Arylcyclohexylamine derivatives, pharmaceutical compositions on their basis

 

(57) Abstract:

Derivatives killglance formula I, where R is the residue of formula (a), (b), (C), where R5is 1 to 4 substituent selected from H, alkyl, hydroxy, alkoxy, alkylalkoxy, carboxy, cyano, -NHC(O)C1-3-alkyl, -OC1-3-alkylphenyl, -OCH2O-, -C(O)-O-C1-4-alkyl, halogen, amino, nitro, -NH-C1-4-alkyl, -N(C1-4-alkyl)2; X = O, S, N-H, N-C1-6-alkyl; R2= H, C1-6-alkyl, -C/O/-C1-6-alkyl; R2= H, alkyl, -CO-C1-6-alkyl; R3= 1 to 3 substituent chosen from H, alkyl, COC1-6-alkyl, C/ - O/-O-C1-6-alkyl, OH, OC1-6-alkyl, O-C/O/-C1-6-alkyl, halogen; R3= H, OH, O-C1-6-alkyl, OCO-alkyl, COOH, COO-alkyl, OCO-alkyl - NH2O-CO-alkyl-NH-alkyl, OCO-alkyl-N(alkyl)2; n = 0, 1, or 2 and a represents optional optional single bond. The connection I have shown anti-inflammatory properties and may be useful for the treatment of for the treatment of inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, and cancer. 2 s and 5 C.p. f-crystals, 1 Il., 5 table.

The invention relates to new arylcyclohexylamine derivatives, pharmaceutical compositions based on them.


R3- OH,

R4a- H, isoprenyl or isopentyl,

and which are effective for the treatment of diseases caused by hypersecretion of androgens, for example, prostate hypertrophy, alopecia in men, common acne or seborrhea /Japan Patent N 281022/.

Also known compounds of the above formula 1a, in which

R1- substituted phenyl;

R2Is H, OH, acetoxy, carboxymethoxy or ethoxycarbonylmethoxy;

R3- OH, methoxy, benzyloxy, H;

R4a- H, isoprenyl, isopentyl,

these compounds have activity against hyaluronidase /Japan Patent N 026775/.

In addition, the known compounds of formula 1a, in which

R1- substituted phenyl,

R2- OH, acetoxy, carboxymethoxy, ethoxycarbonylmethoxy,

R3- OH, methoxy, H,

a single or double bond,

R4a- isoprenyl, isopentyl, n-propyl or H, and are useful inhibitors alsoreported used for the treatment of complications caused by diabetes, such as cataracts, retinity, neurological disorders, or kidney disease /the Japan Patent 142166/.

And the connection is the first connection,

R4a- H,

are useful inhibitors alsoreported used for the treatment of inflammatory complications, called diabetes /the Japan Patent 248389/.

The compounds of formula 1a, in which

R1- substituted phenyl,

R2Is H or OH,

R3Is H or OH,

a - double bond,

R4aIs H or OH,

are useful inhibitors of C-kinase and anticancer remedies /the Japan Patent N 144717/.

The compounds of formula 1a, in which

R1- substituted phenyl,

R2- H, halogen, lower alkyl, lower alkoxy, CN, carboxy, nitro,

R3- H, halogen, lower alkyl, lower alkoxy, CN, carboxy, nitro, hydroxy, substituted derivative of acetic acid,

R4a- has the values specified for R3,

has inhibitory activity against hydroxyprostaglandin-dehydrogenase. They may have the potential local activity against disorders of the gastrointestinal tract, such as stomach ulcers and ulcerative colitis. Other possible applications include the treatment of rheumatic arthritis, circulatory disorders, cancer, lack of fertility and cellular regulation /EP N 150166/.

Connection script,

R4a- OH,

are selective inhibitors of 5-lipoxygenase and have excellent anti-allergic action, presenting a safe anti-allergic drug, such as anti-asthmatic, anti-inflammatory and immunoactivity drug /Patent Japan N 167288/.

