6,7-unsaturated 7-carbamoyl substituted morphinanderivative

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compound of general formula (I): , where R1 and R2, each independently, represent hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, etc., R3 represents hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkinyl, optionally substituted lower alkoxy, etc, R4 represents hydrogen or lower alkyl, R5 represents hydrogen, lower alkyl, cycloalkyl-lower alkyl or lower alkenyl, or its pharmaceutically acceptable salt or solvate.

EFFECT: obtaining pharmaceutical composition for treatment and/or prevention of nausea, vomiting and/or constipation.

13 cl, 68 tbl, 4 ex

 

The technical field to which the invention relates

The invention relates to 6,7-unsaturated 7-carbamoylmethyl derived morphinan that are useful as agents for treatment and/or prophylaxis of nausea, vomiting and/or constipatio, especially as an agent for attenuating and/or prevention of side effects (nausea, vomiting, and/or constipatio etc)caused by the compound having an agonistic activity to opioid receptor (for example, opioid µ-receptor).

The level of technology

Agonist of opioid receptor, such as morphine and the like, which is used as analgetika is very effective for the patient with cancer pain, but as a side effect of causing nausea, vomiting, higher, enuresis and itching. Clinically apply various antiemetic agents and agents against constipatio, but we cannot say that any of them exhibits a sufficient effect, and there is a need in the award-winning agent, debilitating side effects to improve the QOL of the patient.

In patent literature references 1 and 2 and non-patent literature 1 describes that a derived morphinane is effective in the treatment or prevention of nausea and vomiting induced by agonist opioid µ-receptor and non-patent literature Silke described, what 6,7-saturated 7-carbamoylation derivatives morphinan have antagonism for the δ opioid receptor. However, none of them described or offered this connection.

Patent literature 1 - publication of International patent application WO 2004-007503.

Patent literature reference 2 - publication of International patent application WO 95/13071.

Non-patent literature 1 - Journal of Medicinal Chemistry 41, 4177-4180.

Non-patent literature reference 2 - Chemical and Pharmaceutical Bulletin, 52 (66) 747-750 (2004).

Description of the invention

Problems that must be solved by the invention

The inventors discovered that 6,7-unsaturated 7-carbamoylation derivatives morphinan are useful as compositions for the treatment and/or prophylaxis of nausea, vomiting and/or constipatio.

The way to solve problems

The present invention provides:

(1) the compound represented by formula (I):

,

where R1and R2each independently represents hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower quinil, optionally substituted lower alkylsulfonyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl the sludge, optionally substituted aryl, optionally substituted heterocyclic group or optionally substituted arylsulfonyl, or R1and R2taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle;

R3represents hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower quinil, optionally substituted lower alkoxy, mercapto, optionally substituted lower alkylthio, optionally substituted amino, optionally substituted carbarnoyl, optionally substituted acyl, optionally substituted, acyloxy, optionally substituted aryl or optionally substituted heterocyclic group;

the group represented by the formula:

can be

,

where ring a or ring B, each independently, represents an optionally substituted nitrogen-containing heterocycle, optionally containing an additional nitrogen atom, an oxygen atom and/or sulfur atom in the ring;

the dotted line means the presence or absence of communication;

when the dotted line means the presence of communication, p is 0;

when the dashed line indicates the lack of communication, R is 1;

Rais own the th hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower quinil;

and Rbrepresents hydrogen or oxo;

R4represents hydrogen or lower alkyl;

R5represents hydrogen, lower alkyl, cycloalkyl-lower alkyl or lower alkenyl,

or its pharmaceutically acceptable salt or MES;

(1') a compound represented by the formula (I):

,

where R1and R2each independently represents hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heterocyclic group, or R1and R2taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle;

R3represents hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower quinil, optionally substituted lower alkoxy, mercapto, optionally substituted lower alkylthio, optionally substituted aryl or optionally substituted heterocyclic group;

R4represents hydrogen or lower alkyl;

R 5represents hydrogen, lower alkyl, cycloalkyl-lower alkyl or lower alkenyl;

or its pharmaceutically acceptable salt or MES;

(2) the compound according to (1) or (1'), where R3represents hydroxy,

or its pharmaceutically acceptable salt or MES,

(3) the compound according to (1) or (1'), where R3represents optionally substituted amino,

or its pharmaceutically acceptable salt or MES;

(4) the compound according to (1) or (1'), where R3represents amino, substituted optionally substituted by arylsulfonyl,

or its pharmaceutically acceptable salt or MES;

(5) the compound according to any one of (1)to(4) and (1'), where R1represents hydrogen or lower alkyl, R2represents an optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted cycloalkyl or optionally substituted heterocyclic group, and R5is cyclopropylmethyl,

or its pharmaceutically acceptable salt, or MES;

(6) the compound according to any one of (1)to(5) and (1'), where R1represents hydrogen, R2represents lower alkyl, optionally substituted heterocyclic group, or lower alkoxy, optionally substituted aryl, phenyl, optionally substituted is issim the alkyl or lower alkoxy, cycloalkyl, substituted lower alkylcarboxylic, or heterocyclic group, the substituted lower alkoxy or aryl, R4represents hydrogen, and R5is cyclopropylmethyl,

or its pharmaceutically acceptable salt or MES;

(7) a pharmaceutical composition comprising a compound according to any one of (1)to(6) and (1') or its pharmaceutically acceptable salt or MES,

(8) the composition having antagonistic activity for opioid receptor-containing compound according to (1)to(6) and (1') or its pharmaceutically acceptable salt or MES;

(9) the composition for treating and/or prophylaxis of nausea, vomiting and/or constipatio containing compound according to any one of (1)to(6) and (1') or its pharmaceutically acceptable salt or MES;

(10) the composition for loosening and/or prevention of side effects caused by the compounds having an agonistic activity to the opioid receptor-containing compound according to any one of (1)to(6) and (1') or its pharmaceutically acceptable salt or MES;

(11) a composition for treatment and/or prevention according to (10), where a side effect is nausea, vomiting and/or higher;

(12) an agent for the treatment and/or prevention according to (10) or (11), where a compound having an agonistic activity to opioid prescription is RA, is morphine, oxycodone or its pharmaceutically acceptable salt or MES;

(13) the use of compounds according to any of (1)to(6) and (1') or its pharmaceutically acceptable salt or MES to obtain drugs for the treatment and/or prophylaxis of nausea, vomiting and/or constipatio;

(14) the use of compounds according to any of (1)to(6) and (1') or its pharmaceutically acceptable salt or MES to get medicines to alleviate and/or prevent side effects caused by the compounds having an agonistic activity to the opioid receptor;

(15) the method of treatment and/or prophylaxis of nausea, vomiting and/or constipatio, comprising introducing the compound according to any one of (1)to(6) and (1') or its pharmaceutically acceptable salt or MES;

(16) a method of reducing and/or preventing side effects caused by the compounds having an agonistic activity to the opioid receptor, comprising introducing the compound according to any one of (1)to(6) and (1'), its pharmaceutically acceptable salt or MES;

(17) the composition for analgesia containing the compounds having an agonistic activity to the opioid receptor and an effective amount of a compound according to any one of (1)to(6) and (1') or its pharmaceutically acceptable salt or MES to mitigate or prevent adverse effects, caused by the introduction of compounds with agonistic activity for opioid receptor;

(18) a composition for analgesia containing the compounds having an agonistic activity to the opioid receptor and an effective amount of a compound according to any one of (1)to(6) and (1') or its pharmaceutically acceptable salt or MES for the treatment and/or prophylaxis of nausea, vomiting and/or constipatio caused by the introduction of compounds with agonistic activity for opioid receptor;

(19) an analgetic according to (17) or (18), where a compound having an agonistic activity to the opioid receptor, is morphine, oxycodone, its pharmaceutically acceptable salt or MES.

The effect of the invention

The compound (I) of the present invention have activity in the treatment and/or prophylaxis of nausea, vomiting and/or constipatio, especially nausea, vomiting and/or constipatio caused by compounds having an agonistic activity to opioid receptor (for example, opioid µ-receptor), and is useful as a means to mitigate adverse effects from the patient who is administered a compound having an agonistic activity of opioid receptor, or which is in the middle stage of its introduction.

The best way of carrying out the invention

Used the nd here the term "halogen" includes fluorine, chlorine, bromine and iodine. Halogen part of the lower halogenoalkane", "lower halogenoalkane" and "lower allogenicity" has the same meaning.

"Lower alkyl" includes an unbranched or branched alkyl with 1-10 carbon atoms, preferably with 1-6 carbon atoms, more preferably 1-3, and examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl. Preferred are methyl, ethyl, isopropyl, n-butyl, sec-butyl, tert-butyl and 1-ethylpropyl.

Examples of the substituent of the "optionally substituted lower alkyl" include halogen, hydroxy, lower alkoxy, lower halogenoalkane, lower hydroxyalkoxy, lower alkylthio, lower alkylamino, acylamino, acyl, acyloxy, cyano, carboxy, lower alkoxycarbonyl, carbarnoyl, lower allylcarbamate, cyanocarpum lowest alkylsulphonyl, arylsulphonyl, sulfamoyl lowest alkylsulfanyl, lower alkylsulfonyl, cycloalkyl, optionally substituted by one or more substituents selected from the group of substituents α (where a group of substituents α are halogen, hydroxy, lower alkyl, lower halogenated, lower hydroxyalkyl, lower alkoxy-lower alkyl, lower carboxy shall lcil, lowest alkoxycarbonyl-lower alkyl, lower aminoalkyl, lower alkylamino-lower alkyl, acylamino-lower alkyl, lower cianelli, lower alkoxy, lower halogenoalkane, lower hydroxyalkoxy, lower alkylthio, lower allogenicity, acyl, acyloxy, amino, lower alkylamino, acylamino, cyano, carboxy, lower alkoxycarbonyl, carbarnoyl, lower allylcarbamate, arylcarbamoyl, cyanocarpum lowest alkylsulphonyl, sulfamoyl lowest alkylsulfanyl, lower alkylsulfonyl, aryl, optionally substituted lower alkylenedioxy, and heterocyclic group), cycloalkenyl, optionally substituted by one or more substituents selected from the group substituents α, aryl, optionally substituted by one or more substituents selected from the group of substituents α, aryloxy, optionally substituted by one or more substituents selected from the group of substituents α, aaltio, optionally substituted by one or more substituents selected from the group of substituents α, heterocyclic group, optionally substituted by one or more substituents selected from the group of substituents α, and heterocyclic, optionally substituted by one or more substituents selected from the group of substituents α.

