Use isoxazol derivative for the treatment of irritable bowel syndrome (mucous colitis) and pharmaceutical composition

 

(57) Abstract:

A new tool and a pharmaceutical composition based on it for the treatment of irritable bowel syndrome. The tool is an isoxazol derivative, 2-(di-n-propylamino)-8-(isoxazol-5-yl)-1,2,3,4-tetrahydronaphthalen; S-(-)-2-(di-n-propylamino)-8-isoxazol-5-yl)-1,2,3,4-tetrahydronaphthalen; R(+)-2-(di-n-propylamino)-8-(isoxazol-5-)-1,2,3,4-tetrahydronaphthalen; 2-(di-n-propylamino)-8-(3-bromination-5-yl )-1,2,3,4-tetrahydronaphthalen; 2-(di-n-propylamino)-8-(4-methylisoxazol-5-yl)-1,2,3,4-tetrahydronaphthalen; 2-(di-n-propylamino)-8-(3-methylthiotetrazole-5-yl)-1,2, 3,4-tetrahydronaphthalen; 2-(di-n-propylamino)-8-(3-methyl-isoxazol-5-yl )-1,2,3,4-tetrahydronaphthalen; 2-(di-n-propylamino) -8-(4-methoxyethoxy-5-yl)-1,2,3,4-tetrahydronaphthalen, or its pharmaceutically acceptable salt or MES. The invention expands the Arsenal of tools for the treatment of irritable bowel syndrome. 2 S. and 1 C.p. f-crystals, 2 tab.

The present invention relates to a method of treating irritable bowel syndrome /mucous colitis/ in mammals and is suitable for this circuit pharmaceutical compositions.

The syndrome of irritation of the colon is a violation of the motor actiology. This syndrome is characterized by symptoms that are strongly influenced by psychological factors and stressful life situations.

The irritable bowel syndrome or mucous colitis is one of the most common disorders of the gastrointestinal tract. From 20 to 50% of patients with gastrointestinal clinic, suffer from irritable bowel syndrome. The symptom of this phenomenon is manifested in average 14% of healthy people. This is one of the poorly understood disorders, as it is not a disease but a syndrome consisting of a number of phenomena that have a similar manifestation.

Most of the symptoms of irritable bowel syndrome /deviation from the normal functioning of the bowels, pain in the intestines and swelling of the abdomen/ manifested in increasing intestinal motility and hypersecretion of gastric juice.

The activity of the gastrointestinal tract is modulated by the activity of the Central nervous system via the parasympathetic and sympathetic innervation and peripheral nervous system of the gastrointestinal tract, located in the gastrointestinal tract.

The nervous system of the gastrointestinal tract takeee in the absence of a Central pulse.

For more information, see

Goyal, R. K. "Neurology of the Gut", Gastrointestiron Disorners, Ed., Sleisenger and Fordtran, Saunders 1983/, pp. 97 - 114.

Serotonin /5-hydroxytryptamine, 5HT/ directly or indirectly associated with the majority of physiological phenomena, such as appetite, anxiety and depression. A. glernon. J. Med. Chem. 30, 1 /1987,. The 5HT receptors were detected in the Central nervous system and peripheral tissues, including the gastrointestinal tract, lungs, heart, blood vessels and many other tissues of smooth muscles.

It was found that there are many types 5 HT receptors. Receptors have been classified as 5-HT1, 5-HT 2, 5-HT3 and 5-HT4, and at least one 5-HT1-receptor was later subdivided into subclasses and identified as 5-HT1A, 5-HT1C AND 5-HT1D.

In the Central nervous system 5-HT receptors are postsynaptic from neutrons, receiving serotonergic presynaptic impulse and have released 5-HT neurons. It is believed that presinapticheskie receptors act in such a way that the means to sense the concentration of 5-HT in the synaptic cleft and, accordingly, to further modulate the secretion of 5-HT.

In General, the term "agonist" should be interpreted as chemical soedinenii serotonin are chemicals, associated with them, mimic the action of serotonin or serotonin receptors.

Agonists of serotonin, acting eposredstvenno, are chemical substances that increase the concentration of serotonin in the synaptic cleft. Agonists of serotonin, with indirect effects include inhibitors media, specific to the absorption of serotonin, a substance that produce serotonin pellet-substances /precursors of serotonin/ enhancing the formation of serotonin, monoamine oxidase inhibitor, blocking the breakdown of serotonin and thus increasing the possible number.

As you know, serotonin has many functions in the gastrointestinal tract. It is also known that intravenous infusion of 5-HT or 5-HTP /5-hydroxytryptophan/ person reduce the volume and acidity of the secretion of the gastrointestinal tract, occurring spontaneously or induced by histamine, while increasing the amount of mucus.

Hordbook of Experomental Pharmarology, T. XIX, "5-Hydroxytryptamine and Related Indolealkylamibes", V. Erspamer new York, 1966, pp. 329-335. It is unknown, however, whether associated with one or more combinations of 5-HT receptors to cause this decline, and what receptors in it which are intermediaries reduce these tissues. The bottom of the rat stomach and the ileum of the Guinea pig are widely used for in vitro studies of agonists and antagonists of 5-HT. Enterochromaffin cells of the gastrointestinal tract represents the largest production of 5-HT in the body.

The ability to contractile activity of the intestine is under the strong influence of cholinergic receptors. It is known that acetylcholine increases the ability of the gastrointestinal tract by acting on muscarinic receptors. However, we know at least five different muscarinic receptors M1 /M5/. See

Ball B. Wolfe: In the Muscorinic Receptors. In J. Brown, The Huma Press, new York, 1989, PP 125-150/.

The relative role of these receptors in modulating the ability of the gastrointestinal tract to reduce not installed because they were not identified selective agonists and antagonists of these receptors. When irritable bowel syndrome compounds acting as antagonists muscarine, such as, for example, bentil have valuable therapeutic effects, but differ in a number of side effects.

Treatment of irritable bowel syndrome is limited to drugs t is know spasticity and pain in the abdomen when this was over. On the other hand antagonists histamine H2receptor, reduce the secretion of gastric juice and can thus alleviate the symptoms of digestive disorders. A therapeutic agent that can remove or alleviate the symptoms of irritable bowel syndrome, at present has not yet been found.

It was found that agonists of 5 HT1 reduce the secretion of gastric juice by direct effects on 5 4HT-receptor, facilitating thus the symptoms of indigestion /dyspepsia/. The authors were able to find a whole series of such compounds - agonists, which, as it turns out, have an affinity with M1-cholinergic receptors in the binding and exhibit in vitro anti-spastic activity. Hence, the present invention compounds will be particularly useful in the treatment of irritable bowel syndrome and most of the related phenomena.

The object of the present invention is a group of compounds that are agonists of direct effects on 5-HT1A and are substances that directly affects M1-cholinergic receptors. Since these two characteristics are very important for normal functioning of the intestines, relieving pain and bloating alive is the impact on the ability to contractile activity of the gastrointestinal tract, will be useful in the treatment of a specified disease and a whole range of related phenomena. In addition, the subject of the present invention are new compositions acceptable for a patentable method.