The present invention relates to compounds of the formula I, in which

< / BR>
where R1residue, selected from

< / BR>
where R5is one, two, three or four residue, which independently from each other include H, C1-C6-alkyl, substituted C1-C6-alkyl, hydroxy, C1-C6-alkoxy, C1-C4-alkyl-O-C1-C4-alkyl, carboxy, cyano, -NHC(O)C1-3-alkyl, -OC1-3alkylphenyl, -OCH2O-, -C/ - O/-O-C1-C4-alkyl, halogen, amino, nitro, -NH - C1-C4-alkyl, -n-N/C1-C4-alkyl/2;

X = O, S, N-H, N-C1-C6-alkyl;

R2- H, C1-C6-alkyl, -C/O/-C1-C6-alkyl;

R3- one, two, or three residue, which independently of one another represent H, C1-C6-alkyl, -C/O/-C1- C6-alkyl, -C/ - O/-O-C1-C6-alkyl, OH, -O-C1-C6- is>alkyl, -C/O/-OH, -C/ - O/-O-C1-C6-alkyl,

< / BR>
< / BR>
< / BR>
n = 0, 1, or 2;

a represents an optional single bond.

The preferred compounds are the compounds of formula II

< / BR>
in which R1, R2, R3, R4and a have the above values.

From this group of compounds are preferred such compounds in which R1is

< / BR>
where R5means H, C1-C6-alkyl, substituted C1-C6-alkyl, hydroxy, C1-C3-alkoxy, halogen;

R4denotes H, OH or

< / BR>
X represents O, NH, S, N-C1-C6-alkyl and

a denotes an optional bond.

Especially preferred are the compounds of formula III

< / BR>
in which R2represents H or C1-C3-alkyl;

R5means one or two halogen or one or two C1-C6-alkyl or C1-C3-CNS group, and a denotes an optional single bond.

The above term "substituted alkyl" means alkyl, preferably C1-3alkyl, preferably substituted by one halogen, girlam or carboxy-C1-C4-alkyl.

Compounds of the present invention contain two asymmetric center, marked with asterisks in the formula II, in the connection points of R4for example, the compound of formula II in which R4- H/ and aryl group in the carbocyclic ring; therefore, you may receive four isomers, denoted separately as CIS-/+/, CIS -/ -/ TRANS -/+/ - and TRANS-/-/ forms.

The present invention includes all four isomers alone or as a mixture of two or more of the four isomers.

Examples of particularly preferred compounds include:

1. TRANS-/+/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/4-chlorophenyl)// prop-2-enoyl]phenylcyclohexanol;

2. TRANS-/+/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/2 - chlorophenyl// -prop-2-enoyl]phenylcyclohexanol;

3. TRANS-/+/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/3-chlorophenyl)// prop-2-enoyl]phenylcyclohexanol;

4. TRANS-/+/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/2-bromophenyl// prop-2-enoyl]phenylcyclohexanol;

5. TRANS-/+/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/3-bromophenyl// prop-2-enoyl]phenylcyclohexanol;

6. TRANS-/+/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/4-bromophenyl// prop-2-enoyl]phenylcyclohexanol;

7. TRANS-/+/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/4-fortianalyzer;

9. TRANS-/+/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/4-were// prop-2-enoyl]phenylcyclohexanol;

10. TRANS-/+/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/2,3 - dichlorophenyl//prop-2-enoyl]phenylcyclohexanol;

11. TRANS-/+/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/2,6 - dichlorophenyl//prop-2-enoyl]phenylcyclohexanol;

12. TRANS-/+/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/2,6 - dichlorophenyl// prop-2-enoyl]phenylcyclohexanol.

