - or polycyclic hydrocarbon structure having a single radical and comprising 3-12 carbon atoms. Illustrative monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl and cyclohexyl. Illustrative of polycyclic cycloalkyl patterns include substituted and norbornyl.

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

"Branched" alkenyl means that one or more alkyl groups such as methyl, ethyl or propyl, replace one or two hydrogen group-CH2- or-CH=linear alkenylphenol chain. Illustrative alkeneamine groups include ethynyl, 1 - and 2-propenyl, 1-, 2 - and 3-butenyl, 3-methylbut-2-enyl, 2-propene is l, heptenyl, octenyl and decenyl.

The term "cycloalkenyl" means a non-aromatic monocyclic or polycyclic hydrocarbon structure containing carbon-carbon double bond having a single radical and comprising from 3 to 12 carbon atoms. Illustrative monocyclic cycloalkenyl patterns include cyclopropyl, cyclopentyl, cyclohexenyl or cycloheptenyl. Illustrative of polycyclic cycloalkenyl structure is norbornanyl.

The term "aryl" means a carbocyclic aromatic structure containing one, two or three rings, which can be connected to each other through the (lateral) simple bond or fused and containing one radical. Illustrative aryl groups include phenyl, naphthyl and acenaphthyl.

The term "heterocycle" means cyclic compounds having one or more heteroatoms (atoms other than carbon 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 hetero-monocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinil; saturated (3-6)and a member of the nye hetero-monocyclic group, containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl; saturated (3-6)-membered hetero-monocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as diazolidinyl. Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran and dihydrofuran. Other heterocyclic groups may represent a cyclic structure with 7-10 carbon atoms, substituted by heteroatoms, such as, for example, oxynil and ciocanel. In those cases, when the heteroatom is sulfur, the sulfur may represent sulfur dioxide, as, for example, tiaanidine.

The term "heteroaryl" means unsaturated heterocyclic radicals, where "heterocycle" is defined as described earlier. Illustrative heteroaryl groups include unsaturated (3-6)-membered hetero-monocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyridyl, pyrimidyl and pyrazinyl; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, such as indolyl, chinosol and ethanolic; unsaturated (3-6)-membered hetero-monocyclic group containing an oxygen atom, such as furyl; unsaturated (3-6)-membered hetero-monocyclic group containing a sulfur atom, such as thienyl; unsaturated (3-6)-membered hetero-monocyclic group that contains Asie 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl; unsaturated (3-6)-membered hetero-monocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl. The term "heteroaryl also includes unsaturated heterocyclic radicals, where "heterocycle" is defined as previously described, and in which the heterocyclic group is condensed with an aryl group, where aryl is defined as described earlier. Illustrative condensed radicals include benzofuran, benzodioxan and benzothiophen.

Used herein, the term "heterocyclyl-C1-4-alkyl", "heteroaromatic cycle-From1-4-alkyl" and the like refer to a cyclic structure associated with1-4is an alkyl radical.

As is obvious to a person skilled in the art, all cyclic structures disclosed herein may be attached at any point, if such a connection is possible.

Used herein, the term "patient" includes human or animal, such as a pet or cattle.

Used herein, the term "halogen" includes fluoride, bromine is d, chloride, iodide or albumid.

It is assumed that the invention disclosed here, encompasses all pharmaceutically acceptable salts disclosed therein compounds. Pharmaceutically acceptable salts include, but are below does not limit the scope of protection of the present invention) 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 amines, such as salt, triethylamine salt of pyridine, picoline salt, ethanolamine salt, triethanolamine salt, salt dicyclohexylamine, 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.

In addition, it is assumed that the invention disclosed here, covers all prodrugs disclosed therein compounds. Believe that the prodrugs are any covalently associated with drug carriers, which in vivo release of the original active drug.

In addition, it is assumed that the invention encompasses in vivo meta is licencie products disclosed therein compounds. The above products can be due to, for example, oxidation, recovery, hydrolysis, amidation, esterification and thepwnageninja compounds, primarily due to enzymatic processes. Thus, the invention includes compounds obtained by the process comprising contacting compounds of the present invention with (body) of the mammal over a period of time sufficient to obtain a product of its metabolism. Such products generally identify, receiving a radiolabelled compound of the present invention, by injecting it parenterally in a detectable dose to an animal such as rat, mouse, Guinea pig, monkey, or to man, allowing sufficient time for the process of transformation (metabolism) and separating the products of its transformation from urine, blood or other biological samples (physiological fluids).

It also assumes that the claimed invention covers disclosed therein compounds that are labeled with the isotope compounds having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be introduced in the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as2 H,3H,13C,14C,15N18O,17O,31P,32P,35S18F and36Cl respectively. Some of the disclosed here, the compounds can contain one or more asymmetric centers and can therefore give the enantiomers, diastereomers, and other stereoisomeric forms. It is implied that the present invention covers all the above are possible isomeric forms, as well as their racemic and separated forms and their mixtures. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise stated, we mean that the invention includes both E-and Z-geometric isomers. It is assumed that the scope of the present invention also includes all of the above tautomers.

Used herein, the term "stereoisomers" is a General term for all isomers of individual molecules that differ only by the orientation of their atoms in space. The term includes enantiomers and isomers of compounds with more than one chiral center that are not mirror 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 that is not what oddysey combination with its reflection and therefore optically active, while the enantiomer rotates the plane of polarized light in one direction, and its mirroring rotates the plane of polarized light in the opposite direction.

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

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

The term "modulate", as used here in relation to receptor ORL-1, means mediating pharmacodynamic responses (e.g., analgesia) in the subject on the basis of (i) the inhibition or activation of the receptor, or (ii) direct or indirect impact on the normal regulation of the activity of the receptor. For compounds that modulate the activity of the receptor, are agonists, antagonists, mixed agonists/antagonists and compounds that directly or indirectly affect the regulation of the activity of the receptor.

Some preferred compounds of the present invention include:

8-(4-propylcyclohexyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one;

8-(5-metrex-2-yl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one;

8-norbornyl-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one;

8-(decahydro-2-naphthyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one;

8-(cyclooctylmethyl)-1-dryer is l-2,3,8-treetopia[4,5]Decan-4-one;

8-(1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one;

8-[4-(2-propyl)cyclohexyl]-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one;

8-(1,3-dihydroindol-2-yl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one;

8-[(naphthas-2-yl-methyl)]-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one;

8-(p-phenylbenzyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one;

8-[4,4-Bis(4-forfinal)butyl]-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one;

8-(benzyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one;

8-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one;

8-(3,3-Bis(phenyl)propyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one;

8-(p-benzyloxybenzyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one;

8-(cyclooctylmethyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one; and

their pharmaceutically acceptable salt and solvate.

Another preferred compound is 8-(acenaphthen-9-yl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one and its pharmaceutically acceptable salt and solvate.

In addition, the present invention provides the use of any of the disclosed compounds to obtain drugs for the treatment of pain and other conditions of disease, modulating opioid receptors, such as receptor ORL-1.

A detailed description of the invention

Compounds of the present invention can be entered to anyone who requires modulation of opioid receptor and receptor ORL-1. BB is doing can be done through the mouth, topically, by suppository, by inhalation or parenterally.

In addition, the present invention includes all pharmaceutically acceptable salts of the aforementioned compounds. The person skilled in the art it is obvious that salt accession acids claimed in the present invention compounds can be obtained by the interaction of the compounds with the appropriate acid through a number of known methods.

Can be used in a variety of oral dosage forms, including such solid forms as tablets, gelatin capsules, capsules, caplet, granules, pellet and granular powders, and liquid forms, such as emulsion, solution and suspension. Compounds of the present invention can be introduced as such, or they can be combined with various pharmaceutically acceptable carriers and excipients known to specialists in this field, including, but not limited to the following, thinners, suspendresume funds soljubilizatory, leavening agents, preservatives, dyes, lubricants, etc.