Other objects of the invention, its ability and benefits presented in the further description of the invention and the points of his formula.

The present invention is a treatment of irritable bowel syndrome in a mammal, and includes the introduction of mammals needed to treat the number of compounds with the formula I /effective dose/,

< / BR>
in which R represents hydrogen, C1-3-alkyl, allyl or

R1is hydrogen, C1-3-alkyl, allyl, or -(CH2)n-X;

n = 1-5;

X represents a substituted or unsubstituted phenyl, C1-3-alkoxy, or C1-3-alkylthio;

R2and R3independent from each other hydrogen, C1-3-alkyl, C1-3-alkoxy, C1-3-alkylthio, halogen, CN or phenyl, or together are -(CH2)p- where p = 3 - 6 integer;

Y IS-CH2-, -O-, -SOm-, where m = 0, 1, or 2,

or pharmaceutically acceptable salt is a product of accession acid or MES.

The compounds of formula I is altoadige of the invention is a pharmaceutical composition, suitable for the treatment of this syndrome, including the compound of formula I or pharmaceutically acceptable salt or MES it, in combination with one or more pharmaceutically acceptable fillers, solvents or additives. Major chemical names used in the formula are commonly used value. For example, the term "alkyl" represents promoteyou or branched alkyl chain containing the specified number of carbon atoms. C1-3-alkyl groups are methyl, ethyl, ethyl, n-propyl and isopropyl, a is cyclopropylmethyl

The halogen is bromine, chlorine, fluorine or iodine.

Substituted or unsubstituted phenyl is a phenyl ring which may contain one or two substituent selected from the following group C1-3-alkyl, C1-3-alkoxy, C1-3-alkylthio, halogen, NO2and CN.

The irritable bowel syndrome is the most suitable and accurate term is usually applied to the disorders that can be treated in accordance with the patented method. This term emphasizes that the violation is the result of changes in physical activity, which manifests itself in the form estrago tract. Many commonly used items this kind of disorders such as nervous, unstable, or spastic colitis, are inadequate and inaccurate, or both.

The message of the international working group define irritable bowel syndrome as dysfunction of the gastrointestinal tract, manifested in /1/ abdominal pain and/or symptoms of bowel emptying /urge for defecation, swelling of the abdomen, feeling of incomplete bowel emptying, changing the shape of the chair /consistency/ frequency/ time bowel/ or /3/ feeling gravity /overflow/.

They proposed new criteria disharmony gastrointestinal abdominal pain or discomfort, impaired defecation or associated with this change in frequency or consistency of stools, and three or more of the following criteria:

/1/ altered stool frequency,

/2/ the modified form of chair /solid, soft or watery stools/,

/3/ altered stool passage /the urge for defecation or swelling of the abdomen, feeling of incomplete emptying,

/4/ the release of mucus, and

/5/ the feeling of fullness or bloating. See

Schuster, M. M. Gastroenterology Clinies of Health to be used for the treatment of irritable colon, which in the current and subsequent definitions are manifested specified symptoms.

Symptoms that help to distinguish irritable bowel syndrome from organic disorders, the following: /1/ visible bloating, relieve when you massage the abdomen, /3/ removing pain after defecation and more frequent defecation, and /4/ soft stool, accompanied by pain.

Schuster M. M. Gastrointestenal Diseases, Izd-vo Shesenger u Fordtram, Saunders /1983/, 880-895.

As mentioned above, the compounds suitable for practical application, the present invention method include pharmaceutically acceptable salts of the addition products of acids,derivatives of these compounds having values of formula I. Since these compounds are amines, they are basic in nature and therefore can interact with a number of inorganic and organic acids to form salts. Since the free amines of these compounds are typical oils at room temperature, it is advisable to convert them into the corresponding pharmaceutically acceptable salt to facilitate the work with them, and since the latter at room temperature predstavlyayuschie acid, type hydrochloric, Hydrobromic, itestosterone, sulfuric, phosphoric and similar acids, and organic acids such as para-toluensulfonate, methanesulfonate, oxalic acid, para-bromophenylacetate acid, carboxylic acid, succinea acid, citric acid, benzoic acid, acetic acid and the like. Thus as an example, pharmaceutically acceptable salts can be called sulfate, persulfate, bisulfate, sulfite,bisulfite, phosphate, acidic monophosphate, acidic diphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, decanoate, kaprilat, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-Butin-1,4-diet, 3-hexyne-2,5-diet, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, Y-gidroksibutirata, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate etc. Preferred pharmaceutical acceptable salts of the acid products of accession can be considered to be those of N. the organic acids, for example maleic acid.

In addition, some of these salts are able to form a solvate with water or organic solvents, for example ethanol. Such solvate are also one of the objects of the present invention.

Patent-pending connections can be used for the treatment of irritable bowel syndrome because of their unusual ability to modulation functions as a 5-HT1A- and muscarinic /M1/ receptors in mammals. Preferred compounds of formula I are those compounds in which (a) R - C1-3-alkyl or (b) R1- C1-3-alkyl or (b) R1- propyl, (g) R2and R3independent of each other is hydrogen or C1-3-alkyl, (d) R2and R3together with represent -(CH2)p, (e) Y - O-or -(CH2)-.

Particularly preferred can be considered such classes of compounds of formula I, in which (a) R is propyl, and (b) R2and R3independent of each other is hydrogen or methyl.

The best option of the compounds of formula I are the following compounds: (a) 8-/isoxazol-5-yl/-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalen; (b) 8-/4-methylisoxazol-5-yl/2-dipropylamino-1,2,3,4-tetrahydro, the above classes of compounds of formula I can be combined with each other, getting more options for connections.

Patented compounds contain an asymmetric carbon represented by the carbon atom, which is marked with an asterisk on the following formula:

< / BR>
By itself, each of the compounds exist as separate d - and l-stereoisomers, as well as in the form of their racemic mixtures. In accordance with this present invention compounds include not only the dl-racemate, but their optically active isomeric d - and l - forms.