13. TRANS-/+/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/4-chlorophenyl)// prop-2-enoyl]-phenylcyclohexanol;

14. TRANS-/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/4-chlorophenyl)// prop-2-enoyl]phenylcyclohexanol;

15. TRANS-/+/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-methoxyphenyl)// prop-2-enoyl]phenylcyclohexanol;

16. TRANS-/-/-2-[4,6-dimethoxy-2-hydroxy-3/3-/3-methoxyphenyl)// prop-2-enoyl]phenylcyclohexanol;

17. TRANS-/+/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/4-chloro-3 - nitrophenyl// prop-2-enoyl]phenylcyclohexanol;

18. TRANS-/-/-2-[4,6-dimethoxy-2-hydroxy-3-/3-/4-chloro-3 - nitrophenyl// prop-2-enoyl]phenylcyclohexanol;

19. TRANS-/+/-/-1-[4,6-dimethoxy-2-hydroxy-3-/2-/ -amino /acetoxy/-cyclohexyl]phenyl-1-/3-/3,4-dimethoxy/phenyl/propyl alcohol hydrochloride.

Also the present invention relates to a method of preparing compounds of formula I, described above, in accordance with which the connection is processed by the complex of borane with the solvent with subsequent oxidation, /B/ to obtain the compounds of formula VI, a compound of formula V is treated with percolate and thus obtained epoxide is treated with a hydride, /C/, the compound of the formula VI are obtained by condensation of the corresponding arena with cyclohexanediol in the presence of an acid catalyst, /D/ and then the compound of formula VI is treated with acetic anhydride and mineral acid with the formation of the compounds of formula VII

< / BR>
in which R2is methyl, and R4is O-C/O/-Me, and /E/ the compound of the formula VII, as described in paragraph (/D/, demetrious by treatment with Lewis acid or demetrious agent with the formation of the compounds of formula VII, in which R2means H and R4mean OC/O/Me, /F/, the compound of the formula VII, in which R2is H, and R4means OH, is obtained by treatment of the compound obtained in paragraph (/E/, dilute alkali, /G/, the compound of formula VII into a compound of the formula I /a - additional communication/ by treatment with the appropriate aldehyde in the presence of a base and a compound of the formula I /a - no additional communication/ produced by hydrogenation of compounds of formula I /a - additional communication/ in which R1, R2and R3if there is no tvii with ways, well-known experts in this field. Usually they are obtained by adding argillite formula IV to cyclohexanone followed by dehydration catalyzed by acid, with the formation of the compounds of formula IV, in which R2and R3have the above values.

< / BR>
Acceptable complex of borane with the solvent used in stage A above sequence of operations is, for example, the complex with borane-tetrahydrofuran or borane with dimethyl sulfide. The oxidation can be performed using alkaline hydrogen peroxide. Acceptable percolate for stage B is, for example, chloroperbenzoic acid. Example of an acceptable hydride is alumoweld lithium.

Stage C can be used as arena 1,3,5-trimethoxybenzene, while the acid catalyst may be aluminum chloride.

Mineral acid required for the implementation stage can be, for example, phosphoric acid,

Stage E is used as the Lewis acid trichromate boron, and as demetrious agent Filatov metal. The preferred dilute alkali used at the stage of the palladium G, may be, for example, sodium hydroxide.

The products obtained in accordance with the above-mentioned stages of the reactions, can be used in subsequent reactions with the aim of producing compounds of the present invention. Most of these reactions can be performed in accordance with the procedures described in the application for the European patent N 0241003. For more information about the original products, intermediate compounds and reactions obtain the derivatives of the compounds can be obtained from the patent literature cited in the introductory part of the description.

The physical parameters of some preferred compounds of the present invention are shown in table 1.

The new compounds of the present invention show interesting pharmacological effect when tested in pharmacological models; compound 4 shown in the table above will be used in examples as typical connection.

As shown in the examples, the compounds of the present invention have anti-inflammatory properties. These compounds are particularly useful for inhibiting or antagonistic effects on the reaction, the mod is thus the compounds of the present invention, individually or in the form of a acceptable composition, are useful drugs for the treatment of inflammatory diseases, in particular chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma and malignant tumors.

