Derivatives benzoxazolone, possessing anti-inflammatory activity

 

(57) Abstract:

Usage: in medicine, in particular as substances with anti-inflammatory activity. The essence of the invention: derivatives of benzoxazolone f-ly 1, where Alk - Cndivalent alkyl radical; n is an integer from 0 to 5; R1-C1-C3-alkyl, C1-C3-alkoxy, halogen; R is chosen from the group comprising: a) a group of f-crystals 2, where R2and R3- H or C1-C4-alkyl; X is methylene, N, O, S or SO; the dashed line is the possibility of additional communication; C) group f-crystals 3 or 4, where a and B are oxygen or sulfur; (C) group f-crystals 5, 6, 7, 8 or 9; d) group f-crystals, 10, 11, 12, 13 or 14, where R4and R5- H or C1-C4-alkyl; broken line-the possibility of endo - or Exo-7-oxabicyclo [2.2.1] heptane-1-yl; (e) group f-crystals 15: CH3-(CH2)m-Y , where m=1, 2, or 3; Y Is 0, S or SO. table 4.

The invention relates to benzoxazolinone, more specifically to certain benzoxazolinone, substituted not only in position 6 amine side chain, but also in the provisions of 4,5 or 7 of the benzene ring. Such compounds have an inhibitory effect on the enzymes lipoxygenase and/or cyclooxygenase and can be used as inhibitor is of various allergic and inflammatory diseases in mammals.

In European patent application N 249407 disclosed benzoxazolinone connection with alkylamino group in position 6, which are inhibitors of lipoxygenase and/or cyclooxygenase.

The present invention discloses new benzoxazolinone the compounds of formula I

O where Alk is unbranched or branched divalent alkyl group WITHnwhere n = 0,1,2,3,4, or 5;

R1-(C1-C3)-alkyl, (C1-C3)-alkoxy or halogen;

R is chosen from the group including:

(a)

where R2and R3each independently from each other hydrogen or (C1-C4)-alkyl; X is methylene, nitrogen, oxygen, sulfur or sulfoxide, and the dotted line indicates an optional connection,

(b) or where a and b each independently of one another represent oxygen or sulfur;

(C), or

(d) , , ,

or where R4and R5each independently of one another represent hydrogen or (C1-C4)-alkyl, and broken line indicates that the group containing such a broken line, can be an endo - or Exo-7-oxabicyclo[2.2.1]heptane-1-yl; and

(e) CH3-(CH2)m-Y- , where m is 1,2 or 3;

Y is oxygen, sulfur or Compostela group of compounds includes those in which n is 0 or 1; R1is halogen; R is a radical selected from the group (a). Especially preferred those in which R1-5 - fluoro and X is oxygen.

A second preferred group of compounds is that in which consists of compounds with n = 1; R1is halogen and R is a member selected from group (C). Particularly preferred such compounds in which R1-5-fluoro.

A third preferred group of compounds includes compounds with n equal to 1; R1-(C1-C3)-alkyl, R is a radical selected from the group (a). Particularly preferred compounds in which R1-5-ethyl and X is oxygen.

A fourth preferred group of compounds is the group which consists of compounds with n = 1 and R is a radical selected from the group (d). Especially preferred those in which R1-5-fluoro.

The fifth preferred group of compounds is the group formed by compounds with R1is halogen and R is a radical from the group (e). Particularly preferred compounds in which R1-5-fluoro, m is 1 and Y is oxygen.

The sixth preferred group of compounds is one that includes connections with R1-(C1-C3)-alkoxy and R is a radical selected The compounds of formula I may contain an asymmetric center and therefore, can exist as pairs of enantiomers. The present invention includes each pure enantiomer, racemate, mixture of enantiomers, partially or completely optically split.

The new compounds of formula I can be obtained in accordance with the following reaction scheme:

< / BR>
In the above formula Alk, R and R1correspond to the above definitions and n is 0,1,2,3 or 4. In the first stage, approximately equimolar amounts of reactants, such as amine (II) and the aldehyde (III), is mixed in a suitable organic solvent. Although the reaction is preferably carried out at ambient temperature, it is possible to use higher temperatures such as the boiling temperature under reflux, and it will not result in any significant adverse complications. Among the suitable organic solvents include (C1-C4)-alkanols (e.g. methanol or ethanol), benzene, toluene, and tetrahydrofuran. It is possible that the use of dehydrating substances will give certain advantages. As dehydrating substances preferred molecular sieves. To accelerate the reaction arbitrarily add small amounts of lower almoet to stand out and be cleaned by standard methods, for example recrystallization or chromatography, when the received Imin mates with unsaturated group. However, more preferably the product is not to highlight and expose it (i.e., location) of the reaction in the second stage.

In the second stage reaction is carried out restoration C=N double bond under the action of an acceptable source of hydrogen. Although recovery can be performed using a wide range of reducing agents, which are known as reducing agents carbon-nitrogen double bond, in accordance with the preferred method used metal hydride or carry out the reaction of catalytic hydrogenation. Among the acceptable for this reaction hydrino include borohydride sodium, cyanoborohydride sodium and cyanoborohydride lithium. Usually the recovery is carried out at ambient temperature in the presence of excess hydride in (C1-C4)-alkanol, such as methanol or ethanol. The catalytic hydrogenation is carried out in the presence of catalytic amount of the catalyst is a noble metal, such as palladium on coal or Pt2in an atmosphere of hydrogen. After the recovery of the target product of the formula (I) was isolated by standard methods. Clean about what inane formula (I), in which n is 0 and R is a radical selected from group (a) also receive substantially the same way with the only difference that instead of aldehyde (III) used in the reaction ketone. As such, the preferred one of the following ketones:

RR3RR3RR3where X is methylene, nitrogen, oxygen or sulfur and R2and R3defined above. For example, in the reaction of a combination of compound (II) with the ketone (V) receive Imin formula (VIII)

< / BR>
The last connection is easily restored to the target compounds. The reaction conditions for the implementation of the said two-step conversion is slightly different from those used in the synthesis of compounds (I) in which n is not equal to 0.

