Method for preparing derivatives of phenylacetic acid

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

SUBSTANCE: invention relates to methods for preparing 2-phenylamino-5-alkylphenylacetic acids of the general formula (I)

intermediate compounds for their preparing, their pharmaceutically acceptable salts and pharmaceutically acceptable prodrug esters wherein R, R1, R2, R3, R4 and R5 have corresponding values. Compound of the general formula (I) is prepared by splitting lactam of the formula (II): wherein symbols have values given in the description with a base, its precursors and methods for preparing these precursors. Abovementioned methods can comprise if necessary the temporal protection of all reaction groups showing effect followed by isolation of the prepared compound. Invention provides preparing compounds of the general formula (I) representing pharmaceutically active compounds that represent selective inhibitors of cyclooxygenase-2.

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

10 cl, 1 sch, 9 ex

 

The present invention relates to methods of producing 2-phenylamino-5-alkylperoxy acids (compounds of the following formula (I), intermediates for their production, to their pharmaceutically acceptable salts and their pharmaceutically acceptable proletarienne esters

in which R denotes methyl or ethyl;

R1denotes a chlorine atom or fluorine;

R2denotes a hydrogen atom or fluorine;

R3denotes a hydrogen atom, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy or hydroxyl;

R4denotes a hydrogen atom or a fluorine atom;

R5represents an atom of chlorine, fluorine, trifluoromethyl or methyl, provided that when R is ethyl, a R3denotes N, all R1, R2, R4and R5denote fluorine atoms.

Thus, the first object of the invention proposes a method of obtaining compounds of formula I, its pharmaceutically acceptable salts, its pharmaceutically acceptable and physiologically split procarcinogen of ester, including the splitting of the lactam of formula II

in which the symbols have the same meanings as above, base.

The above mentioned methods may include, if necessary, temporary protection of all influencing R is actionspane groups, and then the allocation of the compounds according to the invention and, if necessary, conversion of the free carboxylic acid of the compounds of formula I, its pharmaceutically acceptable ester derivative, and/or, if necessary, the transformation of the free acid of formula I in salt or salt obtained into the free acid or into another salt.

The above methods can be performed under conditions that are known in the art against hydrolytic cleavage of lactams, preferably a strong base, such as aqueous sodium hydroxide (30%aqueous NaOH solution), optional in a medium miscible with water, an organic solvent, such as ethanol and methanol, preferably at elevated temperature, for example at a temperature in the range of from about 50° to 100°With (for example, as set forth in the General US 3558690). The reaction mixture is usually neutralized with acid, for example mineral acid, such as hydrochloric acid, obtaining as a product of the free acid of formula I, which can be isolated by crystallization, for example, cooling the reaction mixture to room temperature and filtering.

Pharmaceutically acceptable proletarienne esters are ester derivatives, which are capable of developing the village is edstam of solvolysis or physiological conditions to the free carboxylic acids of formula I. Such esters are, for example, lower, respectively (NISS.), aliphatic esters (such as methyl and ethyl esters), carboxy(lower)aliphatic esters, such as carboxymethoxy ester, nitroxy(lower)aliphatic esters (such as 4-nitroacetanilide ester), etc.

Pharmaceutically acceptable salts are metal salts, such as salts of alkaline and alkaline-earth metals, for example salts of sodium, potassium, magnesium or calcium, and ammonium salts, which receive, for example, using ammonia and mono - and dialkylamino, such as salt diethylamine, and using amino acids, such as salts of arginine and histidine.

Preferred compounds of formula I which may be obtained in accordance with the present invention include

5-methyl-2-(2',4'-dichloro-6'-methylaniline)phenylacetic acid;

5-methyl-2-(2',3',5',6'-tetrafluoroaniline)phenylacetic acid;

5-methyl-2-(2',3',4',6'-tetrafluoroaniline)phenylacetic acid;

5-methyl-2-(2',6'-dichloraniline)phenylacetic acid;

potassium salt of 5-methyl-2-(2',6'-dichloraniline)phenylacetic acid,

sodium salt of 5-methyl-2-(2',6'-dichloraniline)phenylacetic acid;

5-methyl-2-(2'-chloro-6'-foronline)phenylacetic acid;

5-methyl-2-(2',6'-dichloro-4'-methylaniline)phenyl who xunwu acid;

5-methyl-2-(2'-chloro-6'-methylaniline)phenylacetic acid;

5-methyl-2-(2',4'-debtor-6'-chloroanilino)phenylacetic acid;

5-methyl-2-(2'-fluoro-4',6'-dichloraniline)phenylacetic acid;

5-methyl-2-(2'-chloro-4'-fluoro-6'-methylaniline)phenylacetic acid;

5-ethyl-2-(2'-fluoro-6'-chloroanilino)phenylacetic acid;

5-ethyl-2-(2',-chloro-6'-methylaniline)phenylacetic acid;

5-ethyl-2-(2',3',6'-triptoreline)phenylacetic acid;

5-ethyl-2-(2',3',5',6'-titrator-4'-ethoxyaniline)phenylacetic acid;

5-ethyl-2-(2'-chloro-4',6'-diptiranjan)phenylacetic acid;

5-ethyl-2-(2',4'-dichloro-6'-foronline)phenylacetic acid;

5-ethyl-2-(2',4'-dichloro-6'-methylaniline)phenylacetic acid;

5-ethyl-2-(2'-fluoro-4'-chloro-6'-methylaniline)phenylacetic acid;

5-ethyl-2-(2',4'-debtor-6'-methylaniline)phenylacetic acid;

5-ethyl-2-(2'-chloro-4'-fluoro-6'-methylaniline)phenylacetic acid;

5-methyl-2-(2'-chloro-4'-hydroxy-6'-foronline)phenylacetic acid;

5-methyl-2-(2'-fluoro-6 triptoreline)phenylacetic acid,

5-methyl-2-(2',4'-dichloro-6'-triptoreline)phenylacetic acid,

their pharmaceutically acceptable salts and their pharmaceutically acceptable proletarienne esters.

Especially preferred compounds of formula I which may be obtained in accordance with the present invention include

5-methyl-2-(',3',4',6'-tetrafluoroaniline)phenylacetic acid;

5-methyl-2-(2',6'-dichloraniline)phenylacetic acid;

5-methyl-2-(2'-chloro-6'-foronline)phenylacetic acid;

5-methyl-2-(2',6'-dichloro-4'-methylaniline)phenylacetic acid;

5-methyl-2-(2'-chloro-6'-methylaniline)phenylacetic acid;

5-methyl-2-(2'-chloro-4'-fluoro-6'-methylaniline)phenylacetic acid;

5-ethyl-2-(2'-fluoro-6'-chloroanilino)phenylacetic acid;

5-ethyl-2-(2'-chloro-6'-methylaniline)phenylacetic acid;

5-ethyl-2-(2',3',6'-triptoreline)phenylacetic acid,

5-ethyl-2-(2',4'-dichloro-6'-methylaniline)phenylacetic acid,

their pharmaceutically acceptable salts and their pharmaceutically acceptable proletarienne esters.

Thus, in a preferred embodiment, the methods according to the invention can also be used to obtain compounds of the formula I, in which R denotes methyl or ethyl; R1denotes a chlorine atom or fluorine; R2denotes a hydrogen atom; R3denotes a hydrogen atom, fluorine or chlorine, methyl or hydroxyl; R4denotes a hydrogen atom; R5denotes a chlorine atom or fluorine or methyl; or their pharmaceutically acceptable salts, or pharmaceutically acceptable proletarienne esters.

The lactam of formula II can be obtained by oxidation of the lactam of formula III

in which the symbols have the same meanings, the AK above. Can be used with standard mild oxidation conditions, such as exposure at elevated temperature with a catalytically effective amount of palladium on coal in a suitable solvent, such as xylene.

The lactam of formula III can be obtained by reaction mix aniline derivative of formula IV

in which the symbols have the same meanings as above, with cyclohexanone derivative of the formula Va or eminememinem cyclohexenone derivative of the formula Vb

in which R represents ethyl or methyl, a, R' denotes a lower alkyl or the like

The reaction of the combination of compound IV with compound Va and Vb usually involves removal of water or secondary amine, HNR'2for example, in acidic conditions.

Connection Vb can be obtained by the reaction of eminememinem cyclohexenone derivatives of the formula Vb'

in which R and R' have the same meanings as above, with methyl - or acylglycerol. Connection Vb can be converted into a compound Va by hydrolysis, for example, as described below in the examples.

In another embodiment, the covenants of the formula II is obtained by cyclization of the compounds of formula VII

in which the symbols have the same meanings as above. The process is clitatii usually carried out in the conditions of the alkylation according to Friedel-Crafts, for example in the presence of the catalyst of the Friedel-such as aluminum chloride or ethylaminoethanol, preferably at elevated temperature, for example at a temperature in the range from approximately 100 to approximately 180°C. the cyclization Reaction can be carried out in an inert solvent, such as dichlorobenzene, or in the preferred embodiment, the melt of the compound of formula VII is maintained at an elevated temperature with a catalyst of the Friedel -.

Compound of formula VII receive N-acylation of the diphenylamine of the formula VIII

in which the symbols have the same meanings as above, haloacetonitriles.

For example, the compound of formula VIII is heated, for example, up to about 80°With chloroacetylation. The product can be isolated by diluting the reaction mixture with a solvent, such as 2-propanol, and crystallization.

The compound of formula VIII can be obtained by the reaction of rearrangement and hydrolysis of the compounds of formula IX

in which the symbols have the same meanings as above.

Typically, the compound of formula IX is treated with an organic base, for example an alkali metal alkoxide such as sodium methoxide, preferably with heating, for example, to a temperature of at least about 75&#HWS. During this operation, in the initial rearrangement reaction produces an intermediate product of the formula X

in which the symbols have the same meanings as above, but in the prevailing reaction conditions it is exposed to direct cleavage with the formation of diphenylamino the compounds of formula VIII.

In another embodiment, diphenylamine compound of formula VIII can be obtained by reaction of the appropriate combination halobenzene derivative of the formula XI

where X denotes a halogen atom, such as I or Br, and the other symbols have the same meanings as above, with p-toluidine or 4-ethylaniline.

This reaction mix can be made using chemistry Buchwald. For example, the compound of formula XI and p-toluidine or 4-ethylaniline mixed with an organic base such as tertiary butyl sodium, and the appropriate ligand, for example with BINAP, in an organic solvent such as toluene; add connection palladium or a precursor of a catalyst, such as Pd(dba)2and the reaction mixture is maintained at an elevated temperature. After cooling and treatment with acid, for example HCl, the organic phase of the reaction mixture can be selected diphenylamino product of formula VIII.