In those cases where the compounds of the present invention include oral pills, the above-mentioned tablets can be compressed, RUB in the powder covered intersolubility coated, covered sugar shell, covered with a film cover is receiving, repeatedly pressed or composed of multiple layers. Liquid oral dosage forms include aqueous and non-aqueous solutions, emulsions, suspensions and solutions and/or suspensions, reconstructed from nishiuchi granules, containing suitable solvents, preservatives, emulsifying means, suspendresume tools, diluents, sweeteners, colors and flavors. In those cases where the compounds of the present invention should be injected parenterally, they may be, for example, in the form of an isotonic sterile solution. Alternatively, when the compound of the present invention must be administered by inhalation, they can be included in the dry aerosol or can be prepared in the form of an aqueous or partially aqueous solution.

In addition, when the compounds of the present invention includes the composition of the oral dosage forms, it is assumed that these dosage forms can provide immediate (immediate) release compounds in the gastrointestinal tract or, alternatively, can provide controlled and/or prolonged release through the gastrointestinal tract. Specialists in this field there are a number of compounds monitored and/or prolonged action, and such compositions are considered the AK suitable for use in connection with the compositions of the present invention. Controlled and/or prolonged action can be achieved, for example, by coating the oral dosage form or by incorporating the compound(s) of the present invention in a matrix that provides a controlled and/or prolonged release (drugs).

Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986). Methods and compositions for the preparation of solid oral dosage forms are described in Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) 2ndedition, published by Marcel Dekker, Inc. Methods and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington''s Pharmaceutical Sciences (Arthur Osol, editor), 1553B1593 (1980). Methods and compositions for the preparation of liquid oral dosage forms are described in Pharmaceutical Dosage Forms: Disperse Systems (Lieberman, Rieger and Banker, editors), published by Marcel Dekker, Inc.

In those cases where the compounds of the present invention includes (in part) for parenteral administration by injection (e.g., continuous infusion or injection of bolus), the composition for parenteral administration may be in the form of suspensions, solutions, emulsions in oily or is-breaking solvents (fillers), and the above compositions can optionally include pharmaceutically necessary additives such as a stabilizing means, suspendresume means dispersing means and the like, the compounds of this invention can be in powder form for recovery in the form of an injectable composition.

In some embodiments the embodiment of the compounds of the present invention can be used in combination at least one other therapeutic agent. Therapeutic agents include, but are below does not limit the scope of protection of the present invention) μ-opioid agonists; non-analgesics; non-steroidal anti-inflammatory agents; inhibitors SOH-II; anti-emetics; β-adrenergic blockers; anti-convulsants; anti-depressive funds; blockers of Ca2+channel; an anti-cancer agent, and mixtures thereof.

In some embodiments the embodiment of the compounds of the present invention can be prepared in the form of a pharmaceutical dosage form in combination with agonists μ-opioid receptor. Agonists μ-opioid receptor, which can be included in the compositions of the present invention include, but without limiting the scope of protection of the present invention following, Alfentanil, allylprodine, Alphaprodine, Anileridine, Benz is Morfin, Bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphine, 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 thereof.

In some preferred embodiments the embodiment of agonist μ-opioid receptor is selected from codeine, hydromorphone, hydrocodone, oxycodone, Dihydrocodeine, dihydromorphine, morphine, tramadol, Oxymorphone, their pharmaceutically acceptable salts and mixtures thereof.

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 and inhib the Torah 5-lipoxygenase, and their combinations are described in U.S. patent No. 6136839, which is an integral part of the present description by reference. Inhibitors SOH-II include, but without limiting the scope of protection of the present invention following, 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.

Compounds of the present invention can also be combined in a dosage form with non-analgesics, such as nonsteroidal 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, bulokovu (bucloxic) 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 thereof. The other is the development of suitable non-analgesics, which can be included in the dosage forms of the present invention include the following, but not limited to the scope of protection of the present invention, chemical classes of analgesic, antipyretic, nonsteroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, trisalicylate magnesium, choline, salsalate, diplopia, salicylsalicylic acid, sulfasalazin and olsalazine; derivatives of para-aminophenol, including acetaminophen; indolyl - and indenyl-acetic acids, including indomethacin, sulindac and etodolac; heteroarylboronic acid, including tolmetin, diclofenac, and Ketorolac; Anthranilic acid (fenamate), including mefenamico acid and meclofenamic acid; enologia acid, including oxicam (piroxicam, tenoxicam), and pyrazolidinone (phenylbutazone, exifinterface); and alkenone, including nabumetone. For a more detailed description NSPs that can be included in the composition of medicines used in the present invention, see Paul A.Insel Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the treatment of Gout in Goodman & Gilman''s The Pharmacological Basis of Therapeutics, 617-57 (Perry B. Molinhoff and 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 an integral part of this is completed with the description by reference.

In some embodiments the embodiment of the compounds of the present invention can be prepared in the form of a pharmaceutical dosage form in combination with protivomigrenoznami means. Caused funds include, but without limitation of protection of the present invention following, Alperovich, digidroergotamin, dolasetron, ergocornine, ergocornine, ergocryptine, ergot, ergotamine, flumetralin acetate, fonadin, lisuride, lomerizine, methylsergide oximoron, pizotyline and mixtures thereof.

The other therapeutic agent can also act as an adjuvant to reduce the manifestation of possible side effects, such as anti-emetics. Suitable anti-emetics include, but without limiting the scope of protection of the present invention following, metoclopramide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine, monoethanolamine, alizapride, azasetron, benchenane, betnoti, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, difenidol, dolasetron, meclizine, metallical, metopimazine, nabilone, oxybenzyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinols, tietilperazin, thioproperazine, tropisetron, and mixtures thereof.

In some embodiments the embodiment of the compounds of this image is etenia can be prepared in the form of a 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, buterin hydrochloride, 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 the present invention can be prepared in the form of a pharmaceutical dosage form in combination with anticonvulsant drugs. Suitable anti-convulsants include, but without limiting the scope of protection of the present invention below, 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, atoto is, felbamat, 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, patenet sodium, potassium bromide, pregabalin, primidone, progabid, sodium bromide, Solanum, bromide, strontium, cyclofenil, Altium, atlantain, tiagabine, topiramate, trimethadione, valproate acid, valpromide, vigabatrin and zonisamide.

In some embodiments the embodiment of the compounds of the present invention can be prepared in the form of a pharmaceutical dosage form in combination with antidepressant drugs. Suitable antidepressant tools include, but without limitation, the following, bendalin, Caracazo, citalopram, deltason, fenomen, indalpine, indeloxazine hydrochloride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, tiazesim, trazodone, benmoxin, preclosed, iproniazid, isocarboxazid, nialamide, actimoxi, phenelzine, cotinine, realiseren, rolipram, maprotiline, metralindol, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptyline, amoxapine, butriptyline, clomi is Ramin, 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, chloride rubidium, sulpirid, tandospirone, totaline, ciencin, toloxatone, tranilcipromin, L-tryptophan, venlafaxine, viloxazine and zimeldine.

In some embodiments the embodiment of the compounds of the present invention can be prepared in the form of a pharmaceutical dosage form in combination with blockers of Ca2+-channel. Suitable blockers Ca2+channel include, but without limiting the scope of protection of the present invention following, bepridil, clentiazem, diltiazem, fendilin, gallopamil, mibefradil, prenilamin, remotedir, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elhadidy, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, the NIF is a yiping, nilvadipine, nimodipine, nisoldipine, nitrendipin, Cinnarizine, flunarizin, lidoflazine, lomerizine, benzilan, athenon, fanfaron and perhexiline.