Below the connection more clearly illustrate the compounds covered by the present invention:

8-/isoxazol-5-yl/-2-/di-p-propylamino/tetrahydronaphthalen,

8-/isoxazol-5-yl/-2-/propylamino/tetrahydronaphthalen,

8-/isoxazol-5-yl/-2-/dimethylamine/tetrahydronaphthalen,

8-/isoxazol-5-yl/-2-/di/cyclopropylmethyl/amino/tetrahydronaphthalen,

8-/isoxazol-5-yl/-2-/di allylamino/tetrahydronaphthalen,

8-/3-methylisoxazol-5-yl/-2-/dipropylamino/tetrahydronaphthalen,

8-/3-methylisoxazol-5-yl/-2-/propylamino/tetrahydronaphthalen,

8-/3-methylisoxazol-5-yl/-2-/dimethylamine/tetrahydronaphthalen,

8-/3-methylisocyanate,

8-/4-methylisoxazol-5-yl/-2-/dipropylamino/tetrahydronaphthalen,

8-/4-methylisoxazol-5-yl/-2-/propylamino/tetrahydronaphthalen,

8-/4-methylisoxazol-5-yl/-2-/dimethylamine/tetrahydronaphthalen,

8-/4-methylisoxazol-5-yl/-2-/di/cyclopropylmethyl /aminotetrahydrofuran,

8-/4-methylisoxazol-5-yl/-2-/diallylamine/tetrahydronaphthalen,

8-/3,4-dimethylisoxazol-5-yl/-2-/dipropylamino /tetrahydronaphthalen,

8-/3,4-dimethylisoxazol-5-yl/-2-/propylamino/tetrahydronaphthalen,

8-/3,4-dimethylisoxazol-5-yl/-2-/dimethylamine/ tetrahydronaphthalen,

8-/3,4-dimethylisoxazol-5-yl/2/di/cyclopropylmethyl/amino/ tetrahydronaphthalen,

8-/3,4-dimethylisoxazol-5-yl-2-diallylamine/-tetrahydronaphthalen,

8-/4,5,6,7-tetrahydrobenzo/isoxazol-1-yl/-2-/dipropylamino/ tetrahydronaphthalen,

8-/4,5,6,7-tetrahydrobenzo/isoxazol-1-yl/2-/propylamino/ tetrahydronaphthalen,

8-/4,5,6,7-tetrahydrobenzo/isoxazol-1-yl/-2-/dimethylamine/ tetrahydronaphthalen,

8-/4,5,6,7-tetrahydrobenzo/isoxazol-1-yl/-2-/di/cyclopropylmethyl/-amino/ tetrahydronaphthalen,

5-/4,5,6,7-tetrahydrobenzo/isoxazol-1-yl/-3-/dipropylamino/chroman,

5-/isoxazol-5-yl/-3-/dipropylamino/chroman,

5-/3-methylisoxazol-5-yl/-3-/dipropylamino/chroman,

5-/isoxazol-5-yl/-3-/dipropylamino/thiochroman,

5-/3-methylisoxazol-5-yl/-3-/dipropylamino/thiochroman,

5-/4-methylisoxazol-5-yl/-3-/dipropylamino/thiochroman,

5-/3,4-dimethylisoxazol-5-yl/-3-/dipropylamino/thiochroman,

Submitted by invention compounds can be obtained by well known methods. To receive them can be used in a variety of common reactions. The General scheme of such reactions are given below, in each group the symbols have the following meanings:

R2and R3is hydrogen, C1-3- alkyl, halogen, OH, C1-3- alkoxy, C1-3-alkylthio, NH2, CN, phenyl or-CH2-)p;

Rcis hydrogen or C1-3- alkyl;

X is halogen, SRcORcor N(Rc)2;

Ar - rest of the compounds of formula I, i.e.

< / BR>
/left part is not submitted/

Scheme 1.

< / BR>
Scheme 2.

< / BR>
Scheme 3.

< / BR>
Scheme 4.

< / BR>
Scheme 5.

< / BR>
The above method of synthesis allows to obtain compounds in which the heteroaromatic ring may have or may not have a substituent. The overall reaction representing the methodology of introduction, transformation, and removal of the substituents listed in the Comprehensive Orhanic

Transformations, Richard C. Larocke, VCH Publishers,is possible. Such optically active isomeric forms can be obtained from their respective optically active precursors /previous forms/ in accordance with the methods described above or by decomposition of racemic mixtures. Methods of separation are shown, for example, in European patent application EPA N 498, 490.

Connection recommended as starting products for the synthesis of patented compounds, either well known or can be easily obtained using standard methods recommended in similar cases.

Present invention, pharmaceutically acceptable salt, food acid accession is usually obtained by reaction of a base of the formula I, corresponding to the subject invention with an equimolar or excess amount of acid. The reaction components are usually introduced into the solvent in which they are dissolved, for example diethyl ether or benzene. Drop down in the form of a precipitate from a solution Sol/deposition process continues from one hour to 10 days /allocate filtration method.

The following examples are described above, typical methods of preparing compounds of formula I. Other methods of obtaining the number is, the button to reduce the description of the object of the present invention.

Preparation 1.

Getting 2-/di-n-propylamino/-8-/ isoxazol-5-yl/-1,2,3,4-tergovernmental.

A solution of 2-/di-n-propylamino/-8-acetyl-1,2,3,4-tetrahydronaphthalene /0.3 g of 1.1 mol/ and Tris/dimethylamine/methane /0.32 g, 2.2 mmole/ in toluene is refluxed for 5 hours and at 60oC for 18 hours. Add an additional aliquot quantity of Tris/dimethylamine/methane /0.16 g, 1.1 mmol/ and the reaction continued with stirring for 2 hours at a temperature of 60oC. the Reaction mixture was concentrated to obtain 2-/di-n-propylamino/- -8-/1-oxo-3-/dimethylamine/prop-2-EN-1-yl/-1,2,3,4-tetrahydronaphtalene /0.39 g/ in the form of a viscous orange oil.

To a solution of 2-/di-n-propylamino/-8-/1-oxo-3-/dimethylamino-prop-2-EN-1-yl/ -1,2,3,4-tetrahydronaphtalene /0.75 g, to 2.29 mmole/ acetic acid /5 ml/ add gidroxinimesoulid /0.32 g, 4.6 mmole/ and the reaction is carried out under stirring at room temperature. The reaction mixture was concentrated and the resulting residue is dissolved in water. The solution gives the main character /alkalinized/ by adding a concentrated solution of ammonium hydroxide, olucha viscous, light orange oil. Maleate get the standard method.

After crystallization from a mixture of ethanol /ether to obtain the title compound as off-white crystals /0.24 g/ T. pl. 136 - 138o. After recrystallization of the obtained salt from ethanol colorless crystalline mass /155 ml/, so pl. 139 - 141oC.

Data analysis:

Calculated: C 66,65; H 7,29; N 6,76.

Found: C 66,86; H 7,33; N 6,79.

Preparation 2.

Getting 2-/di-n-propylamino /-8-/3-bromination-5-yl/ -1,2,3,4-tetrahydronaphthalene.

To a solution of 2-/di-n-propylamino/-8-iodide-1,2,3,4-tetrahydronaphtalene /4.3 g, 12,1 mmole/ triethylamine /100 ml/ add iodide /1/ copper /228 mg/ chloride bis /triphenylphosphine/palladium /11/ /841 mg/ and trimethylsilylacetamide /1.7 ml/. The mixture is stirred at room temperature overnight. The mixture was poured into water and extracted with ether. The extract was washed with brine, dried with sodium sulfate and concentrated, obtaining 5 g of crude product. Purification using flash chromatography using a mixture of methylene chloride /methanol/ /20:1/ as solvent gives 4,33 g 2-/di-n-propylamino/-8-/2-trimethylsilylethynyl/ -1,2,3,4-tetrahydronaphthalene, which is used after the g/ and tetraethylammonium /12.1 mmol/ tetrahydrofuran /150 ml stirred at room temperature in a sentence 18 hours and then boiled at reflux for 6 hours. The reaction mixture was concentrated and the resulting residue is dissolved in methylene chloride. The resulting solution was washed with water, dried using sodium sulfate and concentrated to obtain 3.6 g of a brown oil. Purification using flash chromatography with a mixture of methylene chloride /methanol as solvent /20:1/ 2-/di-n-propylamino/-8-ethinyl-1,2,3,4-tetrahydronaphthalen /1.1 g, 36% of the total output/.