For it is one option diphenylamine compound of formula VIII can be obtained by the reaction of a combination of the corresponding aniline derivative of formula IV

as described above, with 4-bromolla or 1-ethyl-4-brombenzene. This reaction mix can be similarly described using chemistry Buchwald. For example, the compound of formula IV and 4-bromthymol or 1-ethyl-4-Brabanthal mixed with an organic base such as tertiary butyl sodium, in an organic solvent such as toluene; the reaction mixture was added the compound of palladium or a precursor of a catalyst, for example Pd(dba)2and a ligand such as P(tBu)3or BINAP, after which the mixture is stirred at elevated temperature, for example 110°With, before the completion of the reaction, for example during the night. Similar to the above from the organic phase of the reaction mixture can be distinguished diphenylamino product of formula VIII, for example, after cooling and treatment with acid, for example HCl.

The compound of formula IX can be obtained by alkylation of the corresponding phenol derivative of the formula XII

in which the symbols have the same meanings as above, 2-chloro-N-(4-were)ndimethylacetamide or 2-chloro-N-(4-ethylphenyl)ndimethylacetamide. For example, the compound of formula XII and 2-chloro-N-(4-were)ndimethylacetamide or 2-chloro-N-(4-ethylphenyl)ndimethylacetamide mixed in an organic solvent such as 2-propanol, presets the following reasons, such as2CO3and the reaction mixture is boiled until completion of the reaction, in particular for approximately 4 h 2-chloro-N-(4-were)ndimethylacetamide and 2-chloro-N-(4-ethylphenyl)ndimethylacetamide can be obtained, for example, the in situ reaction of 4-methyl - or 4-ethylaniline with chloroacetylation. The compound of formula IX may be, if necessary, isolated from the reaction mixture. In the preferred embodiment, however, the compound of the formula IX are not allocated, and is converted into a compound of formula VIII by reaction rearrangement, and the resulting reaction mixture resulting from the alkylation of compounds of formula XII, conduct, as outlined above, the hydrolysis.

In another embodiment, a diphenylamine of the formula VIII can be obtained by oxidation of the corresponding compounds of formula XIII (or tautomer)

in which the symbols have the same meanings as above.

The reaction dehydrogenization can be performed by classical methods, for example by treatment with iodine, for example, I2in THF/Asón.

The compound of formula XIII can be obtained by the reaction of a combination of 1-methoxy-4-methylcyclohexa-1,4-diene or 1-methoxy-4-ethylcyclohexyl-1,4-diene with an aniline derivative of formula IV, as described above.

This reaction mix can be carried out in the presence of a catalyst, such as TiCl4in organic solvents is s, for example in THF and chlorobenzene, preferably with cooling, in particular with the shutter speed at about -40°C.

1-methoxy-4-methylcyclohexa-1,4-diene or 1-methoxy-4-ethylcyclohexyl-1,4-diene can be obtained partial recovery 4-methylanisole or 4-Atalanta on Birch, for example by treatment with Na in liquid ammonia, for example as described Subba Rao and others in the Australian Journal of Chemistry 1992, 45, cc.187-203.

Typically, the compound of formula XIII are not allocated, and after the reaction of a combination between a compound of formula IV and 1-methoxy-4-methylcyclohexa-1,4-diene or 1-methoxy-4-ethylcyclohexyl-1,4-diene carry out the oxidation with getting diphenylamine derivative of formula VIII.

In the original compounds and intermediate products, which convert into compounds of formulas I through XIII above manner contained functional groups such as amino, hydroxy and carboxy groups, does not necessarily protect traditional protection groups, which for preparative organic chemistry usual. Protected hydroxy-, amino - and carboxyl group are such that under mild conditions can be converted into free amino, hydroxy and carboxyl groups without the occurrence of other undesirable side reactions that are possible. For example, the preferred hydroxyamine groups are benzyl or substituted be Zilina group.

Methods of obtaining derivatives of 2-phenylamino-5-alkylperoxyl acid described above is schematically illustrated next.

Getting 2-allmenareliars acids

(inhibitors MOR-2)

A General idea of synthesis methods

Methods of making compounds of formulas II, III, VII, VIII, IX, X and XIII, as presented above, is included in the scope of the present invention.

Thus, further objects of the invention include a method selected from the

method of producing lactam of formula II

which involves the oxidation of the lactam of formula III

b) the method of producing lactam of formula II, as presented above, which involves the cyclization of the compounds of formula VII

b) method of obtaining the compounds of formula III, as described above, comprising the reaction mix aniline derivative of formula IV

with cyclohexanone derivative of the formula Va or eminememinem cyclohexenone derivative of the formula Vb

in which R represents ethyl or methyl, a, R' denotes a lower alkyl or the like;

g) the method of obtaining the compounds of formula VII, which includes the N-acylation of diphenylamine forms the crystals VIII

haloacetonitriles;

d) method of obtaining the compounds of formula VIII, which involves the reaction of rearrangement and hydrolysis of the compounds of formula IX

e) method of obtaining the compounds of formula VIII, which includes the reaction mix halobenzene derivative of the formula XI

in which X denotes a halogen atom, p-toluidine or 4-ethylaniline;

g) the method of obtaining the compounds of formula VIII, which includes the reaction mix aniline derivative of formula IV with 4-bromolla or 1-ethyl-4-brombenzene;

C) method of obtaining the compounds of formula VIII, which includes splitting the compounds of formula X

the method of obtaining the compounds of formula X, which involves the rearrangement reaction of compounds of formula IX;

K) the method of obtaining the compounds of formula IX, which includes alkylation of compounds of formula XII 2-chloro-N-(4-were)ndimethylacetamide or 2-chloro-N-(4-ethylphenyl)ndimethylacetamide;

l) the method of obtaining the compounds of formula VIII, which includes the alkylation of compounds of formula XII 2-chloro-N-(4-were)ndimethylacetamide or 2-chloro-N-(4-ethylphenyl)ndimethylacetamide with subsequent rearrangement reaction and decomposition of the intermediate compound of formula IX;

m) how the floor is placed the compounds of formula VIII, including oxidation of the corresponding compounds of formula XIII (or tautomer)

h) the method of obtaining the compounds of formula XIII, which includes the reaction mix 1-methoxy-4-methylcyclohexa-1,4-diene or 1-methoxy-4-ethylcyclohexyl-1,4-diene with an aniline derivative of formula IV, as described above;

(o) the method of obtaining the compounds of formula VIII comprising the reaction mix 1-methoxy-4-methylcyclohexa-1,4-diene or 1-methoxy-4-ethylcyclohexyl-1,4-diene with an aniline derivative of formula IV with subsequent dehydrogenase, where all symbols have the same meanings as above.

Upon receipt of the compounds of formula I can be applied one or more of the methods a) to (o) compliance with the corresponding sequence (see the above reaction scheme).

Thus, the invention further proposes a method of obtaining compounds of formula I

in which the symbols have the same meanings as above, which includes implementing one or more methods selected from the methods a) to (o)as they are presented above, optionally in combination with the method in accordance with the first object of the invention.

Yet further according to the invention features a compound of formula I or its farmaci is almost acceptable salt, or its pharmaceutically acceptable Proletarskiy ester, when he obtained according to the method, which includes providing one or more methods a) to (o)as they are presented above, preferably in combination with the method in accordance with the first object according to the invention.

Themselves compounds of formulas II, III, VII, VIII, IX, X and XIII is included in the scope of the present invention.

Thus, other objects of the invention features a compound selected from

a) the compounds of formula II

b) the compounds of formula III

C) the compounds of formula VII

g) compounds of formula VIII

d) the compounds of formula IX

e) compounds of the formula X

and

g) compounds of formula XIII or tautomer

in which the symbols have the same meanings as above.

The compounds of formula XII, in which one of R1and R6denotes a chlorine atom and the other denotes a fluorine atom, can be obtained by methods known in the field of engineering chlorination of phenols, preferably in the presence of catalytically effective amounts of a secondary amine, such as diisopropyl the amine. In a preferred embodiment in accordance with the present invention, the chlorination reaction involves the simultaneous introduction into the reaction mixture of chlorine and phenol, preferably using hexane fraction as a solvent. It was found that the simultaneous introduction of at least part, preferably the most part, chlorine and phenol in the reaction mixture results in high productivity and selectivity obtain the target product in comparison with undesirable by-products. Moreover, the use of hexane fractions allows you to select target phenolic product with a high degree of purity (e.g., 99%) crystallization.

The invention is further described illustrative only by the following examples.

EXAMPLES

Diphenylamino the compounds of formula VIII

get on chemistry Buchwald as described below in examples 1 and 2, or by reaction mix aniline derivative of formula IV

4-bromolla or 1-ethyl-4-brombenzene as set forth in example 1, or by reaction mix halobenzene derivative of the formula XI

with p-toluidine or 4-ethylaniline described in example 2. Thus obtained compounds of formula VIII can bytereverse into the corresponding compounds of formula I of the implementation of the methods described below.

Example 1A

N-(2',3',4',6'-tetrafluorophenyl)-methylaniline

The mixture 0,72 g 2,3,4,6-tetrafluoroaniline (4.4 mmole), 0.8 g of 4-bromthymol (4.7 mmole), 55 ml of toluene, 0.8 g of tert-butoxide sodium (8.3 mmole), 130 mg titre-butylphosphine (of 0.64 mmole) and 125 mg bisbenzimidazole(0) (0.2 mmole) is kept in a nitrogen atmosphere at 85°C for 3 hours After cooling, add 50 ml of water, 10 ml of concentrated aqueous HCl and 1 g of the product hyflo (auxiliary substance for filtering) and stirring is continued for about one hour followed by filtration. The organic phase is twice washed with water, evaporated and the residue is subjected to rapid chromatography on silica (45 g) using as eluent heptane/toluene (2:1 ratio), receiving in the form of oil, which crystallizes, 0,92 g N-(2',3',4',6'-tetrafluorophenyl)-4-methylaniline (3.6 mmole) (tPL64-65°).

1H-NMR (400 MHz, DMSO-d6): of 2.20 (s, 3H, CH3); 6,63 [d, 8,2 Hz, 2H, HC (2), HC (6)]; 6,99 [d, 8,2 Hz, 2H, HC (3), HC (5)]; 7,56 [symmetric m, 1H, HC (5')]; to 7.84 (s, 1H, NH).

As a by-product produce N,N-bis-p-tolyl-2,3,4,6-tetrafluoroaniline, tPL94,96°C.

Example 16

N-(2',3',5',6'-tetrafluorophenyl)-ethylaniline

A mixture of 4.5 g of 2,3,5,6-tetrafluoroaniline (27.3 mmole), 5.0 g of 4-eternamente (27 mmol), 50 ml of the of alwala, of 4.67 g of tert-butoxide sodium (48 mmol), 217 mg titre-butylphosphine (1,07 mmole) and 260 mg bisbenzimidazole(0) (0.45 mmole) is kept in a nitrogen atmosphere at 85°in the course of 15.5 hours the Mixture is cooled to room temperature and add 30 ml of water, 20 ml of concentrated hydrochloric acid and the product hyflo. After stirring for 45 min the mixture is filtered and the organic phase is washed three times with water. The solvent is evaporated under vacuum and the residue chromatographic on silica using hexane/toluene (ratio of from 9:1 to 3:1), with liquid N-(2',3',5',6'-tetrafluorophenyl)-ethylaniline.