In some embodiments the embodiment of the compounds of the present invention can be prepared in the form of a pharmaceutical dosage form in combination with anticancer agents. Suitable anti-cancer tools include, but without limitation, the following, acivicin; aclarubicin; acetasol hydrochloride; Acronis; adozelesin; aldesleukin, altretamine; ambomycin; ametantrone acetate; aminoglutetimid; amsacrine; anastrozole; astromicin; asparaginase; aspirin; azacytidine; asettaa; azotomycin; batimastat; benzodepa; bikalutamid; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; breiner sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; karubitsin hydrochloride; carzelesin; Cedeira; chlorambucil; cirolemycin; cisplatin; cladribine; Kristol mesilate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; decompletion; deazaguanine; deazaguanine mesilate; diazinon (diaziquone); docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; deatomizer; edatrexate; eflornithine hydrochloride; Altamar the CIN; anoplate; enpromate; epirubicin; epirubicin hydrochloride; arbolada; zorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; atopen; fadrozole hydrochloride; fazarabine; phenetidine; floxuridine; fludarabine phosphate; fluorouracil; fluorocytosine; fashion (fosquidon); fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubitsin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II or rIL2), alpha-2 interferon, alpha-2b interferon, alpha-n1, pegylated interferon, alpha-n3, interferon beta-Ia interferon; gamma-Ib interferon; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; lioresal hydrochloride; lometrexol sodium; lomustin; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; Matorin; matureup; maintain; metatarsi; 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; Cartosat sodium; sparsomycin; spirogermanium hydrochloride; spiramycin; spiroplatin; streptonigrin; streptozocin; alienor; talisayan; tecogen sodium; tegafur; Alexandre hydrochloride; ]; teniposide; teraxion; testolactone; timipre; tioguanin; thiotepa; teatterin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate the glucuronate; triptorelin; tubulosa hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; benefitin sulfate; Inglesina sulfate; villarodin sulfate; vinorelbine tartrate; vinpocetin sulfate; ventolin sulfate; vorozole; triplatin; zinostatin; zorubicin hydrochloride. Other anti-cancer tools include, but listed below do not limit the scope of protection of the present invention: 20-EPI-1,25 dihydroxyvitamin D3; 5-itinerarary; abiraterone; aclarubicin; allfusion; Adelina; adozelesin; aldeslakin; antagonists ALL-TK; altretamine; ambamustine; amidax; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; Andrographolide; inhibitors of angiogenesis; D; antagonist G; entrelacs; anti-dorsal morphogenetic protein-1; antiandrogen prostate cancer; antiestrogen; antineoplaston; touch oligonucleotides; aphidicolin glycinate; modulators of apoptosis gene; regulators of apoptosis; apurinovaya acid; ara-CDP-DL-PTBA; argininosuccinate; isolagen; atamestane; attemptin; achinstein 1; achinstein 2; achinstein 3; azasetron; anatoxin; asteroid; derivatives baccatin III; balana; batimastat; antagonists BCR/ABL; benzocaine; benzoyltartaric; derivatives of beta-lactam beta-alamin; butaclamol In; Betulinol acid; inhibitor of bFGF; bikalutamid; bisantrene; besuseradminclient; bisnafide; bitrate And; bizelesin; Brevet; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin; derivatives camptothecin; canarypox IL-2; capecitabine; carboxamidine; carboxamidates; CARest M3; CARN 700; inhibitor derived from cartilage; carzelesin; inhibitors caseinline (ICOS); castanospermine; cecropin; cetrorelix; chlorins; chloroquinoxalin the sulfonamide; cicaprost; CIS-porphyrin; cladribine; analogues clomiphene; clotrimazole; colimycin a; colimycin; combretastatin A4; similar combretastatin; convenin; kambezidis 816; Kristol; cryptophycin 8; derivatives cryptophycin a; curacin a; cyclopentadecanone; cyclopean; cephamycin; cytarabine akfast is t; cytolytic factor; cytostatin; daclizumab; decitabine; dehydrodidemnin; deslorelin; dexamethasone; Taxifolin; dexrazoxane; dexverapamil; diazinon (diaziquone); didemnin; detox; diethylnitrosamine; dihydro-5-azacytidine; 9-dihydroxy; dioxazine; diphenylpyraline; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen, elastin; edelfosine; edrecolomab; eflornithine; elements; emiterror; 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 receptor insulin-like growth factor-1; interferon agonists; interferons; interleukins; iobenguane; iododeoxyuridine; 4-ipomeanol; ireplace; irsogladine; isomerases; isohemagglutinins; fusetron; aspecial is d; kahalalide F; lamellarin-N triacetate; lanreotide; linamarin; lenograstim; lentinan sulfate; leptostachys; letrozole; leukemia-inhibitory factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leiprorelina; levamisole; lioresal; linear analogue polyamine; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinum 7; lobaplatin; lubricin; lometrexol; lonidamine; losoxantrone; lovastatin; doxorubin; lurtotecan; Lu texaphyrin; lisofylline; lytic peptides; maytansine; sandostatin a; marimastat; masoprocol; maspin; inhibitors matrilysin; inhibitors of matrix metalloproteinases; menogaril; merbanan; peterlin; methionine; metoclopramide; inhibitor of MIF; mifepristone; miltefosine; Miramistin; double-stranded RNA with incorrectly paired bases; mitoguazone; mitolactol; analogues of mitomycin; mitonafide; saporin-growth factor ecotoxicologie fibroblast; mitoxantrone; Maarten; molgramostim; monoclonal antibody, human chorionic gonadotropin; monophosphorylated A+myobacterial cell wall sk; mopidamol; inhibitor of the gene of resistance to drugs; the main treatment aimed at suppressing multiple tumor; mustard-like (mustard) an anti-cancer agent; megaproxy; extract cell wall of mycobacteria; Miri the UNDP; N-azetidinone; N-substituted benzamide; nafarelin; Agresti; naloxone+pentazocine; nipawin; Natterer; nartograstim; nedaplatin; nemorubicin; Nejdanov acid; neutral endopeptidase; nilutamide; nizamettin; modulators of nitric oxide (NO); antioxidant nitroxide; nitrolon; O6-benzylguanine; octreotide; okizeme; oligonucleotides; onapristone; ondansetron; oracin; oral inducer of cytokine; ormaplatin; asteron; oxaliplatin; axiomized; paclitaxel; analogues of paclitaxel, derivatives of paclitaxel; palyulin; palmitoylation; pamidronovu acid; panaxytriol; promife; pyrabactin; pallidin; pegaspargase; peltatin; pentosan polysulfate sodium; pentostatin; petrosal; perflubron; perforated; parallelly alcohol; fansinating; phenylacetate; inhibitors of phosphatase; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placedin a; Platin; inhibitor of plasminogen activator; a complex of platinum; platinum compounds; complex platinum-triamine; porfimer sodium; porfiromycin; prednisone; propyl bis-acridan; prostaglandin J2; inhibitors proteasome; immune modulator on the basis of protein A, an inhibitor of protein kinase C, inhibitors of protein kinase C; microalgal; inhibitors of protein-tyrosine-phosphatase; inhibitors of the purine-nucleoside phosphorylase; purpurin; pyrazoloacridine; conjugate of pyridoxine is consistent hemoglobin and polyoxyethylene; antagonists raf; raltitrexed; ramosetron; inhibitors of ras farnesyl-protein transferase; ras inhibitors; inhibitors of ras-GAP; reality demetilirovanny; rhenium Re-186 etidronate; rhizoxin; enzymes ribosomal type (ribozymes); RII retinamide; reglated; rohitukine; romantic; rainmax; rubiginosa B1; robaxin; safingol; sintobin; SarCNU; sarcophyton A; sargramostim; mimetics Sdi 1; semustine; inhibitor 1 aging; touch oligonucleotides; inhibitors of signal transduction; modulators of signal transduction; single-chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solvera; protein binding somatomedin; sonarmen; sportsbuy (sparfosic) acid; spicamycin D; spiramycin; splenopathy; spongistatin 1; squalamine; inhibitor of stem cells; inhibitors of the division of stem cells; stipend; inhibitors stromelysin; solifenacin; super active antagonist of vasoactive intestinal peptide; coralista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; terramycin; tazarotene; tecogen sodium; tegafur; tolerability; telomerase inhibitors; ]; temozolomide; teniposide; tetrachlorodecaoxide; tetrasomy; teleblaster; thiocoraline; thrombopoietin; mimetic of thrombopoetin; thymalfasin; agonist of the receptor of thymopoietin; timorian; thyroid-stimuler is a walking hormone; tin ethyl adipocere; tirapazamine; titanocene bichloride; topsentin; toremifene; factor totipotent stem cells; inhibitors broadcast; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostin; inhibitors UBC; ubenimex; factor inhibiting the growth of urogenital sinus; antagonists of the receptor for urokinase; vapreotide; violin; vector system for gene therapy of erythrocyte system; valarezo; vermin; verdini; verteporfin; vinorelbine; Wincanton; vitaxin; vorozole; centeron; triplatin; cerasorb and zinostatin stimulater.

