The method of obtaining derivatives tetrasilicate acid

 

(57) Abstract:

Usage: in the pharmaceutical industry to obtain drugs having activity of suppressing the aldose reductase. The inventive method of obtaining derivatives tetrasilicate acid of General formula I, in which R , R2and X have defined meanings. Reagent 1: compound of formula II; reagent 2: gloriouse agent. The obtained intermediate chlorimipramine formula III interacts with the reagent 3: sodium azide to obtain the target product Ia, where R is a lower alkyl group, Ia optionally hydrolyzing with receiving Ib, where R is hydrogen. The structure of the compounds of formulas I, II, III

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table 4.

The invention relates to compounds having activity of suppressing the aldose reductase and, in particular, derived tetrasilicate acid and inhibitor, an aldose reductase, which as an effective component includes a derived tetrasilicate acid and which is effective as a preventive medication and/or means for diabetic complications, as well as methods of mitigation or attenuation of diabetic complications.

It is known that in the but is described in the article of Dr. T. Tanimoto (Department of biological chemistry and reference levels, State Institute of health Sciences, see Farmacia, 1988, 24, N 5, S. 459-463). This article reveals the chemical structure and the 50% inhibitory concentration (IC50) characteristic inhibitors of the aldose reductase inhibitor, such as alrestatin, tolrestat, 4-isopropyl-ROOTED, sorbinil, M-79175, alkenyl, ADP-138, epalrestat, CT-112 and static.

The inventors have already conducted an audit of the new inhibitor, an aldose reductase, found that the compounds represented by the following General formula III

(III) where R1represents a hydrogen atom or a group: A-COOR5(in which a represents alkylenes group having 1-4 carbon atoms, and R5represents a hydrogen atom or lower alkyl), and R2, R3and R4can be the same or different and each represents a hydrogen atom, halogen atom, alkyl, alkoxygroup, phenyl, phenoxy group, a nitro group, a residue represented by the formula: -NHCOCOOR6(in which R6represents a hydrogen atom or nitroalkyl group), or a residue represented by the following formula

in which a and R5have these values have a very high inhibitory activity of reducta the acetic acid and its ethyl ester [1] this article, However, revealed only way to obtain these substances, but nothing is said about their biological activity.

The aim of the invention is to develop a substance, which has an excellent inhibitory activity of the aldose reductase has a low toxicity to organisms and is very effective as a preventive medication and/or means for diabetic complications, and more specifically the development of derived tetrasilicate acid. In addition, development inhibitor, an aldose reductase inhibitor, as an effective component includes a derived tetrasilicate acid and is effective as a preventive medicine and/or means for diabetic complications.

According to one aspect of the invention, a new derived tetrasilicate acid of General formula I

(I) where R1represents a hydrogen atom or alkyl, R2represents a hydrogen atom, alkyl, aralkyl, halogen atom, haloalkyl, a hydroxyl group, alkoxygroup, alkoxyalkyl group, amino group, aryl group, alkyl or aryl thio group, alkyl or aryl, carbylamine group, alkyl or aryl, sulfonylamino group, alkyl or aryl aminosulfonyl group, alkyl or aryl sulfonyloxy group Il who you are, [5-(2-furyl)- tetrazol-1-yl]acetic acid and their ethyl esters, or their salts.

According to another aspect of the invention, it is proposed inhibitor, an aldose reductase, which includes a derived tetrasilicate acid represented by the General formula II

(II) where R1represents a hydrogen atom or alkyl group; R2a hydrogen atom, alkyl group, aracelio group, halogen atom, haloalkyl group, hydroxyl group, alkoxy group, alkoxyalkyl group, amino group, aryl group, alkyl or aryl thio group, alkyl or aryl, carbylamine-Gruppo, alkyl or aryl, sulfonylamino group, alkyl or aryl aminosulfonyl group, alkyl or aryl sulfonyloxy group or alkyl or aryl sulfonyloxy group; X represents-O - or-S- (or its salt) and a pharmaceutically acceptable carrier.

According to another aspect of the invention proposes a method of alleviating or reducing diabetic complications, which applies the derived tetrasilicate acid represented by the General formula II:

(II) where R1represents a hydrogen atom or alkyl group; R2a hydrogen atom, alkyl, y is an alkyl group, amino group, aryl group, alkyl or aryl thio group, carbonyl-aminoalkyl group or carboalumination group, sulfanilamilny or sulfonylamino group, aminosulfonyl - alkyl or aminosulfonyl group, sulfonylamino or sulfonylamino group or sulfonylamino or sulfonylamino group; X represents-O - or-S-, or its salt.

Below are more details derived tetrasilicate acid and inhibitor, an aldose reductase and a way of alleviating diabetic complications according to the invention.

Explanation of zamestiteteley in formulas I and II.

The alkyl group represented by R1or R2is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, kalkilya group includes, for example, phenylpropyl or benzyl; examples of alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy group; examples alkoxyalkyl groups are methoxy-methyl and butoxymethyl; haloalkyl groups are, for example, mono-, di - or trihalomethyl, such as chloromethyl, methyl bromide, vermeil and chlorbutol; tiukinhoy or tiarellas luchot, for example, mono - or dialkylaminoalkyl - phoneline groups, such as methylaminomethyl, ethylaminomethyl, propylaminosulfonyl and butylaminoethyl; sulphanylquinoline or sulfanilamilny groups are, for example, methylsulfonylamino, etisalt - ylamino, butylmethylamine, phenylcarbonylamino group; examples carboalumination or carbylamine aryl groups are methylcobalamine, ethylcarbodiimide, propylnitrosamine, fenethylline group; examples sulfonylureas or sulfonylamino groups are methylsulphonyl, ethylsulfonyl, butylsulfonyl and piperidinemethanol; examples alkylsulfonyl groups are methylsulfinyl, ethylsulfinyl and butylsulfonyl group. These substituents may be introduced in any position in the furan or thiophene ring.

In addition, pharmaceutically acceptable are salts of the above compounds represented by formulas I and II, in which R1a hydrogen atom, and their typical examples include inorganic salts such as alkali metal salts (e.g. sodium and potassium salts), salts of alkaline-earth metals (e.g. calcium salts and magnesium salts) and soya salt and ethanolamine salt) and salt in the presence of basic amino acids, for example arginine.

Reductase inhibitors of aldose, according to the invention contain, as a main component at least one compound represented by formula II and are effective as prophylactic drugs and/or means for diabetic complications. It is known that the expression "diabetic complications" means a number of diseases, such as peripheral disorder, retinopathy, nephrosis, cataract and keratopathy. These diseases or disorders are stimulated by hyperglycemia caused by diabetes disease resulting in abnormally accelerated the production of sorbitol in the polyol metabolic system and result in cells accumulate large amounts of sorbitol. This leads to the beginning of such diseases.

Inhibitors of the aldose reductase inhibitors of the invention can suppress the production of sorbitol by strong inhibition activity of the aldose reductase, which disrupts the production of sorbitol in the polyol metabolic system and, through this, contribute to the excellent prophylactic and/or therapeutic effects on these various diabetic complications.

Doses of the substances according to formula (I) and (II) determined soutwest from 1 to 1000 mg per day for adult, entered at the same time or after some time. Substances may be administered by any means for the treatment, such as oral, subcutaneous injections, intravenous injections and local application.

Inhibitors of the aldose reductase inhibitors of the invention can typically contain, in addition to the mentioned components as basic substances, pharmaceutically acceptable carriers, binders and other additives. The inhibitors of the invention can be used in any dosage form such as tablet, powder, fine particles, granules, capsules, pills, liquid preparations, solutions and suspensions for injection and eye drops.

Further provides methods for producing compounds (I) as main components, the conditions for them or similar, with reference to the following reaction schemes.

The reaction scheme 1:

Getting tetrazole rings.

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Incidentally, when used in the chlorination reaction SOCl2DMF is removed by-product that would be formed in the case of use in the reaction of chlorination PCl5in the reaction using NaN3.

The reaction scheme 2:

The conversion of R1in the hydrogen atom.

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The reaction scheme 2 means that the compounds of formula (I) in which R1is a hydrogen atom, can be obtained by hydrolysis of ester carboxylic acid obtained by the reaction scheme 1. The hydrolysis can be carried out in the presence of a base such as sodium hydroxide or potassium hydroxide, or acids, such as hydrochloric acid, sulfuric acid, acetic acid or tetracarboxylate acid.

The compounds of formula (I) obtained by the previous method, isolate and purify usually promenaea thus products are peeled and used as basic components for inhibitor, an aldose reductase of the invention.

The invention is described in more detail with reference to the following non-restrictive working examples and the effects achieved in practice with the invention, also described in detail with reference to examples of tests.

P R I m e R 1 (1-1). Obtaining methyl [5-(2-thienyl)tetrazol-1-yl] acetate.

In a solution of 1 g (5,02 mmol) N-(2-thenoyl)licensedialog ester in 15 ml of anhydrous methylene chloride was slowly added 1.5 g (7.2 mmol) of phosphorus pentoxide at room temperature under stirring, the resulting mixture was stirred for 30 min, and the reaction solution was concentrated at 40aboutWith under reduced pressure. The resulting residue was dissolved in 5 ml of N, N-dimethylformamide. The solution is dropwise added to a suspension of 1.6 g (24.6 mmol) of sodium azide in 3 ml of N,N-dimethylformamide at room temperature for 30 min under stirring. After drip additives and mixing for a further 30 min at room temperature the mixture was poured into ice water and was extracted with ethyl acetate. The organic phase is washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to chromatography on a column of silica gel, eluent: atasol-1-yl)acetate.

So pl. 73-74aboutC.

NMR (CCl3) , ppm (parts per million):

of 3.84 (s, 3H), of 5.34 (s, 2H), 7,24 (DD, 1H, J 5,20, of 3.60 Hz), 7,58 (DD, 1H, J 3,60, 1.20 GHz), the 7.65 (DD, 1H, J 5,20, 1,20 Hz).

IRCVG(cm-1): 3400, 1730, 1650, 1540, 1370, 1230.