The lower alkyl part, lower halogen is Qila", "lower hydroxyalkyl", "lower aminoalkyl", "acylamino-lower alkyl", "acyloxy-lower alkyl", "cycloalkyl-lower alkyl", "lower alkoxy", "lower halogenoalkane", "lower hydroxyalkoxy", "lower alkoxy-lower alkyl", "lower alkoxycarbonyl", "lower carboxyethyl", "lower alkoxycarbonyl-lower alkyl", "lower alkylthio", "lower allogenicity", "lower alkylamino", "lower alkylamino-lower alkyl", "lower alkylcarboxylic", "lower alkylsulfonyl", "lower alkylsulfonyl", "aryl-lower alkyl", "tri-lower alkylsilane", "lower alkyldimethyl", "Triaryl lowest alkylsilane", "lower alkoxy-lower alkoxy-lower alkyl", "lower alkylthio-lower alkyl", "aryl-lower alkoxy-lower alkyl", "lower alkylsulfonyl", "lower alkylsulfonyl", "lower alkylcarboxylic", "lower cyanoalanine", "lower alkoxycarbonyl", "lower alkylenedioxy" and heterocyclyl-lower alkyl" is the same as the above "lower alkyl".

Deputy "optionally substituted lower alkoxy", "optionally substituted lower alkylthio" and "optionally substituted lower alkylsulfonyl" is the same as above Deputy "optionally substituted lower alkyl".

"Lower Elke the sludge includes unbranched or branched alkenyl with 2-10 carbon atoms, preferably the number of carbon atoms 2-8, more preferably, with a number of 3-6 carbon atoms, having one or more double bonds in any position. In particular, examples include vinyl, allyl, propenyl, Isopropenyl, butenyl, Isobutanol, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexanol, hexadienyl, heptenyl, octenyl, nonanal and decanal. Lower alkenyl in R5preferably represents allyl.

Deputy "optionally substituted lower alkenyl" is the same Deputy as the Deputy of the "optionally substituted lower alkyl".

"Lower quinil includes unbranched or branched quinil with the number of carbon atoms from 2 to 10, preferably with the number of 2-8 carbon atoms, more preferably with the number of 3-6 carbon atoms, having one or more triple bonds in any position. In particular, examples of it include ethinyl, PROPYNYL, butynyl, pentenyl, hexenyl, heptenyl, octenyl, nominal and decenyl. They may optionally have a double bond at an arbitrary position.

Deputy "optionally substituted lower quinil" is the same Deputy as the Deputy of the "optionally substituted lower alkyl".

Examples of the substituent of the "optionally substituted amino" include lower alkyl, neoba is consequently substituted by one or more substituents, selected from the group of substituents α, cycloalkyl, optionally substituted by one or more substituents selected from the group of substituents α, acyl, optionally substituted by one or more substituents selected from the group of substituents α, amino, optionally substituted by one or more substituents selected from the group of substituents α, aryl, optionally substituted by one or more substituents selected from the group of substituents α, sulfamoyl lowest alkylsulfonyl, optionally substituted by one or more substituents selected from the group of substituents α, arylsulfonyl, optionally substituted by one or more substituents selected from the group of substituents α, the lower alkylsulfonyl, optionally substituted by one or more substituents selected from the group of substituents α, arylsulfonyl, optionally substituted by one or more substituents selected from the group of substituents α, arylamino, optionally substituted by one or more substituents selected from the group of substituents α, and heterocyclic group, optionally substituted by one or more substituents selected from the group of substituents α.

Deputy "optionally substituted of carbamoyl" is the same Deputy, as will replace the l "optionally substituted amine".

"Cycloalkyl" represents a carbocyclic group with 3-10 carbon atoms, preferably with the number of 3-8 carbon atoms, more preferably with 4-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloneii and cyclodecyl. It can optionally be condensed with aryl"described below, or "heterocyclic group"described below, in a derived position.

As cycloalkyl" in R1and R2preferred are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Cycloalkyl part cycloalkyl-lower alkyl" and "cycloalkylcarbonyl" is the same as the above "cycloalkyl".

As "cycloalkyl-lower alkyl in R5it is preferable to cyclopropylmethyl.

Examples of the substituent of "optionally substituted "cycloalkyl include one or more substituents selected from the group of substituents α. The Deputy may be located in any position and can be the carbon atoms having a relationship cycloalkyl.

The term "cycloalkenyl includes cycloalkenyl having one or more double bonds in any position in the ring above cycloalkyl, and examples of it include cyclopropyl, cyclobutyl, cyclopentenyl, qi is lorexane, cycloheptenyl, cyclooctyl and cyclohexadienyl.

As cycloalkenyl" in R1and R2preferred are cyclopropyl, cyclobutyl, cyclopentenyl and cyclohexenyl.

Cycloalkenyl part of cycloalkylcarbonyl" is the same as the above "cycloalkenyl".

Deputy "optionally substituted cycloalkenyl" is the same Deputy as Deputy to the above "optionally substituted cycloalkyl".

"Aryl" includes phenyl, naphthyl, antril and tenantry, especially preferred is phenyl.

The aryl part of "aryloxy", "aristeo", aryl-lower alkyl", "lower alkyldimethyl", Triaryl lowest alkylsilane, "aryl-lower alkyloxy-lower alkyl", "arylsulfonyl", "arylsulfonyl", "arylamino", "arylcarbamoyl" and "arylsulfonyl" is the same as the above "aryl".

Examples of the substituent of "optionally substituted aryl", "optionally substituted phenyl and optionally substituted arylsulfonyl include Deputy group α, a phenyl, substituted by one or more groups selected from the group of substituents α, phenoxy substituted by one or more groups selected from the group of substituents α, and lower alkylenedioxy.

"Heterocyclic group" includes heterocyclics the th group, having in the ring one or more heteroatoms arbitrarily selected from O, S and N, and in particular includes a 5-6-membered heteroaryl, such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolin, thiazolyl, thiadiazolyl, furyl and thienyl; bicyclic condensed heterocyclic group such as indolyl, isoindolyl, indazoles, indolizinyl, indolinyl, isoindolyl, hinely, ethanolic, cinnoline, phthalazine, hintline, naphthyridine, honokalani, purinol, pteridinyl benzopyranyl, benzimidazolyl, benzisoxazole, benzoxazole, benzoxadiazole, benzothiazolyl, benzotriazolyl, benzothiazolyl, benzofuran, isobenzofuran, benzothiazyl, benzotriazolyl, imidazopyridine, triazolopyridine, imidazothiazoles, pyrazinamidase, hintline, hinely, ethanolic, naphthyridine, dihydropyridin, tetrahydroquinolin and tetrahydrobenzene; tricyclic condensed heterocyclic group, such as carbazolyl, acridines, xantener, phenothiazinyl, phenoxathiin, phenoxazines and dibenzofuran; non-aromatic heterocyclic group, such as dioxane, thiiranes, ciorani, titanyl, oxiranyl, oxetanyl, oxathiolane, azetidine, tiani, pyrrolidinyl, pyrrolyl, imidazolidin the sludge, imidazolines, pyrazolidine, pyrazoline, piperidyl, piperazinil, morpholinyl, morpholino, thiomorpholine, thiomorpholine, dihydropyridin, dihydrofuran, tetrahydrofuran, tetrahydropyranyl, tetrahydrofuryl and tetrahydrocortisol. Preferred is a 5-6-membered heteroaryl or non-aromatic heterocyclic group.

As the "heterocyclic group" in R1and R2preferred are pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl, thiadiazolyl, furyl, thienyl, indolyl, indazoles, hinely, ethanolic, benzoxazolyl, benzothiazolyl, oxetanyl, tetrahydrofuryl and tetrahydropyranyl. More preferred are pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. Especially preferred are pyridyl and pyrimidinyl.

As the heterocyclic group of the "optionally substituted lower alkyl" in R1and R2preferred are isoxazolyl, oxazolyl and oxadiazolyl. Especially preferred is oxadiazolyl.

Heterocyclic part of heterocyclic" and "heterocyclyl-lower alkyl" is the same as the above "heterocyclic group".

Examples of the substituent of the "optionally substituted heterocyclic group" include one or more groups selected from the group status is the present of substituents group α, and oxo. The Deputy may be located in any position or may be a carbon atom or a nitrogen atom having a link heterocyclic group.

"Acyl" includes such an unbranched or branched chain aliphatic acyl with the number of carbon atoms of 1-10, preferably with 1-6 carbon atoms, more preferably with 1-4 carbon atoms, cycloaliphatic acyl with the number of carbon atoms from 4 to 9, preferably the number of carbon atoms 4-7, aroyl and heterocalixarenes. Here, the term "similar chain aliphatic radical" includes the above "lower alkyl"above "lower alkenyl" and above "lower quinil". The term "cycloaliphatic radical" includes the above "cycloalkyl" and above "cycloalkenyl". Heterocyclic part of geterotsiklicheskikh is the same as the above "heterocyclic group". Examples of acyl include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propiolic, methacryloyl, crotonoyl, cyclopropanecarbonyl, cyclohexylcarbonyl, cyclooctylmethyl, benzoyl, pyridylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinomethyl and the like.

Acyl part of acyloxy", "acylamino", "acylamino-lower alkyl" and "acyloxy-lower alkyl" is the same as the above "acyl".

Deputy "optionally substituted acyl" or "optionally substituted" is the same as Deputy to the above "optionally substituted lower alkyl", when the "acyl" is similar chain aliphatic acyl, and includes one or more groups selected from the group of substituents α, when the "acyl" represents cycloaliphatic acyl, aroyl or heterocalixarenes.

"Optionally substituted heterocycle"formed when R1and R2taken together with the nitrogen atom to which they are attached, includes a 5-membered or 6-membered heterocycle containing the nitrogen atom is attached to R1and R2and additionally optionally containing one or more heteroatoms selected from N, S and O. for Example, included case whenrepresents a saturated heterocyclic group, such as

,

or unsaturated heterocyclic group, such as

,

where R6, R7and R8each independently represents hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, acyl, acyloxy, amino, lower alkylamino, acylamino, lower alkoxycarbonyl, carboxy or lower alkoxycarbonyl, and preferably saturated, heterotic the practical group, such as the ring of the research, the ring pyrrolidine, piperidine ring, piperazine ring, and the like, optionally substituted by hydrogen, halogen, hydroxy or lower alkyl.

Deputy "optionally substituted heterocycle, which is formed when R1and R2taken together with the nitrogen atom to which they are attached, is the same Deputy as the Deputy of the "optionally substituted heterocyclic group".

The radical of the formularepresents a radical of the formulathat includes, for example, the following radicals:

,

where Rahas the above significance, and R represents hydrogen or a group selected from the group of substituents α.

Here "MES" includes, for example, MES organic solvent, hydrate, and the like. When hydrate is formed, may be coordinated by any number of water molecules.

The compound (I) includes pharmaceutically acceptable salt. The examples include salts with alkali metals (lithium, sodium or potassium), alkaline earth metals (magnesium or calcium), ammonium, organic bases or amino acids, and salts with inorganic acids (hydrochloric acid, sulfuric acid, nitric what Isletas, Hydrobromic acid, phosphoric acid and itestosterone acid) or organic acids (acetic acid, triperoxonane acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, almond acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzosulfimide acid, p-toluensulfonate acid, methanesulfonic acid or econsultancy acid). Especially preferred is hydrochloric acid, phosphoric acid, tartaric acid or methansulfonate acid. These salts can be obtained by a common way.