Compounds of the present invention and other (additional) therapeutic agent can act additively or, more preferably, synergistically. In a preferred variant embodiment of the composition comprising the compound of the present invention, is administered concurrently with the introduction of another therapeutic agent, which may be part of the same composition or may be in a composition different from compositions containing the compounds of the present invention. In another variant embodiment of the composition comprising the compounds of the present invention, are administered before or after administration of another therapeutic agent.

Compounds of the present invention, with the introduction of, for example, the R, mammal oral, parenteral or local paths can be represented in a dose in the range from about 0.01 mg/kg to about 3000 mg/kg of body weight of the patient per day, preferably from about 0.01 mg/kg to about 1000 mg/kg of body weight per day, administered once or in divided doses. However, this will be variations in dose depending, among other things, on body weight and physical condition (e.g., liver and kidney function) of the subject to be treated; a disease to be treated; the severity of symptoms, route of administration, frequency of dosing interval, the presence of any harmful side effects and specific connection.

Compounds of the present invention preferably have a binding affinity of Kiwith regard to the human receptor ORL-1 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 testing using membranes from recombinant cells HEK-293 expressing the human receptor(ORL-1), similar to the opioid receptor, as described below.

The following examples illustrate various aspects of the present invention, and it should be borne in mind that these examples in no way limit the claims.

EXAMPLE 1

Synthesis spiritlessly head groups

Technique:

To a solution of their LDA in THF (1.1 EQ.) at -40°add a solution of 1 (1 equiv.) in THF. The reaction mixture allow to warm to room temperature (CT) and stirred for 1 h, After cooling to -20°With added dropwise a solution of benzoyl chloride (2, 1.2 EQ.) in THF. After stirring at -20°C for 1 h and at RT for 16 h the reaction mixture was poured into water and extracted with ethyl acetate. The organic extracts are washed with saturated ammonium chloride, saturated salt solution, dried over MgSO4, filtered and the solvent is evaporated, obtaining the crude product 3 in the form of oil, which is used without purification in the next stage.

1H-NMR (CDCl3): d a 1.08 (t, 3H), 2,28 (t, 4H), 2,43 (m, 2H), 2,54 (m, 2H), 3.46 in (s, 2H), 4,13 (kV, 2H), 7,21-7,31 (m, 5H), 7,39 (m, 2H), 7,49 (m, 1H), 7,79 (m, 2H).

To a solution of 3 (1 EQ.) in ethanol add hydrazinehydrate (3 EQ.). After boiling under reflux for 12 h, the reaction mixture was cooled to CT, and the crude product filtered off. The solid is recrystallized from ethanol, getting 4 in the form of a white solid.

1H-NMR (DMSO): d 1,67 (d, 2H), 2,23 (dt, 2H), 2,62 (DD, 2H), and 2.83 (dt, 2H), of 3.56 (s, 2H), 7,25 (m, 1H), 7,35 (m, 4H), to 7.50 (m, 3H), 7,78 (m, 2H).

Compound 4 (1 EQ.) and Pd(OH)2(0.2 EQ.) in methanol hydronaut when CT and hydrogen pressure of 50 psi for 20 h Filtration and evaporation give 5. Recrystallization from ethanol yields pure 5 as a white solid.

1H-NMR (DMSO): d 1,50 (d, 2H), 2,12 (m, 2H), by 2.73 (m, 2H), or 3.28 (m, 2H), 7,45 (m, 3H), 7,86 (d, 2H).

EXAMPLE 2

The accession of end groups

End groups attached to the head groups according to the following methods:

The General procedure for alkylation:

To a solution of amine (1 EQ) and triethylamine (1 EQ.) in dimethylformamide was added 1 EQ. allylbromide or alkylchloride in one piece. The mixture is stirred and heated at 80°With during the night. TLC (TLC) indicates the completion of the reaction. Then the reaction quenched by addition of water followed by the addition of 1H. NaOH to pH 10. The mixture is extracted with 2 times by Et2O. the combined organic extracts are dried over potassium carbonate and the solvent is evaporated, after which the resulting residue is subjected to chromatography to obtain the pure product.

A General method for gidroaminirovaniya:

To a mixture of ketone or aldehyde (1 EQ.), amine (1 EQ.) and acetic acid (1 EQ.) in methanol add nutritionbased (1.4 EQ) in one portion. The mixture is stirred over night at room temperature. TLC is found at the end of the reaction. The reaction is quenched by addition of water followed by the addition of 1H. NaOH to pH 10. The mixture is extracted with 2 times by Et2O. the combined organic extracts are dried over potassium carbonate and the solvent is evaporated, after which the resulting residue is subjected to chromatography, obtaining a pure product.

The following compounds are joining end groups, using the techniques described above.

8-(benzyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

MS: m/z 342,2 (M+Na)

1H-NMR (DMSO): d 1,67 (d, 2H), 2,23 (dt, 2H), 2,62 (DD, 2H), and 2.83 (dt, 2H), of 3.56 (s, 2H), 7,25 (m, 1H), 7,35 (m, 4H), to 7.50 (m, 3H), 7,78 (m, 2H).

8-[(naphthas-2-ylmethyl)]-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC (LC): 97,7%

MS: m/z 370,6 (M+1)

1H-NMR (CDCl3): 1,80 d (OSiR., 2H), 2,50 (m, 2H); 2,80 (user., 2H), 2,03 (t, 2H, in), 3.75 (s, 2H), 7,50 (m, 5H), 7,60 (d, 1H), 7,80 (m, 6H), 8,42 (user., 1H).

8-(p-phenylbenzyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC: 90.1%of

MS: m/z 396,6 (M+1)

1H-NMR (CDCl3): 1,80 d (OSiR., 2H), of 2.51 (m, 2H), 2,80 (user., 2H), to 3.02 (m, 2H, in), 3.75 (s, 2H), 7,35-of 7.70 (m, 12H), 7,85 (user., 2H), and 8.50 (user., 1H).

8-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC: 100%

MS: m/z 444,2 (M+Na)

1H-NMR (CDCl3): d 1,75 (user., 2H), 2,35 (m, 2H), 2,61 (user., 2H), 2,85 (m, 4H), 4,11 (m, 2H), 4,20 (s, 1H), 7,10-7,28 (m, 8H), was 7.45 (m, 3H), a 7.85 (m, 2H), and 8.5 (s, 1H).

8-[4,4-Bis(4-forfinal)butyl]-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC: 96,9%

MS: m/z

1H-NMR (CDC 3): d 0,75-2,90 (m, 10H), of 3.60 (m, 2H), 3,80 (m, 1H), 3,90 (m, 1H), 4,55 (m, 1H), 6.90 to-to 7.50 (m, 11H), 7,80 (user., 2H), 8,45 (user., 1H).