The compounds of formula (I) in which R is a member of group (a), and X - sulfoxide; or R is a member of group (e) and Y - sulfoxide, obtained by oxidation of the corresponding compounds in which X and Y is sulfur. Oxygenated compounds get in the way described above. Acceptable conditions of oxidation include, but are not limited to, the reaction of such compounds with metaperiodate sodium oxide of aluminum is carried out in an acceptable solvent such as a (C1-C3-alkanol or/and tetrahydrofuran.

Olefinic products is diversified inhibitors of lipoxygenase enzymes and cycloxygenase and also serve as intermediates for obtaining the appropriate restored compounds of the formula

(Alk)- (IX)

A particularly preferred method of such recovery includes the hydrogenation of compounds of formula (I) that are recovered hydrogen in the presence of a catalyst is a noble metal in an appropriate solvent. Acceptable solvents in this hydrogenation are, for example, sulphuric ether, tetrahydrofuran, dioxane, ethyl acetate, and (C1-C3-alkanol, such as methanol or ethanol. Catalysts based on noble metals are, for example, Nickel, palladium, platinum and rhodium. Particularly preferred catalysts are platinum oxide and palladium on coal. The platinum catalyst is sometimes preferred because it is harder to catch grey. For such hydrogenation is not required high pressure of hydrogen (1-4 ATM), and it proceeds at ambient temperature. After completion of the hydrogenation (for about 2-24 h) the catalyst is filtered off, and then produce the product of formula (IX) and, if necessary, purified by a standard method.

6-Aminobenzimidazole-2(II) receive a variety known in the art methods are illustrated in the examples below). Required for the synthesis of aldehydes and ketones are produced by the industry, or they can the enzymes lipoxygenase and/or cyclooxygenase. This suppression is demonstrated in experiments on rats on resident cells of the abdominal cavity, in which is determined the effect of these compounds on metabolize arachidonic acid.

In this experiment, some preferred compounds showed low IC50values in the range of 0.5-30 μm, in relation to suppress as lipoxygenase and cyclooxygenase.

Below are attached table. 1 and 2. Table.1 lists data in vitro RPC IC505 = LO/CO and the data on mortality PAF for some compounds EP 249 407.

Table. 2 lists these data for compounds of the present invention. Test in vitro RPC was performed according to published methods I. Cheng et al. Eur. I. Pharmacol. 107,215 (1985). Test on mortality PAF was conducted according to published methods Joung I. M. et. al. Prostaglandins 30,545 (1985).

Further, on the basis of available information, the compounds of the present invention do not have a high toxicity.

The ability of the compounds of the present invention to suppress the enzymes lipoxygenase and/or cyclooxygenase allows them to control symptoms caused by endogenous metabolites resulting from the collapse of arachidonic acid in mammals. The who is the accumulation of metabolites of arachidonic acid, such as allergic bronchial asthma, rheumatoid arthritis, osteoarthritis, thrombosis, and skin diseases.

The proposed activity of the compounds can also be illustrated in the standard experiments on rats in case carrageenan induced paw oedema (C. A. Winter with TCS. Proc. Soc. Exp.Biol, III, R. 544, 1962).

Thus, the compounds of formula (I) are particularly useful in the treatment or alleviation of allergic or inflammatory diseases in humans, as well as the suppression of enzymes cyclohexenes and lipoxygenase.

In the treatment of the above diseases, the compounds of formula (I) can be administered to patients either alone or in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition, preferably, in accordance with the usual practice. The connection may be entered in various ways, including oral, parenteral and by inhalation. When administered orally daily dose patients ranges from about 0.1 to 20 mg/kg weight of the patient, preferably about 0.1-1.0 mg/kg, and is used as a single or divided into several doses. When parenteral daily effective dose ranges from 0 is shown above the limits as the dosage must be changed depending on the age, weight and response of the individual patient, as well as the complexity of the symptoms and the activity of the specific compound.

When oral administration of the compounds of formula (I) can be included in such forms as tablets, powders, syrups, capsules, pills. In the case of oral tablets, as the media usually used lactose and corn starch. In addition, usually add a lubricant such as magnesium stearate. When using capsulated forms diluents are lactose and dry starch. When oral administration are aqueous suspensions of the active ingredient combined with an emulsifier and suspensorium substance. If necessary, you can add certain sweet and/or flavoring agents. For intramuscular, intraperitoneal, subcutaneous and intravenous injection is usually used sterile solutions of the active component, and is required for the proper regulation of pH solutions and introducing the buffer components. For intravenous use, the total concentration of the solution should be adjusted so that he was isotonic.

6). The peak positions were expressed in parts per million, counting from tetramethylsilane. The form was expressed as follows: s - singlet, d - doublet, t - triplet, m = multiplet, sh - wide.

P R I m e R 1. 5-fluoro-6-(5,6-dihydro-2H-Piran-3-yl)methylamino) benzoxazole-2-it.

To a solution of 0.97 g (5.7 mmol) 6-amino-5-fluoro-benzoxazole-2-she and 0.71 g (6.3 mmol) of 3-formyl-5,6-dihydro-2H-Piran in 40 ml of ethanol was added 1 g of molecular sieves 4A. The mixture was boiled under reflux for 3 hours After cooling, the mixture was filtered and the filtrate was concentrated to obtain a solid product, which was washed with ethanol. The product was dissolved in methanol (200 ml) and then the parts were added at room temperature borohydride sodium. The reaction mixture was stirred for several hours. The reaction mixture was concentrated and added water. The organic material was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated. The obtained residue was recrystallized from methanol, getting 420 mg of the desired product (28%) CH), 3,97 (W, 2N), of 5.53 (W, 1H), 5,74 (W, 1H), of 6.68 (d, 1H), 6.90 to (d, 1H), 11,23 (s, 1H).

P R I m e R s 2-7. Similarly, apply the appropriate aldehydes (III) in the procedure described in example 1, was obtained the corresponding compounds of formula (I) listed in table.3.