1H-NMR (400 MHz, CDCl3): of 1.26 (t, 3H, CH3); to 2.65 (q, 2H, CH2); the 5.65 (s, 1H, NH); 6.73 x [tt, 1H, H-C(4')]; 6,88 [d, 2H, H-C (2,6)]; 7,15 [d, 2H, H-C(3,5)].

MS, m/z: 268 (M-H), 248 (M-HF).

Example 1V

N-(2'-chloro-4'-fluoro-6'-were)-4-methylaniline

is 3.08 g (19,3 mmole) of 2-chloro-4-fluoro-6-methylaniline (obtained from N-acetyl-4-fluoro-2-methylaniline by chlorination and subsequent hydrolysis) and of 3.48 g (a 20.3 mmole) of 4-bromthymol dissolved in 55 ml of toluene and, after the addition of 3.43 g (36 mmole) of tert-butoxide sodium, 166 mg (0,82 mmole) titre-butylphosphine and 460 mg (0.8 mmole) bisbenzimidazole(0) the mixture was kept with stirring in nitrogen atmosphere at 90°in for 40 minutes In plain water acid (50 ml in the s, 10 ml of concentrated HCl, 1 g of the product hyflo, filtering, washing the organic phase with water, drying and evaporation) in the form of oily substance obtain 5.5 g of crude product which can be purified Express chromatography using silica and heptane as eluent to obtain to 3.52 g of N-(2'-chloro-4'-fluoro-6'-were)-4-methylaniline.

1H-NMR (400 MHz, DMSO-d6): to 2.18 (s, 3H, CH3); 6,37 (d, 2H, H-C (2,6)]; 6,92 [d, 2H, H-C (3,5)]; 7,19 (dd, 1H, H-C (5')]; to 7.32 (s, 1H, NH); to 7.35 (dd, 1H, HC (3')].

Example 1G

N-(2'-chloro-6'-were)-4-methylaniline

50 mg of toluene in a nitrogen atmosphere at 90°C for 20 min and at 60°during the night, spend the reaction of 1.02 g (7.2 mmole) of 2-chloro-6-methylaniline, 1,23 g (7.2 mmole) of 4-bromthymol and 1.15 g (12 mmole) of sodium tert-butoxide, 160 mg (0.7 mmole) titre-butylphosphine and 130 mg (0,23 mmole) bisbenzimidazole(0). In the water processing (3h. HCl, the product hyflo, washing the organic phase with water) and rapid chromatography on silica using heptane/toluene (ratio 4:1) as eluent get 1,49 g of N-(2'-chloro-6'-were)-4-methylaniline.

1H-NMR (400 MHz, CDCl3): of 2.21 (s, 3H, C-6'-CH3); to 2.29 (s, 3H, C-4-CH3); 5,61 (s, broad, 1H, NH); 6,57 [d, 2H, HC (2,6)];? 7.04 baby mortality [d, 2H, HC (3,5)]; 7,07 [t when the signal at? 7.04 baby mortality, 1H, HC (4')]; 7,16 [d, 2H, H(C5')]; 7,33 [d, 1H, H(C3')]. As poboon the th product produce N,N-bis-p-tolyl-2-chloro-6-methylaniline (9 mg).

Example 1D

N-(2'-chloro-6'-were)-4-ethylaniline

In a solution of 5.2 g (37 mmole) of 2-chloro-6-methylaniline and of 6.95 g (of 37.6 mmole) of 4-eternamente in 50 ml of toluene added 6.5 g (68 mmole) of tert-butoxide sodium, 180 mg (0,89 mmole) titre-butylphosphine (dissolved in 2 ml of toluene) and 300 mg (0,52 mmole) bisbenzimidazole(0). In nitrogen atmosphere, the mixture was kept at 90°C for 3 h, and then cooled to room temperature. Add 1 g of the product hyflo, 30 ml of water and 10 ml of concentrated hydrochloric acid and after stirring for 30 min the mixture is filtered. The organic phase is washed twice with 30 ml water and evaporated. The residue is subjected to rapid chromatography on 75 g of silica, elwira heptane, with the receipt of 5.3 g (21.6 mmole, 58%) of N-(2'-chloro-6'-were)-4-ethylaniline in the form of almost colorless liquid.

1H-NMR (300 MHz, CDCl3): of 1.10 (t, 3H, CH3-CH2-); 2,10 [s, 3H, CH3-C(6')]; of 2.50 (q, 2H, CH3-CH2-); 5,54 (s, broad, 1H, NH); 6.48 in [d, 2H, HC (2,6)]; 6,93 [t, 1H, H(C4')]; 6,95 [d, 2H, HC (3,5)]; 7,05 [d, 1H, HC (5')]; 7,22 [d. 1H,HC (3')].

Example 1E

N-(2',4'-dichloro-6'-were)-4-ethylaniline

The mixture 3,313 g of 2,4-dichloro-6-methylaniline (18,8 mmole), of 3.64 g of 4-eternamente (20 mmole), 3,41 g of tert-butoxide sodium (35 mmole), 0,274 g of racemic BINAP (of 0.44 mmole), 250 mg bisbenzimidazole is s(0) (0.43 mmole) and 50 ml of toluene is refluxed in nitrogen atmosphere for 22 hours The mixture is cooled, treated with 40 ml of water, 10 ml of concentrated HCl, 1.7 g of product hyflo, stirred for an additional 30 minutes and filtered. The organic phase is washed twice with water and evaporated. The crude product (6,88 g) clean Express chromatography (silica, toluene) with the receipt of 2.93 g of N-(2',4'-dichloro-6 methylphenyl)-ethylaniline.

1H-NMR (300 MHz, CDC3): to 1.15 (t, 3H, CH3-CH2-Ar); of 2.08 (s, 3H, C-6'-CH3); of 2.50 (q, 2H, CH3-CH2-Ar); 5,42 (s, broad, 1H, NH); 6,50 [d, 2H, HC (2,6,a)]; of 6.96 [d, 2H, HC (3,5)]; 7,10 [s, 1H, HC (5')]; 7,25 [s, 1H, HC (3')].

The reaction proceeds much faster even at 85°when BINAP replace titre-butylphosphino, however, when using excess 4-eternamente, as a by-product in large quantities is formed of N,N-di-(4-ethylphenyl)-2',4'-dichloro-6'-methylaniline. This by-product can be isolated in the form of solids, tPL74-75°C;

1H-NMR (400 MHz, CDCl3): of 1.24 (t, 6H, CH2-CH3); is 2.09 (s, 3H, C-6'-CH3); 2,61 (q, 4H,CH2-CH3); 6,89 [d, 4H, HC (2,6)]; 7,06 [d, 4H, HC (3,5)]; 7,20 [s, 1H, HC (5')]; of 7.36 [s, 1H, HC (3')]; MS: 383 (M+), 368 (M-CH3), 354 (M-CH2CH3).

Example 2

N-(2',3',6'-tryptophanyl)-4-ethylaniline

In a solution of 1.21 g of 4-ethylaniline, 1.10 g 2,3,6-triterpenols in 10 g of toluene successively added 350 mg of BINAP, 300 mg bid benzylideneacetophenone(0) [Pd(dba) 2] in 3 ml of toluene and 0.9 g of tert-butoxide of sodium in 3 ml of toluene. The mixture is blown with nitrogen and incubated for 6 h at boiling temperature under reflux. After cooling to room temperature, add 30 ml of water, 10 ml of concentrated hydrochloric acid and 1 g of the product hyflo and the stirring is continued for 1 h the Mixture is filtered and the filtrate is divided into phases. The organic phase is washed three times with water, dried using magnesium sulfate and evaporated to dryness. The balance can be used without processing at the next stage, or purified Express chromatography on silica using toluene as eluent to obtain 1.13 g N-(2',3',6'-tryptophanyl)-ethylaniline.

1H-NMR (300 MHz, CDCl3): 1.14 in (t, 7.7 Hz, 3H, CH3-CH2-Ar); 2,53 (q, 7.7 Hz, 2H, CH3-CH2-Ar); from 5.29 (broad s, 1H, NH); 6,7-for 6.81 [m, 2H, C-4'-H, HC (5')]; 6,75 [d, 2H, HC (2,6)]; 7,02 [d, 8.5 Hz, 2H, HC (3,5)].

Diphenylamino the compounds of formula VIII, for example, obtained in the foregoing examples 1 and 2, is transformed into the corresponding compounds of formula VII

as described in example 3

Example 3A

N-(2',3',4',6'-tetrafluorophenyl)-N-chloroacetyl-4-methylaniline

A mixture of 0.82 g N-(2',3',4',6'-tetrafluorophenyl)-4-methylaniline (3.2 mmole) and 1.6 g of chloroacetanilide stand with peremeci what W at 90° C in nitrogen atmosphere for a 1.3 hours To decompose the excess of carboxylic acid is added 2-propanol and water (2 ml each) and stirring is continued overnight at room temperature. After adding 20 ml of toluene, the mixture is extracted with sodium bicarbonate and the organic phase is dried with magnesium sulfate and evaporated to dryness. The residue is purified Express chromatography (silica, toluene) to obtain in the form of oil 0,98 g N-(2',3',4',6'-tetrafluorophenyl)-N-chloroacetyl-4-methylaniline (2,95 mmole).

Example 3b

N-(2'3'5'6'-tetrafluorophenyl)-N-chloroacetyl-4-ethylaniline

2,05 g N-(2',3',5',6'-tetrafluorophenyl)-ethylaniline and 1.99 g chloroacetanilide mixed without solvent and incubated with stirring at 90°C in nitrogen atmosphere for 20 hours, After cooling, add 10 ml of tetrahydrofuran and aqueous sodium bicarbonate and stirring is continued for about 1 hour the Organic phase is diluted with toluene, washed three times with water and dried over magnesium sulfate. Evaporation and chromatography of the residue (silica, toluene) to obtain 1.84 g N-(2',3',5',6'-tetrafluorophenyl)-N-chloroacetyl-4-ethylaniline in the form of solid, which is recrystallized from heptane, tPL72°C.

1H-NMR (400 MHz, DMF-d7, 140° (C): a 1.25 (t, 3H, CH3); 2,70 (q, 2H, CH2); to 4.28 (s, 2H, CH2-What about); 7,35 [d, 2H, HC (3,5)]; 7,43 [d, 2H, HC (2,6)]; 7,65 [tt, 1H, HC (4')].

Example 3b

N-(2'-chloro-4'-fluoro-6'-were)-N-chloroacetyl-4-methylaniline

At 90°C for 30 min conducting the reaction of 1.32 g of N-(2'-chloro-4'-fluoro-6'-were)-4-methylaniline from 1.76 g chloroacetanilide. Cooled the mixture is stirred for 30 min with 20 ml of toluene and aqueous sodium carbonate and the organic phase is evaporated. The residue is purified Express chromatography on silica using toluene, to obtain 1.04 g of N-(2'-chloro-4'-fluoro-6'-were)-N-chloroacetyl-4-methylaniline in the form of solid, which is recrystallized from heptane/2-propanol (in the ratio 9:1), tPL96-97°C.