In addition, compound (I) is not limited to a specific isomer, but includes all possible isomers and racemates. For example, when R3the compound (I) is hydroxy, the compound (I) includes another tautomer, that is, the following compound (I').

The present compound (I) can be obtained in the following way.

Method And

,

where RArepresents the balance of ester, RBrepresents hydrogen or hydroxyamino group, and other symbols have the meanings specified above.

Here the residue of ester includes lower alkyl, such as is ethyl, ethyl and the like, aryl-lower alkyl, such as benzyl, phenethyl and the like, acyloxy-lower alkyl, such as acetoacetyl and the like, etc.

Hidroxizina group is not limited to, but includes lower alkyl (methyl, tert-butyl etc), aryl-lower alkyl (triphenylmethyl, benzyl etc.), three-lower alkylsilane (trimethylsilyl, tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl etc), lower alkyldimethyl (tert-butyldiphenylsilyl etc), Triaryl lowest alkylsilane (transiciel etc), lower alkoxy-lower alkyl (methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl etc), lower alkoxy-lower alkoxy-lower alkyl (methoxyethoxymethyl etc.) lower alkylthio-lower alkyl (methylthiomethyl etc), optionally substituted tetrahydropyranyl (tetrahydropyranyl-2-yl, 4-methoxyacridine-4-yl and so on), tetrahydrothiopyran (tetrahydrothiopyran-2-yl and so on), tetrahydrofuranyl (tetrahydrofuran-2-yl and so on), tetrahydrofuranyl (tetrahydrothiopyran-2-yl and so on), aryl-lower alkyloxy-lower alkyl (benzoyloxymethyl etc), lower alkylsulfonyl (methanesulfonyl, econsultancy etc), acyl (acetyl, etc.) and arylsulfonyl (p-toluensulfonyl etc).

The first stage

First, a known compound or compound (IV)obtained from him, freed from the protective groups of the common ways is om.

For example, when the protective group is benzyl, the compound is dissolved or suspended in a suitable solvent (ethyl acetate, methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide, acetic acid, dilute hydrochloric acid or mixtures thereof), and a hydrogenation reaction using palladium catalyst (palladium hydroxide, palladium on charcoal, palladium on barium sulfate, palladium on alumina, palladium mobiles etc) get the compound (III). The reaction can be conducted at a temperature from about 0°to about 100°C., preferably from approximately 20°to approximately 50°C for from about 15 minutes to about 24 hours, preferably from about 1 hour to about 5 hours.

The second stage

Then the resulting compound (III) directly lidiruyut, thus obtaining the compound (Ia).

For example, the compound (III) and the compound (II) can be subjected to reaction by heating in a suitable solvent (methanol, ethanol, tetrahydrofuran, dimethylformamide, diethyl simple ether, dichloromethane, dichloroethane, toluene, xylene, chlorobenzene, orthodichlorobenzene, 2-methoxyethanol and dimethyl ether of diethylene glycol or mixtures thereof) or without solvent at a temperature from about 0°C. to about 250°C, PR is doctitle from approximately 80°to approximately 200°C for from about 30 minutes to about 24 hours, preferably about 1-12 hours, in the presence or in the absence of amine compounds (ammonia, dimethylamine, triethylamine, pyridine, dimethylaniline, dimethylaminopyridine, lutidine and so on).

For the effective conduct of the reaction can be performed by irradiation with microwaves. The reaction temperature and the exposure time is not specifically restricted, but it is conducted at a temperature of from about 100°to about 200°C. and for from about 5 minutes to about 5 hours, preferably from about 10 minutes to about 1 hour. The solvent preferably used polar solvent, such as methanol, ethanol, 1-propanol, ethylene glycol, glycerol, 2-methoxyethanol, 2-ethoxyethanol, N,N-dimethylformamide, dimethyl ether of diethylene glycol, and the like.

When R4consider the compound (I) is a lower alkyl, the compound can be obtained generally accepted by the reaction of a simple ester in an arbitrary stage.

Method In

,

where R3arepresents hydroxy or optionally substituted lower alkoxy, and the other symbols have the meanings specified above.

The first stage

When R3consider the compound (I) represents an optionally substituted lower ALK is XI, first known compound (IV) is transformed into a simple ether conventional method.

For example, the connection is subjected to interaction with an alkylating agent or an alcohol having a group R3acorresponding to the group of the considered compounds, in the presence of a base (sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium methoxide, ethoxide sodium tert-butoxide potassium, bicarbonate of sodium or metallic sodium) or in terms of Mitsunobu in a suitable solvent (N,N-dimethylformamide, dimethyl sulfoxide, toluene, benzene, xylene, mixtures thereof or the like, cyclohexane, hexane, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dioxane, acetone, methylethylketone, acetonitrile, water or mixtures thereof), thus obtaining the compound (VII). The reaction can be conducted at a temperature of from -70 to 180°C, preferably approximately 0-150°C for from about 15 minutes to about 24 hours, preferably from about 1 hour to about 5 hours.

The second stage

Then the compound (VII) hydrolyzing to obtain the compound (VI). The reaction can be carried out at the temperature of the cooling with ice to a temperature of phlegmy solvent for from priblizitelen is 15 minutes to about 24 hours, preferably from 1 hour to about 5 hours with the use of inorganic bases (sodium hydroxide, lithium hydroxide or potassium hydroxide) in a suitable solvent (methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide or mixtures thereof).

The third stage and the fourth stage

Then the compound (VI) lidiruyut and the resulting compound (V) release from protective group, while receiving the considered compound (Ib). These reactions can be performed by the same methods as the methods of the second stage and the first stage in the method And, respectively. In stage amidation reaction can be conducted, if necessary, in the presence of a condensing agent (N,N'-dicyclohexylcarbodiimide, N-dimethylaminopropyl-N'-ethylcarbodiimide, diethylphosphoramidite, diphenylphosphinite etc).

In addition, when R4consider the compound (I) is a lower alkyl, the reaction of formation of simple ether can be carried out at an arbitrary stage, as described above.

Way

,

where L represents a leaving group, R3brepresents hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower quinil, optionally substituted lower alkoxy, mercapto, optionally zamestnanosti alkylthio, optionally substituted amino, optionally substituted carbarnoyl, optionally substituted aryl or optionally substituted heterocyclic group, and other symbols have the meanings specified above.

The first stage

When R3consider the compound (I) is an R3bleaving group L (for example, trifloromethyl, methanesulfonyl, ether phosphoric acid, etc.) introducing well-known compound (IV). For example, the connection is subjected to interaction with triftormetilfullerenov anhydride, triftormetilfullerenov, methanesulfonamido, methanesulfonyl anhydride, p-toluensulfonate, N-phenyltrichlorosilane or different tarifitsiruemye reagents phosphoric acid in the presence of a base (pyridine, triethylamine, ammonia, dimethylamine, dimethylaniline, dimethylaminopyridine, 2,6-lutidine or 2,6-di-tert-butylpyridinium) using dichloromethane, chloroform, tetrahydrofuran, benzene, toluene, dimethylformamide, ethyl acetate or mixtures thereof as a solvent.

The second stage

Thus obtained compound (VIII) is subjected to well-known reaction of introducing a substituent to obtain compound (IX).

The third stage, fourth stage and fifth stage

The compound (IX) hydrolyzing, lidiruyut and freed from the protective groups so the mi methods, as methods of the second stage in the method, the second step in the method a and the first stage in the method And, respectively, while receiving the considered compound (Ic).

In addition, when R4consider the compound (I) is a lower alkyl, the reaction of formation of simple ether can be carried out at an arbitrary stage, as described above.

Method D

The compound (VIII) receive the first stage of the method, lidiruyut according to the method of the fourth stage of the method, and subjected to reaction injection Deputy R3breaction unprotect and hydrolysis according to the methods of the second stage, third stage and the fifth stage of the method, respectively, thereby obtaining the compound (I).

All of the thus obtained of the present compounds possess antagonistic activity for opioid receptor and are useful as medicines, among the compounds represented by formula (I), the following compounds are particularly preferred:

a) compound, in which R1represents hydrogen or lower alkyl,

b) compound, in which R1represents hydrogen or C1-C3-alkyl,

(C) compound, which R2represents:

(i) lower alkyl, optionally substituted by one or more groups selected from the group sweep the oil β (here the group of substituents β are cycloalkyl, optionally substituted by hydroxy, halogen, hydroxy, lower alkoxy, lower halogenoalkane, lower alkylthio, amino, lower alkylamino, carboxy, lower alkoxycarbonyl, cyano, lower alkylsulfonyl, aryl, aryloxy and lower alkylenedioxy),

(ii) phenyl, optionally substituted by one or more groups selected from the group consisting from the group of substituents β, lower alkyl and lower halogenoalkane,

(iii) aryl-lower alkyl, optionally substituted by one or more groups selected from the group of substituents β,

(iv) cycloalkyl, optionally substituted by one or more groups selected from the group of substituents β,

(v) heterocyclic group optionally substituted by one or more groups selected from the group of substituents β, or

(vi) heterocyclyl-lower alkyl, optionally substituted by one or more groups selected from the group of substituents β,

d) compound, in which R2represents:

(d-1) lower alkyl, optionally substituted hydroxy, cycloalkyl, optionally substituted by hydroxy, lower alkoxy, lower alkylthio, lower alkylamino or aryloxy,

(d-ii) phenyl, optionally substituted with halogen, lower alkyl, lower halogenation, lower alkoxy, lower halogenoalkane, lower alkylthio, amino, n is slim alkylamino, cyano, lower alkylsulfonyl or lower alkylenedioxy,

(d-iii) aryl-lower alkyl, optionally substituted lower alkoxy or a lower alkylthio,

(d-iv) cycloalkyl, optionally substituted lower alkyl, carboxy or lower alkoxycarbonyl,

(d-v) heterocyclic group optionally substituted lower alkyl, lower alkoxy or phenyl, or

(d-vi) heterocyclyl-lower alkyl, optionally substituted lower alkyl or aryl,

e) compound, in which R1and R2taken together with the N atom to which they are attached, form a 5-membered or 6-membered saturated a heterocycle,

f) compound, in which R3represents hydroxy or lower alkoxy,

g) compound, in which R3represents hydroxy,

h) compound, in which R3represents amino, optionally substituted by one or more groups selected from the group of substituents α,

i) a compound in which R3represents halogen, lower alkyl or amino, substituted arylsulfonyl, optionally substituted lower alkoxy,