P R I m e R 8. 5-fluoro-6-[(tetrahydro-4H-Piran-3-yl)propylamino] benzoxazole-2-he

At room temperature to a solution of 2.1 g (12.5 mmol) 6-amino-5-fluoro-benzoxazole-2-it in 80 ml of methanol was added 1,95 g (13.7 mmol) of 3-(tetrahydro-2H-Piran-3-yl) propionic aldehyde and 1 ml of acetic acid, and the mixture was stirred for 1 h was Added 0,867 g (13.7 mmol) of cyanoborohydride sodium and continued stirring the reaction mixture for 17 h at room temperature. The reaction mixture was concentrated in vacuo, and the residue was treated with an aqueous solution of ammonium chloride. Organic matter was extracted with ethyl acetate - tetrahydrofuran. The extracts were washed with brine, dried over magnesium sulfate and concentrated, to give crude product. The latter was recrystallized from methanol and received 1.40 g of target compound with so pl. 144-145aboutC.

IR-spectrum (KBr): 1770, 1090 cm-1.

The NMR spectrum of 1.00-1.30 (m, 3H), 1,38-to 1.63 (m, 5H), 1,75-of 1.85 (m, 1H), 2.91 in-3,03 (m, 3H), 3 is using the appropriate aldehydes (III) or ketones (V)-(VII) in accordance with the procedure of example 8, obtain the corresponding compounds of formula (I), the data in the table.4.

O where Alk is a (CH2)n.

P R I m e R 34. 5-fluoro-6-[(tetrahydro-4H-Piran-3-yl) methylamino]-2-benzoxazolone

To a solution of 1.0 g (3.88 mmol) 6[(5,6-dihydro-2H-Piran-3-yl) methylamino] -5-fluoro-2-benzoxazolone in 100 ml of methanol was added 50 mg of platinum oxide, the mixture was first made at a pressure of 1 ATM and at room temperature for 1 h Then the mixture was filtered, the filtrate was concentrated in vacuo and the resulting solid residue was washed with ethanol. By recrystallization from ethanol was obtained of 0.48 g of the desired product (47%) with T. pl. 177-178aboutC.

IR-spectrum (KBr): 1760, 1510, 1090, 950 cm-1.

NMR spectrum: 1,15-1,30 (m, 1H), 1,35-of 1.65 (m, 2H), 1,75-1,80 (m, 2H), 2,90-2,95 (m, 2H), 3,05 is 3.15 (m, 1H), 3,70-of 3.85 (m, 2H), 5.25 in (m, 1H), 6.75 in (d, 1H), 6.89 in (d, 1H), 11,30 (W, 1H).

P R I m e R 35. 5-fluoro-6-[(tetrahydropyran-2-yl)]-methylamino - benzoxazole-2-it.

By the way, is similar to that described in example 34, from 5-fluoro-6-[(3,4 - dihydro-2H-Piran-2-yl)methylamino] benzoxazole-2-she's got a target connection so pl. 185-186aboutC.

IR-spectrum (CH2Cl2): 3500, 1790, 1780 cm-1.

NMR-spectrum (CCl3): 1,36-1,67 (m) 1,89 (m, 1H), 3.04 from (DD, 1H, j = 8, 12 Hz), and 3.16 (DD, 1H, I = 3,5, 12 Hz), 4-tetrahydro-2-naphthyl)methylamino]-benzoxazole-2-it.

Following the procedure of example 34 and using as a source of reagent 5-fluoro-6-[3,4-dihydro-2-naphthyl)methylamino] -benzoxazole-2-it, and instead of platinum oxide and 5% palladium on coal, has been the target product with so pl. 177-178aboutC.

IR-spectrum (KBr): 1770, 1660, 1520 cm-1.

NMR spectrum: 1,30-1,50 (m, 1H), 1,90-2,10 (m, 2H), 2.49 USD (DD, 1H), 2,65-2,95 (m, 3H), 3,06 (DD, 2H), are 5.36 (m, 2H), 6,79 (d, 1H), 6,93 (d, 1H), 11,21 (s, 1H).

P R I m e R 37. 5-fluoro-6-[(chroman-3-yl)methylamino]benzoxazole-2-it.

Following the procedure of example 34, using as starting reagent 5-fluoro-6-[(4-chloro-2H-chromen-3-yl)methylamino] -benzoxazole-2-he Giriraja in the presence of triethylamine, received target connection so pl. p.223-224aboutC.

IR-spectrum (KBr): 1750, 1510, 1490 cm-1.

NMR spectrum: 2,25-of 2.38 (m, 1H), 2,53-2,60 (m, 1H), 2,87 (DD, 1H), 3,06 (d, 1H), 3,09 (d, 1H), a 3.87 (DD., 1H), 4,22-4,27 (m, 1H), of 6.71-6.75 in (m, 1H), 6,78-6,84 (m, 2H), 6,91 (d, 1H), 7.01-was 7.08 (d, 2H), 11,20 (W, 1H).

P R I m e R 38. 5-Methoxy-6-[tetrahydropyran-3-yl)methylamino]- benzoxazole-2-he

Following the procedure of example 34, from 5-methoxy-6-[3,5-dihydro-2H-Piran-3-yl)methyl - amino] benzoxazole-2-she's got a target connection so pl. 155aboutC (with decomposition).

IR-spectrum (nujol): 3200, 1780, 1740, 1680, 1640 cm-1.

P R I m e R 39. 5-Ethyl-6-[tetrahydropyran-3-yl)methylamino]-benzoxazole-2-he

Following the procedure of example 34, from 5-ethyl-6-[(5,6-dihydro-2H-Piran-3-yl)methylamino] benzoxazole-2-she's got a target product with so pl. 148-150aboutC.

IR-spectrum (nujol): 3200, 2750, 1775, 1630 cm-1.

NMR spectrum: between 1.25-1.30 (m, 1H), 1,86 is 2.00 (m, 4H), 2,04 (s, 3H), 2.91 in-2,95 (m, 2H), 3,13-3,17 (m, 2H), 3.72 points III.S., 1H), 3,84 (sh.S., 1H), 5,01-5,08 (m, 1H), 6,40 (s, 1H), gold 6.43 (s, 1H).

P R I m e R 40. 5-fluoro-6-[(2,6-dimethyltetrahydrofuran-3-yl)methylamino] -benzo - oxazoline-2-he

Following the procedure of example 34, from 5-fluoro-6-[(2,6-dimethylbicyclo-2H-Piran-3 - yl)methylamino] benzoxazole-2-she's got a target product with so pl. 123-139aboutC (methanol).