1H-NMR (400 MHz, DMF-d7, 120°With all the peaks seem to be broadened or split): 2,43 (s, 3H, CH3); or 4.31 (s, 2H, Cl-CH2-CO); 7,31 [d, 1H, HC (5')]; 7,32 and 7,40 [AB, 4H,-NS (2,6) and NA (3,5)]; 7,45 [s, 1H, HC (3')].

Example 3G

N-(2'-chloro-6'-were)-N-chloroacetyl-4-methylaniline

A solution of 1.4 g of N-(2'-chloro-6'-were)-4-methylaniline in of 2.21 g chloroacetanilide maintained at 90°C for 4 h the Mixture is diluted with toluene (25 ml), cooled to room temperature and washed with aqueous sodium carbonate. The organic phase is dried, evaporated and the residue is subjected to rapid chromatography [57 g of silicon dioxide, toluene and toluene/ethyl acetate(in the ratio 98:2)] to obtain 1.45 g of N-(2'-chloro-6'-were)-N-chloroacetyl-4-methylaniline, which is crystallized from heptane, tPL113-114°C.

Example 3D

N-(2'-chloro-6'-were)-N-chloroacetyl-4-ethylaniline

of 4.95 g of N-(2'-chloro-6'-were)-N-4-ethylaniline (20 mmole) is treated 3,23 g chloroacetanilide (28.5 mmole) and the mixture was kept with stirring in a nitrogen atmosphere at 95°C for 40 minutes After addition of 5 ml of 2-propanol and cooling to room temperature the mixture is diluted with toluene and extracted with aqueous sodium bicarbonate. The organic phase is washed with water and evaporated to dryness. Rapid chromatography on silica (55 g) using toluene as eluent in the form of a viscous liquid get to 5.66 g (to 17.6 mmole, yield: 88%) of N-(2'-chloro-6'-were)-N-chloroacetyl-4-ethylaniline.

1H-NMR (400 MHz, DMF-d7, 140° (C): to 1.22 (t, 3H, CH3-CH2-), 2,32 (s, 3H, CH3-C6'); to 2.65 (q, 2H, CH3-CH2-); 4,12, 4,18 (AB, 2H, CH2-Cl); 7,22 and 7,31 [each d, each 2H, HC (2,6) and NA (3,5)]; 7,3-7,5 [m, 3H, NS(3',4',5')].

Example 3E

N-(2',4'-dichloro-6'-were)-N-chloroacetyl-4-ethylaniline

4.83 g of N-(2',4'-dichloro-6'-were)-4-ethylaniline [in the form of a mixture with N,N-di-(4-ethylphenyl)-2',4'-dichloro-6'-methyl-aniline production as a byproduct] dissolve 4.18 g chloroacetanilide and incubated at 100°for 1.5 hours the Mixture is cooled, diluted with 50 ml toluene and extracted with aqueous sodium bicarbonate. The organic phase is evaporated to dryness and chromatographic on silica (75 g), elwira toluene, to obtain the unreacted N,N-di-(4-ethylphenyl)-2',4'-dichloro-6'-methylaniline and 2.95 g of N-(2',4'-dichloro-6'-were)-N-chloroacetyl-4-ethylaniline. Crystallized sample melts at 83-84°C.

1H-NMR (400 MHz, DMF-d7, 140° (C): to 1.22 (t, 3H, CH3-CH2); 2,31 (s, 3H, C-6'-CH3); of 2.56 (q, 2H, CH3-CH2); 4,20 (s, split, 2H, Cl-CH2-CO); 7,35, 7,42 [AB, 4H, HC (2,6) and NA (3,5), respectively]; 7,40 [s, broad, 1H, HC (5')]; 7,53 [s, broad, 1H, HC (3')].

In another embodiment, the compounds of formula VIII can be obtained by a method comprising the reaction of a combination of 1-methoxy-4-methylcyclohexa-1,4-diene or 1-methoxy-4-ethylcyclohexyl-1,4-diene with an aniline derivative of formula IV, as described above, to obtain the intermediate compounds of formula XIII (or tautomer)

which oxidize without allocation of obtaining the compounds of formula VIII described below in example 4.

Example 4A

N-(2',6'-dichlorophenyl)-4-methylaniline

A solution of 4.35 g of 2,6-dichloraniline in 4 ml of tetrahydrofuran and 35 ml of chlorobenzene is cooled to temperatures from -40 to -45°C. at this temperature the solution add 5,09 g of titanium tetrachloride, followed by the introduction of 5.0 g of 1-methoxy-4-metill logics-1,4-diene. The reaction mixture is allowed to warm to approximately -35°C and stirred at this temperature for 2 hours Then the reaction mixture was added dropwise a solution 10,18 g of iodine in 20 ml of tetrahydrofuran and 2.3 ml of acetic acid and the reaction mixture allowed to warm to 0°C. the Mixture is stirred for 1 h at 0°C and 16 h at 25°C. Then the reaction mixture was added 3.4 g of iodine is added and stirring is continued for an additional 24 h at 25°C. Finally the reaction is quenched by pouring the reaction mixture into a mixture of 250 ml of aqueous sodium bisulfite (38-40%) and 400 ml of saturated aqueous sodium carbonate. The aqueous phase is extracted with 1 serving of 200 ml and 2 portions of 100 ml of ethyl acetate, an ethyl acetate phases are combined and washed with 100 ml of water. The organic phase is dried over anhydrous sodium sulfate and evaporated under vacuum to obtain 11,44 g of dark sludge. This sludge is dissolved in hexane/tert-butylmethylether ether and the solution is filtered through silica gel to obtain, after evaporation of the solvent 5.75 g of crude product. The product can be used directly in the next stage. Alternatively it can be cleaned, for example, by column chromatography on silica gel using hexane/tert-butyl methyl ether (ratio 9:1) as eluent to obtain pure N-(2',6'-dichlorophenyl)-4-methylaniline.

1N the Mrs (CDCl 3, 400 MHz, 300 K) δ: 2,31 (s, 3H, CH3); 3,6-4,8 (broad signal, 1H, NH); of 6.68 (d, J=8 Hz, 2H; H-C (2) and H-C (6)); 7,02 for 7.12 (m, 3H, H-C (3); H-C (5) and H-C (4')); 7,38 (d, J=8 Hz, 2H, H-C (3') and H-C (5')).

MS (EI): m/z 251(M+), 216 (M-Cl)+, 181 (M-2Cl)+

Example 4B

N-(2'-chloro-6'-forfinal)-4-methylaniline

The solution 3,91 g of 2-chloro-6-foronline in 4 ml of tetrahydrofuran and 35 ml of chlorobenzene is cooled to temperatures from -40 to -45°C. at this temperature the solution add 5,09 g of titanium tetrachloride, followed by the introduction of 5.0 g of 1-methoxy-4-methylcyclohexa-1,4-diene. The reaction mixture is allowed to warm to approximately -35°C and stirred at this temperature for 2 hours Then the reaction mixture was added dropwise a solution 10,18 g of iodine in 20 ml of tetrahydrofuran and 2.3 ml of acetic acid and the reaction mixture allowed to warm to 0°C. the Mixture is stirred for 1 h at 0°C and 16 h at 25°C. Then the reaction mixture was added 3.4 g of iodine is added and stirring is continued for an additional 24 h at 25°C. Finally the reaction is quenched by pouring the reaction mixture into a mixture of 250 ml of aqueous sodium bisulfite (38-40%) and 400 ml of saturated aqueous sodium carbonate. The aqueous phase is extracted with 1 serving of 200 ml and 2 portions of 100 ml of ethyl acetate, an ethyl acetate phases are combined and washed with 100 ml of water. The organic phase is dried over anhydrous sulfate is m sodium and evaporated under vacuum to obtain a yellow viscous liquid. This liquid was dissolved in hexane/tert-butylmethylether ether and the solution is filtered through silica gel to obtain, after evaporation of the solvent to 4.33 g of crude product. The product can be used directly in the next stage. Alternatively it can be cleaned, for example, by column chromatography on silica gel using hexane/tert-butyl methyl ether (ratio 9:1) as eluent to obtain pure N-(2'-chloro-6'-forfinal)-4-methylaniline.

1H-NMR (DMSO-d6, 500 MHz, 300 K) δ: 2,17 (s, 3H, CH3); 6,53 [dd, J=8.5 Hz, JH-F=1.5 Hz, 2H, HC (2) and NA (6)]; 6,94 [d, J=8.0 Hz, 2H, HC (3) and HC (5)]; 7,16 [ddd, J=8.0 Hz, JH-F=6,0 Hz, 1H, HC (4')]; 7,25 [ddd, J=8,0, 1.5 Hz, JH-F=8,0, 1H, HC (5′)]; 7,34 [ddd, J=8,0, 1.5 Hz, JH-For =1.5, 1H, HC (3′)]; 7,63 (s, 1H, NH).

MS (EI) m/z 235 (100, M+), 200 (35, (M-Cl)+), 185 (55)

Example 4B

N-(2'-chloro-6'-were)-4-ethylaniline

A solution of 3.0 g of 2-chloro-6-methylaniline in 3.5 ml of tetrahydrofuran and 31 ml of chlorobenzene is cooled to temperatures from -40 to -45°C. at this temperature the solution is added to 4.01 g of titanium tetrachloride, followed by the introduction 6,18 g 1-methoxy-4-ethylcyclohexyl-1,4-diene. The reaction mixture is allowed to warm to approximately -35°and at this temperature, stirred for 3 hours, the reaction mixture was added a solution of 8.06 g of iodine in 16.4 ml of tetrahydrofuran and 1,8 ml of acetic acid and the reaction mixture allowed to warm to 0° C. the Mixture is stirred for 30 min at 0°C and 2 h at 25°C. Then the reaction mixture of 2.68 g of iodine is added and stirring is continued for an additional 24 h at 25°C. Again type of 2.68 g of iodine is added and stirring is continued for a further 72 h at 25°C. Finally the reaction is quenched by pouring the reaction mixture into a mixture of 250 ml of aqueous sodium bisulfite (38-40%) and 450 ml of saturated aqueous sodium carbonate. The aqueous phase is extracted with ethyl acetate (1 portion 200 ml 2 100 ml), an ethyl acetate phases are combined and washed with 100 ml of brine. The organic phase is dried over anhydrous sodium sulfate and evaporated under vacuum to obtain a dark viscous liquid. This liquid was dissolved in heptane/toluene and the solution is filtered through silica gel to obtain, after evaporation of the solvent 2.0 g of crude product. The product can be used directly in the next stage. In another embodiment, it can be cleaned, for example, by column chromatography on silica gel using heptane/toluene (ratio 7:3) as eluent to obtain pure N-(2'-chloro-6'-were)-4-ethylaniline.