8-(3,3-Bis(phenyl)propyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC: 100%

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

1H-NMR (CDCl3): 1,80 d (OSiR., 2H), 2,35 (m, 2H), 2,50 (m, 4H), 2,78 (user., 2H), 2.95 and (m, 2H), of 4.05 (t, 1H), 7,20 (m, 2H), 7,30 (m, 8H), was 7.45 (m, 3H), 7,85 (user., 2H), 8,70 (user., 1H).

8-(p-benzyloxybenzyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC: 97,6%

MS: m/z to 426.2

1H-NMR (CDCl3): 1,80 d (OSiR., 2H), a 2.45 (dt, 2H), 2,80 (user., 2H), 2.95 and (m, 2H), 3,60 (s, 2H), 5,10 (s, 2H), 6,95 (d, 2H), 7,30-to 7.50 (m, 10H), 7,88 (m, 2H), 8,71 (s, 1H).

8-(1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC: 95.3%of the

MS: m/z 360,2 (M+1)

1H-NMR (CDCl3): d 1,85-1,90 (m, 3H), 2,42 (user., 1H), 2,85 is 3.15 (m, 6H), 3,20 (user., 2H), 3,40 (m, 2H, in), 3.75 (m, 1H), 7,10-7,20 (m, 4H), to 7.50 (m, 3H), of 8.00 (d, 2H).

8-(4-propylcyclohexyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC: 100%

MS: m/z 354,2 (M+1)

1H-NMR (CDCl3): d 1,95 (t, 3H), of 1.35 (m, 6H), to 1.60 (m, 2H), 1,80 (m, 3H), 1,95 (d, 4H) 2,25 (d, 1H), 3,05 (t, 3H), 3,30 (d, 2H), and 3.8 (q, 2H), 7,50 (t, 1H), 7,60 (m, 2H), 8,00 (d, 2H).

8-(5-metrex-2-yl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC: 100%

MS: m/z 328,2 (M+1)

1H-NMR (CDCl3): d 0,9-of 1.65 (m, 12H), 2.00 (evens userd, 4H), 2.05 is-is 2.30 (m, 5H), of 3.95 (t, 2H), 7,50 (t, 1H), 7,60 (t,2H), 8,02 (d, 2H).

8-norbornyl-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

MS: m/z 324,2 (M+1)

1H-NMR (CDCl3): d 0,80-3,90 (m, N), 4,20 (m, 2H), 4,85 (user., 1H), 7,40 to 7.62 (m, 3H), with 8.05 (m, 2H), 8,75 (user., 1H).

8-(decahydro--naphthyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC: 100%

MS: m/z 366,2 (M+1)

1H-NMR (CDCl3): d 0,95-of 2.15 (m, 17H), is 2.30 (m, 1H), 3,10 (m, 3H), at 3.35 (m, 2H), 3,95 (m, 2H), 7,55 (t, 1H), 7,65 (t, 2H), 8,02 (d, 2H).

8-(cyclooctyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC: 100%

MS: m/z 340,2 (M+1)

1H-NMR (CDCl3): d 1,40 was 2.25 (m, N), 3,10 (m, 2H), 3,20 (user., 2H), 3,38 (m, 1H), was 4.02 (m, 2H), 7,50 (t, 1H), 7,60 (t, 2H), 8,02 (m, 2H).

8-[4-(2-propyl)cyclohexyl]-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC: 100%

MS: m/z 354,2 (M+1)

1H-NMR (CDCl3): d of 0.9 (m, 6N), 1,45-of 1.65 (m, 3H), of 1.78 (m, 2H), 2.00 (evens of user., 6N), 2,30 (d, 1H), 3,10 (m, 3H), 3,30 (t, 2H), 3,95 (kV, 2H), 7,50 (t, 1H), 7,60 (t, 2H), 8,00 (m, 2H).

8-(1,3-dihydroindol-2-yl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC: 100%

MS: m/z 346,1 (M+1)

1H-NMR (CDCl3): d 1,90-of 3.80 (m, N), 4,25 (m, 1H), 7,20-of 7.70 (m, 8H), to 7.95 (d, 1H).

8-(cyclooctylmethyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC: of 92.9%

MS: m/z 354.6 M. (M+1)

1H-NMR (MeOH): d of 1.40 and 1.80 (m, 14H), 2,00 (user., 2H), 2,10 (m, 1H), 2,60 (m, 2H), 2,90 (m, 2H), 3,40 (m, 2H), 3,70 (m, 2H), 7,50 (m, 3H), 7,80

8-(acenaphthen-9-yl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one

LC: 100%

MS: m/z 382,2 (M+1)

1H-NMR (CDCl3): d 1,69 (DD, 1H), 1,72 (DD, 1H), 2,36 is 2.44 (m, 2H), 2,52-2,60 (DDD, 1H), 2,83 (userd, 1H), 3,17-3,24 (m, 1H), 3,30-3,44 (m, 2H), 3,60-the 3.65 (m, 1H), free 5.01 (DD, 1H), 7,31 (d, 1H), 7,45-7,49 (m, 4H), 7,52-EUR 7.57 (m, 2H), a 7.62 to 7.64 (d, 1H), 7,69-7,71 (m, 1H), 7,86-7,88 (m, 2H), 8,42 (s, 1H).

Other compounds within the scope of formula (I) or (IA) of the present invention can be synthesized using the same methods.

EXAMPLE 3

Aff is held nociceptin receptor ORL-1 preferred compounds determine using the following test:

Membranes from recombinant cells HEK-293 expressing similar opioid receptor is a human receptor(ORL-1) (Receptor Biology), obtained by lizirovania cells in ice-cold hypotonic buffer (2.5 mm MgCl2, 50 mm HEPES, pH 7.4) (10 ml/10-cm Cup) followed by homogenization of the tissue grinder/Teflon pestle. Membranes are collected by centrifugation at 30000×g for 15 min at 4°and precipitation resuspended in hypotonic buffer to a final concentration of 1-3 mg/ml protein Concentration determined using the reagent for analysis BioRad protein with bovine serum albumin as standard. Aliquots of membrane receptor ORL-1 stored at -80°C.

Functional analyses of binding SGTPgS carried out as follows. Get solution of membranes ORL-1, sequentially adding membrane protein ORL-1 to a final concentration of 0.066 mg/ml saponin to 10 mg/ml, guanozintrifosfat (GDF) to 3 mm and [35S]GTPgS to 0.20 nm to the buffer for binding (100 mm NaCl, 10 mm MgCl2, 20 mm HEPES, pH 7.4) on ice. The resulting solution was membrane (190 ml/well) is transferred into a 96-well polypropylene tablets with shallow wells containing 10 ml of 20x concentrated source solutions agonist obtained in DMSO. Tablets incubated for 30 min at room temperature with shaking. The reaction would cut the Troy filter on 96-well filtration tablets Unifilter GF/B, Packard), using 96-well tissue harvester (Brandel), followed by three filtration washing with 200 ml of ice-cold buffer for binding (10 mm NaH2PO4, 10 mm Na2HPO4, pH 7.4). Then filtration tablets are dried at 50°C for 2-3 hours. Add fifty ml/well scintillation konchella (BetaScint; Wallac) and tablets read in a Packard Top-Count for 1 min/well.