IR-spectrum (nujol): 1757, 1788 cm-1< / BR>
NMR-spectrum (CCl3): 1,22 (d, 3H, j = 6,1 Hz) of 1.27 (d, 3H, j = 6.6 Hz), the 1.44 (m, 2H), 1.77 in (m, 2H), 1.90-2.06 to (m, 1H), 3,17-3,39 (m, 2H), 3,55 (m, 1H), of 3.77 (m, 1H), 4,03 (sh.S., 1H), 6,61 (c, 1H, j = 7,1 Hz), 6,79 (d, 1H, j = 10.3 Hz), 8,70 (sh.S., 1H).

P R I m e R 41. 5-fluoro-6-[(tetrahydrothiopyran-3-yl)methylamino] benzoxazole-2-he

Following the procedure of example 34, from 5-fluoro-6-[(dihydro-2H-thiopyran-3-yl)methylamino]benzoxazole-2-she's got the target connection.

P R I m e R 42. 5-fluoro-6-[(tetrahydrothiopyran-1 oxido-3-yl)methylamino)]-benzoxazole-2-he

To rageragerage was added 5.6 g of metaperiodate sodium on alumina. The mixture was stirred 20 h at room temperature. The alumina was filtered and the solvent was removed in vacuum. The crude product was purified through column chromatography with silica gel by elution with ethyl acetate/tetrahydrofuran/methanol (80: 20:5) and recrystallization from methanol/boric ester. The result has been the target product in the amount of 0.28 g (22% yield).

IR-spectrum (KBr): 1765, 1520, 1020, 940 cm-1.

NMR spectrum: from 1.1 to 1.25 (m, 1H), 1,4-of 1.55 (m, 1H, one isomer, E or Z position of the 1,3-tetrahydrothiopyran-1-oxide cores), 1,65-2,15 (t, 3H), of 2.3 to 2.6 (m, 2H+1H one isomer), of 2,75 2,85 (m, 1H one isomer), a 2.9-3.15 in (m, 2H, one isomer), 5,4-of 5.55 (m, 1H), 6,77-6,85 (m, 1H), 6,91 (d, 1H, I = a 10.6 Hz), and 11.2 (W, 1H).

P R I m e R 43. 5-fluoro-6-[3-(butylsulfonyl]benzoxazole-2-he

Following the procedure of example 42 5-fluoro-6-[3-(butylthio)propylamino]benzoxazol - Lin-2-she's got a target product with so pl. 116-117aboutC (methanol).

IR-spectrum (CH2Cl2): 3480, 1780, 1660 cm-1.

NMR spectrum: from 0.90 (t, 3H, j = 7,3 Hz) of 1.40 (m, 2H), 1,60 (m, 2H), 1.91 a (m, 2H), 2.57 m-is 2.88 (m, 4H), 3,18 (m, 2H), 5,38 (m, 1H), 6,79 (d, 1H, I = = 7,3 Hz), 6.90 to (d, 1H, I = to 11.0 Hz), 11,23 (sh.S., 1H).

Sample preparation A.

6-Amino-5-fermentation-2-he

A1. 4-is UP>aboutWith was added dropwise a solution of 204 g (1.8 mmol), 4-terfenol in 200 ml of acetic acid for 2 hours Stirring was continued for further 2 h at 5aboutC. the Reaction mixture was poured into ice and the resulting yellow solid substance was collected and washed with water. The substance was recrystallized from aqueous methanol (5 g methanol 1 tsp of water). The result has been 198 g of the target product. NMR spectroscopy showed the presence of absorption at 7,17 (double doublet, 1H, j = 9.5 Hz), 7,44-7,52 (multiplet, 1H) and 7,80 (double doublet, 1H, j = 8,3 Hz).

A2. 2-Amino-4-terfenol

To the solution was 48.3 g (0.30 mol) of 4-fluoro-2-NITROPHENOL in 300 ml of ethanol was added 0.24 g of platinum oxide in nitrogen atmosphere. The mixture was first made in the Parr shaker for 8 h at a pressure of 3.15 bar (45 pounds/ per square inch). The catalyst was filtered and the filtrate was concentrated, obtaining a 40.5 g of the desired product as a brown powder.

NMR spectroscopy showed the presence of absorption at 4,79 (broad singlet, 2H), 6,11 (multiplet, 1H), 6,36 (double doublet, 1H, j = 11.3 Hz), 6,53 (double doublet, 1H, j = 5,9 Hz) and 8,89 (singlet, 1H).

A3. 5-Fermentation-2-he

To a solution of 40.5 g (0.32 mol) of 2-amino-4-terfenol in 400 ml of tetrahydrofuran at 0aboutWith was added dropwise 44,8 m the th temperature. Stirring was continued for 2 h Then the reaction mixture was poured into ice, and organic matter was extracted with ethyl acetate (three times 500 ml). The combined extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated, getting them 44.3 g of the desired product as a brown solid mass.

NMR spectroscopy showed the presence of absorption at 6,86-6,90 (multiplet, 1H), 7,01 (double doublet, 1H, j = 8,3 Hz), 7,30 (double doublet, 1H, j = 9.5 Hz) and 11,82 (broad singlet, 1H).

A4.5-fluoro-6-nitrobenzoxazole-2-he

At room temperature to a stirred solution of 300 ml of concentrated nitric acid was added portion and 73.2 g (0.48 mol) of 5-fermentation-2-it. The reaction mixture was heated to 50aboutC and was stirred for 4 h After cooling, the reaction mixture was poured into ice. The precipitate was washed with water and dried, obtaining for 72.8 g of the desired product as a brown powder; so pl. product 207-209aboutC.

IR-spectrum (nujol): 3300, 1810, 1780, 1630 cm-1.

NMR spectrum: 7,35 (doublet, 1H, I = to 11.0 Hz), 8,16 (doublet, 1H, j = 6,6 Hz), and 12.6 (broad singlet, 1H).

A5. 6-Amino-5-fermentation-2-he

To a solution of 20 g (0.1 mol) of 5-fluoro-6-nitrobenzoic is continuous shaking in a Parr shaker for 10 h at 3,15 bar (45 psig). The resulting precipitate was dissolved by addition of tetrahydrofuran. The catalyst was filtered and the filtrate was concentrated, getting to 18.1 g of the target compound as a brown solid.