(j) the compound in which R4represents hydrogen or methoxy,

k) a compound in which R5is cycloalkyl-lower alkyl or lower alkenyl,

l) compound, in which R5is the nd cyclopropylmethyl or allyl,

m) compound, in which R5is cyclopropylmethyl,

n) compound, in which R1represents hydrogen or lower alkyl, R2is a (d-i), R3represents hydroxy or lower alkoxy, R4represents hydrogen, and R5is cycloalkyl-lower alkyl or-lower alkenyl,

o) compound, in which R1represents hydrogen or lower alkyl, R2is a (d-i), R3represents hydroxy or lower alkoxy, R4represents hydrogen, and R5is cyclopropylmethyl,

R) compound, in which R1represents hydrogen or lower alkyl, R2is a (d-i), R3represents halogen, lower alkyl or amino, substituted arylsulfonyl, optionally substituted lower alkoxy, R4represents hydrogen, and R5is cycloalkyl-lower alkyl or-lower alkenyl,

q) the compound in which R1represents hydrogen or lower alkyl, R2is a (d-i), R3represents halogen, lower alkyl or amino, substituted arylsulfonyl, optionally substituted lower alkoxy, R4represents hydrogen, and R5is cyclopropylmethyl,

r) compound, in which R1represents hydrogen or lower alkyl, R2is a (d-ii), R3represents hydroxy or lower alkoxy, R4represents hydrogen, and R5is cycloalkyl-lower alkyl or-lower alkenyl,

s) compound, in which R1represents hydrogen or lower alkyl, R2is a (d-ii), R3represents hydroxy or lower alkoxy, R4represents hydrogen, and R5is cyclopropylmethyl,

t) compound, in which R1represents hydrogen or lower alkyl, R2is a (d-iii), R3represents hydroxy or lower alkoxy, R4represents hydrogen, and R5is cycloalkyl-lower alkyl or-lower alkenyl,

u) compound, in which R1represents hydrogen or lower alkyl, R2is a (d-iii), R3represents hydroxy or lower alkoxy, R4represents hydrogen, and R5is cyclopropylmethyl,

v) compound, in which R1represents hydrogen or lower alkyl, R2is a (d-iv), R3represents hydroxy or lower alkoxy, R4represents hydrogen, and R5before the hat is cycloalkyl-lower alkyl or-lower alkenyl,

w) compound, in which R1represents hydrogen or lower alkyl, R2is a (d-iv), R3represents hydroxy or lower alkoxy, R4represents hydrogen, and R5is cyclopropylmethyl,

x) a compound in which R1represents hydrogen or lower alkyl, R2is a (d-v), R3represents hydroxy or lower alkoxy, R4represents hydrogen, and R5is cycloalkyl-lower alkyl or-lower alkenyl,

y) connection, in which R1represents hydrogen or lower alkyl, R2is a (d-v), R3represents hydroxy or lower alkoxy, R4represents hydrogen, and R5is cyclopropylmethyl,

z) compound, in which R1represents hydrogen or lower alkyl, R2is a (d-vi), R3represents hydroxy or lower alkoxy, R4represents hydrogen, and R5is cycloalkyl-lower alkyl or-lower alkenyl,

AA) compound, in which R1represents hydrogen or lower alkyl, R2is a (d-vi), R3represents hydroxy or lower alkoxy, R4represents hydrogen, and R5PR is dstanley cyclopropylmethyl,

ab) compound, in which R1and R2taken together with the N atom to which they are bound, form a 5-membered or 6-membered saturated a heterocycle, R3represents hydroxy or lower alkoxy, R4represents hydrogen, and R5is cycloalkyl-lower alkyl group or lower alkenyl,

AC) connection, in which R1and R2taken together with the N atom to which they are bound, form a 5-membered or 6-membered saturated a heterocycle, R3represents hydroxy or lower alkoxy, R4represents hydrogen, and R5is cyclopropylmethyl,

or their pharmaceutically acceptable salt or solvate.

In the compound represented by formula (I), the compound in which R4represents hydrogen, R5is cyclopropylmethyl, the combination NR1R2and R3(NR1R2, R3) is the following (see table 1-8 at the end of the description).

Used here, the phrase "nausea, vomiting and/or constipation includes nausea, vomiting and/or constipation that is caused by the ingestion of compounds with agonistic activity for opioid receptor (especially opioid receptor). In particular, examples of compounds with agonistic activity for opioid receptor include morphine, OK is icodin, fentanyl, methadone, codeine, Dihydrocodeine, hydromorphone, Levorphanol, meperidine, propoksifen, dextropropoxyphene, tramadol, and their pharmaceutically acceptable salt or solvate. In particular, when the compound is morphine, oxycodone or its pharmaceutically acceptable salt or MES, the present compound is particularly effective.

The effect of the present invention to nausea or vomiting can be confirmed, for example, the following test.

Thirty minutes after ingestion of food African ferret enter each test compound. The test compound was dissolved in 5% xylitol and is administered in an amount of 5 mg/kg After thirty minutes after administration of the test compound subcutaneously injected with 0.6 mg/kg of morphine and symptoms vomiting usually see up to 30 minutes after administration of morphine.

For each type of nausea (periodic contractile movement of the abdominal part and excretion of nutrients, manifested in the form of vomiting, or similar behavior) note the time of occurrence of vomiting, latency time (time from injection of morphine to the initial occurrence of the symptom of vomiting) and time duration (time from beginning of vomiting before the end of the vomiting).

In addition, the effect of this compound on the higher can be confirmed, for example, the following test.

1) Obtaining feed for testing (with & rsquo; s is m)

Using 0,% wt./about. aqueous solution of Evans blue receive 2.5% wt./about. the solution of salt of carboxymethylcellulose and its use as feed for testing.

2) Animal

You can apply, for example, male Wistar rats (6-7 weeks). Animals kept in a hungry state for about 20 hours or more prior to testing, the water give the number as you want it to animals.

3) Test the connection and environment

The test compound is dissolved in a solvent (DMAA/solutol/5% meglumine = 15/15/70).

DMAA: N,N-dimethylacetamide,

solutol (registered trademark) HS15,

meglumin: D-(-)-N-methylglucamine.

Morphine hydrochloride was dissolved in physiological saline solution.

The test compound, the solvent and morphine, all injected in liquid form in the amount of 2 ml/kg

4) Method

The test compound in the amount of 0.03, 0.1 and 0.3, and 1 or 3 mg/kg (group introduction of the test compound or solvent (for groups of introducing solvent) is injected subcutaneously, and morphine 3 mg/kg injected subcutaneously for all groups after 75 minutes. The control group injected subcutaneously solvent, and physiological saline was injected after 75 minutes.

Food for tests 2 ml/rat orally administered 30 minutes after injection of morphine. Fifteen minutes after the introduction of the CDF is to test (after 120 minutes after administration of the test compounds) in rats separated the area from the esophagus to the ileocecal part near the cardiac orifice of the stomach. Measure the distance from the pyloric part of the stomach to the ileocecal part (full length of the small intestine) and the distance until the dye front (distance, which is the dye).

5) data Processing

The degree of transfer (%) = (the distance that passes dye (cm)/full length of the small intestine (cm) × 100.

MRE (%) = {(degree of transfer of the small intestine (%) group introduction each individual test compound - average degree of transfer of the small intestine (%) group introduction of solvent)/(average degree of transfer of the small intestine (%) control group - average degree of transfer of the small intestine (%) group introduction solvent)} × 100.

The value of the ED50calculate the reverse rating program SAS regression with the use of %MPE and the assumption that the size of the control group is 100%.

The present compound has an antagonistic activity for opioid receptor (especially opioid receptor δ and µ). Therefore, the present compound is effective in the treatment and/or prevention of disorders of passage through the digestive tract, which occurs due to such reasons as acute indigestion, alcohol intoxication, food poisoning, colds, stomach ulcers, duodenal ulcer, stomach cancer, intestinal obstruction, appendicitis, peritonitis, zelnoem the bedroom illness, hepatitis, liver inflammation, encephalitis, meningitis, hypertension, brain, head injury, sickness, vomiting of pregnancy, side effects due to chemotherapy, side effects due to radiation therapy, side effects due to treatment with an anticancer agent, a pressure-stenosis of the digestive tract and healing the digestive tract after surgery, in the treatment and/or prevention of nausea and vomiting that occur due to such causes as increased pressure in the brain due to brain tumors, bleeding in the brain, meningitis, radiation exposure of the brain, and in the treatment and/or prevention of acute constipatio caused such a cause as intestinal obstruction, duodenal ulcer or appendicitis, relaxing constipatio caused such a cause as nervous violation, malnutrition, weakness, lack of vitamins, anemia, decreased sensitivity, or the lack of mechanical stimulation, or the convulsive constipatio caused by such reason as stress, in addition to nausea, vomiting and constipatio caused by compounds having an agonistic activity to the opioid receptor.

Since the present compound has a weak delivery to the brain, it makes side effects, t is something like nausea, vomiting, higher-and the like, caused by agonistic activity for the opioid receptor, with almost no inhibition of analgesic activity of compounds with agonistic activity for opioid receptor that is administered to a patient with the disease, followed by pain (such as cancer pain, pain due to bone passage, nervous tension, increased intracranial pressure, infiltration through the soft tissue, pain due to constipation or muscle spasm, pain, internal organ, muscle, fascia, waist or peripheral portion of the shoulder joint, chronic pain after surgery, AIDS etc). In addition, the present compound has a clear antagonistic activity against opioid receptor and also has the advantage of security issue, namely, that, because inhibiting the activity of hERG channels is low, there is no cardiac toxicity and so on. In addition, this connection is also suitable characteristic of the speaker in the body, such as a high oral absorption ability, high stability in human plasma, high bioavailability, and the like, and is very effective as a medicine.

When the present compound is administered anti-nausea, vomiting and is onstipation, caused by compounds having an agonistic activity to the opioid receptor, its introduction can be performed before, after or simultaneously with the introduction of compounds having an agonistic activity to the opioid receptor. The time interval between the introduction of these two types of drugs are not specifically limited. For example, when the present compound is administered after administration of the compounds having an agonistic activity to the opioid receptor, if the introduction of a directly or through about 3 days, preferably immediately or after approximately 1 day after administration of the compounds having an agonistic activity to the opioid receptor, the present compound is usually more efficient. In addition, when the present compound is administered before administration of the compounds having an agonistic activity to the opioid receptor, if the introduction is conducted immediately before entering or about 1 day, preferably just before the introduction or approximately 12 hours prior to the introduction of compounds having an agonistic activity to the opioid receptor, the present compound is usually more efficient.

When the present compound is administered as an agent for the treatment and/or prophylaxis of nausea, vomiting and/or constipatio, it can be used od is vremenno with another agent for treatment and/or prophylaxis of nausea, vomiting and/or constipatio. For example, the agent can be administered simultaneously with ondansetron hydrochloride, cortical adrenal steroid (methylprednisolone, prednisolone, dexamethasone etc), prochlorperazine, haloperidol, timiperone, perphenazine, metoclopramide, domperidone, scopolamine, chlorpromazine hydrochloride, droperidol, stimulant laxative (sennosides, sodium picosulfate and so on), an osmotic laxative (lactulose and so on) or laxative in the form of salts (magnesium oxide and so on).