2-/di-n-Propylamino/-8-ethinyl 1,2,3,4-tetrahydronaphthalen /900 mg, 3.5 mmol/ mixed at room temperature with 90 ml of ethyl acetate containing 1 ml of water. Add Br2CNOH /715,8 mg/ 10 ml of ethyl acetate and the resulting mixture was stirred at room temperature for 2 days, then add 150 mg of sodium carbonate and 250 mg Br2CNOH. The mixture is then stirred for 4 hours, poured into water and washed with ethyl acetate. The washing water containing ethyl acetate, the combined, dried and concentrated, thus obtaining 1.0 g of residue. The residue is treated by the method of flash-chromatography on a column elwira 20:1 CH2Cl2:MeOH. The appropriate fractions are combined to yield about 120 mg of product. Add the ether and get a solid substance, which distinguish by filtration. The filtrate contains Jalan receive specified in the header link /84 g/, so pl. 113-114oC.

Data analysis:

Calculated: C 55,90; H Of 5.92; N 5,68.

Found: C 55,77; H 5,90; N 5,48.

Preparation of 3.

Getting 2-/di-n-propylamino/-8-/4-methylisoxazol-5-yl/ -1,2,3,4-tetrahydronaphthalene.

2-/di-n-Propylamino/-8-bromo-1,2,3,4-tetrahydronaphthalen /8.5 g, a 27.4 mmol/ dissolved in 80 ml of tetrahydrofuran and cooled to - 78oC, then add 25.7 mm n-utility /1.6 M in hexane/. The mixture was stirred at -78oC for one hour, then add 2.4 ml /32,9 mmol/ Propionaldehyde. The mixture is heated to room temperature, then poured into water and extracted with methylene chloride. The extract is dried over sodium sulfate and evaporated. Gain of 9.1 g of yellow oil.

The oil is passed into a column of silica gel and elute with a mixture of 3% methanol in methylene chloride containing a trace amount of ammonium hydroxide. The appropriate fractions are combined to thereby obtain 6.5 g /82% 2-/di-n-propylamino/-8-/1-hydroxypropyl-1-yl/- 1,2,3,4-tetrahydronaphthalene in the form of a clear oil.

The above product is dissolved in 250 ml of methylene chloride and added 17.0 g /78,7 mmol/ Harrogate pyridinium with 30 g of 4 a molecular sieves. The mixture is stirred for 3 hours PR is, elwira ether.

To dissolve the brown precipitate add methanol/ deposition occurs after addition, the reaction mixture ether/. The resulting product is fed into the column and elute with 10% methanol in methylene chloride. Eluent concentrated to obtain a brown oil, which was further purified through column chromatography with silica gel, elwira mixture of hexanol /ether /2:1/, and then pure ether. The fractions containing the desired product are pooled, while receiving 4.7g 2-/di-n-propylamino/-8-propionyl 1,2,3,4-tetrahydronaphthalen.

2-/di-n-Propylamino/-8-propionyl 1,2,3,4-tetrahydronaphthalen/ 1.5 g, 5.2 mmol/ dissolved in 50 ml of toluene and added dropwise 2.2 ml Tris/dimethyl amino/methane. The mixture is heated overnight at 80oC. the mixture is Then evaporated, and the residue is placed in 15 ml of acetic acid. Add gidroxinimesoulid /730 mg, 10.4 mmol/ and the resulting mixture was stirred at room temperature overnight. The mixture is then poured into water, using ammonium hydroxide establish the pH at 11, and the resulting mixture extracted with methylene chloride. The extract is dried over sodium sulfate and evaporated to obtain 1.5 g of orange oil.

Oil served in a column with silica gel, Beginat together. Obtain 1.0 g /61,3%/ free grounds specified in the connection header.

50 mg of the obtained free base is converted into the maleate by a standard method and recrystallized from a mixture of ethanol and ether. Obtain 55 mg of white crystals with so pl. 118oC.

Data analysis for C24H32N2O5< / BR>
Calculated: C 67,27; H 7,53; N 6,54;

Found: C 66,99; H 7,60; N 6,35.

Preparation 4.

Getting 2-/di-n-propylamino/-8-/4-utilization-5-yl/ -1,2,3,4-tetrahydronaphthalene.

2-/di-n-Propylamino/8-bromo-1,2,3,4-tetrahydronaphthalen /5.0 g, 16,1 mmol/ dissolved in 50 ml of tetrahydrofuran, cooled the mixture to a - 78oC, then add to 21.0 ml of n-utility (0.92 M in hexane/. The mixture is stirred for 30 minutes and add of 1.85 ml /21,0 mmol/ Butyraldehyde. The mixture is then warmed to room temperature and stirred overnight, then poured into water and extracted with methylene chloride. The extract is dried over sodium sulfate and evaporated. Obtain 6.4 g of residue. The residue is treated through column chromatography with silica gel, elwira a mixture of 2% methanol in methylene chloride containing a trace amount of ammonium hydroxide. The appropriate fractions merge what about the matter.

Oil /4.0 g of 13.2 mmol/ dissolved in 200 ml of methylene chloride and added molecular sieve 4 /30 g/. The mixture is stirred and add 10.0 g /46.2 mmol/ Harrogate pyridinium. Stirring is continued at techenie hours at room temperature, after which the mixture was poured onto silica gel and sequentially elute with ether and 3% methane in methylene chloride containing a trace amount of ammonium hydroxide, while receiving the product as a brown oil.

The oily product is processed through column chromatography with silica gel, elwira a mixture of 3% methanol and methylene chloride, containing trace amounts of ammonium hydroxide. The appropriate fractions are combined to thereby obtain oil, which, when dissolved in ether causes precipitation of a brown precipitate. The precipitate is removed by filtration, and the filtrate is evaporated to obtain 3.0 g - 2-/di-n-propylamino/-8 butyryl-1,2,3,4-tetrahydronaphthalene in the form of a light brown oil.

t-butkis potassium /0,82 g, 7,3 mmol/ suspended in 100 ml of tetrahydrofuran. Ethyl formate /1.0 g, 13.3 mmol/ 2-/di-n-propylamino/8 butyryl-1,2,3,4-tetrahydronaphthalen /1.0 g, 3.3 mmol/ tetrahydrofuran added to the mixture. The mixture is stirred at room temperature than the product. The resulting mixture /pH 6/ is stirred at room temperature for 20 hours, then poured into water, maintaining the pH level 12 by adding ammonium hydroxide. The mixture is then extracted with methylene chloride. The extract is dried over sodium sulfate and evaporated. The residue is dissolved in 100 ml of toluene and was added 100 mg of p-toluenesulfonic acid. The mixture is refluxed for 1.5 hours, then poured into water and extracted with methylene chloride. The methylene chloride extract is dried over sodium sulfate and evaporated.