Mass: m/Z 224 (M+)

The following connections get the same as in example (1-1).

(1-2). Methyl(5-(3-methyl-2-thienyl)tetrazol-1-yl)acetate (yield of 51.1%).

Starting material: N-(3-methyl-2-thenoyl)glycemically ether.

NMR (l3) , ppm:

2,43 (s, 3H), of 3.80 (s, 3H), of 5.25 (s, 2H), 7,07 (d, 1H, J 5.0 Hz), 7,52 (d, 1H, J 5.0 Hz).

IRNaCl(cm-1): 3100, 2950, 1760, 1440, 1220, 1000.

Mass: m/Z 238 (M+)

(1-3). Methyl (5-(4-methyl-2-thienyl)tetrazol-1-yl)acetate (output 48.8%)

Starting material: N-(4-methyl-2-thenoyl)glycemically ether

NMR (l3) , ppm:

of 2.34 (s, 3H), 3,83 (s, 3H), 5,33 (s, 2H), 7,22 (d, 1H, J 1.2 Hz), 7,41 (d, 1H, J 1.2 Hz).

IRNaCl(cm-1): 3090, 2950, 1740, 1580, 1440, 1240.

Mass: m/Z 238 (M+)

(1-4). Methyl (5-(5-methyl-2-thienyl)tetrazol-1-yl)acetate (yield 50.1 per cent)

Starting material: N-(5-methyl-2-thienyl)glycemically ether.

So pl. 88-89aboutC.

NMR (l3) , ppm:

to 2.57 (s, 3H), 3,83 (s, 3H), 5,32 (s, 2H), 6.87 in 6,89 (m, 1H), of 7.36 7,39 (m, 1H).

l)tetrazol-1-yl)acetate (yield 52%)

Starting material: N-(3-thenoyl)glycemically ether.

So pl. 106-107aboutC.

NMR (l3) , ppm:

of 3.84 (s, 3H), at 5.27 (s, 2H), of 7.48 (DD, 1H, J 5,01, 1,20 Hz), 7,56 (DD, 1H, J 5,01, 2,80 GHz), to 8.25 (DD, 1H, J 2,80, 1,20 Hz).

IRCVG(cm-1): 3100, 1760, 1580, 1440, 1360, 1230.

Mass: m/Z 224 (M+)

(1-6). Methyl (5-(2-furyl)tetrazol-1-yl)acetate (yield 24%)

Starting material: N-(2-furoyl)glycemically ether

NMR (l3) , ppm:

3,79 (s, 3H), 5,49 (s, 2H), 6,66 )DD, 1H, J 3,60, a 2.01 Hz), was 7.36 (DD, 1H, J 3,60, 0,80 Hz), to 7.64 (DD, 1H, J 2,01, 0,80 Hz)

IRNaCl(cm-1): 3120, 3000, 2950, 1750, 1620, 1520, 1440, 1220, 1010

Mass: m/Z 208 (M+)

(1-7). Methyl(5-(3-furyl)tetrazol-1-yl)acetate (yield 30%).

Starting material: N-(3-furoyl)glycemically ether.

NMR (l3) ,ppm:

of 3.84 (s, 3H), of 5.24 (s, 2H), for 6.81 (sh.with. 1H), 7,63 (sh.with. 1H), of 7.96 (sh.with. 1H)

IRaCl(cm-1): 3140, 2950, 1750, 1440, 1220,

Mass: m/Z 208 (M+)

(1-8). Methyl(5-(5-ethyl-2-thienyl)tetrazol-1-yl)acetate (yield of 44.0%).

Starting material: N-(5-ethyl-2-thenoyl)glycemically ether.

So pl. 45-46oC.

NMR (l3) MRP:

of 1.36 (m, 3H), J of 7.70 Hz), 2.91 in (DV.kV, 2H, J 7,70, 0,80 Hz), 3,83 (s, 3H), 5,32 (s, 2H), 6,91 (l, m, 1H, J 3,60, 0,80 Hz), 7,40 (d, 1H, J of 3.60 Hz).

IR KBR (cm-1): 2960)acetate (yield 38,0%).

Starting material: N-(5-benzyl-2-thenoyl)glycemically ether.

So pl. 71-OS.

NMR (l3) MRP:

of 3.80 (s, 3H), 4,20 (s, 2H), from 5.29 (s, 2H), 6,91 (D. T. 1H, J 4,01, 1,20 Hz); 7.23 percent 7,38 (m, 5H), 7,39 (d, 1H, J 4,01 Hz).

IR KBR (cm-1): 3000, 1740, 1650, 1510, 1460, 1420, 1380, 1270, 1240, 800.

Mass: m/Z 314 (M+)

(1-10). Methyl(5-(5-methylthio-2-thienyl)tetrazol-1-yl)acetate (yield 66%).

Starting material: N-(5-methylthio-2-thenoyl)glycemically ether.

So pl. 64-65aboutC.

NMR (Dl3) , ppm:

2.60 (s, 3H), of 3.84 (s, 3H), 5,31 (s, 2H), 7,07 (d, 1H, J 4,00 Hz), was 7.45 (d, 1H, J 4,00 Hz).

IRCVG(cm-1): 3470, 1750, 1580, 1480, 1440, 1410, 1360, 1260, 1220, 1100, 990, 790.

Mass: m/Z 270 (M+)

(1-11). Methyl(5-(5-bromo-2-thienyl)tetrazol-1-yl)acetate (yield 55,0%)

Starting material: N-(5-bromo-2-thenoyl)glycemically ether

So pl. 45-46aboutC.

NMR (Dl3) , ppm:

of 3.84 (s, 3H), and 5.30 (s, 2H), 7,19 (d, 1H, J 4,90 Hz), 7,30 (d, 1H, J 4,90 Hz)

IRCVG(cm-1): 3450, 1740, 1580, 1490, 1440, 1400, 1270, 1240, 1100, 980, 800.

Mass: m/Z 303 (M+)

(1-12). Methyl(5-(2-methyl-3-thienyl)tetrazol-1-yl) acetate (yield 49.7 per cent).

Starting material: N-(2-methyl-3-thenoyl)glycemically ether.

NMR (Dl3) , ppm:

of 2.58 (s, 3H), of 3.80 (s, 3H, 5,12 (s, 2H),m/Z 238 (M+)

(1-13). Methyl(5-(5-methyl bromide-2-thienyl)tetrazol-1-yl)acetate (yield of 50.9%)

Starting material: N-(5-bromomethyl-2-thenoyl)glycemically ether.

NMR (Dl3) , ppm:

2,49 (s, 3H), 3,85 (s, 3H), and 5.30 (s, 2H), 7,26 of 7.36 (m, 2H),

IRNaCl(cm-1): 2950, 1760, 1580, 1500, 1440, 1270, 1220, 1000, 800.

Mass: m/Z 317 (M+)

(1-14). Methyl(5-(5-phenyl-2-thienyl)tetrazol-1-yl)acetate (yield of 47.1%).

Starting material: N-(5-phenyl-2-thenoyl)glycemically ether.

So pl. 133-134aboutC.

NMR (DCl3) ,ppm:

of 3.85 (s, 3H), 5,38 (s, 2H), 7,39 (d, 1H, J of 3.80 Hz), 7,40, of 7.48 (m, 3H), at 7.55 (d, 1H, J of 3.80 Hz), 7,63 7,66 (m, 2H).

IRCVG(cm-1): 3440, 1760, 1580, 1480, 1420, 1220, 750.

Mass: m/Z 300 (M+)

(1-15). Methyl(5-(3-methylcobalamine-2-thienyl)tetrazol-1-yl)acetate (yield of 16.2%).

Starting material: N-(3-methylcobalamine-2-thenoyl)glycemically ether

So pl. 35-36aboutC.

NMR (l3) , ppm:

2,31 (s, 3H), of 3.84 (s, 3H), of 5.45 (s, 2H), 7,56 (d, 1H, J 5,20 Hz), a 8.34 (d, 1H, J 5,20 Hz).

IRCVG(cm-1): 3240, 1750, 1580, 1490, 1440, 1220, 1180, 930, 750.

Mass: m/Z 281(M+)

(1-16). Methyl(5-(3-propylnitrosamine-2-thienyl)tetrazol-1-yl)acetate (yield of 22.4%)

Starting material: N-(3-propylnitrosamine-2-thenoyl)2H), of 2.51 (m, 3H, J 7,30 Hz); of 3.84 (s, 3H), to 5.56 (s, 2H), 7,56 (d, 1H, J of 5.50 Hz), of 8.37 (d, 1H, J of 5.50 Hz), 10,75 (sh.with. 1H).

IRkVr(cm-1): 3270, 2940, 1740, 1680, 1580, 1440, 1380, 1260, 1240, 1100, 760.

Mass: m/Z 309(M+)

(1-17). Methyl(5-(3-fenethylline-2-thienyl)tetrazol-1-yl)acetate (yield of 28.5%).

Starting material: N-(3-fenethylline-2-thenoyl)glycine methyl ester.

So pl. 96-97aboutWITH

NMR (Dl3) , ppm:

to 2.85 (m, 2H, J of 7.70 Hz), 3,11 (m, 2H, J of 7.70 Hz), 3,83 (s, 3H), 5,43 (s, 2H), 7.18 in 7,30 (m, 5H), at 7.55 (d, 1H, J of 5.50 Hz), a 8.34 (d, 1H, J of 5.50 Hz), 10,75 (sh.with. 1H).

IRCVG(cm-1): 3300, 1760, 1700, 1580, 1440, 1390, 1220, 1100.

Mass: m/Z 371(M+)

(1-18). Methyl(5-(5-methyl-2-furyl)tetrazol-1-yl)acetate (yield 34,1%)

Starting material: N-(5-methyl-2-furoyl)glycemically ether.

NMR (CDl3) , ppm:

2,39 (d, 3H, J 0,98 Hz), 3,80 (s, 3H), of 5.45 (s, 2H), and 6.25 (d, square 1H, J 3,66, and 0.98 Hz), 7.23 percent (D. 1H, J 3,66 Hz).