Alternatively you can enter a combination of the present compounds and compounds having an agonistic activity to the opioid receptor, or a combination of this compound and the other agent for the treatment and/or prophylaxis of nausea, vomiting and/or constipatio.

When the present compound is administered to human, it can be administered orally in the form of powders, granules, tablets, capsules, pills, solutions or the like or parenterally in the form of injections, suppositories, percutaneous absorbable agents, absorbable agents or the like. Preferred are oral agents.

In addition, the present compound can be produced in the form of pharmaceutical preparations, the addition of pharmaceutical additives, such as exci anti, binders, wetting agents, dezintegriruetsja agents, lubricating agents and the like, which are suitable for such drugs, and effective amounts of the present compounds.

This connection can be made in the form of pharmaceutical mixtures which contain compounds having an agonistic activity to the opioid receptor, and/or another agent for the treatment and/or prophylaxis of nausea, vomiting and/or constipatio and, if necessary, various pharmaceutical additives.

Dose change depending on the state of the disease, route of administration and the age and weight of the patient, it is usually 0.1 mg to 1 g/day, preferably 0.01 to 200 mg/day when administered orally to an adult human, and usually 0.1 μg to 10 g/day, preferably 0.1 to 2 g/day for parenteral administration.

The following examples and examples of tests illustrate the present invention in more detail, but the present invention is not limited to these examples.

EXAMPLE 1

Obtaining the compound (I-4)

,

where Bn represents a benzyl, Et represents ethyl, and Prirepresents isopropyl.

The first stage - 7-Ethoxycarbonylmethoxy

To a suspension of 3-O-benzyl-7-ethoxycarbonylmethoxy described in non-patent reference 2, (11,16 g, 22,mol) in ethyl acetate (50 ml) and methanol (50 ml) is added palladium hydroxide (catalyst Perlman) (1.2 g) and the mixture vigorously stirred for 2 hours in hydrogen atmosphere. After separation of the catalyst by filtration, the filtrate concentrated and the residue crystallized from ethyl acetate and hexane, thus obtaining 8,96 g (92%) indicated in the title compounds as colorless crystals.

NMR (300 MHz, CDCl3)

δ 0,14-0,17 (m, 2H), 0.55, which is 0.58 (m, 2H), 0,86 (m, 1H), 1,23-of 1.29 (m, 3H), 1,67 (d, 1H, J=9.6 Hz), 2,02 (DD, 1H, J=1,2, 16.2 Hz), 2,20-and 2.79 (m, 8H), is 3.08 (d, 1H, J=18.6 Hz), 3,24 (user., 1H), 4,12-4,20 (m, 2H), 4,96 (s, 1H), 5,17 (user., 1H), 6,59 (d, 1H, J=8.1 Hz), 6,72 (d, 1H, J=8.1 Hz), 12,12 (s, 1H).

Elemental analysis (C23H27NO6• 0,2 H2O).

The calculated size, 66,24; N, 6,62; N, 3,36.

Found the size, 66,29; N, Of 6.50; N, 3.45 points.

The second stage - 7-Isopropylaminocarbonyl

A solution of 7-ethoxycarbonylmethoxy obtained in the first stage (200 mg, 0,484 mmol), Isopropylamine (0,412 ml, 4,84 mmol) and triethylamine (0,202 ml of 1.45 mmol) in 2-methoxyethanol (1.5 ml) was stirred at 180°C for 45 minutes under the irradiation with microwaves. After cooling to room temperature, to the reaction mixture, add 7 ml of 5 mol/l hydrochloric acid and stirring is continued at 70°C for 20 minutes. After cooling, the reaction mixture regulate the pH value to 8.5 aqueous ammonia, followed by extraction with ethyl acetate. The organic layer is washed with water and dried, and the solvent is evaporated. The residue is purified column chromatography on silica gel (chlorop the RM:methanol = 99:1-94:6), while receiving 140 mg specified in the connection header with the yield 68%.

NMR (300 MHz, d6-DMSO)

δ 0,12-0,15 (m, 2H), 0,44-of 0.53 (m, 2H), or 0.83 (m, 1H), of 1.02 (d, 3H, J=6.6 Hz), a 1.08 (d, 3H, J=6.6 Hz), 1,41 (d, 1H, J=11.4 in Hz)of 1.85 (d, 1H, J=15.6 Hz), 2,04-2,62 (m, 8H), 3.04 from (d, 1H, J=18.6 Hz), 3,24 (m, 1H), of 3.96 (m, 1H), 4,71 (s, 1H), 4,74 (s, 1H), 6,51 (d, 1H, J=8,4 Hz), 6,56 (d, 1H, J=8,4 Hz), 7,40 (user. d, 1H, J=7,2 Hz), 9,16 (s, 1H), 14,50 (s, 1H).

Elemental analysis (C24H30N2O5• 0,2 H2O).

The calculated size, 67,02; N, 7,12; N, 6,51.

Found the size, 67,02; N, 7,20; N, of 6.49.

EXAMPLE 2

Obtaining the compound (I-44)

,

where Bn represents a benzyl, Me represents methyl, Et represents ethyl, and Prirepresents isopropyl.

The first stage - 3-O-Benzyl-7-etoxycarbonyl-6-O-methylnaltrexone

To a solution of 3-O-benzyl-7-ethoxycarbonylmethoxy described in non-patent reference 2, (504 mg, 1 mmol) in tetrahydrofuran (10 ml) was successively added 1,1'-azodicarbonamide (379 mg, 1.5 mmol), tri-n-butylphosphine (370 μl, 1.5 mmol) and methanol (41 μl, 1 mmol)and the mixture was stirred at room temperature for 7 hours. The reaction solution is concentrated under reduced pressure, and the residue is purified column chromatography on silica gel (hexane/ethyl acetate), obtaining mentioned in the title compound (421 mg, 81%) as a demon who Vatan oil.

1H NMR (CDCl3, δ ppm): 0,10-0,20 (m, 2H), 0,50-0,65 (m, 2H), 0.88 to (m, 1H), 1.26 in (t, J=6.6 Hz, 3H), 1,67 (d, J=11,4 Hz, 1H), 2,15 is 2.80 (m, 8H), 3.00 and-3,30 (m, 2H), 3,93 (s, 3H), 4,05-4,20 (m, 2H), 4,86 (user. s, 1H), further 5.15 (s, 2H), 5,18 (user. s, 1H), to 6.57 (d, J=8,1 Hz, 1H), 6,72 (d, J=8,1 Hz, 1H), 7,28 was 7.45 (m, 5H).

The second stage - 3-O-Benzyl-7-isopropylaminocarbonyl-6-O-methylnaltrexone

To a mixed solution of 3-O-benzyl-7-etoxycarbonyl-6-O-methylnaltrexone obtained in the first stage (145 mg, 0.28 mmol), in methanol (6 ml) and dioxane (2 ml) is added 50% aqueous potassium hydroxide solution (2 ml)and the mixture stirred at 50°C for 30 minutes. The reaction mixture is cooled to room temperature and pH adjust up to 4 0.5m aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer is successively washed with water, saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crystalline residue, 3-O-benzyl-7-carboxy-6-O-methylnaltrexone, used in the next reaction without purification. To a solution of the above residue in dimethylformamide (3 ml) was successively added the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (40 mg, 0.2 mmol), 1-hydroxybenzotriazole (27 mg, 0.2 mmol) and Isopropylamine (16 μl, of 0.182 mmol), and the mixture is stirred at room temperature for 15 hours. The reaction solution was poured into the ode, and the mixture is extracted with ethyl acetate, and the organic layer washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (chloroform/methanol = 9/1), while receiving specified in the title compound (39 mg, 44%) as a colourless foam.

1H NMR (CDCl3, δ ppm): 0,10-0,20 (m, 2H), 0,50-0,65 (m, 2H), 0.88 to (m, 1H), 1,13 (d, J=2.1 Hz, 3H)and 1.15 (d, J=1.8 Hz, 3H), 1,58 (d, J=11,4 Hz, 1H), 2,08 is 2.80 (m, 8H), 2,99-3,30 (m, 2H), of 3.94 (s, 3H), 4,06 (m, 1H), a 4.83 (user. s, 1H), 5,14 (d, J=2.4 Hz, 2H), 5,23 (user. s, 1H), 6,56 (d, J=8,4 Hz, 1H), 6,72 (d, J=8,4 Hz, 1H), 7,28 was 7.45 (m, 6N).

The third stage - 7-Isopropylaminocarbonyl-6-O-methylnaltrexone

To a solution of 3-O-benzyl-7-isopropylaminocarbonyl-6-O-methylnaltrexone obtained in the second stage (33 mg, 0,073 mmol)in tetrahydrofuran (5 ml) is added palladium hydroxide (33 mg) and the mixture is stirred for 1 hour in a hydrogen atmosphere. The reaction solution is filtered through celite, and the filtrate concentrated under reduced pressure. The residue is purified column chromatography on silica gel (chloroform/methanol = 9/1), while receiving specified in the title compound (13 mg, 41%) as a colourless foam.

1H NMR (CDCl3, δ ppm): 0,10-0,15 (m, 2H), 0,50-0,70 (m, 2H), 0,85 (m, 1H), 1,12 (d, J=0.9 Hz, 3H), 1.14 in (d, J=0.9 Hz, 3H), of 1.66 (d, J=11,4 Hz, 1H), 2.06 to 2,80 (m, 8H), 3.00 and-3,30 (m, 2H), 3,92 (s, 3H), of 4.05 (m, 1H), 4,80 (user. s, 1H), 5,26 (user. s, 1H), 6,56 (d, J=8,1 Hz, 1H), 6,69 (d, J=8,1 Hz, 1H), was 7.36 (d, J=7.8 Hz, 1H).

EXAMPLE 3

,

where Bn represents a benzyl, Me represents methyl, Et represents ethyl.

The first stage

A solution of the compound (1) (28,7 g, to 57.0 mmol) in tetrahydrofuran (250 ml) cooled to -10°C. and to the solution was added 1,1'-azodicarbonamide (21,6 g, 85,5 mol), tri-n-butylphosphine (21,4 ml of 85.5 mmol) and benzyl alcohol (6,50 ml, 62,7 mmol)and the mixture was stirred at room temperature for 6 hours and 45 minutes. The reaction solution is filtered, and the filtrate concentrated under reduced pressure, and the residue is purified column chromatography on silica gel (chloroform→chloroform/methanol = 50/1), while receiving with a quantitative yield of the considered connection (2) cases (33.8 g) as a pale yellow oil.

1H NMR (CDCl3, δ ppm): 0,10-0,20 (m, 2H), 0,50-0,65 (m, 2H), 0.88 to (m, 1H), were 0.94 (t, J=7.2 Hz, 3H), 1,20-of 3.60 (m, 11N), 4,14 (sq, J=7.2 Hz, 2H), 5,10 to 5.35 (m, 5H), to 6.58 (d, J=8,1 Hz, 1H), 6,74 (d, J=8,1 Hz, 1H), 7,15-7,50 (m, 10H).