So pl. product 180-182aboutC (with decomposition).

IR-spectrum (nujol): 3400, 3280, 1750, 1630 cm-1.

NMR spectrum: is 4.93 (broad singlet, 2H), of 6.71 (doublet, 1H, j = 7,3 Hz), 6,84 (doublet, 1H, j = 10 Hz), and 11.2 (broad singlet, 1H).

Preparatory example B.

6-Amino-5-ethylbenzothiazoline-2-he

5-Ethyl-2-benzoxazolone synthesized by condensation of 2-amino-4-ethylphenol with urea, following the procedure described by U. j.The Kloss with TCS. S. Am. Chem. 71, 1265 (1949). Similarly preparatory example a 5-ethylbenzothiazoline-2-she's got 6-amino-5-ethylbenzamide with so pl. 146-147aboutC.

IR-spectrum (nujol): 3430, 3340, 3130, 1710, 1640 cm-1.

NMR spectrum: 1,10 (t, 3H, j = 7,3 Hz), 2,43 (q, 2H, j = 7,3 Hz), 4,73 (sh.S., 2H), 6,56 (s, 1H), 6,64 (S., 1H), 10,99 (sh.S., 1H).

Preparatory example Century.

Used the procedure of preparatory example for the synthesis of 6-amino-4-methylbenzoxazolium-2-it, 6-amino - 5-methylbenzoxazolium-2-it, 6-amino-5-triftoratsetilatsetonom-2-it, 6-amino-5-methoxybenzimidazole-2-it, 6-amino-7-chlorobenzoxazole-2-she and 6-amino-7-fermentation-2-it.

Preparatory example,

3-(Tetrahydropyran-2-yl) propionic aldehyde

G1. Ethyl-3-(5,6-dihydro-2H-Piran-3-yl) acrylate

To a stirred suspension of sodium hydride (60% in mineral oil, 1,43 g, 35,7 mmol) in 50 ml of tetrahydrofuran at room temperature was added dropwise 8,35 g (37,2 mmol) triethylphosphate in nitrogen atmosphere. The reaction mixture was stirred for 15 minutes To it was added dropwise a solution to 3.34 g (29,8 mmol) of 3-formyl-5,6-dihydro-2H-Piran (Japanese publication 59-167584, BASF) in 20 ml of tetrahydrofuran. The resulting mixture was stirred 1 h the Reaction was stopped by adding acetic acid. Then the reaction mixture was concentrated and added an aqueous solution of sodium bicarbonate. Organic matter was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and was evaporated to obtain oil. The crude oil was purified through column chromatography with silica gel, elwira 25% ethyl acetate-hexane. Was obtained 3.1 g of the target compound.

The NMR spectrum showed the presence of absorption at 1,26-to 1.38 (m, 3H), 2,34 (W., 2H), 3,8 (Tr., 2H, j = 5 Hz), 4,15-4,30 (m, 4H), 5,63 (D. 1H, j = 17 Hz), 6,28 (W., 1H) and 7,21 (d, 1H, I = =17 Hz).

G2. Ethyl-3-(tetrahydro-2H-Piran-3-yl) propionate

In the atmosphere water is ihydro-2H-Piran-3-yl) acrylate in 50 ml of methanol. The catalyst was filtered and the filtrate was concentrated, obtaining the crude oil. The crude product was purified through column chromatography with silica gel, elwira 50% ethyl - acetohexamide mixture (1:1). Received 3.0 g of the target product.

NMR spectroscopy showed the presence of absorption of 1.10-1.20 (m, 1H), 1.26 in (Tr. 3H, j = 7 Hz), 1,45-to 1.63 (m, 5H), 1,82 is 1.91 (m, 1H), 2,27-of 2.34 (m, 2H), 3,06 (DD, 1H, I = 9,5, 11 Hz), 3,30 is 3.40 (m, 1H), 3,83-to 3.89 (m, 2H) and to 4.23 (q, 2H, j = 7 Hz).

G3. 3-(Tetrahydro-2-N-Piran-3-yl) Propionaldehyde

In nitrogen atmosphere at a temperature of -78aboutTo a solution of 3.0 g of ethyl-3-(tetrahydro-2H-Piran-3-yl)propionate was added dropwise 16 ml (1.5 M) of toluene solution of Diyala. Stirring was carried out for 1 h the Reaction was stopped by adding a mixture of methanol-water. The resulting solution was cooled to room temperature. Removed the resulting solid precipitate. The filtrate was dried over magnesium sulfate and concentrated, to give crude oil. The crude product was purified by distillation and obtained 2.0 g of the target product.

The NMR spectrum showed the presence of absorption at 1,09 of 1.28 (m, 1H), 1,42-of 1.65 (m, 5H), 1,80 is 1.91 (m, 1H), 2,42-2,49 (m, 2H), of 3.07 (DD, 1H, I = 9, 11 Hz), 3,31 is 3.40 (m, 1H), 3,84-to 3.89 (m, 2H) and 9,78 (s, 1H).

Preparation example D

3-Methylcyclohexanecarboxylic acid in acetic acid was added 0.1 g of platinum oxide. The mixture was first made in the mixer parry at 2.45 MPa (35 psi). Upon completion, the catalyst was filtered and the filtrate was concentrated to dryness, obtaining 12 g of the target compound.

The NMR spectrum showed the presence of absorption at 0.84 (doublet, 3H), 0,90 (doublet, 3H), 0,99-1,13 (multiplet, 1H), 2.21 are 1,46 (multiplet, 3H), 1,54-1,65 (multiplet, 3H), 1.70 to 1,98 (multiplet, 2H) and 1,23-2,41 (multiplet, 1H).

2. 1-Hydroxymethyl-3-methylcyclohexane

To borane-sulfide methyl complex (1.7 ml, 0,028 mol) in 7 ml of tetrahydrofuran at 0aboutWith dropwise added 2 g of 3-methylcyclohexanecarboxylic acid (0.014 mol) in 7 ml of tetrahydrofuran. Was stirred for 1 h, the Reaction mixture was diluted with ether and washed with 1 N. aqueous sodium hydroxide solution and then brine. Concentration and distillation was allowed to get to 1.34 g of the target product.