The residue is treated through column chromatography with silica gel, elwira mix /2: 1/ hexane/ether containing trace amounts of ammonium hydroxide. The appropriate fractions are pooled. Get 0.9 g specified in the connection header.

Mass spectrum /FD/: 327 /100/.

Preparation 5.

Getting 2-/di-n-propylamino/-8-/3-methylisoxazol-5-yl/ -1,2,3,4-tetrahydronaphthalene.

t-Butkis potassium 450 mg, 4.0 mmol/ suspended in tetrahydrofuran and add 0.7 ml /7,3 mmol/ ethyl acetate and 0.5 g /1.8 mmol/ 2-/di-n-propylamino-8-acetyl-1,2,3,4-tetrahydronaphthalene in tetrahydrofuran. Total used tetrahydrofuran 30 ml Killingholme. The reaction mixture was stirred at room temperature for 64 hours. The mixture is then poured into the water, supporting with ammonium hydroxide the pH level 6-12. After that, the mixture is extracted with a mixture of isopropyl alcohol and chloroform, taken in the ratio 1:3. The extract is dried over sodium sulfate and evaporated. Receive 450 mg of solid product. The obtained product is dissolved in toluene, add a small amount of p-toluenesulfonic acid, after which the mixture is refluxed for 2 hours. The mixture is then poured into water. The pH is maintained at level 12, using for this purpose ammonium hydroxide, after which the mixture is extracted with methylene chloride. The methylene chloride extract is dried over sodium sulfate and evaporated. Obtain 390 mg of a brown oil.

The oil is processed through column chromatography with silica gel, elwira with methylene chloride containing 2% methanol and a trace amount of ammonium hydroxide. The appropriate fractions are combined and obtain 210 mg /35%/ free grounds specified in the connection header.

Using the standard method of connection is converted into malate, which is recrystallized from a mixture of ethanol and ether to obtain 200 mg of the analysis for C24H31N2O5< / BR>
Calculated: C 67,27; H 7,53; N 6,54;

Found: C 67,52; H 7,29; N 6,48.

Preparation of 6.

Getting 2-/di-n-propylamino/ -8-/3-phenylisoxazol-5-yl/- 1,2,3,4-tetrahydronaphthalene.

Acetophenone /750 mg, 5.5 mol/ dissolved in tetrahydrofuran and cooled the mixture to -5oC. Add n-utility /12.0 ml, 11.1 mmol/ and stirred the mixture for one hour at -5oC. 2-/di-n-propylamino/-8-methoxycarbonyl-1,2,3,4-tetrahydronaphthalen /0.8 g, 2.8 mmol/ dissolved in tetrahydrofuran, is added to the mixture, so that the total number of in tetrahydrofuran mixture was 100 ml, and then heat the mixture to room temperature. The mixture is then poured into water and extracted with methylene chloride. The extract is dried over ammonium sulfate and evaporated. Obtain 1.4 g of residue.

The residue is treated through column chromatography with silica gel, elwira with a mixture of hexane and ether containing trace amounts of ammonium hydroxide. The appropriate fractions are combined, thereby obtain 220 mg of the free base specified in the connection header.

Using standard methodology, the free base is converted into the hydrobromide, which perakis is which is 171,5 - 173oC. Mass spectrum /FD/: 374/100.

Data analysis for C25H30N2OBr

Calculated: C 65,83; H 6,86; N 6,15;

Found: C 65,74; H 6,86; N Of 5.92.

Preparation 7.

Getting 2-/di-n-propylamino /-8-/3-methylthiazole-5-yl/-1,2,3,4-tetrahydronaphthalene.

2-/di-n-Propylamino/ 8-/3,3-di/methylthio/-1-oxoprop-2-EN-1-yl/ -1,2,3,4-tetrahydronaphthalen /0.64 g, 1.7 mmol/ dissolved in a mixture of toluene and acetic acid. Add gidroxinimesoulid /1.2 g, 17 mmol) and sodium acetate /1.2 g, 14 mmol/ 10 ml of water. Then add ethanol /10 ml/ to make the mixture homogeneous. The mixture is heated to 100oC for 18 hours, then add 0.6 g of hydroxylaminopurine. The mixture was stirred at 100oC within four hours and add another 0.6 g of hydroxylaminopurine. After that, the mixture is stirred for 2 hours at 100oC and even over night at room temperature. The mixture was poured into water and the aqueous mixture washed twice with ether, then extracted with 10% hydrochloric acid. The aqueous layer was combined and give them the main character /pH 12/. The mixture is then extracted with methylene chloride and the extract is dried over sodium sulfate and evaporated. Obtain 560 mg of a dark Zheltov is matanya in methylene chloride, contains trace amounts of ammonium hydroxide. The appropriate fractions are combined to getting 230 mg of product. The product is converted into the maleate and recrystallized from a mixture of ethyl acetate and hexane. Obtain 210 mg specified in the connection header with so pl. 118 - 119,5oC. Mass spectrum /FD/: 344/100.

Data analysis:

Calculated: C 62,59; H 7,00; N BETWEEN 6.08;

Found: C 62,84; H? 7.04 Baby Mortality; N 6,02.

Preparation of 8.

Getting 2-/di-n-propylamino/-8-/4-methoxyethoxy-5-yl/- 1,2,3,4-tetrahydronaphthalene.

2/di-n-Propylamino/-8-ure-1,2,3,4-tetrahydronaphthalen /5.0 g, 16,1 mmol/ dissolved in 25 ml of tetrahydrofuran and cooled to - 78oC, after which add up 3.22 ml n-utility /1M in hexane/. The mixture was kept at -78oC for 1.5 hours. The resulting solution is passed through the cannula into the solution methylmetacrylate /7.5 ml, 160 mmol/ tetrahydrofuran at -78oC. the Reaction mixture was stirred at room temperature overnight, poured into NaHCO3- solution and extracted with CH2Cl2. The extract is dried over sodium sulfate and concentrated. Obtain 6.8 g of crude product.

The material is then processed through column chromatography with silica gel, elwira 4% metrologica at the same time 1.4 g 2-/di-n-propylamino/ -8-methoxyacetyl-1,2,3,4-tetrahydronaphthalene.

A solution of 2-/di-n-propylamino/-8-methoxyacetyl-1,2,3,4-tetrahydronaphtalene /1.0 g/ and Tris/di-methylamino/ methane /1.5 ml/ toluene /25 ml/ refluxed for 1.5 hours. The reaction product is concentrated to obtain 2-/di-n-propylamino/-8-/1-oxo-2-methoxy-3-/dimethylamino-prop-2-enyl/ -1,2,3,4-tetrahydronaphthalene unprocessed /1.2 g/.