The second stage

To a mixed solution of the compound (2)obtained in the first stage cases (33.8 g, to 57.0 mmol)in methanol (130 ml) and dioxane (43 ml) is added 4N aqueous potassium hydroxide solution (43 ml) and the mixture was stirred at 50°C for 14 hours and 35 minutes. The reaction solution is cooled to room temperature and concentrated under reduced pressure, and pH balance Regulus shall have up to 3-4 ice water and 2N hydrochloric acid, followed by extraction with a mixed solution of ethyl acetate and tetrahydrofuran. The organic layer is washed successively with water and saturated salt solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue is converted into a powder by a simple ether, thus obtaining the considered connection (3) (24.8 g, 77%) as a colorless powder.

1H NMR (DMSO-d6, δ ppm): 0,20-0,40 (m, 2H), 0,50-0,65 (m, 2H), 0,95 (m, 1H), 1.30 and of 3.60 (m, 11N), 5,00-a 5.25 (m, 5H), of 5.39 (s, 1H), of 6.68 (d, J=8,1 Hz, 1H), to 6.88 (d, J=8,1 Hz, 1H), 7,27-7,52 (m, 10H).

The third stage

To a solution of compound (3)obtained in the second stage (350 mg, 0,619 mmol)in tetrahydrofuran (4 ml) was successively added the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (142 mg, 0,743 mmol), 1-hydroxybenzotriazole (100 mg, 0,743 mmol), hydrochloride of the methyl ester of dimethylglycine (114 mg, 0,743 mmol) and N-methylmorpholin (82 μl, 0,743 mmol)and the mixture stirred at room temperature over night. The reaction solution was poured into ice water and saturated aqueous sodium bicarbonate solution followed by extraction with ethyl acetate, and the organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (chloroform/methanol = 50/1), while receiving the considered connection (4) (300 mg, 73%) as a pale yellow foam.

1H NMR (CDl 3, δ ppm): 0,08-0,20 (m, 2H), 0.50 to 0.60 (m, 2H), 0.87 (m, 1H), 1,13 (c, 3H), 1,22 (s, 3H), 1.55V is 2.80 (m, 11N), 3,62 (s, 3H), 4,85 (user. s, 1H), 5,13-of 5.40 (m, 5H), to 6.58 (d, J=8,4 Hz, 1H), 6,76 (d, J=8,4 Hz, 1H), 7,26-of 7.48 (m, 10H), 7,94 (s, 1H).

The fourth stage

To a solution of compound (4)obtained in the third stage (290 mg, 0,436 mmol), in methanol (4 ml) is added palladium hydroxide (60 mg), followed by stirring for 3 hours in hydrogen atmosphere. The reaction solution is filtered through celite, and the filtrate concentrated under reduced pressure. The residue is crystallized using a mixture of hexane/ethyl acetate, thus obtaining the considered compound (I-49) (181 mg, 86%) as colorless crystals.

1H NMR (DMSO-d6, δ ppm): 0,10-0,20 (m, 2H), 0,40-0,57 (m, 2H), 0,84 (m, 1H), 1,33 (c, 3H), of 1.37 (s, 3H), 1,40 is 3.40 (m, 11N), 3,55 (s, 3H), 4.72 in (s, 1H), 4,77 (user. s, 1H), of 6.52 (d, J=8,1 Hz, 1H), to 6.57 (d, J=8,1 Hz, 1H), 7,68 (user. s, 1H), 9,18 (user. s, 1H), 13,78 (user. s, 1H).

According to the same procedure it is possible to synthesize other compounds (I). Structural formulae and physical constants shown below.

In the tables, Me represents methyl, Et represents ethyl, Prirepresents isopropyl, and Ph represents a phenyl (see tab. 9-68).

In addition, in tables

means

(Measuring conditions LC/MS)*1:

Column: Chromolith Flash ROD PP-18e, C,6 mm ID.

Flow rate: 2 ml/mi is.

UV detection: 280 nm.

The solvent system: [A]=N2Oh, 0.05% HCOOH, [B]=Meon, 0.05% HCOOH.

Gradient: 0 min, 90% [A], 10% [B]; 0,2 min, 90% [A], 10% [B]; 1,0 min, 10% [A]90% [B]; 1,80 min, 10% [A]90% [B].

Note: the values with ** refer to the following measurement conditions:

column: Phenomenex Luna 5 micron, C18(2) 100A, size C,60 mm,

gradient: linear gradient 10%-100% acetonitrile over a 3.0 min 3.0 ml/min

Example 1 tests. The analysis of binding opioid δ receptor

1) Method of preparing a membrane sample for analysis linking

Used the brain of rats (Slc:SD), which was kept at -80°C. To the brain, which was weighed, added a 20-fold amount of ice buffer 10 mm Tris-HCl (pH 7.0), and the mixture is homogenized (about 25000./min, 30 seconds) homogenizer Histocolon (NITI-ON) and was centrifuged at 36600×g for 20 minutes. To the resulting precipitate was added 15 ml of the same buffer, and the mixture was treated similarly homogenizer Histocolon and centrifuged. This process of washing was performed twice. After centrifugation to the formed precipitate was added 15 ml of a buffer of 50 mm Tris-HCl (pH 7.4), and the mixture was treated with a homogenizer Histocolon, and finally re-suspended in 10-fold amount of the same buffer, and the product was used as a crude membrane fraction (Life Sci. 48, 111-116, 1991). These membrane clicks the set of technical documents were frozen and kept at -80°C, and in the analysis, the sample was rapidly thawed and diluted to a concentration of about 900 ug/ml buffer 50 mm Tris-HCl (pH 7.4) after centrifugation and processing Histocolon, and was used in the experiment. To measure the protein concentration of the membrane sample was used set for analysis of protein Micro BCA (PIERCE).

2) Method of analysis of binding of δ-receptor and data analysis

To a solution of 10 μl of the test compound, diluted to stage a 10-fold dilution was added to 10 μl final 3 nm [3H]-DADLE (51,5 CI/mmol: Perkin-Elmer)as the ligand. In the test tube was placed 480 μl of the membrane fraction of rat brain, to which was added 100 mm choline chloride, 3 mm MnCl2and 100 nm DAMGO, and the mixture is incubated at 25°C for 2 hours. After incubation, the mixture was filtered with suction through a filter Whatman GF/C, which was pre-treated with 0.5% polyethylenimine, and washed with 2.5 ml ice buffer 10 mm Tris-HCl (pH 7.4) four times. After washing, the filter was transferred into miniprobe for scintillation counter, were added 5 ml of scintillator (Cleasol I), the tube was kept overnight and the radioactivity was measured for 3 minutes scintillation counter Tri-Carb 2200CA (PACKARD). For total binding (total binding: TB) for data analysis was used DMSO, and 20 μm of levallorphan used for non-specific with what Azania (nonspecific binding: NB), and to calculate the Ki value of the test compounds with the use of KD values (2,93 nm), obtained in advance by analyzing the graphs Sketched.

The results are shown in table 69.

Table 69

From the above results show that the compound (I) possesses an affinity for the δ opioid receptor.

Example 2 testing. The analysis of binding opioid µ-receptor

1) Method of preparing a membrane sample for analysis linking

Used the brain of rats (Slc:SD), which was kept at -80°C. To the brain, which was weighed, added a 20-fold amount of ice buffer 10 mm Tris-HCl (pH 7.0), and the mixture is homogenized (25000 rpm, 30 seconds) homogenizer Histocolon (NITI-ON) and was centrifuged at 36600×g for 20 minutes. To the resulting precipitate was added 15 ml of the same buffer, and the mixture was treated similarly to the homogenizer Histocolon and centrifuged. This process of washing was performed twice. After centrifugation to the formed precipitate was added 15 ml of a buffer of 50 mm Tris-HCl (pH 7.4), and the mixture was treated by a homogenizer Histocolon, and finally re-suspended in 10-fold amount of the same buffer, and the product was used as a crude membrane fraction (Life Sci. 48, 111-116, 1991). The obtained membrane sample was frozen and kept at -80°C, and when conducting the Academy of Sciences of the Lisa, the sample was rapidly thawed and diluted to a concentration of about 900 ug/ml buffer 50 mm Tris-HCl (pH 7.4) after centrifugation and processing Histocolon, and used in the experiment. To measure the protein concentration of the membrane sample was used set for analysis of protein Micro BCA (PIERCE).

2) Method of analysis of binding µ-receptor and data analysis

To a solution of 10 μl of the test compound, diluted to stage a 10-fold dilution of the test compounds were added to 10 μl final 2 nm [3H]-DAMGO (51,5 CI/mmol: Perkin-Elmer) as a ligand, then the tube was placed 480 μl of the membrane fraction of rat brain and the mixture is incubated at 25°C for 2 hours. After incubation, the mixture was filtered with suction through a filter Whatman GF/C, which was pre-treated with 0.5% polyethylenimine, and washed with 2.5 ml ice buffer 10 mm Tris-HCl (pH 7.4) four times. After washing, the filter was transferred into miniprobe for scintillation counter, were added 5 ml of scintillator (Cleasol I), the tube was kept overnight and the radioactivity was measured for 3 minutes scintillation counter Tri-Carb 2200CA (PACKARD). For total binding (total binding: TB) for data analysis was used DMSO, and 20 μm of levallorphan was used for nonspecific binding (nonspecific binding: NB), and calculate the Ki value of the test compounds with the use of KD values (1,72 nm), obtained in advance by analyzing the graphs Sketched (Anal. Biochem. 107(1), 220-239, 1980).

Results while the Ana in table 70.

Table 70

Example 3 tests. Analysis of the transfer of the coal powder

1) Preparation of feed for testing (coal powder)

Using 10% wt./about. aqueous solution of Arabian gum was obtained containing 5% wt./about. active coal slurry, which is used as feed for testing.

2) Animal

Used male mice (5-6 weeks of age) line ddY.

Animals fasted for about 20 hours or more prior to analysis, water was given without restrictions.

3) Test the connection and environment

The test compound was dissolved in the solvent (DMAA/solutol/5% meglumine = 15/15/70).

DMAA: N,N-dimethylacetamide,

solutol: solutol (registered trademark) HS15,

meglumin: D-(-)-N-methylglucamine.

Morphine hydrochloride was dissolved in physiological saline. The test compound, the above-mentioned solvent and morphine, all introduced in liquid form in an amount of 10 ml/kg

4) Method of analysis

The test compound in the amount of 3 mg/kg (group introduction of the test compound or solvent (for groups of introducing solvent) was injected subcutaneously, and 3 mg/kg morphine was administered subcutaneously to all groups after 15 minutes. The control group was subcutaneously injected solvent and after 15 minutes were injected with physiological saline solution.