IRNaCl(cm-1): 3120, 2950, 1740, 1620, 1570, 1440, 1220, 1020, 790.

Mass: m/Z 222(M+)

(1-19). Methyl(5-(5-butyl-2-furyl)tetrazol-1-yl)acetate (yield of 27.2%).

Starting material: N-(5-butyl-2-furoyl)glycemically ether.

NMR (Dl3) , ppm: of 0.95 (t, 3H, J 7,33 Hz), 1,31 1,45 (m, 2H), of 1.57 to 1.70 (m, 2H), 2,70 (t, 2H, J EUR 7.57 Hz), 3,79 (s, 3H), of 5.45 (s, 2H), 6,24 (d, 1H, J 3>)

(1-20). Methyl(5-(5-bromo-2-furyl)tetrazol-1-yl)acetate (yield 34%).

Starting material: N-(5-bromo-2-furoyl)glycemically ether.

So pl. 106-107aboutWITH

NMR (Dl3) , ppm:

of 3.84 (s, 3H), of 5.45 (s, 2H), return of 6.58 (d, 1H, J of 3.54 Hz), 7,31 (d, 1H, J 3,54 Hz).

IRNaCl(cm-1): 3100, 3000, 1730, 1620, 1520, 1440, 1280, 1100, 1000, 780.

Mass: m/Z 287(M+)

(1-21). Methyl(5-(5-methylthio-2-furyl)tetrazol-1-yl)acetate (yield 29%).

Starting material: N-(5-methylthio-2-furyl)glycemically ether.

NMR (CDCl3) , ppm: 2,48 (s, 3H), 3,82 (s, 3H), vs. 5.47 (s, 2H), 6,55 (d, 1H, J 3,66 Hz), 7,32 (d, 1H, J 3,66 Hz).

IRNaCl(cm-1): 3100, 2950, 1750, 1610, 1500, 1440, 1220, 1100, 1010, 780.

Mass: m/Z 254 (M+)

(1-22). Methyl(5-(2-bromo-3-furyl)tetrazol-1-yl)acetate (yield 27.4 per cent).

Starting material: N-(2-bromo-3-furoyl)glycemically ether.

NMR (CDCl3) , ppm:

3,81 (s, 3H), 5,23 (s, 2H), 6,70 (d, 1H, J of 2.20 Hz), 7,52 (d, 1H, J of 2.20 Hz).

IRNaCl(cm-1): 3150, 2950, 1750, 1620, 1530, 1440, 1220, 960.

Mass: m/Z 287(M+)

(1-23). Methyl(5-(2-(Oct-4-yl)-3-furyl)tetrazol-1-yl)acetate (yield of 50.4% ).

Starting material: N-(2)-Oct-4-yl)-3-furoyl)glycemically ether

NMR (CDCl3) , ppm:

0,82 (T. 6N, J 7,20 Hz), 1,10 1,27 (m, 6N), 1,52 1,850, 1750, 1620, 1530, 1440, 1220, 1000, 960.

Mass: m/Z 320(M+)

(1-24). Methyl(5-(2-methylthio-3-furyl)tetrazol-1-yl)acetate (yield 57,1%).

Starting material: N-(2-methylthio-3-furoyl)glycemically ether.

So pl. 71-72aboutWITH

NMR (DCl3) , ppm:

of 2.51 (s, 3H), of 3.78 (s, 3H), of 5.25 (s, 2H), of 6.65 (d, 1H, J of 2.20 Hz), 7,63 (d, 1H, J of 2.20 Hz).

IRNaCl(cm-1): 3150, 2950, 1750, 1600, 1530, 1430, 1220, 960, 740.

Mass: m/Z 254(M+)

(1-25). Methyl(5-(3-methylsulphonyl - amino-2-thienyl)tetrazol-1-yl)acetate (yield 36,8%)

Starting material: N-(3-methylsulfonylamino-2-thenoyl)glycemically ether

So pl. 154-155aboutWITH

NMR (CDCl3) , ppm:

a 3.01 (s, 3H), of 3.78 (s, 3H), 5,38 (s, 2H), 7,52 (d, 1H, J 5,61 Hz)= at 7.55 (d, 1H, J 5,61 Hz), 9,92 (sh.with. 1H).

IRCVG(cm-1): 3150, 3100, 1740, 1560, 1370, 1220, 1150, 760.

Mass: m/Z 317(M+).

(1-26). Methyl(5-(3-butylsulfonyl-2-thienyl)tetrazol-1-yl)acetate (yield of 74.4%).

Starting material: N-(3-butylsulfonyl-2-thenoyl)glycemically ether.

NMR (CDCl3) , ppm: of 0.87 (t, 3H, J to 7.32 Hz), 1,35 1,44 (m, 2H), of 1.57 to 1.75 (m, 2H), 3,14 (t, 2H, J 7,94 Hz), of 3.84 (s, 3H), of 5.45 (s, 2H), 7,54 (d, 1H, J 5,49 Hz), a 7.62 (d, 1H, J5,49 Hz), 9,98 (sh.with. 1H).

IRNaCl(cm-1): 3100, 1750, 1560, 1370, 1220, 1150.

Mass: m/Z 359(M+)
<(3-phenylcarbonylamino-2-thenoyl)glycemically ether.

So pl. 124-125aboutWITH

NMR (CDCl3) , ppm:

and 3.72 (s, 3H), 5,23 (s, 2H), 7,31 7,47 (m, 5H), 7,53 (d, 1H, J 5,62 Hz). 7,58 to $ 7.91 (m, 2H), 10,16 (sh.with. 1H).

IRCVG(cm-1): 3120, 2950, 1750, 1560, 1520, 1430, 1380, 1240, 1160, 760, 580.

Mass: m/Z 379(M+)

(1-28). Methyl(5-(2-methyl-3-furyl)tetrazol-1-yl)acetate (yield 40,0%).

Starting material: N-(2-methyl-3-furoyl)glycemically ether.

So pl. of 54.5-56aboutWITH

NMR (CDCl3) , ppm:

of 2.58 (s, 3H), 3,82 (s, 3H), 5,19 (s, 2H), 6,44 (d, 1H, J 2.00 Hz), was 7.45 (d, 1H, J 2.00 Hz).

IRCVG(cm-1): 3410, 3150, 1760, 1620, 1540, 1460, 1370, 1230.

Mass: m/Z 222(M+)

(1-29). Methyl(5-(5-N-methyl-N-(2-(methoxyethoxy)ethyl)-aminosulfonyl)-2-tie - nil) tetrazol-1-yl)acetate (yield 82,4%).

Starting material: N-(5-N'-methyl-N'-(2-(methoxyethoxy)ethyl(aminosulfonyl)-2-thenoyl) glycemically ether.

NMR (CDCl3) , ppm: 2,77 (s, 3H), 3,14 (t, 2H, J lower than the 5.37 Hz), 3,32 (s, 3H) and 3.59 (t, 2H, J lower than the 5.37 Hz), and 3.72 (s, 3H), 4,56 (s, 2H), total of 5.21 (s, 2H), 7,25 (d, 1H, J 5,13 Hz), 7,71 (d, 1H, J 5,13 Hz).

IRCVG(cm-1): 2950, 1750, 1440, 1350, 1220, 1150, 1040, 750, 710.

Mass: m/Z 405(M+)

P R I m m e R 2.

(2-1). 0.5 g (2.1 mmol) of methyl[5-3-methyl-(2-thienyl)tetrazol-1-yl]acetate obtained in example (1-2), dissolved in 5 ml ethanol was added 2 ml of 4n. water speakers. After cooling the mixture to room temperature it was diluted with water followed by removal of impurities by ethyl acetate and separation of the aqueous phase. The aqueous phase was acidified with hydrochloric acid, precipitated precipitated crystals were filtered, washed with water and recrystallization of the 50% mixture of ethanol-water to obtain of 0.37 g (yield 78%) of (5-(3-methyl-2-thienyl)tetrazol-1-yl)acetic acid.

So pl. 165-166aboutC (decomposition)

NMR (SO-d6) MRP:

to 2.42 (s, 3H), 3,7 (sh.C.), 5,20 (s, 2H), 7.06 (d, 1H, J 5.2 Hz), 7,53 (d, 1H), J 5.2 Hz).

IRCVG(cm-1):

3100, 2500, 1720, 1570, 1510, 1420, 1220.

Mass: m/Z 224(M+)

The following compounds were obtained as in example 2-1:

(2-3). (5-(4-Methyl-2-thienyl)tetrazol-1-yl)acetic acid (yield 76%).

Starting material: methyl(5-(4-methyl-2-thienyl)tetrazol-1-yl)acetate.

So pl. 154-155aboutC (decomposition).

NMR (DM SO-d6) , ppm:

of 2.34 (s, 3H), from 5.29 (sh.with. 3H), 7,22 (d, 1H, J 1.2 Hz); 7,41 (d, 1H, J 1.2 Hz).

IRCVG(cm-1): 3500, 2550, 1730, 1520, 1450, 1270, 1240, 1120.

Mass: m/Z 224(M+)

(2-4). (5-(5-Methyl-2-thienyl)tetrazol-1-yl)acetic acid (yield 82%).

Starting material: methyl(5-(5-methyl-2-thienyl)tetrazol-1-yl)acetate

So pl. 150-141about(ptx2">

IRCVG(cm-1): 3400, 2990, 1730, 1580, 1520, 1440, 1260, 1240, 1000.

Mass: m/Z 224(M+)

(2-5), (5-(3-Thienyl)tetrazol-1-)acetic acid (yield 71%).

Starting material: methyl(5-(3-thienyl)tetrazol-1-yl)acetate.

So pl. 172-173aboutC (decomposition).

NMR (DM SO-d6) , ppm:

3,33 (sh.with. 1H), to 5.58 (s, 2H), EUR 7.57 (DD, 1H, J 5,20, 1.20 GHz), the 7.85 (DD, 1H, J 5,20, 2,80 GHz), to 8.25 (DD, 1H, J 2,80, 1,20 Hz).

IR KBR (cm-1): 3380, 3120, 1730, 1580, 1280

Mass: m/Z 210(M+)

(2-6). (5-(2-Furyl)tetrazol-1-yl)acetic acid (yield 21%).