Gidroxinimesoulid /1.2 g/ added to a solution of 2-/di-n-propylamino/-8-/1-oxo-2-methoxy-3-/dimethylamino-prop-2-enyl - 1,2,3,4-tetrahydronaphtalene /1.1 g/ in methanol and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue is dissolved in toluene. To the solution was added p-toluensulfonate and refluxed for 2 hours, then concentrated and the residue is dissolved in water and methylene chloride. The mixture was poured into sodium bicarbonate solution and the resulting mixture extracted with methylene chloride. The extract is dried with magnesium sulfate and concentrate. Receive 600 mg of oily product. The product was then purified using flash chromatography elwira 1:1 mixture of ether/hexane, to obtain 160 mg of the free base specified in the connection header. Get the hydrobromide. After re-peristalsis /86 mg/, so pl. 178oC.

Data analysis:

Calculated: C 5868; H 7,14; N 6,84;

Found: C 58,88; H Of 7.23; N 6,60.

Preparation of 9.

Getting S-/-/-8/ isoxazol-5-yl/2-dipropylamino-1,2,3,4-tetrahydronaphthalene.

Solution S-/-/-8-acetyl-2-dipropyl-1,2,3,4-tetrahydronaphtalene /5.0 g, and 18.3 mmol and Tris/dimethylamine/methane /7,6 ml of 45.8 mmol in toluene /200 ml/ heated to 80oC for 20 hours. The solvent is removed, and the residue is dissolved in acetic acid /50 ml/. Add gidroxinimesoulid /2.5 g, 36.6 mmol/ and the reaction mixture stirred at room temperature for 20 hours. The mixture is then poured into water. The mixture is alkalinized with NaOH and extracted with methylene chloride. The extract is dried with sodium sulfate and concentrated to obtain a dark red oil. Purify the mixture by the method of flash-chromatography /1:2 ether/hexane /NH4OH// obtaining 4.3 g /79%/ desired product. By joining maleic acid are salt. After crystallization from a mixture of ethanol/ether to obtain crystals of pale yellow /5.3g, so pl. 127-128,5oC/.

The data of mass-spectrum /FD : 298/100/.

Data optical rotation: []D= -33,04o(C = 1.0 in H2O):

(UB>2O

Calculated: C 66,07; H 7,33; N 6,70;

Found: C 65,95; H 6,92; N 7,08.

Preparation 10.

Getting R-/+/ /-8-/ isoxazol-5-yl/2-dipropylamino-1,2,3,4-tetrahydronaphthalene.

A solution of R-/+/ -8-acetyl-2-dipropyl-1,2,3,4-tetrahydronaphtalene /5.0 g, 18,3 mg/ DL and Tris/dimethylamine/methane /7,6 ml of 45.8 mmol/ toluene /200 ml/ heated to 80oC for 20 hours. The solvent is distilled off and the residue is dissolved in acetic acid /25 ml/. Add gidroxinimesoulid /2.5 g, 36.6 mmol/ and the reaction mixture was stirred at room temperature for 20 hours. The mixture was poured into water and washed with ether. The obtained aqueous layer was alkalinized using NaOH solution and extracted with methylene chloride. The extract is dried with sodium sulfate and concentrate. Get a 5.1 g of crude product. After purification by means of flash-chromatography /1: 2 ether/hexane /NH4OH/ get 4,6 g /83%/ desired base. Salt is obtained by reaction with maleic acid. After crystallization from a mixture of ethanol/ether to obtain white solid /5,4 g, so pl. 127-128,5o/.

Data mass spectrum: /FD/: 298/100

Data analysis for C19H26N2O C4H4O40,2 H2O:

A solution of R /+/-8-propionyl-2 dipropylamino-1,2,3,4-tetrahydronaphthalene /2.0 g, 7.0 mmol/ and Tris/dimethylamine/methane /2,54 g, 2.9 ml of 17.4 mmol/ toluene /65 ml/ refluxed for 3 hours. The solvent is distilled off and the residue is dissolved in acetic acid /20 ml/. Add gidroxinimesoulid /0.97 g, 14 mmol/ and the reaction mixture was stirred at room temperature for 3 days. Then the reaction mixture was poured into water. The mixture is alkalinized with NaOH solution and extracted with a 1:3 mixture of isopropanol and chloroform. The extract is dried with sodium sulfate and concentrate. Get oily product is yellowish-orange color. Purify using flash chromatography /1: 1/ ether/hexane /NH4OH/. Get 1,46 g /67%/ colorless oil. The resulting hydrobromide crystallized twice from a mixture of tetrahydrofuran/hexane. Formed white crystals /1,32 g, so pl. 167 - 169o/.

Data optical rotation: []D= +27,26o/ s = 1,0, H2O/,

[]365= +40,90o/ s = 1, 0 H2O/.

Data analysis for C20H28N2O HBr:

Calculated: C 61,07, H 7,43, N 7,12

Found: C 61,21 H 7,50 N 6,97

Preparation 12.

Getting 5-/5-isoxazolyl/-3-/DIPROPYLENE/methane /540 mg, 5.4 mmol/ toluene /20 ml boiling under reflux for 2 hours. Analysis by thin layer chromatography shows the presence of a new product with low Rf. The reaction mixture was diluted with diluted NaOH solution and extracted with a 1:3 mixture of isopropanol and chloroform. The extract is dried with sodium sulfate and concentrate. Get oily product is dark yellow. The product is dissolved in acetic acid /10 ml and add solid gidroxinimesoulid. The reaction mixture was stirred at room temperature for 17 hours, diluted with water, alkalinized Paon and extracted with a 1:3 mixture of isopropanol and chloroform. The extract is dried with sodium sulfate and concentrate. Receive 534 mg of an orange oil. The product was then purified using flash-chromatography /1: 1, ether: hexane/ NH4OH. Get colorless oily product /482 mg, 88%/. The product is converted into its hydrobromide and crystallized from a mixture of ethyl acetate/hexane obtaining a white solid. So pl. which is 171,5 - 173oC.

The data of mass-spectrum /FD/ : 300/100/

Data analysis for C18H24N2O2HBr:

Calculated: C 56,70; H is 6.61; N 7,35;

Found: C 56,71; H 6,56; N 7,54.

As mentioned above, predstave /M1/.

The following examples demonstrate the experimental part the ability of the present invention compounds to bind to 5-HT1A receptors. Specific areas labeled containing the third 8-hydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene /3H-8-OH-DPAT/, identified as 5-HT1A-receptors. The General methodology is described in the work of Wong and researcher.

J. Neural Transm 71: 207 - 218 /1988/.

Binding receptors 5:HT1A at experiments in vitro

Male rats breed Spragne-Dawley /110-150 g/ supplied by the company Harlan Industries (Cumberland, IN), fed enough at least for the last 3 days before the beginning of the research. Rats kill method decapitate. Quickly remove the brain and reveal the cerebral cortex at 4oC.