10 ml/kg of feed for testing oral was administered 15 minutes after the injection of morphine. Thirty minutes after administration of feed for testing (60 minutes after administration of the test compound), all rats were separated region from the esophagus to the ileocecal part near the cardiac orifice of the stomach. Measured the distance from the pyloric part of the stomach to the ileocecal part (full length of the small intestine) and the distance to reach the coal powder front (distance of movement of the coal powder). Antagonistic activity directed against the activity of morphine, inhibiting the transfer of carbon powder, was calculated as MPE (%) using the following equation. The results are shown in table 71.

The degree of transfer (%) = (the distance that passes the coal powder)/full length of the small intestine (cm)) × 100

MRE (%) = {(degree of transfer of the small intestine (%) for group introduction each individual test compound - average degree of transfer of the small intestine (%) for the group, the introduction of solvent)/(average degree of transfer of the small intestine (%) for the control group - average degree of transfer of the small intestine (%) for the group of injection solvent)} × 100.

Table 71

Example 1 ready preparative form

Obtain granules containing the following ingredients.

Ingred the UNT The compound represented by formula (I)10 mg
Lactose700 mg
Corn starch274 mg
HPC-L16 mg
1000 mg

The compound represented by formula (I), and lactose are passed through a sieve of 60 mesh. Corn starch is passed through a sieve of 120 mesh. These components are mixed by a mixer, V-type. To the mixed powder to add an aqueous solution of HPC-L (hydroxypropylcellulose low viscosity), the mixture is kneaded, granularit (granulation by extrusion, the pore diameter of 0.5 to 1 mm) and dried. The resulting dry granules are passed through a sieve using vibrating sieve (12/60 mesh), thus obtaining the desired granules.

Example 2 ready preparative form

Get pellets for filling capsules containing the following ingredients.

IngredientThe compound represented by formula (I)15 mg
Lactose90 mg
Corn starch42 mg
HPC-L3 mg
150 mg

The compound represented by formula (I), and lactose are passed through a sieve of 60 mesh. Corn starch is passed through a sieve of 120 mesh. These components are mixed, the mixed powder add a solution of HPC-L, substances get mixed up, granularit and dried. The size of the resulting dry pellets regulate and hard gelatin capsule No. 4 fill 150 mg of the obtained granules.

Example 3 ready preparative form

Receive a tablet containing the following ingredients.

IngredientThe compound represented by formula (I)10 mg
Lactose90 mg
Microcrystalline cellulose
SMS-Na
30 mg
15 mg
5 mg
150 mg

The compound represented by formula (I), lactose, microcrystalline cellulose, CMC-NA (sodium carboxymethyl cellulose) pass through a sieve of 60 mesh and mixed. The mixed powder is mixed with magnesium stearate, while receiving mixed powder for tableting. Specified mixed powder is pressed to obtain 150 mg tablets.

Example 4 ready preparative form

The following ingredients are heated, mixed and sterilized to obtain an injectable preparation.

IngredientThe compound represented by formula (I)3 mg
Nonionic surfactant15 mg
Purified water for injections1 ml

Industrial applicability

The present invention is an agent useful for weakening side effects, such as nausea, vomiting and/or higher.

1. The compound represented by formula (I)

where R1and R2each independently represents hydrogen, optionally substituted lower alkyl, optionally substituted lower alkylsulfonyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic group, optionally substituted arylsulfonyl or R1and R2taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle;
R3represents hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower quinil, optionally substituted lower alkoxy, optionally substituted amino, optionally substituted carbarnoyl or optionally substituted heterocyclic group;
the group represented by the formula:
can be
or
where ring a and ring each independently represents an optionally substituted nitrogen-containing heterocycle, optionally containing an additional nitrogen atom in the ring;
the dotted line means the presence or absence of communication;
when the dotted line means the presence of communication, p is 0;
when the dashed line indicates the lack of communication, R is 1;
Rarepresents hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl
and Rbrepresents hydrogen or oxo;
R4represents hydrogen or lower alkyl;
R5represents hydrogen, cycloalkyl-lower alkyl,
or its pharmaceutically acceptable salt or MES.

2. The compound according to claim 1, where R3represents hydroxy, or its pharmaceutically acceptable salt or MES.

3. The compound according to claim 1, where R3represents optionally substituted amino, or its pharmaceutically acceptable salt or MES.

4. The compound according to any one of claims 1 to 3, where R1represents hydrogen or lower alkyl, R2represents an optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted cyclol the sludge or optionally substituted heterocyclic group, and R 5is cyclopropylmethyl,
or its pharmaceutically acceptable salt or MES.

5. The compound according to claim 1 or 2, where
R1represents hydrogen;
R2represents lower alkyl, optionally substituted heterocyclic group, optionally substituted by aryl or lower alkoxy; phenyl, optionally substituted lower alkyl or lower alkoxy; cycloalkyl, substituted lower alkylcarboxylic, or heterocyclic group, the substituted lower alkoxy or aryl;
R3represents hydroxy;
R4represents hydrogen and
R5is cyclopropylmethyl,
or its pharmaceutically acceptable salt or MES.

6. Pharmaceutical composition having antagonistic activity for opioid receptor-containing compound according to any one of claims 1 to 5, or its pharmaceutically acceptable salt, or MES.

7. Composition for treatment and/or prophylaxis of nausea, vomiting and/or constipatio containing compound according to any one of claims 1 to 5, or its pharmaceutically acceptable salt, or MES.

8. Composition for loosening and/or prevention of side effects caused by the compounds having an agonistic activity to the opioid receptor-containing compound according to any one of claims 1 to 5, or its pharmaceutically als is salt, or MES.

9. The composition of claim 8, where the side effect is nausea, vomiting and/or higher.

10. The composition of claim 8 or 9, where the compound having an agonistic activity to the opioid receptor, is morphine, oxycodone or its pharmaceutically acceptable salt or MES.

11. The use of compounds according to any one of claims 1 to 6, or its pharmaceutically acceptable salt, or MES to obtain a pharmaceutical composition for the treatment and/or prophylaxis of nausea, vomiting and/or constipatio.

12. The method of treatment and/or prophylaxis of nausea, vomiting and/or constipatio, comprising introducing the compound according to any one of claims 1 to 5, or its pharmaceutically acceptable salt, or MES.

13. Composition for analgesia containing the compounds having an agonistic activity to the opioid receptor and an effective amount of a compound according to any one of claims 1 to 5, or its pharmaceutically acceptable salt, or MES to mitigate and/or prevent side effects caused by the introduction of compounds with agonistic activity for the opioid receptor.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of purifying plant extracts which mainly consist of noroxymorphone compounds and contain α,β-unsaturated noroxymorphone compounds as impurities, through (a) conversion of a plant extract or product of the next step in synthesis of the selected noroxymorphone compound as a result of conversion of hydroxyl groups present in the mixture to groups of formula -OR2 which can be split, in which R2 is an introduced radical of the said group which can be split, (b) said groups, if necessary, can be removed once more, after which (c) the obtained mixture is subjected to selective hydrogenation so that a saturated bond forms in the α,β-position of unsaturated noroxymorphone compounds and all the remaining groups which can be split are converted to a hydroxyl group, after which (d) a pure noroxymorphone compound is extracted; processing the purified noroxymorphone to naltrexone or naloxone or a salt of these compounds or a quaternary derivative of these compounds, which are known pharmaceutically active compounds particularly used for reducing psychological dependency and during drug abuse.

EFFECT: improved purification of compounds.

21 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride having sustained quality of production and high purity. Crystalline forms of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride are proposed, including A-forms, B-forms or C-forms, and method of producing said forms.

EFFECT: obtaining compounds which have analgesic, diuretic and antipruritic effect.

10 cl, 8 dwg, 2 tbl, 8 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new 6-amino-morphinane derivatives of formula I wherein meanings of R1-R4 and X are as defined in specification; composition based on the same having analgesic action, and uses thereof as high active analgesics.

EFFECT: new high active analgesics.

9 cl, 4 tbl, 5 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to compounds, namely, to derivative of 14-hydrxoynormorphinone of the formula (IV) , derivative of morphinone of the formula (III) , derivative of morphine of the formula (II) wherein R1 represents (C1-C7)-alkyl; R2 represents benzyl or benzyl substituted with one or some (C1-C6)-alkoxy-groups, or benzyl substituted with one or some halogen atom. Also, invention relates to a method for synthesis of derivative of 14-hydroxynormorphinone of the formula (IV) involving interaction of compound of the formula (III) with cobalt (II) as oxidant in the presence of a weak base and air or oxygen as co-oxidant. Also, invention relates to a method for synthesis of derivative of morphinone of the formula (III) involving interaction of derivative of morphine of the formula (II) with oxidizing agent that is effective in oxidation of allyl hydroxy-groups. Mainly, invention relates to a method for synthesis of noroxymorphone. The process involves oxidation of derivative of morphinone of the formula (III) to derivative of 14-hydroxynormorphinone of the formula (IV), removal of protection from 3-position and reduction of double bond at 7,8-position in derivative of 14-hydroxynormorphinone of the formula (IV) to yield derivative of 3,14-hydroxynormorphinone of the formula (V) and hydrolysis of derivative of 3,14-hydroxynormorphinone of the formula (V) to yield noroxymorphone of the formula (VI) wherein formulae (V) and (VI) are given in the invention description. Invention provides synthesis of noroxymorphone using novel intermediate compounds.

EFFECT: improved method of synthesis.

25 cl, 1 sch, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery and endocrinology, and can be used in the patients requiring a conservative treatment of acute pancreatitis. That is ensured by a standard medical therapy by the introduction of infusion preparations, anaesthetics, spasmolytics, vasoconstrictors, antibiotics, novocaine, cytostatics, omeprazole, sandostatin. For the period of treatment, hunger with voluminous drinking is prescribed. Pit of the stomach is cooled. In addition, procaine blocks in the round ligament of liver are applied that implements the introduction of at least 200 mg of Immunomax and 10 ml of 5-fluorouracil. During 2 days, at least 1.0 g of metronidazole, 0.1 g of furaginum, at least 15.0 g of Enterosgel are intaken. During the whole therapeutic course, at least 1 ml of Sporobacterine suspension together with cooled water is taken once a day. Starting from the sixth day and during the whole therapeutic course of hospital treatment, 1 tablet of Mezym forte 2 times a day is prescribed. For at least two weeks after discharge from the hospital, treatment in a locally available health resort is continued.

EFFECT: method allows reducing considerably the probability of acute pancreatitis transition into a destructive form due to the effect of specified therapy by various pathogenesis links of specified disease.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, namely to preparation of a composition for body fat reduction. A group of inventions is offered: the composition for body fat reduction, containing astaxanthin as an effective ingredient in amount 0.001-99.9% of total weight; the composition for body fat reduction which is prepared by grinding Haematococcus alga and extraction of ground Haematococcus alga in a solvent in which Haematococcus alga extract containing astaxanthin is found in amount 0.001-99.9% of total weight; an agent for body fat reduction which contains any of compositions; food and beverage for body fat reduction which contain any of compositions and the method of body fat reduction which involves the introduction or intake by an individual of any composition in amount 0.2-100.0 mg a day at free astaxanthin.