Data analyzed using the curve fitting functions in GraphPad PRISMO, v.3.0, and the results are presented below in Table 1:

Table 1

Nociceptive affinity
ConnectionThe expect. Ki(nm)
8-(4-propylcyclohexyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one29,7
8-(5-metrex-2-yl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one11,5
8-norbornyl-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one897
8-(decahydro-2-naphthyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one1,1
8-(cyclooctyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one8,1
8-(1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one52,3
8-[4-(2-propyl)cyclohexyl]-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one1,5
8-(1,3-dihydroindol-2-yl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one43
8-[(naphthas-2-ylmethyl)]-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one402
8-(p-phenylbenzyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one7171
8-[4,4-Bis(4-forfinal)butyl]-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one2589
8-(benzyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one293
8-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one282
8-(3,3-Bis(phenyl)propyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one75
8-(p-benzyloxybenzyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one138
8-(cyclooctylmethyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one61
8-(acenaphthen-9-yl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one0,06

The following table 1A gives similar data for a number of additional compounds of the present invention, obtained by the applicant and confirming the amount of the compounds according to the invention.

Table 1a

Nociceptive affinity to the receptor ORL-1 for additional connections
Connectionis ascit. Toi(nm)
Compounds with different substituents W
2-(Cyanomethyl)-8-(3,3-bis(phenyl)propyl)-4-phenyl-2, 3,8-treetopia[4.5]Dec-3-EN-1-he39
2-(Carboxymethyl)-8-(3,3-bis(phenyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he1518
2-(Ethoxycarbonylmethyl)-8-(3,3-bis(phenyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he145
2-(2-Ethoxycarbonylethyl)-8-(3,3-bis(phenyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he73
2-(2-Carboxyethyl)-8-(3,3-bis(phenyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he1429
2-(4-Ethoxycarbonylbutyl)-8-(3,3-bis(phenyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he203
2-(4-Carboxybutyl)-8-(3,3-bis(phenyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he4880
2-(Ethoxycarbonylmethyl)-8-(3,3-bis(phenyl)propyl)-4-(4-methyl)phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he1313
2-(Aminocarbonylmethyl)-8-(3,3-bis(phenyl)propyl)-4-(4-methyl)phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he3959
2-(2-(Methanesulfonamido)ethyl)-8-(3,3-bis(phenyl)propyl)-4-(4-methyl)-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he1317
Typical connections with a variety of C is Mascitelli R 2
8-(Benzyl)-4-(4-methyl)phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he928
8-(Benzyl)-4-(3-methyl)phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he620
8-(Benzyl)-4-(2-methyl)phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he2192
8-(Benzyl)-4-(4-chloro)phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he325
Typical compounds with different substituents-Z-R1
8-(3,3-Bis(phenyl)-3-(dimethylaminoethyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he362
8-(3,3-Bis(phenyl)-3-(methoxycarbonyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he37
8-(3,3-Bis(phenyl)-3-cyanopropyl)-4-phenyl-2,3,8-TeliaSonera[4.5]Dec-3-EN-1-he2834

EXAMPLE 5

The affinity to the receptor μ for some compounds of the present invention are determined according to the following test:

Get solution of membranes opioid receptor μsequentially adding to a final concentration of 0.075 ág/ál of the desired membrane protein, saponin to 10 µg/ml of GDP to 3 μm and [35S]GTPγS to 0.20 nm to the buffer for binding (100 mm NaCl, 10 mm MgCl2, 20 mm HEPES, pH of 7.4) on ice. The resulting solution was membrane (190 μl/well) is transferred into a 96-well polypropylene planches who you're with shallow holes, containing 10 ál of 20x concentrated source solutions agonist obtained in DMSO. Tablets incubated for 30 min at room temperature with shaking. The reaction being removed by rapid filtration onto 96-well filtration tablets Unifilter GF/B, Packard)using a 96-well tissue harvester (Brandel), followed by three filtration washing with 200 ml of ice-cold buffer for binding (10 mm NaH2PO4, 10 mm Na2HPO4, pH 7,4). Then filtration tablets are dried at 50°C for 2-3 hours. Add fifty ml/well scintillation cocktail (MicroScint20, Packard) and tablets read in a Packard Top-Count for 1 min/well.

Data analyzed using the curve fitting functions in GraphPad PRISM™, v.3.0, and the results are presented below in Table 2:

Table 2

The affinity to the receptor μ
ConnectionThe expect. Toi(nm)
8-(1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one115
8-[(naphthas-2-ylmethyl)]-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one84
8-(benzyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one56
8-(cyclooctylmethyl)-1-phenyl-2,3,8-treetopia[4,5]Decan-4-one191

Yes the data on the toxicity of the compounds according to the invention

Below presents representative data on the inhibition of CYP3A4, indicating low toxicity of the compounds of the present invention. Numerical values indicate the % activity of CYP3A4, continuing through 40 minutes

ConnectionCYP3A4
8-(Benzyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he100
8-(4-Propylcyclohexyl)-4-phenyl-2,3,8-treetopia[4.5]-Dec-3-EN-1-he90
8-(5-Metrex-2-yl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he93
8-(Norbornyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he90
8-(Decahydro-2-naphthyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he89
8-(Cyclooctyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he95
8-(1,2,3,4-tetrahydro-2-naphthyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he89
8-(4-(2-propyl)cyclohexyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he88
8-(1,3-dihydroindol-2-yl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he100
8-(cyclooctylmethyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he89
8-(p-benzyloxybenzyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he99
8-(3,3-Bis(phenyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he100
8-(10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he100
8-(3,3-Bis(phenyl)-3-(dimethylaminoethyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he82
2-(4-Carboxybutyl)-8-(3,3-bis(phenyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he88
2-(2-Ethoxycarbonylethyl)-8-(3,3-bis(phenyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he68
2-(4-Ethoxycarbonylbutyl)-8-(3,3-bis(phenyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he78
2-(Ethoxycarbonylmethyl)-8-(3,3-bis(phenyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he73
2-(2-Carboxyethyl)-8-(3,3-bis(phenyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he99
2-(Carboxymethyl)-8-(3,3-bis(phenyl)propyl)-4-phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he96
8-(Benzyl)-4-(4-methyl)phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he100
8-(Benzyl)-4-(3-methyl)phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he87
8-(Benzyl)-4-(2-methyl)phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he100
8-(Benzyl)-4-(4-methoxy)phenyl-2,3,8-triaza the Piro[4.5]Dec-3-EN-1-he 94
8-(Benzyl)-4-(4-chloro)phenyl-2,3,8-treetopia[4.5]Dec-3-EN-1-he95

1. Connection spiroperidol General formula (I)

where W denotes hydrogen; C1-10-alkyl; C3-7-cycloalkyl; cyano-C1-10-alkyl; the group-C1-4alkyl-COOV1where V1selected from N and C1-6-alkyl; the group-C1-5alkyl-C(=O)W1where W1means an amino group; or a group-C1-5alkyl-NHS(=O)2W1where W1means1-10-alkyl;

Q means phenyl;

n represents the integer 0 or 1;

A, b and C denote hydrogen;

Z is selected from the group consisting of simple communication, methylene, and ethylene;

R1selected from the group consisting of C3-12-cycloalkyl, optionally substituted C1-10-alkyl; bicyclic aryl group such as naphthyl, tetrahydronaphthyl, decahydronaphthalene, indenyl or norbornyl; tricyclic aryl groups, such as dibenzocycloheptadiene or 9-acenaphthyl; phenyl, optionally substituted benzyloxy; biphenyl; and (C1-10-alkyl, optionally substituted by 1-3 substituents selected from the group consisting of phenyl, cyano, -COOV1where V1means1-6-alkyl, and-C1-5alkyl-C(=O)W1where W1means amino, C1-4-and what calamine or di-C 1-4-alkylamino;

R2selected from the group consisting of C1-10-alkyl, C3-7-cycloalkyl and halogen;

or their pharmaceutically acceptable salt, or MES.

2. The compound according to claim 1, where W is selected from the group consisting of-CH2C=ONH2, cyclopentyl, cyclohexyl, CH2CH2NHSO2CH3and cyanomethyl.