Starting material: methyl(5-(2-furyl)tetrazol-1-yl)acetate.

So pl. 157-158aboutC (decomposition).

NMR (DCl3SO-d6) , ppm:

4,79 (sh.C.), the 5.45 (s, 2H), for 6.81 (DD, 1H, J 3,60, 1.60 Hz), 7,37 (d, 1H, J 3.5 Hz), 8,08 (d, 1H, d, J 1.70 Hz).

IRCVG(cm-1): 3010, 2970, 2520, 1730, 1620, 1520, 1220, 1020.

Mass: m/Z 194(M+)

(2-7). (5-(3-Furyl)tetrazol-1-yl)acetic acid (yield 30%).

Starting material: methyl(5-(3-furyl)tetrazol-1-yl)acetate

So pl. 150-151aboutC (decomposition).

NMR (DM SO-d6) , ppm:

3,33 (sh.with. 1H), 5.56mm (s, 2H), 7,00 W.with. 1H), 7,97 (sh.with. 1H), 8,46 (sh.with. 1H).

IRCVG(cm-1): 3370, 2430, 1720, 1620, 1350, 1240

Mass: m/Z 194(M+)

(2-8). (5-(5-Ethyl-2-ment is)acetate.

So pl. 131-138aboutWITH

NMR (SO-d6) , ppm:

of 1.36 (dt, 3H, J 7,70, 1,20 Hz), 2,93 (sq. 2H, J of 7.70 Hz), 3,28 (sh.with. 1H), 5,28 (s, 2H), 6,92 (DD, 1H, J 3,60, 1,20 Hz), 7,41 (DD, 1H, J 3,60, 1,20 Hz).

IRCVG(cm-1): 3490, 2950, 1740, 1580, 1500, 1410, 1220, 1110, 800.

Mass: m/Z 238(M+)

(2-9). (5-(5-Benzyl-2-thienyl)tetrazol-1-yl)acetic acid (yield 77%).

Starting material: methyl (5-(5-benzyl-2-thienyl)tetrazol-1-yl)acetate.

So pl. 148-149aboutWITH

NMR (SO-d6) , ppm:

as 4.02 (s, 2H), 4,70 (sh.with. 1H), a 5.25 (s, 2H), 6,92 (DD, 1H, J 3,60, 0,80 Hz), 7.23 percent 7,38 (m, 5H), 7,41 (d, 1H, J of 3.60 Hz).

IRCVG(cm-1): 2950, 1750, 1580, 1510, 1430, 1230.

Mass: m/Z 300(M+)

(2-10). (5-(5-Methylthio-2-thienyl)tetrazol-1-yl)acetic acid (yield 67%).

Starting material: methyl (5-(5-methylthio-2-thienyl)tetrazol-1-yl)acetate

So pl. 179aboutC (decomposition)

NMR (SO-d6) , ppm:

2,61 (s, 3H), of 5.34 (s, 2H), 7,10 (d, 1H, J 4,01 Hz), 7,49 (d, 1H, J 4,01 Hz).

IR CVG(cm-1): 3400, 1730, 1570, 1480, 1410, 1210.

Mass: m/Z 256(M+)

(2-11). (5-(5-Bromo-2-thienyl)tetrazol-1-yl)acetic acid (yield 67%)

Starting material: methyl(5-(5-bromo-2-thienyl)tetrazol-1-yl)acetate.

So pl. 200aboutC (decomposition)

NMR (SO-d6) , ppm:

5,30 (s, 1100, 980, 880, 800.

Mass: m/Z 289(M+)

(2-12). (5-(2-Methyl-3-thienyl)tetrazol-1-yl)acetic acid (yield 62%).

Starting material: methyl (5-(2-methyl-3-thienyl)tetrazol-1-yl)acetate.

So pl. 144aboutC (decomposition)

NMR (SO-d6) , ppm:

to 2.57 (s, 3H), to 5.08 (s, 2H), 7,06 (d, 1H, J 5,20 Hz), 7,27 (d, 1H, J 5,20 Hz).

IR CVG(cm-1): 2900, 1740, 1570, 1440, 1400, 1340, 1260, 1220.

Mass: m/Z 224(M+)

(2-13). (5-(5-Bromomethyl-2-thienyl)tetrazol-1-yl)acetate.

So pl. 192aboutC (decomposition)

NMR (SO-d6) , ppm:

2,49 (s, 3H), 4,62 (sh.with. 1H), 5,28 (s, 2H), 7,39 7,41 (m, 2H).

IRCVG(cm-1): 3000, 1740, 1500, 1240, 1140.

Mass: m/Z 303(M+)

(2-14). (5-(5-Phenyl-2-thienyl)tetrazol-1-yl)acetic acid (yield 66%).

Starting material: methyl (5-(5-phenyl-2-thienyl)tetrazol-1-yl)acetate.

So pl. 210aboutC (decomposition)

NMR (SO-d6) , ppm:

4,06 (sh. C. 1H), are 5.36 (s, 2H), of 7.36 of 7.48 (m, 3H), 7,42 (d, 1H, J 4,01 Hz), 7,58 (d, 1H, J4,01 Hz), of 7.64 to 7.67 (m, 2H).

IRCVG(cm-1): 3000, 17340, 1580, 1480, 1430, 1240, 1110, 760.

Mass: m/Z 286(M+)

(2-15). (5-(3-Methoxy-2-thienyl)tetrazol-1-yl)acetic acid (yield 72.1 per cent)

Starting material: methyl (5-(3-methoxy-2-thienyl)tetrazol-1-yl)acetate.

IR CVG(cm-1): 3110, 2950, 1740, 1580, 1520, 1440, 1250, 1200, 1070, 800, 750.

Mass: m/Z 240(M+)

(2-16). (5-(3-Butoxy-2-thienyl)tetrazol-1-yl)acetic acid (yield 65.6 per cent).

Starting material: methyl(5-(3-butoxy-2-thienyl)tetrazol-1-yl)acetate.

So pl. 197-198aboutC (decomposition)

NMR (SO-d6) , ppm:

of 0.95 (t, 3H, J 7,30 Hz), 1,34 1,41 (m, 2H), 1,70 of 1.81 (m, 2H), 4,13 (t 2H, J 6,60 Hz), 4,80 (W,C. 1H), to 5.35 (s, 2H), 6,94 (d, 1H, J of 5.50 Hz), 7,54 (d, 1H, J 5,50 Hz).

IRkg(cm-1): 3500, 2950, 1730, 1570, 1510, 1400, 1250, 1200, 1070, 800, 750.

Mass: m/Z 282(M+)

(2-17). (5-(3-Methylcobalamine-2-thienyl)tetrazol-1-yl)acetic acid (yield 55.1 per cent).

Starting material: methyl(5-(3-methylcobalamine-2-thienyl)tetrazol-1-yl)- acetate.

So pl. 221aboutC (decomposition).

NMR (SO-d6) , ppm:

of 2.92 (s, 3H), 3,80 4,80 (sh.with. 1H), 5,42 (s, 2H), to 7.59 (d, 1H, J of 5.40 Hz). of 8.28 (d, 1H, J5,40 Hz).

IRCVG(cm-1): 3250, 2920, 1740, 1650, 1580, 1440, 1390, 1240, 1220, 1110, 760.

Mass: m/Z 267(M+)

(2-18). (5-(3-Propylnitrosamine-2-thienyl)tetrazol-1-yl)acetic acid (yield 60.6 per cent).

Starting material: methyl(5-(3-propylnitrosamine-2-thienyl)tetrazol-1-yl)- acetate.

So pl. 192aboutC (decomposition).

I ,30 (d, 1H, J of 5.50 Hz), a 10.74 (sh.with. 1H).

IRCVG(cm-1): 3310, 2960, 1720, 1590, 1530, 1440, 1180, 760.

Mass: m/Z 295(M+).

(2-19). (5-(3-Fenethylline-2-thienyl)tetrazol-1-yl)acetic acid (yield 59,7%).

Starting material: methyl(5-(3-fenethylline-2-thienyl)tetrazol)1 - yl)acetate,

So pl. 178aboutC (decomposition).

NMR (SO-d6) , ppm:

and 2.83 (t, 2H, J of 7.70 Hz), to 3.09 (t, 2H, J of 7.70 Hz), 4,22 (sh.with. 1H), of 5.39 (s, 2H), 7.18 in 7,30 (m, 5H), 7,60 (d, 1H, J of 5.50 Hz), of 8.27 (d, 1H, J of 5.50 Hz), of 10.72 (sh.with. 1H).

IRCVG(cm-1): 3450, 2920, 1740, 1640, 1580, 1440, 1400, 1220, 1110.

Mass: m/Z 357(M+)

(2-20). (5-(5-butyl-2-thienyl)tetrazol-1-yl)acetic acid (yield 89%).

Starting material: methyl (5-(5-butyl-2-thienyl)tetrazol-1-yl)acetate.

So pl. 103-104aboutWITH

NMR (DCl3+ SO-d6) , ppm:

of 0.95 (t, 3H, J 7,33 Hz), 1,35 1,49 (m, 2H), 1,76 1,65 (m, 2H), 2,89 (t, 2H), J 7,33 Hz), at 5.27 (s, 2H), 6.89 in (d, 1H, J 3,66 Hz), 7,41 (d, 1H, J 3,66 Hz).

IRCVG(cm-1): 2920, 1730, 1580, 1520, 1420, 1220, 800.

Mass: m/Z 266(M+)

(2-21). (5-(5-Phenylpropyl-2-thienyl)tetrazol-1-yl)acetic acid (yield 89.8% of the).

Starting material: methyl (5-(5-phenylpropyl-2-thienyl)tetrazol-1-yl)acetate.

So pl. 85-86aboutWITH

NMR (CDCl30 Hz), 7,18 7,33 (m, 5H), 7,42 (d, 1H, J of 3.80 Hz).

IRCVG(cm-1): 2920, 1720, 1580, 1510, 1420, 1220, 1130, 800.

Mass: m/Z 328(M+).