EFFECT: body fat reduction without weight variations.

12 cl, 4 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cosmetology and can be used for skin care. For this purpose, artesian water synthetically enriched with active oxygen forms is used. It is applied on face or body skin by means of a guided pulveriser-sprayer.

EFFECT: method provides minimum duration of application of irrigation procedure, enables the permanent intended use regardless of time and a place.

FIELD: medicine, veterinary science.

SUBSTANCE: invention concerns veterinary. The preparation contains the following drugs: L-arginine monohydrochloride in amount 48-72 mg/l, L-lysine monohydrochloride in amount 48-72 mg/l, L-histidine monohydrochloride in amount 13.8-20.8 mg/l, L-isoleucine in amount 13.8-20.8 mg/l, L-leucine in amount 41.6-62.4 mg/l, L-methionine in amount 10.4-15.6 mg/l, L-phenylalanine in amount 17.2-25.8 mg/l, L-threonine in amount 20.8-31.2 mg/l, L-tryptophan in amount 7.9-10.3 mg/l, L-glutamine in amount 68.8-103.2 mg/l, L-valine in amount 17.2-25.8 mg/l, L-tyrosine in amount 27.7-41.5 mg/l, L-cystine monochloride in amount 17.9-26.9 mg/l, L-serine in amount 17.2-25.8 mg/l, glycine in amount 34.4-54.6 mg/l, L-alpha-alanine in amount 17.2-25.8 mg/l, L-proline in amount 25.6-38.4 mg/l, L-aspartic acid in amount 18.0-30.0 mg/l, L-oxyproline in amount 7.9-10.3 mg/l, L-glutamic acid in amount 48-72 mg/l, L-cysteine monohydrochloride in amount 0.12-0.70 mg/l, choline chloride in amount 0.4-3.0 mg/l, folic acid in amount 0.01-0.09 mg/l, calcium pantothenate in amount 0.01-0.09 mg/l, thiamine hydrochloride in amount 0.01-0.09 mg/l, nicotinic acid in amount 0.03-0.22 mg/l, pyridoxal monohydrochloride in amount 0.03-0.22 mg/l, riboflavin in amount 0.012-0.09 mg/l, nicotinamide in amount 0.03-0.22 mg/l, D-biotin in amount 0.01-0.09 mg/l, myoinositol in amount 0.06-0.45 mg/l, pyridoxine hydrochloride in amount 0.03-0.22 mg/l, calciferol in amount 0.01-0.09 mg/l, ascorbic acid in amount 0.06-0.45 mg/l, p-amino-benzoic acid in amount 0.06-0.45 mg/l, glucose in amount 800-1200 mg/l, and the following inorganic salts: sodium chloride in amount 7.2-8.8 g/l, potassium chloride in amount 360-440 mg/l, one-substituted potassium phosphate in amount 54-66 mg/l, two-substituted 12-aqueous sodium phosphate in amount 13.5-16.5 mg/l, 6-aqueous calcium chloride in amount 24.8-30.4 mg/l, 6-aqueous magnesium chloride in amount 9.9-11.6 mg/l, 7-aqueous magnesium sulphate in amount 9.0-11.0 mg/l, 9-aqueous ferrous nitrate in amount 0.65-0.79 mg/l, 3-aqueous sodium acetate in amount 7.1-8.7 mg/l. The method for prevention and correction of diseased conditions in animals consists in the injection introduction in an animal of said preparation in the form of an aqueous solution for prevention 2 times a week for a month in dosage 1.5-2.0 ml per 10 kg of body weight, for therapy in dosage 3.0-5.0 ml per 10 kg of body weight 2 times a day for 3-5 days, at synthetic and/or food poisoning intoxications - in a tenfold therapeutic dose. And, if a dose of the preparation exceeds 20 ml, it is injected in more points.

EFFECT: invention provides higher therapeutic and preventive effectiveness.

6 cl, 8 tbl

FIELD: chemistry; biochemistry.

SUBSTANCE: present invention relates to immunology and biotechnology. The invention discloses versions of a cytotoxically active CD3-specific binding structure. The structure comprises a first domain specifically binding to human CD3 and an Ig-derived second binding domain which is specific to molecules on the cell surface. The invention describes a coding nucleic acid, a vector for expressing the structure and an eukaryotic cell transformed by the vector. The invention discloses versions of compositions based on the structure for treating, preventing or alleviating various diseases and corresponding methods of treating the diseases. A method of obtaining the structure is disclosed.

EFFECT: use of the invention provides a structure with low immunological potency, which has cytotoxicity comparable to the initial structure, which may find further use in medicine.

60 cl, 18 dwg, 15 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of purifying plant extracts which mainly consist of noroxymorphone compounds and contain α,β-unsaturated noroxymorphone compounds as impurities, through (a) conversion of a plant extract or product of the next step in synthesis of the selected noroxymorphone compound as a result of conversion of hydroxyl groups present in the mixture to groups of formula -OR2 which can be split, in which R2 is an introduced radical of the said group which can be split, (b) said groups, if necessary, can be removed once more, after which (c) the obtained mixture is subjected to selective hydrogenation so that a saturated bond forms in the α,β-position of unsaturated noroxymorphone compounds and all the remaining groups which can be split are converted to a hydroxyl group, after which (d) a pure noroxymorphone compound is extracted; processing the purified noroxymorphone to naltrexone or naloxone or a salt of these compounds or a quaternary derivative of these compounds, which are known pharmaceutically active compounds particularly used for reducing psychological dependency and during drug abuse.

EFFECT: improved purification of compounds.

21 cl, 8 ex

FIELD: medicine.

SUBSTANCE: lytic exoenzyme of Cellulomonas cellulans strain RNCIM AS-870 of molecular weight within 100 to 30 kDa and specific activity 48.3 UN/mg of protein and more is used. A preparation for treating mycotic infections contains lytic exoenzyme of Cellulomonas cellulans strain RNCIM AS-870 of molecular weight within 100 to 30 kDa and specific activity 48.3 UN/mg and more of protein and represents a topical drug.

EFFECT: lower probability of recurrences in treating mycotic infections without normal flora suppression.

10 cl, 4 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: for correction of endothelial dysfunction in experiment on rats dysfunction is modelled by preliminary sensitisation of animal with staphylococcus anatoxin in doze 0.1 ml subcutaneously. Then after 24 hours in the same place as anatoxin introduced is suspension of Staphylococcus aureus subcutaneously in dose 60 billions of microbial bodies in 1 ml. After that for following generalisation of infectious agent, daily massage of injection place is carried out. At this background introduced is macrolidal medication azithromycin intragastrically in dose 30 mg/kg/day.

EFFECT: method ensures activation of endothelial dysfunction correction.

1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: in order to estimate resorbtion function of peritoneum time during which animals achieve stage of surgical sleep in case of intraperitoneal introduction of ethaminal is determined.

EFFECT: method allows to estimate indirectly resoptive function of peritoneum in norm and under impact of aggressive factors.

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to surgery. Solution of dye is introduced in proper segmental vessel by direct injection method. Preliminarily, before introduction of dye solution, feeding artery is compressed for 2-3 minutes, dye solution is introduced more distally than compression place and after 1-2 minutes respective vein is compressed. Simultaneously area of supposed staining is influenced by source of constant magnet, placed outside of the organ surface.

EFFECT: method extends arsenal of means for marking intraorgan zones, segments of parenchymatous organs.

2 ex

FIELD: medicine.

SUBSTANCE: solid dosage form consists of a core containing, wt %: bisacodyl - 1.5-12; potato starch - 0.5-10; pregelatinised starch - 2-15; croscarmellose sodium - 0.5-4; colloidal silicon dioxide - 0.2-5; stearic acid and/or its salts - 0.3-1.07; lactose - the rest; and a coating containing, wt %: polyethylene glycol - 0.05-0.2; staining agent - 0.05-0.25; titanium dioxide - 5-25; talc - 20-54; triethyl citrate - 1-7; colloidal silicon dioxide 0.5-2; sodium hydrocarbonate - 0.5-2; sodium lauryl sulphate - 0.1-1 and copolymer of methacrylic acid and ethyl acrylate - the rest.

EFFECT: invention ensures good strength and disintegration of a tablet in the neutral or alkalescent intestinal environment.

8 cl, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine and pharmaceutics and concerns an agent gastrointestinal stimulation, specifically for prevention or treatment of functional gastric distresses, appetite regulation etc., containing TIR agonist representing cyclamate or amide derivative of formula as an active agent, a based pharmaceutical composition or a foodstuff and a method for gastrointestinal stimulation.

EFFECT: present invention provides improved life quality of the patients.

27 cl, 7 dwg, 3 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to gastroenterology, and concerns treating gastrointestinal disorders. That is ensured by administration of the effective amount of a halogenated prostaglandin compound and/or its tautomer.

EFFECT: method provides effective treatment in patients of any age and sex without involving electrolyte balance even in long-term introduction for 1 to 6 months and more.

54 cl, 8 tbl, 14 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: present invention refers to medical products, particularly to large depletion mixture containing the following components per litre of aqueous solution: polyethylene glycol 90 to 150; ascorbic acid and/or ascorbic acid salt 5 to 15; alkaline or earth metal sulphate or mixed alkaline or earth metal sulphates 5 to 10; and electrolyte (sodium chloride, potassium chloride and sodium hydrocarbonate). The mixture agents are chosen so that the osmolarity of the aqueous solution reduced to 1 litre is within 300 to 550 mOsmoles/litre. Besides the invention concerns a cleaning agent, a component set for large intestine depletion, to application of polyethylene glycol as a large intestine depletion agent and to method of large intestine depletion.

EFFECT: higher mixture safety and tolerance.

39 cl, 29 tbl, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: IBAT antioxidant application (transport of bilious acids in a iliococcygeus gut), chosen of 1,2,5-benzothiadiazines in treatment and-or prevention of coprostasia at warm-blooded animals, such as the person (versions), corresponding method of treatment and a pharmaceutical composition is described.

EFFECT: increase in quantity of excrements at the expense of strengthening of impellent function of intestines, increase in quantity of water in its bottom part content, softening of the content and decrease in a stretching of walls of intestine, reduction of feeling of pain.

16 cl, 3 tbl

FIELD: medicine.

SUBSTANCE: method involves giving patient to drink 100 ml of lactulose syrup with 250 ml of liquid at the day before examination. 2-3 h later, intestinal lavage is carried out with 10-15% aqueous lactulose solution being prepared as 100 ml of the syrup diluted with water to volume of 1 l, giving 250 ml to drink every 15 min. Next day, intestinal lavage is carried out with 1 l of aqueous polyethylene glycol solution 3-4 h before performing examination.

EFFECT: enhanced effectiveness in cleaning large intestine with smaller volume drugs consumed; improved aged patient tolerance to the procedure.

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