The NMR spectrum showed the presence of absorption at 0,54-0,74 (multiplet, 1H), 0,90-0,93 (singlet, 3H), 1,17-1,53 (multiplet, 3H), of 1.65-1.77 in (multiplet, 3H) and 3,39-3,52 (multiplet, 2H).

D3. 3-Methylcyclohexanecarboxylic

In a nitrogen atmosphere to a solution of 6.8 g (0,053 mol) of 1-hydroxymethylcytosine in 150 ml of dichloromethane was added 22.9 g (0,106 mol) RCC (so - Approx. the translator). The mixture was stirred 1 h PR target compound.

The NMR spectrum showed the presence of absorption at about 0.90, 0.95 (doublet, 3H, j = 8 Hz), 0,86-2,32 (multiplet, 10H) and 9,68, 9,70 (doublet, 1H, j = 2 Hz).

Preparatory example E.

Endo-7-oxabicyclo (2.2.1) heptane-2-carboxaldehyde

Following the procedure of example G, 3 endo-2-carbomethoxy-7-oxabicyclo (2.2.1) heptane (M. P. Kunstmann with TCS. J. Amer. Chem. Soc, 84, 4115 (1962) (2,13 g, 12.5 mmole) was restored to the target compound (1.51 g).

NMR spectrum revealed the presence of absorption at a 1.46-1,95 (multiplet, 6N), 3,07 (multiplet, 1H), 4,68 (multiplet, 1H), 4,86 (double doublet, 1H, j = 5.6 and 5.6 Hz) and 9,73 (doublet, 1H, j = 1.5 Hz). Similarly Exo-2-carboxymethoxy-7-oxabicyclo (2,2,1) heptane was restored to the corresponding Exo-7-oxabicyclo (2,2,1)-heptane-2-carboxaldehyde.

Preparatory example J.

5-fluoro-6-[(4-chloro-2H-chromen-3-yl)-methylamino]-benzoxazole-2-he

W1. 4-Chloro-3-formyl-2H-chromen

Following the method described in J. A. Vigilio with TCS. Organic synthesis and methods of 14.9 (1982), received the target connection.

G. 5-fluoro-6-[(4-chloro-2H-chromen-3-yl)methylamino]benzoxazole-2-he

To a solution 2,02 g (12 mmol) 6-amino-5-fermentation-2-it in 100 ml of ethanol was added the product of W 1 (2,53 g, 13 mmol). The mixture was stirred 6 h at room the t washed with ethanol. The product was dissolved in 150 ml of methanol and portions were added borohydride sodium at room temperature. Stirring is continued for several hours. The reaction mixture was concentrated and added aqueous ammonium chloride. Organic matter was extracted with ethyl acetate/tetrahydrofuran. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated. The rest of chromatogra - firvale on silica gel, elwira with ethyl acetate/hexane (1:3). Was obtained the crude product, after recrystallization from ethanol was obtained from 0.90 g of target compound (22% yield) with so pl. 197aboutC (decomposition).

Preparatory example 3.

6-Oxabicyclo[3.2.1] Oct-1'-ylmethanol

3.1. 6-Oxabicyclo[3.2.1]Oct-1'-ylmethanol

A mixture of 10.0 g (70 mmol) of 3-cyclohexene-1,1-dimethanol (Aldrich chemical, company") and 13.7 g (77 mmol) of NBS in 200 ml of dichloromethane was stirred at room temperature for 13 hours Then the reaction mixture was washed twice with water (100 ml) and brine and was dried over sodium sulfate. The solvent drove and got a pale yellow oil (17.0 g). To a mixture of this oil and 20 ml of toluene was added 0.2 g of ALBN and then of 21.5 g (84 mmol) of n-tributyltinhydride under stirring. The mixture was heated to 110

NMR-spectrum (CCl3) showed absorption at 1,28-of 1.52 (m, 3H), 1,66-of 1.84 (m, 6N), of 3.57 (DD, 2H, I = 1,84 Hz, 5.50 Hz), the 3.65 (DD, 1H, I = 1,84 Hz, of 7.69 Hz), 3,84 (d, 1H, I = 7,69 Hz), and 4.40 (Tr. 1H, I = 5,31 Hz).

3.2. 6-Oxabicyclo[3.2.1]Oct-1'-iceboxlogic

For 1 h at room temperature was stirred mixture of 3.55 g (25 mmol) of 6-oxabicyclo[3.2.1]Oct-1'-ylmethanol, ROS (8,08 g, 37.5 mol) and 100 ml of dichloromethane. The resulting mixture was diluted with 100 ml of sulphuric ether and filtered through silica gel. The silica gel was washed seven times sulphuric ether 100 ml each time. The filtrate and washing were combined, the solvent evaporated and obtained target compound (3.00 g, yield 86%).

NMR-spectrum (in Cl3) showed absorption at 1,29-of 1.40 (m, 1H), 1,57-1,90 (m, 6N), 2,19-of 2.26 (m, 1H), 3,89 (d, 1H, j = 8,4 Hz), a 4.03 (DD, 1H, j = 1,8 Hz and 8.4 Hz), a 4.53 (DD, 1H, j = 4,8 Hz and 5.9 Hz), of 9.56 (s, 1H).

Preparatory example I.