(2-22). (5-(5-Methoxymethyl-2-thienyl)tetrazol-1-yl(acetic acid (output 48,9%).

Starting material: methyl (5-(5-methoxymethyl-2-thienyl)tetrazol-1-yl)acetate.

So pl. 124-125aboutWITH

NMR (CDCl3+ SO-d6) , ppm:

3,43 (C. 3H), of 4.67 (d, 2H, J 0,73 Hz), from 5.29 (s, 2H), 7,10 (dt, 1H, J 3,66, to 0.73 Hz), 7,49 (d, 1H, J 3,66 Hz).

IRCVG(cm-1): 2900, 1740, 1580, 1420, 1220, 1020, 800.

Mass: m/Z 254(M+)

(2-23). (5-(5-Butoxymethyl-2-thienyl)tetrazol-1-yl)acetic acid (yield 82.3 per cent).

Starting material: methyl (5-(5-butoxymethyl-2-thienyl)tetrazol-1-yl)acetate.

So pl. 67-68aboutWITH

NMR (CDCl3+ SO-d6) , ppm:

0,93 (so 3H, J 7,20 Hz), 1,38 1,47 (m, 2H), 1,55 1,66 (m, 2H), 3,54 (t, 2H, J 6,47 Hz), of 4.67 (d, 2H, J 0,73 Hz), 4,07 (s, 2H), 5,27 (s, 2H), 7,07 (d, 1H, J 3,79 Hz), 7,47 (d, 1H, J 3,79 Hz).

IR KSh(cm-1): 2950, 1730, 1580, 1420, 1230, 1090, 800.

Mass: m/Z 296(M+)

(2-24). (5-(2-Bromo-3-thienyl)tetrazol-1-yl)acetic acid (yield 48,9% ).

Starting material: methyl(5-(2-bromo-3-thienyl)tetrazol-1-yl)acetate.

So pl. 145-146aboutWITH

NMR (CDCl3+ SO-d6) , ppm:

4,56 (the

Mass: m/Z 289(M+)

(2-25). (5-(2-(Oct-4-yl)-3-thienyl)tetrazol-1-yl)acetic acid (yield of 80.6)

Starting material: methyl (5-(2-(Oct-4-yl)-3-thienyl)tetrazol-1-yl)acetate

So pl. 79-80aboutWITH

NMR (DCl3+ SO-d6) , ppm:

0,78 0,84 (m, 6N), 1,13 1,25 (m, 6N), 1,45 1,71 (m, 4H), 3.15 and up 3.22 (m, 1H, 5,00 (s, 2H), 7,01 (d, 1H, J lower than the 5.37 Hz), was 7.36 (DD, 1H, J lower than the 5.37, 0,73 Hz)

IRCVG(cm-1): 2900, 1740, 1570, 1440, 1220, 720.

Mass: m/Z 322(M+)

(2-26). (5-(2-Methylthio-3-thienyl)tetrazol-1-yl)acetic acid (yield 75,3%).

Starting material: methyl (5-(2-methylthio-3-thienyl)tetrazol-1-yl)acetate.

So pl. 134-135aboutWITH

NMR (CDCl3+ SO-d6) , ppm:

of 2.51 (s, 3H), 5,14 (s, 2H), 7,18 (d, 1H, J 6,50 Hz), 7,47 (d, 1H, J 5,50 Hz).

IR CVG(cm-1): 3100, 2900, 1730, 1550, 1440, 1220, 800

Mass: m/Z 256(M+)

(2-27). (5-(5-Methyl-2-furyl)tetrazol-1-yl)acetic acid (yield 42.7 percent ).

Starting material: methyl (5-(5-methyl-2-furyl)tetrazol-1-yl)acetate.

So pl. 150-151aboutC (decomposition).

NMR(DCl3+ SO-d6) MRP:

to 2.41 (s, 3H), of 5.40 (s, 2H), 6,23 (DD, 1H, J 3,42, and 0.98 Hz), 7,20 (d, 1H, J 3.42 Hz).

IRCVG(cm-1): 3500, 3100, 1720, 1570, 1440, 1240, 800.

Mass: m/Z 208(M+)

(2-28). (5-(5-Butyl-2-furyl)tetrazol-1-ptx2">

So pl. 109-110aboutWITH

NMR (CDCl3+ SO-d6) , ppm:

to 2.41 (s, 3H), of 5.40 (s, 2H), 6,23 (DD, 1H, J 3,42, and 0.98 Hz), 7,20 (d, 1H, J 3.42 Hz).

IRCVG(cm-1): 3500, 3100, 1720, 1570, 1440, 1240, 800.

Mass: m/Z 208(M+).

(2-30). (5-(5-Methylthio-2-furyl)tetrazol-1-yl)acetic acid (yield of 42.3%).

Starting material: methyl(5-(5-methylthio-2-furyl)tetrazol-1-yl)-acetate.

So pl. 160,5-161,5aboutC (decomposition).

NMR (DCl3SO-d6) MRP:

of 2.51 (s, 3H), 5,43 (s, 2H), 6,55 (d, 1H, J 3,66 Hz)= 7,28 (d, 1H, J 3,66 Hz).

IRCVG(cm-1): 3100, 3000, 1730, 1620, 1500, 1440, 1210, 1200, 800.

Mass: m/Z 240(M+)

(2-31). (5-(2-Bromo-3-furyl)tetrazol-1-yl)acetic acid (yield of 60.5% ).

Starting material: methyl(5-(2-bromo-3-furyl)tetrazol-1-yl)acetate.

So pl. 138-139about(decomposition).

NMR (DCl3+ SO-d6) , ppm:

of 5.17 (s, 2H), 4,33 (P.F. 1H), 6,74 (d, 1H, J of 2.20 Hz), 7,54 (d, 1H, J of 2.20 Hz).

IRCVG(cm-1): 3100, 3000, 1720, 1620, 1520, 1440, 1260, 1100, 1010, 930.

Mass: m/Z 273(M+)

(2-32). (5-(2-Methylthio-3-furyl)tetrazol-1-yl)acetic acid (yield 78% )

Starting material: methyl(5-(2-methylthio-3-furyl)tetrazol-1-yl)acetate.

So pl. 120-122aboutWITH

NMR (CDCl3+ SO THE-1): 3300, 3150, 2950, 1730, 1590, 1440, 1220, 960, 810, 740.

Mass: m/Z 240(M+)

(2-33). (5-(2-Phenylthio-3-thienyl)tetrazol-1-yl)acetic acid (yield 67.6 per cent).

Starting material: methyl(5-(2-phenylthio-3-thienyl)tetrazol-1-yl)acetate.

So pl. 133-134aboutC (decomposition).

NMR (CDCl3+ SO-d6) , ppm:

of 5.50 (s, 2H), 7.23 percent 7,29 (m, 6N), to 7.59 (d, 1H, J and 5.30 Hz).

IRCVG(cm-1): 3100, 3000, 1720, 1570, 1480, 1430, 1390, 1260, 870, 730.

Mass: m/Z 318(M+)

(2-34). (5-(5-Phenylthio-2-thienyl)tetrazol-1-yl)acetic acid (yield 61,0%).

Starting material: methyl(5-(5-phenylthio-2-thienyl)tetrazol-1-yl)acetate.

So pl. 125-126aboutC (decomposition).

NMR (CDCl3+ SO-d6) , ppm:

3,37(sh. C. 1H) and 5.9 (s, 2H), 7,27 7,38 (m, 6N), 7,51 (d, 1H, J 3,90 Hz).

IRCVG(cm-1): 3000, 1730, 1580, 1480, 1430, 1410, 1220, 1130, 800, 730.

Mass: m/Z 318(M+)

(2-35). (5-(5-(N,N-diethylaminomethyl)-2-thienyl)tetrazol-1-yl)acetic acid (yield 80,0%).

Starting material: methyl(5-(5-(N, N-diethylaminomethyl)-2-thienyl)tetrazol - 1-)acetate.

So pl. 134-135aboutWITH

NMR(CDl3+ SO-d6) , ppm:

a 1.01(t, 6N, J was 7.08 Hz)= 3,10 (q, 4H, J was 7.08 Hz), 3,32 (sh.with. 1H), a 5.25 (s, 2H), 7.23 percent (d, 1H, J 5,13 Hz), 8,18 (d, 1H, J 5,13 Hz).

Starting material: methyl(5-(5-(N, N-dibutylaminoethanol)-2-thienyl)tetrazol-1-yl)acetate.

NMR (CDCl3) , ppm:

of 0.79 (t, 6N, J to 7.32 Hz), 1,09 1,23 (m, 4H, 1,30 1,41 (m, 4H), 2,87 (t, 4H, J EUR 7.57 Hz), 5,14 (s, 2H), 7,11 (d, 1H, J 5,12 Hz), to 7.61 (d, 1H, J 5,12 Hz).

IRNaCl(cm-1): 2950, 1740, 1340, 1220, 1150.

Mass: m/Z 401(M+)

(2-37). (5-(5-Piperidinomethyl-2-thienyl-1-yl)acetic acid (yield 55,0%).

Starting material: methyl(5-(5-piperidinomethyl-2-thienyl)tetrazol-1-yl)ACE - tat.

So pl. 143-146aboutWITH

NMR(CDCl3) , ppm:

1,38 1,39 (m, 2H), 1,58 1,48 (m, 4H), of 2.86 (t, 4H, J lower than the 5.37 Hz), further 5.15 (s, 2H), 7,16 (d, 1H, J 5,13 Hz), 7,66 (d, 1H, J 5,13 Hz).

IRKBr(cm-1): 3450, 2950, 1735, 1340, 1230, 1160.

Mass: m/Z 357(M+)

(2-38). (5-(2-(N,N-diethylaminophenyl)-3-thienyl)tetrazol-1-yl)acetic acid (yield of 66.1%).

Starting material: methyl(5-(2-(N, N-diethylaminophenyl)-5-trimethylsilyl-3-thienyl) tetrazol-1-yl)acetate.