The present invention also relates to methods of using the above compounds for the treatment and prevention described inflammatory diseases by introducing active amount of one or more compounds of the present invention. In addition, an object of the present invention are pharmaceutical compositions comprising one or more compounds described above. These pharmaceutical compositions can be obtained and entered in accordance with methods known in this field.

The present invention is further illustrated by the following examples and claims.

Example I

The inhibition caused by leukotrienes ileal contractions, remote from Guinea pigs

Guinea pigs of both sexes weighing 300-350 g were senzibilizirani suspension gel of aluminum hydroxide and egg albumin. After 21 days, animals were subjected to aerosol to selected only those animals, have developed allergic bronchostenosis.

Animal researchers within one week after antigenic exposure, and then were killed by a blow to the head and opening the carotid artery. Quickly removed easily and put it in an aerated solution of Tyrode, the temperature of which was equal to 37oC. Lung was cut into equal strips and each strip was placed in the bath for bodies containing remote in Guinea-pig ileum, connected to a potentiometric recorder through isotonic transducer in the presence of a solution of Tyrode with the temperature of the 37oC. After stabilization for 30 minutes tested the reactivity of the ileum to histamine by stimulating her 100-200 ng/ml histamine. Then perfusing liquid was replaced by a solution of Tyrode containing atropine /10-7M/, mepyramine /10-7M/ and methylsergide /10-7M/. After three minutes, the strip light stimulated egg albumin /25 µg/ml and controlled release of leukotrienes in the form of slow contractions of the ileum. The contraction of the ileum lasted for 10 to 15 minutes, after which was achieved permanent status. Following this test was administered the Oia in respect of leukotrienes was determined by inducing contraction of the ileum of Guinea pigs such agonists, as histamine, acetylcholine and KCl. Compounds affecting the reduction caused by lipoxygenase usually do not inhibit the contraction induced by histamine, acetylcholine and KCl. The obtained data are presented in table 2.

Any effect on the contraction induced by histamine and KCl, were not up to concentrations equal 7,11 10-5M.

Connection 4, which is a typical representative of the new compounds of the present invention, inhibits the contraction induced by leukotrienes.

Example II

Inhibition of granuloma caused cotton balls in rats

This model allows to determine the potential activity of compounds against inhibition induced granuloma. The implantation of cotton balls soaked in carragenin, causes the formation of large well-defined granulomas, which are easily excised. The effectiveness of the compounds evaluated by measuring the magnitude of the reduction in the formation of granulomatous tissue.

Preparation of salt solution and cotton balls soaked in carragenin.

For sterilization of used cotton swabs weighing 40 mg. Half of all the cotton balls were immersed in saline RNA", Springfield/ where they were until saturation, then lightly pressed to remove excess salt solution or carrageenin.

Cotton balls were dried over night under the lamp. Took balls, the weight of which was 42-44 mg.

Preparation of animals:

Rats /group, 6 animals, males or females, Charles river, Wistar, weight 140-150 g/ antistatically simple ether. The hair on the back was removed and the skin cleaned, rubbed with alcohol and in the lower area of the middle part of the back made the cut length of one centimeter. Using blunt tweezers created bilateral channel where we put one cotton ball. From the section delete the air and on the wound had stitches. The tested compound was prepared in 0.5% carboxymethyl cellulose and administered orally at a daily dose of 10, 20 and 30 mg/kg for seven days. Three hours after the last dose on the seventh day the animals were killed. Cotton balls were removed by incision of the skin along the midline of the back and separate the skin from the body in both lateral directions. Cotton balls weighed, and then at night were placed in a drying Cabinet at a temperature of 140oC. the Value of mass in the dry state were recorded and determined the size of granulomas by subtraction ODA of the differences between the masses in the left and right speakers /see table 3/.

