Derivatives pyrrolo(2,1-b)thiazole and derivatives of 2 - dioxopyrimidine as intermediates for obtaining derivatives pyrrolo(2,1-b)thiazole

 

(57) Abstract:

Usage: in medicine as substances that have the ability to suppress the denaturation and necrosis of hepatocytes. The inventive product 1 - derived pyrrolo [2,1-b]thiazole of the formula I, where R1- lower alkyl or cyclo(lower) alkyl, R2- lower alkoxygroup, amino, lower mono - or dialkylamino or cyclic amino group, which can contain as a ring atom of oxygen or sulfur, phenylthio - or 4-nitrophenylacetate, R3is a hydrogen atom, lower alkyl, or phenyl, ---------- simple or double bond. Product 2: derivatives of 2-dioxopyrimidine formula II, where R1is lower alkyl, R3is a hydrogen atom, lower alkyl or phenyl. The compounds of formula II are intermediates for the synthesis of derivatives of formula I. the structure of the compounds of formulas I and II. . 2 S. p. f-crystals, 2 tab.

The invention relates to new derivatives of pyrrolotriazine specifically to derived pyrrole /2,1-b/thiazole of the formula I

< / BR>
(I) where R1- lower branched or unbranched alkyl or cyclo(lower) alkyl,

R2- lower alkoxygroup, amino, lower mono - or dialkylamino or phenylthio - or 4-nitrophenylacetate,

R3is a hydrogen atom, a lower branched or unbranched alkyl, or phenyl, simple or double bond.

The compounds of formula I are suitable for the prevention (prophylaxis) or treat hepatic (liver) disease.

The invention relates to derivatives of 2 dioxopyrimidine formula II:

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where R1- lower branched or unbranched alkyl,

R3is a hydrogen atom, a lower branched or unbranched alkyl or phenyl, as intermediates for obtaining derivatives pyrrolo /2,1-b/thiazole.

The compounds of formula (I) are highly effective at suppressing the denaturation and necrosis of hepatocytes and improvement in Hepatology. Thus, they serve as extremely effective pharmaceutical forms for the prevention or treatment of hepatic diseases.

Pitiriasis and interferon often used in the treatment of liver (hepatic) disease. However, each of them is used in the form of injections, which are not suitable pharmaceutical forms for treatment for a long period. Therefore, they are not always satisfactory from a clinical point of view in Bernie research with the to find the connection that would be effective in suppressing the denaturation and necrosis of hepatocytes, and improvement in hepatic disorders, and has shown to be very safe to use tematicheskim way. The result is the present invention.

The present invention relates to compounds of formula (I) for the prevention or treatment of liver diseases.

Among the compounds of the present invention represented by the formula (I), compounds in which R1is a branched lower alkyl group or cycloalkyl group, and R2is lower alkylamino group or a cyclic amino group which may contain as ring atoms oxygen atom or a sulfur atom, are preferred.

Especially preferred compound among the compounds of the present invention are the compounds of formula 1 in which R1is ISO-propyl group or tsiklogeksilnogo group, R2is methylaminopropane, arylaminopoly or morpholinopropan, R3is a methyl group or a hydrogen atom and a double bond between the 5 - and 6-positions is preferred.


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The present invention includes both of these geometric isomers, and mixtures thereof.

In accordance with the present invention a special structure in C3-position in formula (I) is represented by the following formula as a convenient expression, including geometric isomers

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The compound of formula (I) has optical isomers arising from the substituents R1, R2, R3and asymmetric ring carbon to which each is a simple link. These optical isomers and mixtures thereof are contained in the field covered by the present invention.