1H-NMR (CDCl3, 400MHz, 300 K) δ: 1,24 (t, J=7.5 Hz, 3H, H3With(8)); 2,22 (s, 3H, H3C-C(2')); 2,61 (q, J=7.5 Hz, 2H, H2C(7)); 4,0-5,5 (broad signal, 1H, NH); 6,60 (d-like, J=8 Hz, 2H, H-C (2) and H-C (6)); 7,02-7,10 (m, 3H, H-C (3), H-C (5) and N-(4')); 7,10-7,20 (m, 1H, H-C (3'); 7,33 (d-like, J=9 Hz, 1H, H-C (5')).

MS: m/z 245(M+), 230, 214, 194, 180.

1-methoxy-4-methylcyclohexa-1,4-diene and 1-methoxy-4-ethylcyclohexyl-1,4-diene starting materials for example 4 receive in accordance with known literature method.

1-methoxy-4-methylcyclohexa-1,4-Dien

receive in accordance with known literature method: G.S.R. Subba Rao, D.K. Banerjee, L. Uma Devi and Uma Sheriff, Australian Journal of Chemistry 1992, 45, cc.187-203, 1-methoxy-4-ethylcyclohexyl-1,4-Dien

Connection 4 receive in accordance with the same described in the literature by the method described above for 1-methoxy-4-methylcyclohexa-1,4-diene.

The products of examples 4 converted into the corresponding compounds of formula VII, in particular, as set forth in example 3 above and 5 below.

Example 5

N-(2',6'-dichlorophenyl)-N-chloroacetyl-4-methylaniline

At 90°C for 2 h carry out the reaction of a 4.86 g of N-(2',6'-dichlorophenyl)-4-methylaniline with to 3.92 g chloroacetanilide. After dilution with toluene, the mixture was twice washed with aqueous sodium carbonate, 40%aqueous sodium bisulfite and water. The organic phase is dried (MgSO4) and evaporated. The residue is recrystallized from 12 g of ethanol to obtain 2.83 g of N-(2',6'-dichlorophenyl)-N-chloroacetyl-4-methylaniline, tPLof 129.5-130°C.

obtaining an intermediate product of formula VIII, as described above, which make no selection in the compound of formula VII described by the following example.

Example 6A

N-(2',6'-dichloro-4'-were)-N-chloroacetyl-4-methylaniline

12 g (67 mmol) of 2,6-dichloro-4-METHYLPHENOL dissolved in 25 ml of 2-propanol, followed by the introduction of 10.5 g (76 mmol) of potassium carbonate and 12.8 g (70 mmol) of 2-chloro-N-(4-were)ndimethylacetamide. The mixture is refluxed for 4 hours During this time completes the formation of the productAnd-2-(2',6'-dichloro-4'-methylphenoxy)-N-(4-were)ndimethylacetamide.

Slowly add to 13.6 ml of a 30%aqueous solution of sodium methylate in methanol and distillation of 25 ml of the solvent, the temperature was raised to about 85°C. the Mixture is stirred for another 2 h to complete the formation of the productB.

At 70°add 25 ml of water to obtain a 2-phase solution. The bottom layer is thrown away in waste. The upper layer was diluted with 20 ml of heptane fractions and washed with 2 portions of 20 ml of water. The organic phase is separated and concentrated under vacuum obtaining in the form of crude oil, N-(2',6'-dig the ers-4'-were)-4-methylaniline. GC/MS: 265 (100, M+), 195 (130).

This product is in the form of oil heated to 90°and treated with 6.5 ml of chloroacetanilide. After 2 h the mixture is diluted with 60 ml of 2-propanol, cooled to about 20°and make seed. Precipitated suspension is cooled to 0°C. the Crystals are filtered, washed with cold 2-propanol and dried to obtain N-(2',6'-dichloro-4'-were)-N-chloroacetyl-4-methylaniline, tPL140-141°C.

1H-NMR (DMF-d7, 413, 400 MHz) of 2.33 (s, 3H, CH3); is 2.40 (s, 3H, CH3); 4,18 (s, 2H, CH2); 7,22 [d, 2H, HC (5) and NS (3)]; 7,38 [d, 2H, HC (2) and NA (6)]; 7,42 [s, 2H, HC (3') and HC (5')].

Example 6b

N-(2'-chloro-6'-forfinal)-N-chloroacetyl-4-methylaniline

The process is carried out analogously to example 6A, using as starting material 2-chloro-6-terfenol, tPL80-82°C.

1H-NMR (DMF-d7, K, 400 MHz) and 2.4 (s, 3H, CH3); the 4.3 (s, 2H, CH2); 7,35 [d, 2H, HC (3) and HC (5)]; 7,43 [ddd, 1H, HC (5')]; of 7.48 [d, 2H, HC (2) and NA (6)]; 7,55 [d, 1H, HC (3')]; 7,6 [ddd, 1H, HC (4')].

Example 6b

N-(2',3',6'-tryptophanyl)-N-chloroacetyl-4-ethylaniline

Carry out the same method as in example 6A, using as starting materials 2,3,6-tryptophanol and 2-chloro-N-(4-ethylphenyl)ndimethylacetamide. The crude intermediate N-(2',3',6'-tryptophanyl)-4-ethylaniline roughly purified by filtration through silica using toluene as eluent.

tPL49-50°C.1/sup> H-NMR(DMF-d7, 413, 400 MHz) of 1.24 (t, 3H, CH3); 2,70 (q, 2H, CH2-CH3); of 4.25 (s, 2H, CH2-Cl); 7,20 [m, 1H, HC (5')]; 7,34 [d, 2H, HC (3) and HC (5)]; 7,42 [d, 2H, HC (2) and NA (6)]; 7,46 [m, 1H, HC (4')].

Example 6g

N-(2'-chloro-6'-forfinal)-N-chloroacetyl-4-ethylaniline

Carry out the same method as in example 6A, using as starting materials 2-chloro-6-terfenol and 2-chloro-N-(4-ethylphenyl)ndimethylacetamide.

tPL67-68°C.1H-NMR (DMF-d7, 413, 500 MHz) of 1.23 (t, 3H, CH3); in 2.68 (q, 2H, CH2-CH3); 4,20 (s, 2H, CH2-Cl); 7,29 [d, 2H, HC (3) and HC (5)]; 7,34 [m, 1H, HC (5')]; 7,43 [d, 2H, HC (2) and NA (6)]; of 7.48 [m, 2H, HC (3') and NA (4')].

Example 6D

N-(2',6'-dichlorophenyl)-N-chloroacetyl-4-methylaniline

Carry out the same method as in example 6A, using as starting materials 2,6-dichlorophenol and 2-chloro-N-(4-were)ndimethylacetamide. At the end of the acetylation reaction to prevent solidification of the mixture is diluted with a small amount (0.2 parts) toluene.

tPL129-130°C.1H-NMR(DMF-d7, 393 K, 500 MHz) of 2.40 (s, 3H, CH3); to 4.28 (s, 2H, CH2-Cl); 7,30 [d, 2H, HC (3) and HC (5)]; 7,46 [d, 2H, HC (2) and NA (6)]; 7,54 [m, 1H, HC (4')]; to 7.67 [d, 2H, HC (3') and HC (5')].

The compounds of formula VII cyclist with getting lactams of formula II

according outlined in example 7.

Example 7a

N-(2',6'-dichloro-4'-were)-5-methyloxindole

SMEs,85 g (20 mmol) of N-(2',6'-dichloro-4'-were)-N-chloroacetyl-4-methylaniline and to 3.36 g (26 mmol) of aluminofluoride slowly heated to 160-170° C and maintained at this temperature for 3 to 4 hours during this time through the melt continuously bubbled nitrogen. The mixture is diluted with 20 ml of toluene and add 20 ml of warm water. The organic layer was separated, washed with water and evaporated. The residue is crystallized from 20 ml of 2-propanol, receiving N-(2',6'-dichloro-4'-were)-5-methyloxindole, tPL153-154°C.

1H-NMR (DMSO-d6, 500 MHz, 300 K) to 2.29 (s, 3H, CH3- (5)]; 2,41 [s, 3H, CH3-C(4')]; 3,81 ('s. 2H, CH2); 6,27 [d, 1H, HC (7)]; 7,00 [d, 1H, HC (6)]; 7,19 [s, 1H, HC (4)]; 7,58 [s, 2H, HC (3') and HC (5')].

Example 7b

N-(2'-chloro-6'-forfinal)-5-methyloxindole

Carry out the same method as in example 7a.

tPL137-138°C

1H-NMR (DMSO-d6, 500 MHz, 300 K), and 2.27 (s, 3H, CH3); a 3.83 (s, 2H, CH2); 6,35 [d, 1H, HC (7)]; 7,01 [d, 1H, HC (6)]; 7,19 [s, 1H, HC (4)]; 7,52 [d, 1H, HC (5')]; 7,60 [d, 1H, HC (3′)]; 7,63 [d, 1H, HC (4')].

Example 7b

N-(2',3',6'-tryptophanyl)-5-atrakcija

Carry out the same method as in example 7a.

After 4 h of reaction add an additional 10% of aluminofluoride. The total duration of the reaction 6 o'clock

tPL171-172°,1H-NMR (DMSO-d6, 500 MHz, 300 K) of 1.18 (t, 3H, CH3); 2,60 [q, 2H, CH2-CH3]; 3,89 [s, 2H, CH2-FROM]; 6,62 [d, 1H, HC (7)]; 7,09 [d, 1H, HC (6)]; 7,25 [s, 1H, HC (4)]; 7,46 [m, 1H, HC (5')]; 7,76 [m, 1H, HC (4')].

Example 7G

N-(2'-chloro-6'-forfinal)-5-atrakcija

Carry out the same method, the AK in example 7b.

tPL129-130°C.1H-NMR (DMSO-d6, 300 K, 500 MHz) of 1.18 (t, 3H, CH3); 2,59 [q, 2H, CH2-CH3]; 3,86 (s, 2H, CH2-CO); 6,39 [d, 1H, HC (7)]; 7,05 [d, 1H, HC (6)]; 7,24 [s, 1H, HC (4)]; to 7.59 [m, 1H, HC (5')]; to 7.64 [m, 2H, HC (3') and NA (4')].

Example 7D

N-(2',6'-dichlorophenyl)-5-methyloxindole

Carry out the same method as in example 7a.

1H-NMR (DMSO-d6, 500 MHz, 300 K) of 2.30 (s, 3H, CH3); 3,85 (s, 2H, CH2); 6,29 [d, 1H, HC (7)]; 7,02 [d, 1H, HC (6)]; 7,22 [s, 1H, HC (4)], a 7.62 [t, 1H, HC (4')]; 7,76 [d, 2H, HC (3′) and HC (5')].