Connection 4, which is a typical representative compounds of the present invention, inhibits formation of granulomas caused by carragenine.

Example III

Inhibition microinteractions shock in Guinea pigs

Guinea pigs of both sexes weighing 300-350 g were senzibilizirani egg albumin, absorbed over Al/OH/3the gel. 21 days after sensitization, animals were placed in an airtight chamber made of plexiglass and were subjected to aerosol containing 0.5% egg albumin, using a spray gun EEL. Spray EEL were operated by connecting to the source of compressed air through the separator and sphygmomanometer with round scale when creating a constant air pressure equal to 180 mm RT. Art. Noted the time of occurrence of asthma in seconds and the recovery period in minutes.

All animals were exposed to the impact of aerosol on the basis of egg albumin with an interval of 15 days for the preservation of animals comparable response to the antigen. After 3 such control effects animals began to enter medicine. On the day of the experiment, one group of Guinea pigs, including 10 animals, ODA is a medicinal product. Another group of 10 Guinea pigs, 30 minutes before exposure to antigen intraperitoneally injected indomethacin at 10 mg/kg. Another group of 10 Guinea pigs were injected intraperitoneally indomethacin at 10 mg/kg before the start of the experiment and after 30 minutes after administration of indomethacin was administered the test connection /20 mg/intraperitoneal/. Fifteen minutes after administration of the test compounds, animals were subjected to aerosol containing 0.5% egg albumin. In each group noted the time of the attack and recovery time /see table 4/.

Connection 4, which is a typical representative of the new compounds of the present invention, protects animals from bronchostenosis called leukotrienes, after the impact of aerosol on the basis of egg albumin.

Example IV

Inhibition of the synthesis of IL-1 by mononuclear cells human

Purification of mononuclear cells obtained from human blood

From Vienna, located anterior to the elbow joint, with a syringe containing 1 ml of 3.8% sodium citrate, was carefully selected 10 ml of human blood. After dilution to 10 ml RM 16 /Serva, Heidelberg, Germany/ and the ut at a temperature of 20oC. Mononuclear cells, forming a white ring between lymphoprep and plasma was carefully aspirated with a syringe, diluted RM 16 in the ratio of 1:1 and centrifuged with a gradient of 400 x g for 10 minutes. The supernatant was washed with 10 ml RPM1 1640 /Flexible, Berlin, Germany/ additionally containing 300 mg /l L-glutamine, 25 mmol/l HEPES, 100 µg/ml streptomycin and 100 μg/ml penicillin. Finally, using the device for counting cells IT brought a suspension of 5 to 106cells/ml of These cells consisted of approximately 90% lymphocytes and 10% monocytes.

Stimulation of the synthesis of interleukin-1 by mononuclear cells in the laboratory

10 μl of a mixture of dimethyl sulfoxide and water /volume ratio of 1:10/ containing the test compound was added to 480 μl of the suspension containing 5 to 106mononuclear cells. The synthesis of IL-1 stimulated by adding 10 µl of a mixture of dimethyl sulfoxide and water /volume ratio of 1:10/ containing 0.5 μg of lipopolysaccharide /Salmonella abortus equi, Sigma/. After incubation at a temperature of 37oC for 18 hours, the samples were cooled to 0oC and were centrifuged for 1 min in a tabletop centrifuge. 25 μl aliquots of the supernatant liquid was evaluated for activity against IL-1 and the ing/, and in relation to IL-1 beta using typical laboratory set. Control experiments were performed as described above, without the test compound or with cycloheximide as the test compounds.

The effect of compounds 4 as an inhibitor of the synthesis of IL-1 alpha stimulated by LPS /LPS/ /IC50= 200 - 300 nmol/l/, as shown in the drawing.

Connection 4, which is a typical representative compounds of the present invention, inhibits the release of IL-1 alpha stimulated by lipopolysaccharide from mononuclear cells in man in vitro.