Brain tissue is homogenized of 0.32 M sucrose. After centrifugation at 1000g for 10 minutes and then at 17000g for 20 minutes, the precipitated raw synaptosomal fraction. The precipitate in the test tube after centrifugation suspended in about 100. 50 mm Tris - HCl, pH 7,4 incubated at 37oC for 10 minutes, then centrifuged at 5000g for 10 minutes. The process is repeated and the final precipitate in the test tube suspended in ice-cold 50 mm Tris - HCl.Binding3H-8-Onlnie shell, isolated from the cerebral cortex, incubated at 37oC for 10 minutes in 2 ml of 50 mm Tris-HCl, pH of 7.4, 10 mm pargyline, 0.6 mm ascorbic acid, 5 mm CaCl2, 2nm 3H-8-OH-DPAT and 0.1 nm of interest to the authors of the connection. Binding is determined by filtering the samples at reduced pressure through filters made of fiberglass. The filters are washed twice with 5 ml ice buffer and placed in scintillation tubes /containers/ 10 ml PCS /Amersham/Searle/ scintillation liquid. The radioactivity measured using a liquid scintillation spectrometer. Scheduled 8-OH-DPAT in /10 mm/ also injected into a single sample to determine nonspecific binding. Specific binding3H-8-OH-DPAT is defined as the difference in radioactivity in the presence and absence of 10 mm unlabeled 8-OH-DPAT.

The research results are summarized in tables 1 and 2.

5 HTIA-activity in experiments in vivo.

Submitted by invention compounds also investigate in vivo on their activity on brain 5-HIAA and corticosterone in the serum. The male rats weighing 150 - 200 g injected subcutaneously or orally aqueous solutions of the investigated compounds. One hour after injection rats decapitat and collect blood from the body. Then it is really a method of spectrofluorometry according to J. Solem, I. Brinck Johnson, Scand. J. Clin. Inrest Snppl. 80 (17,1) 1965/. The whole brain quickly removed from slaughtered rats, frozen on dry ice and stored at -15oC. the Concentration of 5-HIAA is measured by liquid chromatography with electrochemical determination according to the method described by R. Fuller, H. Snoddy, K. Derry, Life Sei 40, 1921 /1987/. The results are shown in table. 1.

Linking /3H/-pirenzepine in experiments in vitro.

To determine the binding of 3H-pirenzepine in vitro male rats breed Spragne. Dawley (Harlan Spragne, Indianapolis, weighing 100-150 g were scored by the method of decapitatin /behead/, quickly remove the brain and produce the cerebral cortex. Shell brain are prepared for the study by differential centrifugation, washed twice and frozen until use.

The reduction of binding of 3H-pirenzepine with receptors determined by adding the analyte, 1 nm 3H-pirenzepine /a 87.0 Ci/ mmol/. New England Nuclear, Boston, MA and about 100 μm membrane of the brain in 1 ml total volume of 20 mm Tris-HCl buffer, pH 7,4 containing 1 mm MnCl2. After incubation for 1 hour at 25oC the homogenate was filtered through a glass fiber filter (Whatman, GF/c) under vacuum, the filters are washed 3 times with 2 ml of chilled is.). Installed on the filters and radioactivity was determined by liquid scintillation spectrometry. Nonspecific binding is determined using 1 μm atropine.

The results are shown in table. 2.

Inhibition of the secretion of gastric juice.

Reducing the secretion of gastric juice is determined in the gatekeeper doped rats according to the method developed Seem /see Shay H, A. Komorov, M. Greenstein, Effects of vagatomy intheraf, Arch. Surg 59, 210-226, 1949/. Male rats breed Sprague-Dawley weighing about 200 g not fed for 24 hours prior to the experiment. Water yield on demand, under light ether anesthesia produce alloying gatekeeper and at the same time animals injected intraperitoneally or subcutaneously certain dose of the compounds, after which the rats awaken from anesthesia. Gastric juice is collected within 2 hours. At the end of this period, rats score.

The contents of the stomach are removed, measured and titrated to a final value of 7.0. Each experiment is carried out using a control group of animals who enter the filling material, to determine the percentage reduction of excretion /secretion/ gastric juice. The results are shown in table. 1.

Change the owls. Rats bring in a laboratory hammer method decapitate and immediately remove the colon. Faeces wash and longitudinal strips with a length of 4 cm is placed in the bath for the removed organs under the load of 1 g using sensors (Grass FTO3). Tissue balance and process gaseous mixture of 95% oxygen and 5% carbon dioxide. Then the tissue is forced to decrease by carbachol to identify the tonic response. Then add a solution of a medicinal product, specifying the relaxation. The percentage of relaxation expect, whereas the control period before the start of treatment For most compounds have more than one concentration of the drug. In these cases, calculated IC50that is considered as the dose capable of reducing caused by carbachol reaction by 50%. The results are shown in table. 2.

In the following table. 1 and 2 presents the results of the evaluation of various compounds that are the subject of the present invention.

In table. 1 in the first column are the numbers of compositions of the investigated compounds in columns 2 and 3 shows the substituted groups R2and R3in the fourth column are the values of the IC50expressed in nano percentage reduction of gastric juice at a dose or ED50values in mcmol/kg in vivo studies. In column 6 lists the minimum effective dose /MED/ tested compound, injected subcutaneously to reduce 5-5IAA in the brain, in the seventh column gives values of HONEY for the studied compounds, injected subcutaneously to raise the level of corticosterone in the serum. The eighth column shows the same data as in column 6, taking into account the fact that the test substance is introduced orally. Data columns 6-8 represent the activity of the agonist 5-HTIA.

In table. 2 reflected the effect of model compounds of formula I on muscarinic receptors (M1). The first three columns reflect the same values as in table 1. Column 4 gives the values of the IC50expressed in nanomolar concentration required to reduce the binding of 3H-pirenzepine with muscarinic receptors (M1).

Column 5 shows the IC50values in mcm required to reduce caused by carbachol hypertension /increased muscle layer in the smooth muscles of the colon/ when experiments in vitro.

Thus one of the objects of the present invention is a method of treating irritable bowel syndrome, which consists in modulating the activity which I specified syndrome pharmaceutically effective amount of the compounds of formula I.

The term "pharmaceutically active amount" used in this case, indicates the number of patented compounds that bind serotonin /IA/ and muscarinic (M1) receptors. The specific dose of a compound, introduced in accordance with the present invention, it will of course be determined by the specific circumstances with which we deal in this case, including, for example, the purpose of the connection, the method of application /introduction/ and also the conditions in which the treatment is carried out. A typical daily dose is generally from about 0.01 mg/kg to about 20 mg/kg active compounds provided by the present invention. The preferred daily dose is from about 0.05 to about 10 mg/kg, ideal - respectively from 0.1 to 5 mg/kg

Connection, you can enter in a variety of ways, including oral, transdermal, subcutaneous, intravenous, intramuscular, and also through the nose.