So pl. 128,5-130aboutWITH

NMR(CDCl3) , ppm:

1,00 (T. 6N, J was 7.08 Hz), 3.00 and (sq. 4H, J was 7.08 Hz), 5,13 (s, 2H), 7,10 (d, 1H, J 4,88 Hz), a 7.62 (d, 1H, J 4,88 Hz).

IRKBr(cm-1): 2950, 1740, 1340, 1220, 1140.

Mass: m/Z 331(M+)

(2-39). (5-(3-Methylsulfonylamino-2-thienyl)tetrazol-1-yl)acetic acid (yield l. 154-155aboutWITH

NMR(CDCl3) MRP:

a 3.01(s, 3H), of 3.78 (s, 3H), 5,38 (s, 2H), 7,53 (d, 1H, J 5,61, a 7.62 Hz (d, 1H, J 5,61 Hz), 9,92 (sh.with. 1H).

IRKBr(cm-1): 3150, 3100, 1740, 1560, 1370, 1330, 1220, 1150, 760.

Mass: m/Z 303(M+)

(2-40). (5-(3-Butylsulfonyl-2-thienyl)tetrazol-1-yl)acetic acid (yield of 74.4%).

Starting material: methyl(5-(3-butylsulfonyl-2-thienyl)tetrazol-yl)- acetate.

So pl. 158-159aboutC (decomposition).

NMR (CDCl3) , ppm:

of 0.87 (t, 3H, J to 7.32 Hz), 1,35 1,44 (m, 2H), 1,75 1,85 (m, 2H), 3,14 (t, 2H, J of 7.95 Hz), of 3.84 (s, 3H), of 5.45 (s, 2H), 7,54 (d, 1H, J 5,49 Hz), a 7.62 (d, 1H, J 5,49 Hz), 9,98 (sh.with. 1H).

IRKBr(cm-1): 3100, 2950, 1750, 1560, 1370, 1220, 1150.

Mass: m/Z 345(M+)

(2-41). (5-(3-Phenylcarbonylamino-2-thienyl)tetrazol-1-yl)acetic acid (yield 82,4%).

Starting material: methyl(5-(3-phenylcarbonylamino)-2-thienyl)tetrazol-1-yl)acetate.

So pl. 124-125aboutC.

NMR (CDCl3) , ppm:

and 3.72 (s, 3H), 5,23 (s, 2H), 7,31 7,47 (m, 5H), 7,53 (d, 1H, J 5,62 Hz), 7,58 to $ 7.91 (m, 2H), 10,16 (sh.with. 1H).

IRKBr(cm-1): 3120, 2950, 1750, 1560, 1520, 1430, 1380, 1240, 1160, 760, 580.

Mass: m/Z 365(M+)

(2-42). (5-(3-Hydroxy-2-thienyl)tetrazol-1-yl)acetic acid (yield 73.6 per cent).

Starting material: methyl(5-(3-gpm:

4,36 (sh. C. 1H), 5,38 (s, 2H), 6.87 in (d, 1H, J lower than the 5.37 Hz), was 7.45 (d, 1H, J lower than the 5.37 Hz), 10,23 (sh.with. 1H).

IRKBr(cm-1): 3450, 2850, 1720, 1440, 1230, 1120, 1010, 750.

Mass: m/Z 226(M+)

(2-43). (5-(2-Methylsulfinyl-3-thienyl)tetrazol-1-yl)acetic acid (yield of 20.4%).

Starting material: methyl(5-(2-methylsulfinyl-3-thienyl)tetrazol-1-yl)acetate.

So pl. 144-145aboutWITH

NMR (CDCl3+ SO-d6) , ppm:

is 3.08 (s, 3H), of 5.15 (d, 1H, J 17,82 Hz), and 5.30 (d,1H, J 17,82 Hz), 7,34 (d, 1H, J 5,12 Hz), 7,81 (d, 1H, J 5,12 Hz).

IRKBr(cm-1): 3100, 2900, 1700, 1570, 1420, 1300, 1260, 1220, 1000, 760.

Mass: m/Z 272(M+)

(2-44). (5-(2-Methylsulphonyl-3-thienyl)tetrazol-1-yl)acetic acid (yield 76,1%).

Starting material: methyl(5-(2-methylsulphonyl-3-thienyl)-tetrazol-1-yl)acetate.

So pl. 135-136aboutWITH

NMR (CDCl3+ SO-d6) , ppm:

3,32 (sh.with. 1H), 3,48 (s, 3H), lower than the 5.37 (s, 2H), 7,40 (d, 1H, J 5,13 Hz, 8,32 (d, 1H, J 5,13 Hz).

IRKBr(cm-1): 3500, 3100, 3000, 1720, 1310, 1140, 950, 760.

Mass: m/Z 288(M+)

(2-45). (5-(3-Amino-2-thienyl)tetrazol-1-yl)acetic acid, hydrochloride (yield 76,1%).

Starting material: methyl(5-(3-methylcobalamine-2-thienyl)tetrazol-1-yl)- acetate

So pl. 258aboutC (decomposition)

NMR (SO-d6) ,PP 1590, 1530, 1380, 1040, 770.

(2-46). (5-(5-(N-methyl-N-(2-hydroxyethyl)aminosulfonyl(-2-thienyl)tetrazol-1-yl)uksu snakelet (output 76,1%).

Starting material: methyl(5-(5-(N-methyl-(2-(methoxyethoxy)ethyl)aminosweet - Neil)-2-thienyl)tetrazol-1-yl)acetate.

NMR (CD3D) , ppm:

2,77 (s, 3H), of 3.07 (t, 2H, J 5,61 Hz), of 3.60 (t, 2H, J 5,61 Hz), of 5.24 (s, 2H), 7,26 (d, 1H, J 5,13 Hz), 8,02 (d, 1H, J 5,13 Hz).

IR NaCl(cm-1): 3450, 2950, 1740, 1440, 1350, 1150, 1040, 590.

Mass: m/Z 347(M+)

P R I m e R 3. (3-1). Methyl(5-(2-thienyl)tetrazol-1-yl)acetate.

To a solution of 500 mg (2.51 mmol) of N-(2-thionyl)licensedialog ester in 5 ml of anhydrous methylene chloride was added at room temperature 185 mg (2,53 mmol) in anhydrous N,N-dimethylformamide and 418 mg (3,51 mmol) of thionyl chloride, and then the mixture was heated under reflux for one hour. The reaction solution was concentrated at 40aboutWith under reduced pressure and the obtained residue was dissolved with 5 ml of anhydrous N,N-dimethyl - formamide. The resulting solution was dropwise added to a suspension of 410 mg (6.3 mmol) of sodium azide in 3 ml of anhydrous N,N-dimethylformamide at the temperature of the suspension in the range of 5 to 10aboutWith over 30 min with stirring. After drip additive reaction mixture ohms. The organic phase is washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was recrystallization from a mixture of ethyl acetate n-hexane to obtain 395 mg (yield of 70.2% of methyl(5-(2-thienyl)tetrazol-1-yl)acetate.

The results of instrumental analysis of this product correspond to the results for the product obtained in example (1-1).

(3-2). Ethyl(5-(3-thienyl)tetrazol-1-yl)acetate.

To a solution of 1 g (4,69 mmol) of N-(3-thenoyl)licensedialog ester in 10 ml of anhydrous methylene chloride was added at room temperature, 350 mg (4,79 mmol) in anhydrous N,N-dimethylformamide and 800 mg (6,72 mmol) of thionyl chloride, and then the mixture was heated under reflux for one hour. The reaction solution was concentrated at 40aboutWith under reduced pressure and the obtained residue was dissolved in 10 ml of anhydrous N,N-dimethylformamide. The resulting solution was dropwise added to a suspension of 800 mg (12.3 mmol)of sodium azide in 5 ml of anhydrous n, N-dimethylformamide at the temperature of the suspension in the range of 5 to 10aboutWith over 30 min with stirring. After drip additives the reaction mixture was stirred for 30 min at room tessili over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate n-hexane to obtain 730 mg (yield 65,3%) ethyl(5-(3-thienyl)tetrazol-1-yl)acetate.

So pl. 69,5-70,5aboutWITH

NMR (CDCl3) , ppm:

of 1.27 (t, 3H, J of 7.25 Hz), 4.26 deaths (sq. 2H, J of 7.25 Hz); the 5.25 (s, 2H), of 7.48 (DD, 1H, J 5,20, 1,21 Hz), 7,55 (DD, 1H, J 5,20, 2,82 Hz), to 7.84 (DD, 1H, J 2,82, 1,21 Hz).

IRKBr(cm-1): 3100, 2970, 2950, 1740, 1570, 1440, 1370, 1210, 880.

Mass: m/Z 238(M+)

The following compounds were obtained as indicated.

(3-3). Methyl(5-(3-methoxy-2-thienyl)tetrazol-1-yl)acetate (yield 12%)

Starting material: N-(3-methoxy-2-thenoyl)glycemically ether.

So pl. 121-122aboutWITH

NMR (CDCl3) , ppm:

3,76 (s, 3H), 3,90 (s, 3H), of 5.34 (s, 2H), 6,97 (d, 1H, J 5,64 Hz), 7,54 (d, 1H, J 5,64 Hz).

IRKBr(cm-1): 3100, 2950, 1760, 1580, 1520, 1400, 1240, 1220, 1070, 760.

Mass: m/Z 254(M+)

(3-4). Methyl(5-(3-butoxy-2-thienyl)tetrazol-1-yl)acetate (yield 13%)

Starting material: N-(3-butoxy-2-thenoyl)glycemically ether

So pl. 62-62,5aboutC.

NMR (CDCl3) , ppm:

0,88 (so 3H, J 7,26 Hz), 1,28 1,39 (m, 2H), equal to 1.59 to 1.70 (m, 2H), 3,66 (s, 3H), Android 4.04 (t, 2H, J 6.85 Hz), of 5.34 (s, 2H), at 6.84 (d, 1H, J 5,64 Hz), was 7.45 (d, 1H, J 5,64 Hz).

IRKBr(cm-1): 3100, 2950, 1760, 1580, 1510, 1400, 1240, 1220, 1050, 750.