Example 7E

N-(2',3',4',6'-tetrafluorophenyl)-5-methyloxindole

A solution of 0.97 g N-(2',3',4',6'-tetrafluorophenyl)-N-chloroacetyl-4-methylaniline (2.97 mmole) in 2.5 g of chlorobenzene process of 1.05 g trichloride aluminum (7,8 mmole) and the mixture was incubated at elevated temperature (155° (C) with stirring on an oil bath for 5 h, at the same time pulling the flask with nitrogen. Add 30 ml of toluene and 20 ml of water and stirring is continued for 30 min at room temperature. The phases are separated and the organic phase is washed with 2n. hydrochloric acid and water. Evaporation under reduced pressure to obtain 0.84 g of a solid substance (2,85 mmole), which is recrystallized from 2-propanol to obtain pure N-(2',3',4',6'-tetrafluorophenyl)-5-methyloxindole, tPL172-173°C.

1H-NMR (300 MHz, 300 K, CDCl3): of 2.28 (s, 3H, CH3); 3,65 [s, 2H, H2(3)]; ,39 [d, 7.5 Hz, 1H, HC (7)]; 6,85-7,0 [m, 1H, HC (5')]; 6,98 (d, 7.5 Hz, 1H, HC (6)]; 7,09 [s, 1H, HC (4)].

Example I

N-(2'-chloro-6'-were)-5-atrakcija

In the flask of 2.08 g of N-(2'-chloro-6'-were)-N-chloroacetyl-4-ethylaniline mix from 1.16 g of trichloride aluminum and the mixture is blown with nitrogen. The flask is put in an oil bath (155-160° (C) and the mixture is stirred in a stream of nitrogen for 4.5 hours, the Mixture is slightly cooled to about 100°C, treated with 30 ml of toluene and 20 ml of 1N. HCl and stirred for 30 min while gradually lowering the temperature. After phase separation the organic phase is washed with 1N. HCl and water, dried (magnesium sulfate) and evaporated. The remainder chromatographic on the silicon dioxide (86 g)using toluene containing from 5 to 20% of isopropylacetate as eluent, to obtain specified in the title of the product, tPL125-126°

Further oxidation of unsaturated lactam of formula III have different lactams of formula II

which can be obtained, in particular, as described in example 8.

Example 8

Ethyl ester of (5-ethyl-2-morpholine-4-icicles-2-enylidene)acetic acid

of 91.6 g of 4-ethylcyclohexane, 73,6 g research and 2 g of monohydrate p-toluensulfonate acid are dissolved in 400 ml of toluene. The mixture is maintained at a temperature which e boiling under reflux and the water formed is removed using a water separator. After the reaction for about 24 h, the reaction mixture is cooled to 100°and add 2 g of p-toluensulfonate acid with the subsequent introduction for 30 min 157,22 g of ethyl ester of Glyoxylic acid. The mixture is again maintained at the boiling point under reflux for 5 h and allowed to cool to 22°C. Under vacuum, the solvent is evaporated and the crude product is distilled under vacuum at 140-150°/9,5-2the mbar.

1H-NMR (CDCl3, 500 MHz, 277 K) δ: 0,896 frequent./m (t, J=7 Hz, 3H, H3With(17)), amounted to -1,277 (t, J=7 Hz, 3H, H3With(10)), 1,20-of 1.45 (m, 2H, H2With(16)), 1,50-of 1.62 (m, 1H, H-C(4)), 1,876 (ddd, J1=18 Hz, J2=9 Hz, J3=3 Hz, 1H, H-C (3))by 2.13 (m, 1H, H-C (5)), to 2.35 (dt, J1=17 Hz; J2=5 Hz, 1H, H-C (3)), 2,55-to 2.65 (m, 2H, H-C(12) and H-(15)), 2,72 is 2.80 (m, 2H, H-C (12) and H-(15)), 3,55 (dm, J=15 Hz, 1H, H-C (5)), 3,74 (m, 4H, H2With(13) and H2With(14)), 4,152 (q, J=7 Hz, 2H, H2With(9)), 5,46 (dd, J1=5 Hz, J2=3 Hz, 1H, H-C (2)), 6,17 (broad s, 1H, H-C(7)). Allocation in accordance with the numbering of the provisions contained in the formula.

IR (film): intensive bands acquisitions in 2960, 1710, 1624, 1609, 1191, 1156 and 1120 cm-1.

MS (EI): m/z 279 (M+), 250 (M-C2H5)+, 234, 206 (M-CO2C2H5)+, 176, 164, 135, 84.

b) Synthesis of ethyl ester of (5-ethyl-2-oxocyclohexyl)acetic acid

10 g of ethyl ester of [5-ethyl-2-morpholine-4-icicles-2-tiled the n]acetic acid was dissolved in 20 ml of toluene. With vigorous stirring, added dropwise 12 ml of 6 M HCl and the reaction mixture is stirred for another 60 min at 22°C. the Organic layer is separated and washed twice with 25 ml water. The combined aqueous layers extracted with 25 ml of toluene. The combined toluene layers are dried over anhydrous sodium sulfate and is evaporated under vacuum, the solvent is obtaining in the form of oil 6,72 g of ethyl ester of [5-ethyl-2-oxocyclohexyl]acetic acid.

1H-NMR (CDCl3, 500 MHz, 277 K) δ: 0,935 frequent./m (t, J=7 Hz, 3H, H3With(12)), 1,259 (t, J=7 Hz, 3H, H3With(10)), 1,31-of 1.45 (m, 2H, H2C (11)), 1,46-of 1.55 (m, 1H, H-C(5)), 1,59 was 1.69 (m, 1H, H-C (4)), 1,97-2,04 (m, 1H, H-C (5)), 2,296 (ddd, J=17 Hz, 11 Hz and 3 Hz, 1H, H-C (3)), 2,383 (m, 1H, H-C (6)), 2,615 (dt, J=17 and 4 Hz, 1H, H-C (6)), 3,57 (dm, J=17 Hz, 1H, H-C (3)), to 4.17 (q, J=7 Hz, 2H, H2With(9)), 6.42 per (m, 1H, H-C(7)). Allocation in accordance with the numbering of the provisions contained in the formula.

IR (film): intensive bands acquisitions in 1719, 1698 and 1200 cm-1.

MS (EI): m/z 210 (M+), 164 (M-C2H5HE)+, 135.

C) Synthesis of 1-(2-chloro-6-were)-5-ethyl-1,4,5,6-tetrahydroindole-2-it

of 3.45 g of 2-chloro-6-methylaniline are dissolved in 26 ml of toluene. Add 0,227 g p-toluensulfonate acid (monohydrate) and the mixture was kept at boiling temperature under reflux. Dropwise over 75 min add a solution of 5.0 g of ethyl ester of (5-ethyl-2-oxol logicielle)acetic acid in 13 ml of toluene and the resulting water is collected using a water separator. The reaction mixture was kept at the boiling point under reflux for 15 h, and during this time condensing the solvent is often removed and replaced with fresh toluene. For processing, the mixture is cooled to 22°and under intensive stirring and treated with 70 ml of saturated aqueous sodium bicarbonate solution. The layers are separated and the toluene phase is washed with 5%aqueous citric acid solution and finally 10%solution of sodium chloride in water. The aqueous phase is extracted with 70 ml of toluene and the toluene phases are combined. The solvent is evaporated under vacuum obtaining of 7.1 g of crude product as a viscous oil. An analytical sample of the crude product can be purified by chromatography on silica gel using toluene/ethyl acetate (ratio 9:1) as eluent to obtain pure 1-(2-chloro-6-were)-5-ethyl-1,4,5,6-tetrahydroindole-2-it.

1H-NMR (d6-DMSO, 400 MHz, 300 K) δ: 0,894 frequent./m (t, J=7 Hz, 3H, H3With(11)), 1,34 was 1.43 (m, 2H, H2C(10)), 1.70 to to 1.82 (m, 1H, H-C(5)), 1,90-2,02 (m, 1H, H-C(6)), 2,038 (s, 3H, H3With(6')), 2,28-2,40 (m, 2H, H-C(4) and H-C (6)), 2,87 (dd, J1=17 Hz and J2=4 Hz, 1H, H-C (4)), 5,14 (m, 1H, H-C (7)), 5,96 (broad s, 1H, H-C (3)), 7,3-7,5 (m, 3H, H-C (3'), H-C (4'), H-C (5')). Allocation in accordance with the numbering of the provisions contained in the formula.

IR (film): intensive bands acquisitions in 1703, 1660 and 1476 cm-1.

MS (EI): m/z 287 (M+), 272 (M-CH3)+, 2,58 (M-C2H5)+, 252 (M-Cl)+.

g) Synthesis of N-(2-chloro-6-were)-5-atalexandra

1-(2-chloro-6-were)-5-ethyl-1,4,5,6-tetrahydroindole-2-it is possible to oxidize by classical methods, such as 10% Pd-C in boiling (using the back of the refrigerator) xylene, to obtain N-(2-chloro-6-were)-5-atalexandra

1H-NMR and MS spectroscopic data are given in example I.

The lactam of formula II, as presented above, is transformed into the compounds of formula I, as presented above, for example, described in the example below, 9.

Example 9a

5-methyl-2-(2',6'-dichloro-4'-methylaniline)phenylacetic acid

A mixture of 1.5 g of N-(2',6'-dichloro-4'-were)-5-methyloxindole, 18 ml of ethanol and 1 ml of water was kept at boiling temperature under reflux. Slowly add to 1.9 g of 30%sodium hydroxide solution and boiled under reflux continued for 4-5 hours the Solution is cooled to about 40°and is treated by slow addition of a solution of 1.5 g of concentrated hydrochloric acid in 12 ml of water to a pH of 3-4. The resulting suspension is cooled to 20°C. the Crystals are collected by filtration, washed with water and dried, obtaining 5-methyl-2-(2',6'-dichloro-4'-methylaniline)phenyloxazolidine.

tPL179-182°C.1H-NMR (DMSO-d6, 300 K, 500 MHz) 2,22 [s, 3H, CH3- (5)]; 2,32 [s, 3H, CH3-C(4')]; to 3.67 (s, 2H, CH2); 6,18 [d, 1H, HC (3)], 6,87 [s, d, 1H, HC (4)]; 6,97 (s, 1H, NH); 7,02 [s, 1H, HC (6)]; of 7.36 [s, 2H, HC (3') and HC (5')]; 12,68 (broad s, 1H, COOH).

Example 9D

5-methyl-2-(2'-chloro-6'-foronline)phenylacetic acid

Carry out the same method as in example 9a.

tPL152-154°1H-NMR (DMSO-d6, 500 MHz, 300 K) δ: of 2.21 (s, 3H, CH3), to 3.64 (s, 2H, CH2); 6.42 per [dd, 1H, HC (3)], 6,90 [dd, 1H, HC (4)], 7,01 [d, 1H, HC (6)], to 7.09 (s, 1H, NH), 7,09 [ddd, 1H, HC (4')], of 7.23 [ddd, 1H, HC (5')], 7,34 [ddd, 1H, HC (3')], 12,67 (s, 1H, COOH).