Compounds of this application obtained by the techniques presented below.

Example V

Obtaining 1-(2,4,6-trimethoxyphenyl)cyclohexene. Example of compounds of formula V, where R3= 4,6-dimethoxy, R2= CH3.

2,4,6-Trimethoxyphenol (1 EQ.) put in in a flame dried 3-necked flask in a nitrogen atmosphere. Add dry tetrahydrofuran (THF) (988 ml) and the reaction mixture cooled down to -30oC. is added dropwise a solution of p-BuLi (1.3 EQ.) in hexane (commercial), and then the reaction mixture is stirred for 30 minutes by means of thin layer XP is square), diluted with an equal volume of dry THF, and stirred for further one hour at -30oC. At room temperature to the reaction mixture is added 150 ml of water and extracted with ethyl acetate. An ethyl acetate extract is dried with anhydrous sodium sulfate and evaporated. The residue is dissolved in dichloromethane and stirred for 30 min in the presence of catalytic amount of 4-toluenesulfonic acid (9 g). The dichloromethane phase is washed with sodium bicarbonate solution and then with water and dried. The residue is crystallized from diisopropyl ether and receive the specified connection, so pl. 127oC, 64.7 per cent.

Example VI

Obtain TRANS-()-2-(2,4,6-trimethoxyphenyl)cyclohexanol. Example of compounds of formula VI, where R2= CH3, R3= 4,6-dimethoxy and R4= OH.

To the compound of formula V (example 1) (1 EQ.) add sodium borohydride (4 EQ.) and dry THF (2200 ml). The resulting mixture was cooled to 0oC in nitrogen atmosphere and added dropwise cryptographical boron (5.1 EQ.). At the end of the addition the temperature of the mixture was raised to 50oC and stirred for 30 minutes and Then the reaction mixture is cooled to room temperature and added dropwise water to destroy excess DIBORANE. For oxidation organagram 50oC and stirred for 3 hours After completion of the oxidation reaction mass is diluted with water and extracted with ethyl acetate. The extract is dried and evaporated. The crude product was then purified using the rapid chromatography on silica gel, eluent petroleum ether-ethyl acetate 9:1, so pl. 123oC, yield 52%.

Example VII

Polucheniya-()-1-/3-(2-acetoxy)cyclohexyl-2,4,6-trimetoksi/phenyl-1-ethanone. Example of compounds of formula VII, where R3= 4,6-dimethoxy, R2= CH3and R4= OCOCH3.

The product of example II (1 EQ.) dissolved in dry methylene chloride (1520 ml). To the solution was added acetic anhydride (25 EQ.) and phosphoric acid (152 ml) and stirred the mixture at room temperature for one hour. The reaction mixture is neutralized with sodium carbonate solution until an alkaline reaction and extracted with dichloromethane. The organic layer is washed thoroughly with water and dried, the Crude product after evaporation of the solvent is crystallized from petroleum ether, so pl. 87oC, yield 84%.

Example VIII

Getting the TRANS-()-1-/3-(2-acetoxy)cyclohexyl-4,6-dimethoxy-2 - hydroxy/phenyl-1-ethanone. Example of compounds of formula VII, where R2= H, R3= 4,6-dimethoxy and R4= OCOCH3.

Product with the use of a syringe and stirred at 0oC for one hour. Then carefully add water and the product extracted with ethyl acetate. The extract is washed with water, dried with anhydrous sodium sulfate. The crude product is crystallized from ethyl acetate receive the specified connection, so pl. 151oC, 70 - 71%.

Example IX

Obtain TRANS-()-2-/3-acetyl-4,6-dimethoxy-2-hydroxy/- phenylcyclohexanol. Example of compounds of formula VII, where R2= H, R3= 4,6-dimethoxy, R4= OH.