Particularly preferred examples of compounds of the present invention include:

ethyl/7-isopropoxycarbonyl-6-methyl - 2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate;

ethyl/7-methoxycarbonyl-2,3,5,6-Tetra - hidropetrol/2,1-b/ thiazole-3-ilidene/acetate;

ethyl/7-etoxycarbonyl-6-methyl-2,3,5,6 - tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate;

ethyl/7-etoxycarbonyl-6-isopropyl-2, 3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate;

ethyl /7-isopropoxycarbonyl-6-isopropyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate;

ethyl /7-etoxycarbonyl-6-phenyl-2,3,5,6-tetrahydropyrrolo- /2.1 zett,

methyl /7-etoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate

ethyl /7-tration. -butoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate;

ethyl /7-secondary. -butoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate

4-nitrophenyl /7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate;

S-phenyl /7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/ thiazole-3-ilidene/thioacetate,

S-phenyl /7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/ thiazole-3-ilidene/thioacetate;

N-methyl-/7-isopropoxycarbonyl-6-me - til-2,3,5,6-tetrahydropyrrolo /2,1-b/ thiazole-3-ilidene/ndimethylacetamide,

N-methyl-/7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

N-methyl-/7-methoxycarbonyl-2,3,5,6 - tetrahydropyrrolo- /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

N-methyl-/7-etoxycarbonyl-2,3,5,6-tet - rahydropyranyl /2,1-b/thiazole-4-ilidene/ndimethylacetamide,

N-methyl-/7-tration. -butoxycarbonyl - 2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

N-methyl-/7-secondary. -butoxycarbonyl - 2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide;

N-methyl-/7-cyclohexyloxycarbonyl - 6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

N-meil-6-isopropyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

N-methyl-/7-isopropoxycarbonyl-6 - isopropyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

N-methyl-/7-etoxycarbonyl-6-phenyl-2, 3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

N-methyl-/7-isopropoxycarbonyl-6 - phenyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

/7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

N-ethyl-/7-isopropoxycarbonyl-6-me - til-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

/7-isopropoxycarbonyl-2,3,5,6-Tetra - hidropetrol /2,1-b/thiazole-3-ilidene/acetylpiperidine;

/7-isopropoxycarbonyl-2,3,5,6-Tetra - hidropetrol /2,1-b/ thiazole-3-ilidene/acetylmorpholine,

/7-isopropoxycarbonyl-2,3,5,6-Tetra - hidropetrol /2,1-b/thiazole-3-ilidene/acetylthiocholine;

N, N-dimethyl-/7-isopropoxycarbonyl - 2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

/7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene-acetylpiperidine,

/7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetylmorpholine,

N, N-dimethyl-/7-isopropoxycarbonyl - 6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

/7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ylides the ID,

N-methyl-/7-isopropoxycarbonyl-2,3 - dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

N-methyl-/7-isopropoxycarbonyl-ISO - propyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

N-methyl-/7-etoxycarbonyl-6-methyl-2, 3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

/7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

N-ethyl-/7-isopropoxycarbonyl-6-me - til-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

N-methyl-/7-isopropoxycarbonyl-6 - phenyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

/7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/acetylmorpholine,

/7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/acetylthiocholine,

/7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/acetylpiperidine,

N, N-dimethyl-/7-isopropoxycarbonyl - 6-methyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

N-methyl-/7-cyclohexyloxycarbonyl - 6-methyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

N-methyl-/6-ethyl-7-isopropoxycarbonyl - Nile-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide,

methyl /7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/a thiazol-3-yl/acetate

methyl /7-isopropoxycarbonyl-2,3, what about the /2,1-b/a thiazol-3-yl/ndimethylacetamide,

N-methyl-/7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/a thiazol-3-yl/ndimethylacetamide,

N-methyl-/7-isopropoxycarbonyl-6 - methyl-2,3-dihydropyrrolo /2,1-b/a thiazol-3-yl/ndimethylacetamide,

N-methyl-/7-isopropoxycarbonyl-2,3 - dihydropyrrolo /2,1-b/a thiazol-3-yl/ndimethylacetamide,

/7-isopropoxycarbonyl-6-methyl-2,3 - dihydropyrrolo /2,1-b/a thiazol-3-yl/acetylmorpholine, and

/7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo /2,1-b/a thiazol-3-yl/ndimethylacetamide.

Compounds of the present invention represented by formula (I), magub be obtained in various ways. Common examples are given below.