3. The compound according to claim 1, where ZR1selected from the group consisting of cyclohexylamine, cyclohexylmethyl, cyclopentylmethyl, phenylethyl, cyclopentyl, cyclohexyl and exile.

4. The compound according to claim 1, where ZR1or W represents-CH2COOV1.

5. The compound according to claim 1, where ZR1is 3,3-diphenylpropyl, optionally substituted at the 3 carbon of cut group-COOV1, cyano, aminocarbonyl, C1-4-alkylaminocarbonyl or di-C1-4-alkylaminocarbonyl.

6. The compound according to claim 1, where R1is alkyl selected from the group consisting of methyl, ethyl, propyl, butyl, pentile and exile.

7. The compound according to claim 1, where R1is cycloalkyl selected from the group consisting of cyclohexyl and cycloheptyl, or norbornyl.

8. The compound according to claim 1, where R1is tetrahydronaphthyl, decahydronaphthalene or dibenzocycloheptadiene.

9. The compound according to claim 1, where R1represents phenyl.

10. The compound according to claim 1, where R1before the hat bicyclic aromatic structure.

11. The connection of claim 10, where the specified bicyclic aromatic structure is indenyl or naphthyl.

12. The compound according to claim 1, where Z represents a bond or methylene.

13. The compound according to claim 1, selected from the group consisting of the following compounds:

8-(4-propylcyclohexyl)-4-phenyl-2,3,8-treetopia[4,5]Dec-3-EN-1-it;

8-norbornyl-4-phenyl-2,3,8-treetopia[4,5]Dec-3-EN-1-it;

8-(decahydro-2-naphthyl)-4-phenyl-2,3,8-treetopia[4,5]Dec-3-EN-1-it;

8-(cyclooctylmethyl)-4-phenyl-2,3,8-treetopia [4,5]Dec-3-EN-1-it;

8-(1,2,3,4-tetrahydro-2-naphthyl)-4-phenyl-2,3,8-treetopia[4,5]Dec-3-EN-1-it;

8-[4-(2-propyl)cyclohexyl]-4-phenyl-2,3,8-treetopia[4,5]Dec-3-EN-1-it;

8-(1,3-dihydroindol-2-yl)-4-phenyl-2,3,8-treetopia[4,5]Dec-3-EN-1-it;

8-[(naphthas-2-yl-methyl)]-4-phenyl-2,3,8-treetopia[4,5]Dec-3-EN-1-it;

8-(p-phenylbenzyl)-4-phenyl-2,3,8-treetopia[4,5]Dec-3-EN-1-it;

8-(benzyl)-4-phenyl-2,3,8-treetopia[4,5]Dec-3-EN-1-it;

8-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-4-phenyl-2,3,8-treetopia[4,5 ]Dec-3-EN-1-it;

8-(p-benzyloxybenzyl)-4-phenyl-2,3,8-treetopia[4,5]Dec-3-EN-1-it;

8-(cyclooctyl)-4-phenyl-2,3,8-treetopia[4,5]Dec-3-EN-4-one;

and their pharmaceutically acceptable salts.

14. The compound according to claim 1, which is 8-(acenaphthen-9-yl)-4-phenyl-2,3,8-treetopia[4,5]Dec-3-EN-1-one or its farmatsevticheskii salt or MES.

15. A compound selected from the group consisting of the following compounds:

8-(5-metrex-2-yl)-4-phenyl-2,3,8-treetopia [4,5 ]Dec-3-EN-1-it;

8-[4,4-Bis(4-forfinal)butyl]-4-phenyl-2,3,8-treetopia[4,5]Dec-3-EN-1-he; and

8-(3,3-Bis(phenyl)propyl)-4˜phenyl-2,3,8-treetopia[4,5]Dec-3-EN-1-he,

and their pharmaceutically acceptable salts.

16. The pharmaceutical composition capable of modulating a pharmacological response of one or more opioid receptor selected from the receptor ORL-1 and μreceptors containing the compound according to claim 1 and at least one pharmaceutically acceptable excipient.

17. The pharmaceutical composition according to item 16, is suitable for treatment of the condition in the subject, which can be treated by modulation of the specified pharmacological response.

18. The pharmaceutical composition according to 17, where the specified subject is a mammal.

19. The pharmaceutical composition according to 17, where the specified subject is a human, a domestic animal (e.g. dog, cat, pig, cow, sheep, mouse, rat or Guinea pig.

20. The pharmaceutical composition according to 17, where exposed to the treatment condition is a pain or associated disease.

21. The pharmaceutical composition according to 17, where this composition is suitable as analgetika, protivovospalitel the aqueous means, the diuretic, anesthetic, neuroprotective tools, anti-hypertensive funds protivoastmaticheskogo means, means for regulating appetite controller, hearing, antitussives, anti-asthma drugs, modulator locomotor activity modulator of learning and memory controller, release of neurotransmitters and hormones, modulator of renal function, anti-depressant, a treatment for memory loss due to Alzheimer's disease or other types of dementia, antiepileptic drugs, anti-convulsants, tools for the treatment of chronic alcoholism and addiction to the excessive use of drugs (drug abuse), means for regulating water balance, means for regulating the excretion of sodium and means for regulation violations arterial blood pressure.

22. A method of treating pain comprising the administration to a patient in need of such treatment, an effective amount of a compound according to any one of claims 1 to 15.

23. The modulation method pharmacological reactions opioid receptor selected from the receptor ORL-1 and μreceptors, comprising the administration to a patient in need, an effective amount of a compound according to any one of claims 1 to 15.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel 3-phenyl-3,7-diazabicyclo[3,3,1]nonane compounds of the formula (I): wherein R1 means (C1-C6)-alkyl, (C4-C7)-cycloalkyl; R2 means (lower)-alkyl; R3 means (lower)-alkyl, or R2 and R3 form in common (C3-C6)-alkylene chain; R4 means phenyl monosubstituted at ortho- or para-position with nitro-, cyano-group or (lower)-alkanoyl, or disubstituted at ortho- and para-position with nitro-group, and their physiologically acceptable acid-additive salts. Compounds of the formula (I) possess anti-arrhythmic activity and therefore they can be used in pharmaceutical composition used in treatment and/or prophylaxis of cardiac rhythm disorders. Also, invention describes a method for synthesis of these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

8 cl, 6 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

The invention relates to (DL)-1-hydroxy-3,7,7,9,9-pentamethyl-1,4,8-diazaspiro[4.5]decane-2-ONU formula (1)

The invention relates to new spirochetes formula I

< / BR>
where Ar is phenyl, substituted phenyl where the substituents are: alkoxy, alkyl, alkoxyalkyl, phenoxy, halogen, pyridyloxy, alkoxyalkane, halogenfree; R1- H; R2- H1-C4alkyl; W represents O or one or more1-C4alkyl fragments; Y is independently one or more members of the group consisting of H2, SR3, alkoxy; R3- H, alkyl; Z is a carbocyclic or heterocyclic Spiro-fragment with a 3-7 member ring system, where the heterocyclic fragment includes 2 oxygen atom or sulfur, or one nitrogen atom and spirits may be unsubstituted or substituted by hydroxy, C1-C4the alkyl, benzyloxy; n=1-3; optical isomers, diastereomers or enantiomers or pharmaceutically acceptable salts

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 4-(phenylpiperazinylmethyl)-benzamide of the general formula (I): or their salt, or separate enantiomers and their salts wherein R1 means phenyl, pyridinyl, thienyl, furanyl, imidazolyl that can be substituted possibly; R2 means ethyl and isopropyl; R3 means hydrogen, fluorine atom; R4 means -NH2, -NHSO2R5 wherein R5 means (C1-C6)-alkyl. Compounds are useful in therapy, in particular, in treatment of pain. Also, invention describes methods for synthesis of compounds of the formula (I) and a pharmaceutical composition based on thereof.

EFFECT: improved method of synthesis, valuable medicinal property of compounds and pharmaceutical composition.