I1 (1S, 2R, 4R)-7-oxabicyclo[2.2.1] heptane-2-carboxaldehyde, (4S)-3-[(1S, 2R, 4R)-7-oxabicyclo[2.2.1]hept-2-yl-carbonyl]-4 - isopropylimidazole-2-he (4S)-3-[(1R, 2S, 4S)-7-oxabicyclo[2.2.1]hept-2-ylcarbonyl]-4-isopropylimidazole-2-he

Cooled to -78aboutWith a mixed solution of 7.75 g (60 mmol) of (4S)-4-isopropylimidazole-2-it 200 ml tetrahydrof the th Exo-oxabicyclo[2.2.1]heptane-2-carboxylicacid, made from of 8.95 g (63 mmol) of racemic acid and the acid chloride oxalic acid. The reaction mixture was heated to 0aboutC and stirred 1 h Excess carboxylic acid hydrolyzed, was added 50 ml of 1M aqueous potassium carbonate, and then the mixture was stirred for 1 h at room temperature. Organic solvent drove away under reduced pressure. The obtained product was diluted with 200 ml of water and was extracted four times with dichloromethane (200 ml). The combined organic extracts are then washed with 200 ml of water and 200 ml of brine, dried over anhydrous magnesium sulfate and concentrated in vacuum, obtaining 18.0 g of pale yellow oil. Division diastereoisomeric imides was performed on preparative liquid chromatograph/system 500 , using two silicagel Rger-CANCER-500 briquette (57 mg cm, petroleum ether/n-hexane (1:5), flow rate 250 ml/min) at three times the pass. The retention time of less polar and more polar imides are respectively 16 and 22 minutes Less polar imide (6,47 g), which contained an unknown impurity, was purified by recrystallization from ether-hexane and received 4,47 g (yield 29% ) of pure less polar imide, (4S-3-[(1S, 2R, 4R)-7-oxabicyclo[2.2.1] hept-2-ylcarbonyl-4] -isopro is using crystal, obtained by another slow recrystallization in ether-hexane. The more polar imide (4S)-3-[(1R, 2S, 4S)-7-oxabicyclo[2.2.1] hept-2-ylcarbonyl-4]-every-propylacetamide-2-he (6,36 g, 42% yield, 98.5% of de) was used without further purification.

I2. Methyl ester of (1S, 2R, 4R)-7-oxabicyclo[2.2.1] heptane-2-carboxylic acid

To a cooled to 0aboutWith the solution of 4.35 g (17 mmol) of (4S)-3-[(1S, 2R, 4R)-7-oxabicyclo[2.2.1]hept-2-ylcarbonyl]-4-isopropilic - Catholicon-2-it in 350 ml of tetrahydrofuran is slowly dropwise added an aqueous solution of hydroperoxide lithium (prepared from 15 ml of 30% hydrogen peroxide, 1.28 g (30 mmol) of lithium hydroxide and 120 ml of water) with stirring. After stirring for 1 h at 0aboutThe reaction was stopped by adding dropwise 300 ml of 2n. sodium sulfite. After stirring the obtained slurry for 15 min at 0aboutThe mixture was podslushivaet saturated sodium bisulfite and an organic solvent drove in a vacuum. The remaining aqueous mixture was washed with 200 ml of dichloromethane. After acidification with concentrated hydrochloric acid, chiral acid was extracted ten times with 300 ml dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated in vacuum, the Ali excess diazomethane in the air. 15 minutes the excess diazomethane was removed by propulsiveness nitrogen through the solution. The resulting solution was concentrated under reduced pressure and was purified chromatography (100 g silica gel, ether/hexane 1:1), receiving of 2.08 g (76% yield) of target compound in the form of a transparent volatile oil. An analytical sample was purified by distillation: so Kip. 106-109aboutWith/0.9 mm RT.article.

IR-spectrum (nujol): 3000, 2970, 2880, 1736, 1064, 1002, 938 cm-1.

NMR-spectrum (Cl3): 1,42-of 1.55 (m,2H), 1,67 and 1.80 (m, 3H), 2,09-2,17 (m, 1H), 2,61 (DD, 1H, j = 4,9 Hz, 9.1 Hz), 3,70 (s, 3H), of 4.66 (DD, 1H, j = 4,9 Hz, 5.1 Hz), 4,84 (d, 1H, j = 4,9 Hz).

[]D20+ 31,3about(cl,00, methanol).

I3. (1S, 2R, 4R)-7-oxabicyclo[2.2.1]heptane-2-carboxaldehyde

Following the procedure of example, 3, the target connection translated methyl ester (1S, 2R, 4R)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid.

NMR-spectrum (CCl3) showed absorption at a 1.46-1,95 (multiplet, 6N), 3,07 (multiplet, 1H), 4,68 (multiplet, 1H), 4,86 (double doublet, 1H, j = 5.6 Hz, 5.6 Hz), 9,73 (doublet,1H, j = 1.5 Hz).

Preparatory example K.

(1R, 2S, 4S)-7-oxabicyclo[2.2.1]heptane-2-carboxaldehyde

K. 1. Methyl ester of (1R, 2S, 4S)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid

Following the procedure of example I. 2 and using the home 96%, so Kip. 94-98aboutWith 0.5 mm RT.article.

IR-spectrum (nujol): 3000, 2970, 2880, 1736, 1064, 1002, 938 cm-1.

NMR-spectrum (Cl3): 1,42-of 1.55 (m, 2H), 1,67 and 1.80 (m, 3H), 2,09-2,17 (m, 1H), 2,61 (DD, 1H, j = 4,9 Hz, 9.1 Hz), 3,70 (s, 3H), of 4.66 (DD, 1H, j = 4,9 Hz, 5.1 Hz), 4,84 (d, 1H, j = 4,9 Hz).

[]D20-29,8aboutWith (C 1.00, methanol).

K2. (1R, 2S, 4S)-7-oxabicyclo[2.2.1]heptane-2-carboxaldehyde.

Following the procedure of example G3, methyl ester (1R, 2S, 4S)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid was converted to the target compound.

NMR-spectrum (Cl3) showed the presence of absorption at a 1.46-1,95 (multiplet, 6N), 3,07 (multiplet, 1H), 4,68 (multiplet, 1H), 4,86 (double doublet, 1H, j = 5.6 Hz, 5.6 Hz), 9,73 (doublet, 1H, j = 1.5 Hz).