Mass: m/Z 296(M

So pl. 58-59aboutWITH

NMR (CDCl3) ,ppm:

of 0.95 (t, 3H, J to 7.32 Hz), 1,37 1,46 (m, 2H), 1,76 1,65 (m, 2H), 2,88 (t, 2H, J to 7.32 Hz), 3,83 (s, 3H), 5,32 (s, 2H), 6.89 in (d, 1H, J 3,66 Hz), 7,38 (d, 1H, J 3,66 Hz).

IRKBr(cm-1): 2950, 1740, 1580, 1520, 1440, 1380, 1220, 1100, 1000, 800.

Mass: m/Z 280(M+)

(3-6). Methyl(5-(5-phenylpropyl-2-thienyl)tetrazol-1-yl)acetate (yield 74.1 per cent ).

Starting material: N-(5-phenylpropyl-2-thenoyl)glycemically ether

NMR (CDCl3) , ppm:

to 2.06 (sq. 2H, J 57 Hz), a 2.71 (t, 2H, EUR 7.57 Hz); 2.91 in (t, 2H, J EUR 7.57 Hz), 3,83 (s, 3H), 5,31 (s, 2H), 6.90 to (dt, 1H, J 3,72, to 0.73 Hz), 7.18 in 7,34 (m, 5H), 7,40 (d, 1H, J and 3.72 Hz).

IRNaCl(cm-1): 2920, 1750, 1580, 1500, 1440, 1220, 1100, 700.

Mass: m/Z 342(M+)

(3-7). Methyl(5-(5-methoxymethyl-2-thienyl)tetrazol-1-yl)acetate (yield of 72.5%).

Starting material: N-(5-methoxymethyl-2-thenoyl)glycemically ether.

NMR (CDCl3) ,ppm:

3,44 (s, 3H), of 3.84 (s, 3H), of 4.67 (d, 2H, J 0,73 Hz), 5,33 (2N), 7,10 (dt, 1H, J 3,66, to 0.73 Hz), of 7.48 (d, 1H, J 3,66 Hz),

IRNaCl(cm-1): 2950, 1750, 1580, 1440, 1360, 1220, 1000, 800.

Mass: m/Z 268(M+)

(3-8). Methyl(5-(5-butoxymethyl-2-thienyl)tetrazol-1-yl)acetate (yield 68,9%).

Starting material: N-(5-butoxymethyl-2-thenoyl)glycemically ether.

So pl. 48-49aboutC.

NMR (CDCl3J 3,72, to 0.73 Hz), 7,46 (d, 1H, J and 3.72 Hz).

IRKBr(cm-1): 2950, 2850, 1740, 1580, 1420, 1230, 1100, 800.

Mass: m/Z 310(M+)

(3-9). Methyl(5-(2-bromo-3-thienyl)tetrazol-1-yl)acetate (yield 45.9 per cent).

Starting material: N-(2-bromo-3-thenoyl)glycemically ether

NMR(CDCl3) ,ppm:

3,76 (s, 3H), of 5.17 (s, 2H), 7,10(d, 1H, J 5,73 Hz), of 7.48 (d, 1H, J 5,73 Hz).

IRNaCl(cm-1): 3100, 2950, 1750, 1580, 1430, 1220, 1000.

Mass: m/Z 3030(M+)

(3-10). Methyl(5-(2-(Oct-4-yl)-3-thienyl)tetrazol-1-yl)acetate (yield of 35.5% ).

Starting material: N-(2-(Oct-4-yl)-3-thenoyl)glycemically ether.

NMR(CDCl3) ,ppm:

0,78 0,85 (m, 6N), 1,11 1,26 (m, 6N), 1,50 1,67 (m, 4H), 3,12 3,18 (m, 1H), 3,81 (s, 3H), of 5.05 (s, 2H), 6,93 (d, 1H, J are 5.36 Hz), was 7.36 (d, 1H, J lower than the 5.37 Hz).

IRNaCl(cm-1): 2950, 2850, 1760, 1440, 1220.

Mass: m/Z 336(M+)

(3-11) Methyl(5-(2-methylthio-3-thienyl)tetrazol-1-yl)acetate (yield 70.8 per cent).

Starting material: N -(2-methylthio-3-thenoyl)glycemically ether.

So pl. 90-91aboutWITH

NMR(CDCl3) , ppm:

2,47 (s, 3H), of 3.75 (s, 3H), 5,20 (s, 2H), 7,15 (d, 1H, J lower than the 5.37 Hz), 7,47 (d, 1H, J lower than the 5.37 Hz).

IR KBr(cm-1): 3110, 2920, 1750, 1550, 1420, 1220, 1100.

Mass: m/Z 270(M+)

(3-12). Methyl(5-(2-phenylthio-3-thienyl)tetrazol-1-yl)acetate (yield 78.6 per cent). is, 3H), 5,10 (s, 2H), 7,21 7,27 (m, 6N), at 7.55 (d, 1H, J lower than the 5.37 Hz).

IRNaCl(cm-1): 3100, 2950, 1750, 1570, 1480, 1440, 1360, 1220, 1000.

Mass: m/Z 332(M+)

(3-13). Methyl(5-(5-phenylthio%2-thienyl)tetrazol-1-yl)acetate (yield 70.8 per cent).

Starting material: N-(5-phenylthio-2-thenoyl)glycemically ether.

So pl. 102-103aboutWITH

NMR(CDCl3) ,ppm:

is 3.82 (s, 3H), and 5.30 (s, 2H), 7,26 7,37 (m, 6N), 7,49 (d, 1H, J 3,91 Hz).

IRKBr(cm-1): 2900, 1750, 1570, 1480, 1430, 1410, 1360, 1220, 1100, 800.

Mass: m/Z 332(M+)

(3-14). Methyl(5-(5-(N, N-diethylaminomethyl)-2-thienyl)tetrazol-1-yl)acetate (yield of 72.5%).

Starting material: N-(5-(N',N'-diethylaminophenyl)-2-energizingly wet ether

NMR(CDCl3) ,ppm:

a 1.08 (t, 6N, J 7,20 Hz), of 3.07 (q, 4H, 7,20 Hz), and 3.72 (s, 3H), 5,23 (s, 2H), 7,22 (d, 1H, J 5,12 Hz), to 7.67 (d, 1H, J 5,12 Hz).

IRNaCl(cm-1): 3100, 2950, 1750, 1610, 1440, 1350, 1220, 1150, 940, 700.

Mass: m/Z 347(M+)

(3-15). Methyl(5-(5-(N, N-dibutylaminoethanol)-2-thienyl)tetrazol-1-yl)acetate (yield 68,9%).

Starting material: N-(5-(N',N'-dibutylaminoethanol)-2-thenoyl)glycinamido wet air.

NMR (CDCl3) ,ppm:

0,86 (t, 6N, J to 7.32 Hz), of 1.33 to 1.37 (m, 4H), 1,40 1,48 (m, 4H), 2,04 (t, 4H, J to 7.32 Hz), 3,71 (s, 3H), 5,23 (s, 2H), 7,22 (d, 1H, J5,25 Hz)= to 7.67 (d, 1H, J a 5.25 Hz).

Starting material: N-(5-piperidinomethyl-2-thenoyl)glycemically ether

So pl. 133-135aboutWITH

NMR (CDCl3) ,ppm:

1,04 of 1.53 (m, 2H), 1,59 1,68 (m, 4H), of 2.92 (t, 4H, J a 5.25 Hz), 3,71 (s, 3H), 5,23 (s, 2H), 7,26 (d, 1H, J 5,13 Hz), a 7.62 (d, 1H, J 5,13 Hz).

IRKBr(cm-1): 3100, 2950, 1760, 1340, 1220, 1150, 940, 710, 590.

Mass: m/Z 371(M+)

(3-17). Methyl(5-(2-(N, N-diethylaminomethyl)-5-trimethylsilyl-3-thienyl)tet - razol-1-yl)acetate (yield 75.4 per cent).

Starting material: N-(2-(N',N'-diethylaminophenyl)-5-trimethylsilyl-3-the - nail)glycemically ether.

NMR (CDCl3) MRP:

0,37 (s, N), a 1.08 (t, 6N, J 7,20 Hz), 3,06 (q, 4H, J was 7.08 Hz), 3,71 (s, 3H), to 5.21 (s, 2H), 7,24 (s, 1H)

IRNaCl(cm-1): 2950, 1760, 1440, 1350, 1250, 1220, 1140, 1000, 840, 700.

Mass: m/Z 431(M+)

(3-18) Methyl(5-(3-hydroxy-2-thienyl)tetrazol-1-yl)acetate (yield 54.0 percent).

Starting material: N-(3-hydroxy-2-thenoyl)glycemically ether

So pl. 141-142aboutWITH

NMR (CDCl3) ,ppm:

of 3.84 (s, 3H), 5,38 (s, 2H), 6,95 (d, 1H, J lower than the 5.37 Hz), 7,46 (d, 1H, J lower than the 5.37 Hz), 10,12 (sh.with. 1H).

IRKBr(cm-1): 3100, 1760, 1740, 1530, 1220, 1000.

Mass: m/Z 240(M+)

The compound obtained in the preceding examples, are given in table.1.

As mentioned inhibitor, an aldose reductase inhibitor on the . Therefore, it can be used as drugs for the prevention and/or treatment of thoracic inclusive person suffering from diabetes complications, such as nerve disorders, nephrosis, cataract and retinopathy without fear.

The effects and toxicity of the inhibitor, an aldose reductase inhibitor, according to the invention, described below with reference to the following examples of tests.

The test example 1. Test to study the inhibitory effect of an aldose reductase.

Methodology.

Six male SD rats shot with ether and killed. Then immediately removed from them the lens and stored at -80aboutC. the Lens was homogenized in 3 volumes 135 mmol buffer mixture of sodium phosphate-potassium (pH 7.0) and centrifuged at 30,000 rpm for 30 minutes Received floating on the surface of the substance was immediately diarizonae against 0.05 M solution of calcium chloride with the purpose of obtaining a solution of an aldose reductase. All operations were performed at 4aboutC and the enzyme solution was stored at -80aboutC.