Submitted by invention compounds preferably in the form of pharmaceutical compositions. Therefore one of the objects of the present invention is a pharmaceutical composition containing the compound of formula I in combination with a pharmaceutically acceptable placed, guided by the known methods using known and available ingredients. In the preparation of the present invention compositions, the active ingredient suitable to be mixed with filler or diluent, or make it into the shell, which may be in the form of a capsule, paper bag and so on, If the filler acts as a diluent or solvent, it can be solid, semisolid, or liquid, acting as a liquid additive or medium for the active ingredient. Thus the compositions can be prepared in the form of tablets, pills, powders, lozenges, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols /in the form of a solid or liquid medium, ointments containing, for example, to 10% by weight of active compound, soft or hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders, etc.

Example of an acceptable fillers, additives and diluents can serve substances such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum Arabic /Arabian gum, calcium phosphate, alginate, tragant, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water restoree oil. The formulations can additionally include lubricating and wetting agents, emulsifying, suspendresume and preserving agents, sweetening and flavouring tools, etc. Present invention compounds should be prepared in such a way as to ensure rapid and continuous release of active ingredient after administration of medication to the patient.

Preferably, if the compositions are prepared in a single dosage form. Each dosage typically contains from about 1 to about 250 mg of the active ingredient. The term "single dosage form" refers to discrete elements of the unit, acceptable as uniform /standard/ dose to humans and other mammals, and each dose contains a predetermined quantity of the active substance, calculated to produce the desired therapeutic effect, in combination with a pharmaceutically acceptable filler.

The following examples of compositions are illustrated the nature and description of the subject of the invention is in no way limited.

Composition 1.

Hard gelatin capsules are prepared using the following ingredient is dry - 200

Magnesium stearate - 10

Only 460

The above ingredients are mixed and are hard gelatin capsules in the amount of 460 mg.

Part 2.

Tablets made using the following ingredients mg/capsule

2-/di-n-Propylamino/ 8-/4-methyl-isoxazol-5-yl/- 1,2,3,4-tetrahydronaphthalene - 250

Microcrystalline cellulose - 400

Silicon dioxide, steaming - 10

Stearic acid - 5

Just - 665

The components are mixed and pressed into tablets at 665 mg each.

Part 3.

Suspensions each containing 50 mg of active ingredient per 5 ml dose) were prepared as follows, capsule

2 Diallylamine-8-/3-phenylisoxazol-5-yl/- 1,2,3,4-tetrahydronaphthalene, mg - 50

Na-Carboxymethylcellulose, mg - 50

Sulfur, ml - 1,25

A solution of benzoic acid, ml - 0,10

Flavouring tools

Color additives

Distilled water only, ml - 5

The active ingredient is passed through a sieve No. 45 mesh, U.S. and mixed with Na-carboxymethyl cellulose and syrup, thus obtaining a homogeneous paste. A solution of benzoic acid, flavouring tools and color additives razboi amount of water, necessary to obtain the desired volume.

Part 4.

Composition for intravenous administration can be prepared as follows, mg/capsule:

2 Diallylamine-8-/isoxazol-5-yl/- 1,2,3,4-tetrahydronaphthalene - 100

Isotonic - 1000

Solutions containing the above ingredients, usually administered intravenously at a rate of 1 ml/min, the patient is suffering from reduced activity.

1. A means of having agonistic activity to the receptor 5-HT1Aserotonin and M1-muscarinic receptors for the treatment of irritable bowel syndrome selected from the group consisting of 2-(di-n-propylamino)-8-(isoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; S-(-) -2-(di-n-propylamino)-8-(isoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; R (+) -2-(di-n-propylamino)-8-(isoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; 2-(di-n-propylamino)-8-(3-bromination-5-yl)-1,2,3,4-tetrahydronaphthalene; 2-(di-n-propylamino)-8-(4-methylisoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; 2-(di-n-propylamino)-8-(3-methylisoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; 2-(di-n-propylamino)-8-(3-methylisoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; 2-(di-n-propylamino)-8-(4-methoxyethoxy-5-yl)-1,2,3,4-tetrahydronaphthalene or its pharmaceutically p is consisting of 2-(di-n-propylamino)-8-(isoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; S-(-)-2-(di-n-propylamino)-8-(isoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; R-(+)-2-(di-n-propylamino)-8-(isoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; 2-(di-n-propylamino)-8-(4-methylisoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; 2-(di-n-propylamino)-8-(4-methylisoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene.

3. Pharmaceutical composition for the treatment of irritable bowel syndrome, characterized in that it contains from 0.01 to 20.0 mg/kg of the compounds selected from the group consisting of 2-(di-n-propylamino)-8-(isoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; S-(-)-2-(di-n-propylamino)-8-(isoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; R (+) -2-(di-n-propylamino)-8-(isoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; 2-(di-n-propylamino)-8-(3-bromination-5-yl)-1,2,3,4-tetrahydronaphthalene; 2-(di-n-propylamino)-8-(4-methylisoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; 2-(di-n-propylamino)-8-(3-methylisoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene; 2-(di-n-propylamino)-8-(3-methylthiotetrazole-5-yl)-1,2,3,4-tetrahydronaphthalene; 2-(di-n-propylamino)-8-(4-methoxyethoxy-5-yl)-1,2,3,4-tetrahydronaphthalene or its pharmaceutically acceptable salt, or MES, and one or more carriers, excipients or solvents.

 

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The invention relates to a derivative of oxazolidinone formula (I)

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

FIELD: organic chemistry, medicine, pharmacy.

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wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

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21 cl, 2 tbl, 64 ex

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

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5 tbl

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22 cl, 1 tbl, 2 sch, 78 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

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

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

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

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: medicine, organic chemistry.

SUBSTANCE: the present innovation deals with new benzothiazole derivatives and medicinal preparation containing these derivatives for treating diseases mediated by adenosine receptor A2.A.. The present innovation provides efficient treatment of the above-mentioned diseases.

EFFECT: higher efficiency of therapy.

14 cl, 354 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to polycyclic dihydrothiazoles of formula I , containing in substituted alkyl residues in 2-posiiton, as well as physiologically accepted salts thereos, having anorexia action. In formula Y is direct bond; X is CH2; R1 and R1' are independently H, Cl; R2 and R3 are H; R4 is (C8-C16-cycloalkyl, (CH2)n-A-R8, wherein n = 1-6, excepted group of formula -CH2-O-CH2-phenyl with unsubstituted phenyl; A is O, S; R8 is methyl or (CH2)m-aryl, where in m = 0-6; and aryl may represent phenyl, wherein aryl group may be optionally substituted with one or two substituents, selected from Cl, O-(C1-C6)-alkyl or (C1-C6)-alkyl. Also disclosed is method for production thereof.

EFFECT: new anorexia pharmaceuticals.

5 cl, 4 ex, 2 tbl

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