Preparatory example L

2-Oxabicyclo[2.2.1]hept-4-ylmethanol

At 0aboutC and stirring to the mixture 3,74 g (29 mmol) of 3-cyclopentene-1,1-dimethanol prepared in accordance with J. P. Despres with TCS. J. Org.Chem., 49:928 (1984) and H. Paulsen with TCS. Chem.Ber., 144, 346 (1981), 100 ml dichloromethane and 100 ml of tetrahydrofuran was added NBC (5,71 g, 32 mmol). When you are finished adding NBC ice bath was removed and the reaction mixture was stirred at room temperature. After 2.5 h was added another portion of NBC (5,71 g, 32 mmol) and the mixture more the odes. The aqueous phase was extracted with 100 ml of chloroform. The combined organic phases were washed with 0.5 N. sodium sulfate and then brine, dried over magnesium sulfate and evaporated. The residual oil was passed through a column of silica gel (150 g) and suirable 33% ethyl acetate/hexane to approximately 50% ethyl acetate/hexane. Combined fractions containing as a main component of the target product. Evaporation of solvent received 3,47 g of pale yellow oil. The mixture of oil, 5,44 g (to 18.7 mmol) tri-n-butylaldehyde, 0.05 g ALBN and 4 ml of toluene was boiled under reflux for 80 minutes Purification on silica gel (150 g, with a mixture of ethyl acetate-hexane from 50 to 67% ) received target connection number, 1,10

NMR-spectrum (Cl3) showed the presence of absorption at 1,41 (doublet. 1H, j = 9.5 Hz), 1,54-1,79 (multiplet, 5H), 3,67 (double doublet, 1H, j = 2.8 Hz, 6.8 Hz), 3,83 (singlet , 2H), 4,36 (singlet, 1H).

Derivatives benzoxazolone General formula

O

where Alk - Cnis unbranched or branched divalent alkyl radical, n=0, 1, 2, 3, 4 or 5;

R1- C1-C3-alkyl, C1-C3-alkoxy, halogen;

R is chosen from the group including

(a) X

where R2and R3every BR>
the dotted line indicates an optional connection,

(b) or

where a and b are each independently oxygen or sulfur,

(c) ,,

(d)

where R4and R5each independently hydrogen or C1-C4-alkyl;

broken line indicates that the group containing such a broken line, may be endo - or Exo-7-oxabicyclo - [2.2.1] heptane-1-Il,

(e) CH3- (CH2)m-Y-,

where m=1,2 or 3;

Y is oxygen, sulfur or sulfoxide,

possessing anti-inflammatory activity.

 

Same patents:

The invention relates to a method for 4,5,6-trichloroanisole-2, which finds application as an antiseptic
The invention relates to medicine and used to replenish the Arsenal of normalizing the immune status of the organism

The invention relates to medicine and can be used to enhance antibacterial activity and expansion of the spectrum of antibacterial action

The invention relates to medicine, in particular to the surgery and the result they have proved

The invention relates to 7-examinerlawrence heterocyclic Amida - analogues of prostaglandins, which are receptor antagonists AND thromboxane a2(THA2or combined receptor antagonists AND thromboxane a2(thromboxane synthetase inhibitors, and are used, for example, in the treatment of thrombotic disease and/or vascular spasm: have a long duration of action

The invention relates to 7-examinerlawrence heterocyclic Amida - analogues of prostaglandins, which are receptor antagonists AND thromboxane a2(THA2or combined receptor antagonists AND thromboxane a2(thromboxane synthetase inhibitors, and are used, for example, in the treatment of thrombotic disease and/or vascular spasm: have a long duration of action

The invention relates to a new di-tert-butylaniline derivative used for the treatment of inflammatory processes, as well as caused by ischemia cell damage

FIELD: organic chemistry, medicine, pharmacy.

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

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

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

SUBSTANCE: invention relates to a trans-olefinic activator of glucokinase representing compound taken among the group consisting of olefinic amide of the formula (I): wherein R1 and R2 mean independently of one another hydrogen, halogen atom, nitro-group, perfluoro-(lower)-alkyl, (lower)-alkylsulfonyl or (lower)-alkylsulfonylmethyl; R means -(CH2)m-R3 or lower alkyl comprising from 2 to 4 carbon atoms; R3 means cycloalkyl comprising from 3 to 8 carbon atoms; R4 means the group: or unsubstituted, or monosubstituted five- or six-membered heteroaromatic ring linked by ring carbon atom with indicated amino-group wherein this five- or six-membered heteroaromatic ring comprises from 1 to 2 heteroatoms taken among the group consisting of sulfur or nitrogen atom wherein one heteroatom being as nitrogen atom is arranged near with binding ring carbon atom, and wherein indicated monosubstituted heteroaromatic ring is substituted at ring carbon atom not adjacent with mentioned binding carbon atom with a substitute taken among the group consisting of halogen atom and group of the formula: m = 0 or 1; n = 0, 1, 2, 3 or 4; R7 means hydrogen atom or lower alkyl; Δ means trans-configuration relatively to a double bond; or its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition, method for prophylactic or therapeutic treatment of diabetes mellitus of type II and to methods for preparing compounds of the formula (I). Invention provides preparing activators of glucokinase that enhance insulin secretion in treatment of diabetes mellitus of type II.

EFFECT: valuable medicinal properties of compounds.

25 cl, 29 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a medicinal agent made as a gelatin capsule. A medicinal agent as gelatin capsule consists of cycloserine and accessory additives wherein calcium phosphate dihydrate, aerosil and calcium stearate taken in the definite components are used as accessory additives. Also, gelatin capsule comprises additionally glutamic acid, gelatin and water, Invention provides rapid and complete release of agent in intake and the development of a medicinal formulation reducing toxicity of an active substance and eliciting stability in storage.

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

1 tbl, 1 ex

FIELD: organic chemistry, medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to a medicinal preparation used in treatment of chronic cardiac insufficiency. The preparation represents 3-methyl-5-[2-(3-tert.-butylamino-2-oxypropoxy)- phenoxymethyl]-1,2,4-oxadoazole hydrochloride. The preparation provides expanding assortment of medicinal agents used in treatment of chronic cardiac insufficiency.

EFFECT: valuable medicinal properties of drug.

5 tbl

FIELD: organic chemistry, medicine, pharmacology.

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

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

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

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

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: organic chemistry, medicine, pharmacology.

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

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

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

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

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: organic chemistry, medicine, pharmacology.

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

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

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

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

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: medicine, organic chemistry.

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

EFFECT: higher efficiency of therapy.

14 cl, 354 ex

FIELD: organic chemistry, pharmacology.

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

EFFECT: new anorexia pharmaceuticals.

5 cl, 4 ex, 2 tbl

Up!