The product of example IV (1 EQ.) stirred in nitrogen atmosphere with a solution of potassium hydroxide in methanol (20 EQ., MeOH : water = 3:1) for 6 hours the Reaction mass is acidified with diluted HCl, the precipitate is filtered off, washed, dried and crystallized from ethyl acetate, so pl. 161oC, 88 - 89%.

Example X

Obtain TRANS-()-2-[4,6-dimethoxy-2-hydroxy-3-(3-(4-chlorophenyl)prop-2- (E)-enoyl)] phenylcyclohexanol. Example of compounds of formula II, where R1= 4-chlorophenyl, a = another relationship, R2= H, R3= 4,6-dimethoxy, R4= OH.

A mixture of the product of example V (1 EQ.) 4-chlorobenzaldehyde (3 EQ.) and 10% alcohol solution of sodium hydroxide (30 EQ.) stirred at room temperature for 24 hours and Then at a temperature of 0oC the reaction mass UP>oC, yield 68%.

Example XI

Obtain TRANS-()-2-[4,6-dimethoxy-2-hydroxy-3-(3- (4-chlorophenyl)propanol)] phenylcyclohexanol. Example of compounds of formula II, where R1= 4-chlorophenyl, a = no connection, R2= H, R3= 4,6-dimethoxy and R4= OH.

The product of example VI is stirred with 10% Pd/C (5 mol.%) in ethanol in an atmosphere of hydrogen overnight. The catalyst is filtered off, the filtrate is evaporated. Get a named connection, so pl. 190oC, 90%.

Example XII

An alternative method to obtain TRANS-()-2-(2,4,6-trimetoksi)phenylcyclohexanol. Example of compounds of formula VI, where R2= CH3, R3= 4,6-dimethoxy, R4= OH.

2,4,6-Trimethoxybenzoyl (1 EQ.), the cyclohexene oxide (1.5 EQ.) and dry dichloromethane (840 ml) was loaded into a three-neck flask equipped with a stirrer. The reaction mass is cooled to -78oC and in small portions during 1 h added aluminum chloride (1.5 EQ.). Stirring is continued for another 3 h, and then water is added and extracted with ethyl acetate. The crude product is crystallized from petroleum ether, so pl. 123oC, 63 - 64%.

Example XIII

The splitting of ()-TRANS-2-(2,4,6-trimetoksi)phenylcyclohexanol. The compound of formula V is clohexane (50.0 g, 0,18797 mol), 3-nitrophthalic anhydride (26,299 g, 0,18797 mol) and pyridine (42,18 ml, 2,78 0,18797 mol) is heated at 100oC in nitrogen atmosphere for 3 hours, the Reaction mixture was cooled to 0oC, neutralize 2 N. HCl and the resulting solution was extracted with chloroform. The residue after evaporation of the solvent is crystallized from methanol (400 ml) and receive a crystalline compound of formula VI, where R4= 3 nitrophenolate (59.0 g, so pl. 198 - 200oC). The compound obtained (0,1285 mol) is treated with (+)-cinchonine (37,85 g, 0,1285 mol) in methanol (250 ml) on a steam bath for 30 minutes the Solvent is evaporated under vacuum and the remaining salt /96,5 g, OR (+) 84,75o(Hg, 578)/ crystallized from a mixture of ethyl acetate-Petrology ether 1:1 (1400 ml) and receive crystals /45,0 g, OR (+) 75,11o(Hg, 578)/ and the mother solution of 50.0 g, OR (+) 97,30o(Hg, 578)/.

Crystals (45,0 g) optionally recrystallized (three times) from a mixture of ethyl acetate-petroleum ether and get enriched salt of cinchonine /31.0 g, OR (+) 71,08o(Hg, 578)/. Enriched salt at 0oC handle 2 N. HCl and receive (-)-compound of formula VI, where R4is a 3 nitrophenolate /16,1 g, OR (-) 37,15o(Hg, 578)/. Hydrolyzing the compound obtained a 7.5% solution of KOH in methanol in the hydrated ether (24: 160 ml); receive (-)-TRANS-2-(2,4,6-trimetoksi)phenylcyclohexanol /7.0 g, OR (-) 43,43o(Hg, 578)/.