Example 9b

5-methyl-2-(2',3',4',6'-tetrafluoroaniline)phenylacetic acid

A suspension of 350 mg N-(2',3',4',6'-tetrafluorophenyl)-5-meliponinae in 20 ml ethanol and 5 ml of water Tegaserod passing through it within 1.5 h of nitrogen. Then add 260 mg of a 30%aqueous sodium hydroxide and the mixture was kept at boiling temperature under reflux for 6,5 hours Later a large part of the ethanol is removed by distillation, the mixture is cooled to room temperature, followed by the slow introduction 1H. hydrochloric acid (1,05 g) to achieve a pH of about 3. Then the precipitate is filtered off, washed with ethanol/water (ratio 1:1) and dried under vacuum at room temperature to obtain specified in the title of the product.

tPL145-146°C.

1 H-NMR (300 MHz, DMSO-d6): of 2.23 (s, 3H, CH3); the 3.65 (s, 2H, CH2-COO); 6,55 [s, 1H, HC (3)]; 6,92 [d, 1H, HC (4)]; 7,00 [s, 1H, HC (6)]; then 7.20 (s, 1H, NH); 7,50 [m, 1H, HC (5')].

Identical by essentially similar to the above in the compounds of formula I turn the other lactams of formula II.

1. The method of obtaining the compounds of formula I, or its pharmaceutically acceptable salts, or its pharmaceutically acceptable procarcinogen of ester

in which R denotes methyl or ethyl;

R1denotes a chlorine atom or fluorine;

R2denotes a hydrogen atom or fluorine;

R3denotes a hydrogen atom, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy or hydroxyl;

R4denotes a hydrogen atom or a fluorine atom;

R5represents an atom of chlorine, fluorine, trifluoromethyl or methyl,

provided that when R is ethyl, and R3denotes N, all R1, R2, R4and R5denote fluorine atoms; comprising the reaction of rearrangement and hydrolysis of the compounds of formula IX

with the formation of the compounds of formula VIII

with the subsequent conversion of compounds of formula VIII to the compound of formula I and optionally with a temporary protecting any interfering reacts onopolies group, followed by separation of the compounds according to the invention, and, if desired, by conversion of the free carboxylic acid of the compounds of formula I, its pharmaceutically acceptable ester derivative and/or, if desired, by conversion of the free acid of formula I in salt or salt to the free acid or into another salt.

2. The method of obtaining the compounds of formula I, or its pharmaceutically acceptable salts, or its pharmaceutically acceptable procarcinogen of ester

in which R denotes methyl or ethyl;

R1denotes a chlorine atom or fluorine;

R2denotes a hydrogen atom or fluorine;

R3denotes a hydrogen atom, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy or hydroxyl;

R4denotes a hydrogen atom or a fluorine atom;

R5represents an atom of chlorine, fluorine, trifluoromethyl or methyl,

provided that when R is ethyl, and R3denotes N, all R1, R2, R4and R5denote fluorine atoms;

incorporating the following stages:

(a) rearrangement and hydrolysis of the compounds of formula IX

with the formation of the compounds of formula VIII

(b) N-acylation of compounds of formula VIII

haloacetonitriles with obtaining the compounds of formula VII

(C) cyclization of the compounds of formula VII to obtain a lactam of formula II

and

(d) cleavage of the lactam base, and if desired, using the time protecting any interfering reactive group, followed by separation of the compounds according to the invention and, if desired, by conversion of the free carboxylic acid of the compounds of formula I, its pharmaceutically acceptable ester derivative and/or, if desired, by conversion of the free acid of formula I in salt or salt to the free acid or into another salt.

3. The method of receiving according to claim 2, in which the compound of formula IX is obtained by alkylation of compounds of formula XII

2-chloro-N-(4-were)ndimethylacetamide or 2-chloro-N-(4-ethylphenyl)ndimethylacetamide;

4. The method of obtaining the compounds of formula VIII

including rearrangement and hydrolysis of the compounds of formula IX

5. The method of obtaining the compounds of formula VIII

including the splitting of the compounds of formula X

6. The way p is obtaining compounds of formula X

including the rearrangement of compounds of formula IX

7. The method of obtaining the compounds of formula IX

including the alkylation of compounds of formula XII

2-chloro-N-(4-were)ndimethylacetamide or 2-chloro-N-(4-ethylphenyl)ndimethylacetamide.

8. The method of obtaining the compounds of formula VIII

including the alkylation of compounds of formula XII

2-chloro-N-(4-were)ndimethylacetamide or 2-chloro-N-(4-ethylphenyl)ndimethylacetamide with subsequent rearrangement and cleavage.

9. Method of preparing compounds according to any one of claims 1 to 3, selected from:

5-methyl-2-(2',4'-dichloro-6'-methylaniline)phenylacetic acid;

5-methyl-2-(2',3',5',6'-tetrafluoroaniline)phenylacetic acid;

5-methyl-2-(2',3',4',6'-tetrafluoroaniline)phenylacetic acid;

5-methyl-2-(2',6'-dichloraniline)phenylacetic acid;

potassium salt of 5-methyl-2-(2',6'-dichloraniline)phenylacetic acid;

sodium salt of 5-methyl-2-(2',6'-dichloraniline)phenylacetic acid;

5-methyl-2-(2'-chloro-6'-foronline)phenylacetic acid;

5-methyl-2-(2',6'-dichloro-4'-methylaniline)phenylacetic is islote;

5-methyl-2-(2'-chloro-6'-methylaniline)phenylacetic acid;

5-methyl-2-(2',4'-debtor-6'-chloroanilino)phenylacetic acid;

5-methyl-2-(2'-fluoro-4',6'-dichloraniline)phenylacetic acid;

5-methyl-2-(2'-chloro-4'-fluoro-6'-methylaniline)phenylacetic acid;

5-ethyl-2-(2'-fluoro-6'-chloroanilino)phenylacetic acid;

5-ethyl-2-(2'-chloro-6'-methylaniline)phenylacetic acid;

5-ethyl-2-(2',3',6'-triptoreline)phenylacetic acid;

5-ethyl-2-(2',3',5',6'-titrator-4'-ethoxyaniline)phenylacetic acid;

5-ethyl-2-(2'-chloro-4',6'-diptiranjan)phenylacetic acid;

5-ethyl-2-(2',4'-dichloro-6'-foronline)phenylacetic acid;

5-ethyl-2-(2',4'-dichloro-6'-methylaniline)phenylacetic acid;

5-ethyl-2-(2'-fluoro-4'-chloro-6'-methylaniline)phenylacetic acid;

5-ethyl-2-(2',4'-debtor-6'-methylaniline)phenylacetic acid;

5-ethyl-2-(2'-chloro-4'-fluoro-6'-methylaniline)phenylacetic acid;

5-methyl-2-(2'-chloro-4'-hydroxy-6'-foronline)phenylacetic acid;

5-methyl-2-(2'-fluoro-6'-triptoreline)phenylacetic acid,

5-methyl-2-(2',4'-dichloro-6'-triptoreline)phenylacetic acid,

5-methyl-2-(2',3',4',6'-tetrafluoroaniline)phenylacetic acid;

5-methyl-2-(2',6'-dichloraniline)phenylacetic acid;

5-methyl-2-(2'-chloro-6'-fluoro what nilina)phenylacetic acid;

5-methyl-2-(2',6'-dichloro-4'-methylaniline)phenylacetic acid;

5-methyl-2-(2'-chloro-6'-methylaniline)phenylacetic acid;

5-methyl-2-(2'-chloro-4'-fluoro-6'-methylaniline)phenylacetic acid;

5-ethyl-2-(2'-fluoro-6'-chloroanilino)phenylacetic acid;

5-ethyl-2-(2'-chloro-6'-methylaniline)phenylacetic acid;

5-ethyl-2-(2',3',6'-triptoreline)phenylacetic acid,

5-ethyl-2-(2',4'-dichloro-6'-methylaniline)phenylacetic acid,

and their pharmaceutically acceptable salts and their pharmaceutically acceptable proletarienne esters.

10. The method according to one of the preceding paragraphs, in which R denotes methyl; R1denotes chlorine; R2, R3and R4represent hydrogen and R5denotes fluorine.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

The invention relates to compounds of the formula I

< / BR>
where

R denotes methyl or ethyl,

R1denotes chlorine or fluorine,

R2denotes hydrogen or fluorine,

R3denotes hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy or hydroxy,

R4denotes hydrogen or fluorine,

R5denotes chlorine, fluorine, trifluoromethyl or methyl, and their pharmaceutically acceptable salts and

to their pharmaceutically acceptable prodrugs in the form of esters

The invention relates to the field of technology for pharmaceutical preparations, namely, the method of obtaining the derivatives (salts, esters or amides) substituted 2-(phenylamino)phenylacetic acid, which can be used as drugs for various purposes

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds able to prevent the extracellular release of inflammatory cytokines. Proposed compounds including their diastereomeric forms and their pharmaceutically acceptable salts correspond to the formula: wherein R means: (a) -O[CH2]kR3 or (b) -NR4aR4b; R3 means a substituted or unsubstituted (C1-C4)-alkyl, a substituted or unsubstituted phenyl wherein substitutes are taken among halogen atom, cyano-group, trihalidemethyl, (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein R3 means hydrogen atom each among R4a and R4b means independently hydrogen atom or (C1-C4)-alkyl-CO- or benzo(1,3)dioxol; index k has a value from 0 to 5; each among R4a and R4b means independently: (a) hydrogen atom or (b) -[C(R5aR5b)2]mR6 wherein each Ra means hydrogen atom, and R5b means hydrogen atom, linear or branched (C1-C)-alkyl; R6 means vinyl, the group -OR7, -CO2R7, cyclic (C3-C)-alkyl, unsubstituted phenyl or phenyl substituted with (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein each among R3, R4a and R4b means independently hydrogen atom, or unsubstituted 6-membered nitrogen-containing heteroaryl; R7 means hydrogen atom, water-soluble cation or (C1-C4)-alkyl; index m has a value from 0 to 5. Also, invention relates to a pharmaceutical composition comprising the effective dose of compounds corresponding to abovementioned formula, and to a method for inhibition of extracellular release of inflammatory cytokines.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 sch, 6 tbl, 3 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a new compound, i. e. 3-(4-nitrobenzoylmethylene)-1H,4H-hexahydro-2-quinoxalone of the formula (I) possessing anti-inflammatory activity. Proposed compound possesses the reduced toxicity.