12 cl, 1 tbl, 11 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to composition containing at least two active ingredients, opioid analgesic, and opioid agonist in non-swelling diffusive matrix. Releasing characteristics are defined by matrix made of ethylcellulose and at least one fatty alcohol. Also disclosed is pharmaceutical preparation containing 10-150 mg of oxycodone and 1-50 mg of naloxone in standard dose.

EFFECT: composition of long storage time with prolonged invariant and independent releasing of substances.

17 cl, 14 dwg, 16 ex, 19 tbl

FIELD: medicine.

SUBSTANCE: preparation has pharmaceutical composition containing Oxycodon, Naloxon enclosed into matrix with ethyl cellulose, and the like pharmaceutical composition enclosed into matrix with ethyl cellulose and fatty alcohols being used.

EFFECT: prolonged active ingredients release; high storage stability.

25 cl, 7 dwg, 11 tbl

FIELD: medicine, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to a medicinal formulation of tramadol with delayed-release. Proposed medicinal formulation possesses the high effectiveness in treatment of pains of different etiology and can be used in treatment of diseases chosen from the following group: enuresis, cough, inflammatory processes and/or allergic responses, depression states, abuse and/or alcoholism, gastritis, diarrhea, cardiovascular diseases, diseases of respiratory ways, psychic diseases, epilepsy.

EFFECT: improved and valuable medicinal and pharmaceutical properties of formulation.

38 cl, 11 tbl, 4 dwg, 11 ex

FIELD: medicine, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to pharmaceutical salts of the biologically active substance tramadol and at least one sugar substitute chosen from a group comprising saccharin, cyclamate or acesulfam, and a medicament comprising these salts, and its using in treatment of enuresis and pains. The claimed tramadol pharmaceutical salt and sugar substitute possesses the delayed release that provides prolonged curative effect.

EFFECT: improved and valuable medicinal and pharmaceutical properties of salts.

12 cl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 2-pyridincyclohexane-1,4-diamine of the general formula (I): wherein R1, R2 and R3 mean independently of one another hydrogen atom (H), branched or linear (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R4 means H, branched or linear (C1-C8)-alkyl or -C(X)R7 wherein X means oxygen atom (O); R7 means branched or linear (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R5 means group -CHR11R12, -CHR11-CH2R12, -CHR11-CH-CH2R12, -CHR11CH2-CH2-CH2R12 wherein R11 means H, branched or linear (C1-C7)-alkyl or C(O)O-(C1-C6)-alkyl; R12 means H, (C3-C8)-cycloalkyl or five-membered nitrogen-containing heteroaryl optionally condensed with benzene ring as their racemates or pure stereoisomers being at first enantiomers or diastereomers, and as bases or physiologically compatible acid-additive salts. Compounds of the formula (I) elicit analgesic activity and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

15 cl, 1 tbl, 9 ex

FIELD: organic chemistry, medicine, clinical pharmacology.

SUBSTANCE: invention relates to agents used in treatment of pain. Method involves administration to a patient the effective dose of enantiomer of compounds of the formula (Ib) or the formula (IIb) or their mixture. Method provides the antihyperanalgesic effect in acute and chronic pain.

EFFECT: valuable medicinal properties of derivatives.

5 cl, 1 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention represents a pharmaceutical tablet comprising a core and bound envelope wherein (a) core comprises solid particles of water-soluble dye dispersed in matrix, and (b) envelope comprises hellanic gum. Due to the presence of water-soluble dye in the tablet core it shows spotted shape that provides easy recognition of the tablet. The tablet is useful for peroral and intraoral administration.

EFFECT: improved and valuable properties of tablet.

30 cl, 6 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that are able to modulate the pharmacological response of one or some opioid receptors taken among ORL-1 and μ-receptors. Invention describes a compound of the formula (I): wherein W represents hydrogen atom, (C1-C10)-alkyl, (C1-C4)-alkyl-SO2N(V1)2, cyano-(C1-C10)-alkyl, (C1-C4)-alkyl-CON(V1)2, -NH2-SO2-(C1-C4)-alkyl-, (C1-C4)-alkyl-COOV1 wherein all V1 represent (C1-C6)-alkyl; Q represents a 6-membered aromatic group; n represents a whole number from 0 to 3; n' represents a whole number 0 or 1; A, B and C represent hydrogen atom; Z is taken among the group including a bond, linear or branched (C1-C6)-alkylene; R1 is taken among the group including hydrogen atom, (C1-C10)-alkyl, (C3-C12)-cycloalkyl, (C2-C10)-alkylene, (C3-C12)-cycloalkylamino-group, benzyl, (C3-C12)-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl wherein indicated alkyl, cycloalkyl, alkenyl, (C3-C12)-cycloalkylamino-group or benzyl are optionally substituted with substitutes taken among the group including (C1-C10)-alkyl, phenyl, benzyl, benzyloxy-group wherein indicated phenyl, benzyl and benzyloxy-group are substituted optionally with (C1-C10)-alkyl and indicated (C3-C12)-cycloalkyl, (C3-C12)-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl are substituted optionally with 1-3 substitutes taken among the group including (C1-C10)-alkyl and benzyl wherein indicated benzyl is substituted optionally with (C1-C10)-alkyl; R2 represents hydrogen atom and under condition that when n' = 0 then ZR1 doesn't means hydrogen atom (H), or to its pharmaceutically acceptable salt or solvate. Also, the invention describes a pharmaceutical composition based on thereof. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 5 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes analgesic agent possessing the analgesic effect showing effectiveness against the pain by effect on nociceptors. As an active component the proposed analgesic agent comprises compound represented by the general formula (1) or its salt wherein X, Y, E, Q, A1, A2, R1, R3, R4, R5, R2A, R2C, R2D and R2B re determined in the invention claim.

EFFECT: valuable medicinal properties of agents.

3 tbl, 70 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to substituted derivatives of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I in form of racemates, pure stereoisomers, particularly enantiomers or diastereomers in any ratio in mixture, in form of acids, or bases, or salts thereof, preferably physiologically acceptable salts, more preferably in form of hydrochlorides or solvates, in particular hydrates, wherein R1 and R2 are independently H, C3-C10-cycloalkyl, optionally substituted with O-alkylaryl, (C1-C12-alkyl)aryl, with the proviso, that at least one R1 and R2 is not H; R3 is H, SOR12 or COR13; R12 and R13 are independently C1-C10-alkyl, monocyclic 5-membered heterocyclic group having at least one heteroatom selected from sulfur atoms, optionally substituted with halogen; OR20, wherein R20 represents H, C1-C10-alkyl. Invention also relates to method for production of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I including a) compound of formula II interaction with methylenation agent, preferably with Ph3PCH3Br in presence of potassium tert-butylate in tetrahydrofuran (THF) to produce compound of formula III; d) compound of formula III interaction with ethylchloroximidoacetate of formula IV in presence of base, preferably of sodium hydrocarbonate or lithium hydroxide, preferably in organic solvent such as methanol, dichloromethane or TGF to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula V; c) compound of formula V interaction, directly or after previous saponification of functional group presenting in formula V (namely carboxylic acid ethyl ester) and optionally after activation of formed functional group (namely carboxylic acid) with amine of formula HNR1R2 wherein R1 and R2 are as defined above, to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula VI; d) protective group removing from compound of formula VI to produce compound of formula I, wherein R3 is H; and optionally e) converting of compound of formula I, wherein R3 is H, by treatment with acid chloride of formula R12SO2Cl to compound of formula I, wherein R3 is SO2R12 or converting by treatment with carboxylic acid chloride of formula R13COCl to compound of formula I, wherein R3 is COR13. Moreover disclosed is drug having analgesic action and containing at least one substituted 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula I.

EFFECT: new drug with analgesic action.

11 cl, 6 tbl

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