The activity of the aldose reductase was determined by a partially modified method Th.X.Kinoshita and others (Journal of Biological the buffer mixture of sodium phosphate-potassium (pH 6,2), which contained lithium sulfate (final concentration: 400 mmol), restored nicotinamide-adenine - dinucleotide-phosphate (final concentration: 0.15 mmol), enzyme solution, and determine the substance (final concentration: 10-6M, 10-7M or 10-8M) and then the reaction was carried out at 30aboutC for 5 minutes In the reaction was measured changes absorbent capacity at 340 nm. Was determined maximum speed reduction absorbent capacity (V) in the reaction. By subtracting from this value the maximum speed reduction (Vo) at 340 nm of the reaction solution up to an additive substrate (DL-glyceraldehyde), the reaction rate (V V-Vabout) was calculated as the true reaction rate in the presence of the test compound.

The same procedure was repeated, but in the absence of the test compound. The true reaction rate (Vo) when the enzyme was not suppressed, amounted to (Vo U' U o). Inhibitory activity of the aldose reductase of the test compounds was determined by the following formula:

The rate of suppression (%) (VoV)/Vox 100

For comparison, the same tests were carried out using a known inhibitor of reducta the s.

Thus obtained results are shown in table.2. As can be seen from the table. 2, the compounds of the invention, which was subjected to the tests show the inhibitory effect of an aldose reductase identical to or higher than the effect achieved by the known inhibitor, ONO-2235.

Example of test 2. Testing the braking effect of the accumulation of sorbitol in sketicism nerve.

Methodology.

Groups of 6-8-week-old male rats Sprague-Dawley (4 animals in each group) were locked up for 18 h and through the tail vein was entered streptozotocin in the amount of 60 mg/kg to obtain thus diabetes in rats. Immediately after the introduction of streptozotocin each test substance was orally introduced these rats in suspension in a dose of 10, 30 and 50 mg/kg (each was suspended in a 0.5% solution of sodium carboxymethyl cellulose) twice a day (9 a.m. and 5 p.m) for 5 days. During testing, rats were kept on a diet and given drinking water in unlimited quantity. After 4 h after the last dose of medication in the morning on the 5th day (9 am) rats were put to death and then they had removed staticheskii nerve to determine the amount accumulated in it sorbitol.

The results are shown is no remedy was not implemented. The results are given in table.3.

These results show that the compounds of the invention show high inhibitory effect compared with the effect for a known inhibitor, an aldose reductase inhibitor, ONO-2235.

Example of test 3. Tests for acute toxicity.

Methodology.

Each test substance suspended in a 0.5% solution of sodium carboxymethyl cellulose, the resulting suspension oral introduced a 6-week old male mice of the sit (5 animals in the control group). After 14 days after administration of the compounds according to the percentage of mortality was determined the 50% lethal dose (LD50(mg/kg). Mice were kept on a diet, but drinking during the test was given in unlimited quantity.

The results are shown in table.4. As can be seen from the table.4, the compounds of the invention which were subjected to the previous test, show LD50not less than 3,000 mg/kg

The METHOD of OBTAINING DERIVATIVES TETRASILICATE ACID of General formula

< / BR>
where R1is hydrogen or a lower alkyl group;

R2is hydrogen, C1- C8is an alkyl group, a phenyl (lower) alkyl, halogen, halo (lower alkyl) group, a hydroxyl GRU is Il - or phenylthiourea, lower alkyl - or phenylcarbonylamino, di(lower alkyl) aminosulfonyl group, N- (lower) alkyl-N - hydroxy (lower) alkylaminocarbonyl group, piperidinomethyl group, (lower) alkylsulfonyl group or a (lower) alkylsulfonyl group;

X is-O - or-S-,

with the exception of [5-(2-thienyl)tetrazol-1-yl] acetic acid, [5-(2-furyl)-tetrazol-1-yl] acetic acid, [5-(5-bromo-2-furyl)tetrazol-1-yl] acetic acid, [5-(5-phenylsulfonyl-2-furyl)-tetrazol-1-yl] acetic acid and their ethyl esters [5-(5-phenyl-2-furyl)tetrazol-1-yl] acetic acid and its C1- C3alilovic esters or their salts, characterized in that the compound of formula

< / BR>
where R1lower alkyl group;

R2and X have the above values,

subjected to chlorination and any resulting chlorimipramine General formula

< / BR>
where R1lower alkyl group;

R2and X have the above meanings, is subjected to the interaction with sodium azide to obtain the desired product of the formula

< / BR>
where R1lower alkyl group;

R2and X have the above values,

followed, if necessary, by hydrolysis to obtain the compound of formula is

 

Same patents:

The invention relates to new derivatives of alkinoos acid, pyridine, or rather to new 1,3-dioxane-5-Illinois acids containing the residue of pyridine in position 4 1,3-dioxane rings

The invention relates to new pyridine containing heterocyclic compounds, in particular new 1,3-dioxane-5-silt derived alkenovich acids containing pyridyloxy residue attached to position 4 of the 1,3-dioxane ring

The invention relates to new derivatives of benzopyran that have protivogipertenzin activity and can be used in the treatment and prevention of cardiovascular diseases

The invention relates to methods of producing a new derived griseolus acid of the formula I

or its ether complex, is able to inhibit the activity of phosphodiesterase, specific to different cyclic nucleotides

FIELD: color-forming compositions and recording material.

SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.

EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.

21 cl, 14 tbl, 153 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new stable crystalline forms of derivative of pyrimidine nucleoside of the formula (I) eliciting the excellent anti-tumor activity. Also, invention relates to pharmaceutical composition eliciting an anti-tumor effect, applying crystalline form for preparing medicinal agent and to a method for prophylaxis or treatment of tumor diseases.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of derivative.

10 cl, 2 tbl, 4 dwg, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazine of the general formula (I):

wherein R1 means hydrogen (H) or halogen atom; R2, R3 and R5 mean hydrogen atom (H); R4 and R6 mean hydroxy-group optionally protected with acetyl or benzoyl group; A means oxygen atom (O); n = 0; Y means oxygen atom (O), or their salts. Compounds show the excellent anti-viral activity and useful as a therapeutic agent in treatment of viral infections. Also, invention describes a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 2 tbl, 15 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing 5-(1-piperazinyl)-benzofuran-2-carboxamide. Method involves reaction of bromosalicylic aldehyde with compound of the formula (I): L-CH2-COOR1 (I) wherein L represents Cl, Br or J atoms, or reactive esterified group -OH; R1 means (C1-C6)-alkyl or benzyl followed by reaction with formamide to yield 5-L-benzofuran-2-carboxamide (II) and the following its amination with R2-piperazine wherein R2 represents hydrogen atom (H) or amino-protecting group in the presence of a catalyst based on transient metals; in case if R2 is not H then R2 is removed, and/or prepared 5-(1-piperazinyl)-benzofuran-2-carboxamide is converted to one of its salts by treatment with acid. Except for, the invention proposes two additional methods for preparing 5-(1-piperazinyl)-benzofuran-2-carboxamide and intermediate compounds of the formula (V): wherein R2 represents H or amino-protected group; R3 means H or -CH2R6; R4 and R5 in common represent carbonyl; R6 means -CN, -COOH, -COOR7 or -CONH2; R7 means (C1-C6)-alkyl, and also their salts and solvates. Invention provides a new method for preparing the valuable intermediate compound used in preparing pharmaceutical preparations and increase of the yield of the end compound.

EFFECT: improved preparing methods.

6 cl, 10 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: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing 3,4-diaryl(hetaryl)maleimides of the formula (I): wherein R means (C1-C4)-alkyl or benzyl, or phenyl; R1 means bromine atom (Br) or aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group; Ar means aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group with exception for 3,4-di-(2,5-dimethyl-3-thienyl)-1-butylmaleimide. Method involves interaction of aryl(hetaryl)boronic acid of the formula: ArB(OH)2 wherein Ar has abovementioned values with N-substituted 3,4-dibromomaleimide of the formula (III): or N-substituted 3-bromo-4-aryl(hetaryl)maleimide of the formula (IV) wherein R and Ar have abovementioned values and with using palladium catalyst in the presence of base in organic solvent medium. Also, invention to some new derivatives of 3,4-diaryl(hetaryl)maleimides that show photochrome properties.

EFFECT: improved preparing method.

7 cl, 2 dwg, 14 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to novel coumarone derivatives of the general formula (1): wherein two OH-substitutes in phenyl moiety are in ortho-position with respect to one to another; R1 is in ortho-position with respect to one hydroxyl group; X means oxygen atom (O); R1 represents -NO2; R2 represents hydrogen atom or (C1-C6)-alkyl; R3 means -(Y)n-(B)m-COOH or -(Y)n-(B)m-R8 wherein m = 0 or 1; n = 0; Y represents -CO-; B represents (C1-C6)-alkylene; R8 represents phenyl or 5- or 6-membered heterocycle with one-four heteroatoms chosen from nitrogen atom (N) wherein indicated phenyl is substituted optionally with one substitute chosen from halogen atom, -NO2 or (C1-C6)-alkyl; or R2 and R3 form in common -(CH2)r- wherein r = 3, 4 or 5; R4 and R5 form in common -O; R6 means hydrogen atom (H), or to their pharmaceutically acceptable salts or pharmaceutically acceptable esters that are inhibitors of enzyme - catechol O-methyltransferase (COMT). Invention provides preparing novel coumarone derivatives possessing the valuable biologically active effect.

EFFECT: valuable biochemical property of derivatives.

9 cl, 1 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

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

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising S-isomer of compound of the formula (I) or its pharmaceutically acceptable salts and solvates in common with a pharmaceutically acceptable vehicle. Also, invention relates to a method for synthesis of compound S-isomer of the formula (I), and to a method for treatment of disease relating to the group comprising respiratory diseases, allergic diseases, dermatological diseases, gastroenteric diseases and ophthalmic diseases. The composition provides avoiding adverse sedative effects in treatment of indicated diseases.

EFFECT: valuable medicinal properties of compounds.

14 cl, 6 ex

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