EFFECT: improved and valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry of heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new ortho-substituted and N-substituted indoles of the formula (α): or (β): or their pharmaceutically acceptable salts wherein Z1 represents -CR4 or nitrogen atom (N); R4 means hydrogen atom (H), (C1-C6)-alkyl comprising optionally oxygen atom (O) or nitrogen atom (N) possibly substituted with halogen atom, keto-group, 5-6-membered cycloaliphatic radical possibly comprising 1-2 oxygen atoms (O) or nitrogen atom (N); Z2 represents -CH or -CR wherein R means (C1-C6)-alkyl; R1 means compound of the formula: wherein X1 means -CO or its isostere; m = 0, 1; Y represents alkyl that can be substituted; or two Y form in common (C2-C3)-alkylene; n = 0, 1 or 2; Z3 represents -CH; X2 represents -CH, -CH2 or their isostere; Ar represents one or two phenyl groups bound with X2 wherein phenyl can be substituted; R2 represents hydrogen atom (H), (C1-C6)-alkyl or aryl wherein each aryl comprises, possibly, oxygen atom (O) or nitrogen atom (N) and can be substituted. Proposed compounds are selective inhibitors of p38α kinase.

EFFECT: valuable biochemical properties of compounds.

34 cl, 5 tbl, 23 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to composition possessing an anti-inflammatory effect and useful for oral administration in form of emulsion preliminary concentrate. Composition comprises NO-releasing nonsteroid anti-inflammatory drug, surface-active substance, oil or semisolid fat and forms in situ emulsion of type oil-in-water after contact with aqueous medium, such as gastroenteric fluid. Also, invention relates to a medicinal formulation based on thereof, oral emulsion, set based on thereof and a method for treatment of inflammation and pain. Proposed compositions possess the improved availability.

EFFECT: improved and valuable properties of composition.

40 cl, 1 tbl, 20 ex

FIELD: medicine, surgery.

SUBSTANCE: since the 2nd d after operation for 2 wk one should prescribe nimesulide per 100 mg twice daily, and on the 7th - 10th d after operation - microwave therapy onto thyroid area at the power of 2.5 W for 5 min at low-thermal mode, moreover, after hemithyroidectomy one should prescribe physiotherapy since the 7th d, after resection of isthmus - since the 8th d, after subtotal resection - since the 9th d, after total thyroidectomy - since the 10th d. The method provides enhanced secretion of thyroid hormones and compensation of hypothyroidism due to physiotherapy, that enables to get rid of hormonal substitution therapy or decrease its dosage.

EFFECT: higher efficiency.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

FIELD: medicine, rheumatology.

SUBSTANCE: the innovation deals with basic immunomodeling and symptomatic antiphlogistic therapy and additionally - therapy with Calcium-D3 preparation at dosage correction, duration and multiplicity of therapy course being dependent upon phase, activity degree, the nature of disease flow and mineral density of bony tissue (MDBT). At highly progressing RA and during exacerbation phase one should apply Calcium-D3 for 14 d at low degree of activity, for 21 d at average degree and for 28 d in case of high degree of activity, moreover, at MDBT being below the standard one should apply Calcium-D3 at the dosage of 400 IU cholecalciferol (vitamin D3) and 1250 mg calcium carbonate in the evening and 200 IU cholecalciferol and 1250 mg calcium carbonate in the morning. At MDBT ranged within the norm it is necessary to apply Calcium-D3 at the dosage of 800 IU cholecalciferol and 2500 mg calcium carbonate both in the evening and in the morning. At slowly progressing RA for above 2 yr and at the phase of relative remission one should apply Calcium-D3 at the dosage of 200 IU cholecalciferol and 1250 mg calcium carbonate in the evening for prolonged period of time at 1-wk-long interval during 1-2 d. In case of early RA lasted for 2 yr at unknown character of its flow it is necessary to apply Calcium-D3 at the dosage of 400 IU cholecalciferol and 1250 mg calcium carbonate in the evening for 14 d. Therapy course should be carried out in 4-6 mo. The innovation provides optimal therapy for every combination of the phase, activity, the nature of RA flow and MDBT parameters that enables to decrease the chance for relapses and increase remission duration by 1.5-1.8 times.

EFFECT: higher efficiency of therapy.

3 cl, 2 ex

FIELD: medicine, rheumatology.

SUBSTANCE: the innovation deals with therapy with metothrexate at the dosage of 7.5 mg/wk in combination with small dosages of glucocorticosteroids, up to 10 mg/d against prednisolone. Metothrexate should be once introduced at the quantity of 7.5-20 mg/wk, glucocorticosteroids - once at 3 a.m. Therapy course lasts for bout 6 mo, not less followed by decreasing the dosage of glucocorticosteroids for 6 mo up to their complete refusal at keeping maintenance therapy with metothrexate. The innovation enables to achieve maximal increase of antidestructive action at any terms of disease due to preventing the development of new articular erosions and keeping the width of articular fissura at the most physiological scheme of glucocorticosteroids' intake.

EFFECT: higher efficiency of prophylaxis.

4 cl, 12 dwg, 4 ex, 3 tbl

FIELD: pharmaceuticals.

SUBSTANCE: polyvinyl alcohol and magnesium or calcium chlorides polyhydrated complexes are obtained by dissolution of polyvinyl alcohol and magnesium or calcium chlorides in water on boiling water bath. Said components are taken in the next ratio (mass%): polyvinyl alcohol 11.5-11.6; magnesium or calcium chloride 23.2-24.0; and balance: distilled water.

EFFECT: new complex compounds having antiinflammation, resolution and analgesic action.

11 ex

FIELD: medicine.

SUBSTANCE: method involves administering drugs usable for hindering keratoleukoma occurring after carrying out excimer laser keratectomy with an antioxidant agent being added. The agent is used for jet irrigating cornea before setting lens.

EFFECT: enhanced effectiveness in reducing lipid peroxidation products quantity; accelerated cornea epithelialization.

2 cl, 2 tbl

FIELD: medicine, endocrinology, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to nateglynide-containing preparation used in treatment of diabetes mellitus that comprises nateglynide as an active component and a carrier wherein nateglynide in amorphous form and indicated carrier represents hydrophilic material. Amorphous property of crystalline nateglynide is provided by the following methods: 1) by dissolving nateglynide crystals in pharmacologically acceptable solvent in common with hydrophilic materials taken among the group consisting of water-soluble polymers, water-swelling polymers, sugar alcohols and salts followed by granulation in fluidized layer, granulation by stirring at high rate, drying by spraying and process for coat applying for granulation of amorphous nateglynide; 2) by mixing nateglynide crystals with hydrophilic materials taken among the group of water-soluble polymers, water-swelling polymers, sugar alcohols and salts and the following application of the high shift force to the prepared mixture; 3) by mixing nateglynide crystals with hydrophilic materials taken among the group of water-soluble polymers, water-swelling polymers, sugar alcohols and salts and the following plasticizing the prepared mixture in melt by heating and milling at cooling; 4) by dissolving nateglynide crystals in pharmacologically acceptable liquid additives wherein liquid additives represent water-soluble polymers that are liquid at 37°C. Using amorphous nateglynide allows preparing the nateglynide preparation with immediate release wherein the dissolving rate of medicinal agents is high and without crystalline transition during preparing or preserving preparations.

EFFECT: valuable pharmaceutical properties of preparation.

6 cl, 3 tbl, 9 dwg

FIELD: medicine, in particular cardiovascular diseases treatment.

SUBSTANCE: the object of present invention is to provide products containing polyphenols and L-arginine having healthy action of mammalians. Foodstuff and pharmaceutical composition contain procyanidins of cocoa and/or nuts in combination with L-arginine. Said composition represent effective inducers for physiological enhancement of nitrogen oxide production in mammalian. Foodstuff optionally contains chocolate or nut procyanidin. As chocolate dark or milky nut-containing chocolate is used. Natural or synthetic products may be used as procyanidins. As L-arginine sources nut mass, nut paste and/or nut flour, seeds, seed paste and/or seed flour, or gelatin may be used. Abovementioned compositions also are useful in treatment of cardiovascular diseases wherein effective dose is calculated on the base of procyanidin content.

EFFECT: composition having advantageous action of organism, in particular with vasorelaxation effect.

107 cl, 17 tbl, 19 ex

FIELD: medicine, experimental physiology.

SUBSTANCE: the present innovation deals with studying the flow of myocardial infarction at the impact of cardioprotector preparation. For this purpose, infarction in rats should be induced due to applying ligature onto posterior branch of right-hand coronary artery. Moreover, as a cardioprotector remedy one should apply L-arginine which should be once introduced intravenously at the dosage of 50 or 100 mg/kg about 20-30 min before applying a ligature. The innovation provides the chance to study mechanisms to prevent the development of myocardial infarction complications with L-arginine at maximal similarity of infarction model to clinical conditions of human infarction development.

EFFECT: higher efficiency.

FIELD: medicine.

SUBSTANCE: invention relates to a composition used in prophylaxis and treatment of diseases or pathological states associated with destruction of extracellular matrix. Proposed composition can be used in treatment and prophylaxis of destructive diseases, in particular, arteriosclerosis, cancer, infectious and other inflammatory diseases and other diseases. The composition comprises preferable compounds comprising lysine, proline, ascorbate and their derivatives, and synthetic analogues, and vitamins, provitamins and trace elements also. Invention provides reducing destruction and stimulates collagen synthesis simultaneously that prevents the development of the abovementioned diseases.

EFFECT: valuable medicinal properties of composition.

10 cl, 2 tbl, 4 dwg

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in treatment of Parkinson's disease that comprises L-DOPA and at least one compound able to inhibit the external transfer of L-DOPA in renal cells. Indicated blocking agent is taken among the following substances: flavonoid - a derivative of phenylbenzpyrane, a derivative of trans-stilbene and floretin, i. e. [3-(4-hydroxyphenyl)-1-(2,4-trihydroxyphenyl)-1-propanone]. Also, the composition can comprise inhibitor of enzyme amino acid decarboxylase, such as carbi-DOPA or benzerasid and/or inhibitor of enzyme catechol O-methyltransferase, such as entacapon or tolcapon. The composition can be used in a solid formulation and L-DOPA can be administrated simultaneously or successively with a blocking agent of L-DOPA external transfer in renal cells. Invention provides expanding assortment of agents used in treatment of Parkinson's disease.

EFFECT: valuable medicinal properties of composition.

28 cl, 1 tbl, 5 dwg

FIELD: medicine, dermatovenerology.

SUBSTANCE: one should perform diagnostics with the help of fluorescence spectrums of affected sections. Section being of own intensive fluorescence should be irradiated with light at wave length being 630±10 nm and energy density 10-4500 J/sq. cm, sections which has no own intensive fluorescence should be applied with an applicator containing 2-20% solution of 5-aminolevulinic acid and after exposure and applicator's removal they should be irradiated with light at wave length being 630±10 nm and energy density of 10-4500 sq. cm. The flow of irradiation process should be controlled due to fixing fluorescence spectrums at affected skin sections before irradiation, after the use of applicator that contains 5-aminolevulinic acid, after irradiation, moreover, irradiation should be stopped at decreased concentration of porhyrins being below therapeutic values. The innovation decreases cutaneous fatty secretion, quantity and density of eruption.

EFFECT: higher accuracy and efficiency of diagnostics and therapy.

8 cl, 4 dwg, 5 ex

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