The mother solution (50.0 g) is treated with 2 N. HCl at 0oC, the product is then crystallized (three times) from a mixture of ethyl acetate-petroleum ether and receive crystals of (+)-compound of formula VI, where R4is a 3 nitrophenolate /15,1 g, OR (+) 35,65o(Hg, 578)/. The compound obtained by the hydrolysis of a 7.5% solution of KOH in a mixture of ethanol-water (1:2, 548,5 ml) by boiling for 60 h with subsequent crystallization of the product from a mixture of ethyl acetate-petroleum ether (25: 150 ml) gives (+)-TRANS-2-(2,4,6-trimetoksi)phenylcyclohexanol /7,24 g, OR (+) 42,30o(Hg, 578)/.

Example obtain compositions in the form of oral solution

Example 1

300 mg of the active ingredient obtained in example 10, dissolved in about 100 ml of 0.5% solution of carboxymethylcellulose, receiving a solution containing 3 mg/ml of active ingredient. The resulting solution fill in the appropriate containers (tanks). This solution is ready for oral administration to a patient in doses of 10, 20, 30 mg/kg (1 ml for a mouse weighing 130 to 150 g).

Example 2

200 mg of the active ingredient obtained in example 11, was dissolved in about 100 ml of 0.5% solution carboximetilzellulozu ontainer. The solution is ready for oral administration to a patient.

1. Arylcyclohexylamine derivatives of General formula I

< / BR>
in which R1represents a residue selected from

< / BR>
where R5is one, two, three or four residue, which independently from each other include H, C1-C6-alkyl, substituted C1-C6-alkyl, hydroxy1-C6-alkoxy, C1-C4-alkyl-O-C1-C1-alkyl, carboxy, cyano, -NHC(O)C1-3alkyl, -OS1-3alkylphenyl, -och2O-, -C(O)-O-C1-C4-alkyl, halogen, amino, nitro, -NH-C1-C4-alkyl, N-(C1-C4-alkyl)2;

X represents O, S, N-H, N-C1- C6-alkyl;

R2represents H, C1-C6-alkyl, -C(O)-C1- C6-alkyl;

R3is one, two or three residue, which independently from each other include H, C1-C6-alkyl, -C(O)-C1-C6-alkyl, -C(O)-O-C1-C6-alkyl, HE, O-C1-C6-alkyl, -O-C(O)-C1-C6-alkyl, halogen;

R4represents H, -OH, -O-C1-C6-alkyl, -O-C(O)- C1-C6-alkyl, -C(O)-OH, -C(O)-O-C1-C6-alkyl;

< / BR>
< / BR>
< / BR>
n = 0,1 or 2,

a p, the fact they have the formula II

< / BR>
in which R1, R2, R3, R4and a have the meanings specified above.

3. The compounds of formula I under item 1 or 2, wherein R1is

< / BR>
where R5means H, C1-C6-alkyl, substituted C1-C6-alkyl, hydroxy, C1-C3-alkoxy, halogen;

R4means N, HE or

< / BR>
X represents O, NH, S, N-C1-C6-alkyl;

a represents an optional additional bond.

4. Compounds according to any one of paragraphs.1 to 3, characterized in that they have the formula III

< / BR>
in which R2represents H and C1-C3-alkyl;

R5means one or two halogen or one or two1-C6-alkyl or C1-C3-CNS group;

and means optional single bond.

5. Pharmaceutical composition having anti-inflammatory activity, containing the active ingredient and pharmaceutically acceptable additives and/or fillers, characterized in that as the active ingredient using an effective amount of compound I on p. 1.

6. Join one of the PP.1 to 4, obladayuschih compositions possessing anti-inflammatory activity.

 

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