The method of obtaining A: ring closure of thiazole

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where R1and R3indicated above; R21is alkoxygroup, which may have one or more substituents in the alkyl component, aricioglu, which may have one or more substituents in part aryl group, or aryloxy group which may have one or more substituents in part aryl group, and X1and X2each represents a halogen atom.

The compound of formula (II) can interact with the compound of the formula (III) or (IV) in the presence of acid acceptor in sootvetstvuyushie solvents such as methanol, ethanol, isopropanol, etc., ether solvents such as tetrahydrofuran, and benzene solvents such as benzene, toluene, xylene, etc., Examples of acid acceptors include inorganic bases such as potassium carbonate and sodium carbonate, organic bases such as triethylamine, sodium acetate and potassium acetate, etc., the Reaction can be generally carried out at temperatures from room temperature to 100aboutC for several hours to 24 hours

The compound of formula (III) or (IV) may be generally used in ravnomyerno amount relative to the compound of formula (II). In addition, the acid acceptor can be used in the General case in ravnomyerno the number of three - fold molar amount relative to the compound of formula (II).

Way of getting In: amidation

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where R1, R21, R3and have already been defined above; and R4and R5independently represent a hydrogen atom or a lower alkyl group, or R4and R5form a cyclic amino group together with the nitrogen atom, which may contain heteroatoms as ring atoms selected from oxygen atom or sulfur atom.

SOEDINENIYa silver (for example, triptorelin silver, etc.,) or a salt of copper (for example, iodide monovalent copper and so on), without solvent or in water, an organic solvent or their mixtures, in order to obtain the compound of formula (1B). Examples of organic solvents include an alcohol solvent (e.g. methanol, ethanol, isopropanol, etc.,), ether solvent (e.g. dioxane, tetrahydrofuran, etc.,), dichloromethane, chloroform, etc., the Reaction can be generally carried out at temperatures from 0 to 50aboutC for 1-24 hours This reaction can in a preferred embodiment, to carry out in the presence of a metal salt at room temperature for several hours with the use of the compounds of formula (Ia) in which R21is a 4-nitrophenoxy or arylthioureas , as active compounds of ester.

Metal salts can be used in a catalytic amount relative to the compound of formula (Ia). Connection with other4R5can be used in General in ravnomyerno amount or large excess relative to the compound of formula (Ia).

In addition, the compound of formula (Ia) can be hydrolyzed with alkali such as the hydroxide of sodium ylmethanol, ethanol, etc. at room temperature for 1-6 hours the resulting hydrolysate, i.e. the compound of formula (I) in which R2represents a hydroxyl group can interact with the carboxylic acid or organic acid such as Pavlova acid and 2,2-dimethylbutanoate acid, in an inert organic solvent such as dichloromethane, tetrahydrofuran, etc. at a temperature of from 0aboutWith up to room temperature for from several hours to several days to get mixed anhydrides of the acids. Next, the mixed anhydrides of the acids can interact with other4R5in an inert organic solvent such as tetrahydrofuran, dichloromethane, etc. to obtain the connection formula (IB). This reaction can be generally carried out at temperatures from 0aboutWith up to room temperature for from several hours to several days.

The alkali in the General case can be used in a catalytic amount relative to the compound of formula (Ia). Organic acid or carboxylic acid can in General be used in ravnomyerno amount relative to the compound of formula (Ia). In addition, the connection with other4R5in arr CLASS="ptx2">

In addition, the above-mentioned hydrolyzate may interact with other4R5in the presence of 1-oxibendazole and N,N'-dicyclohexylcarbodiimide or N, N'-diisopropylcarbodiimide, or in the presence of 1,1'-carbonyldiimidazole in an inert organic solvent such as tetrahydrofuran, dichloromethane, etc. to obtain the connection formula (IB). The reaction of the hydrolyzate with other4R5in the presence of 1-hydroxybenzotriazole in the preferred embodiment to carry out in the presence of catalytic amounts of an organic base such as 4-di - methylaminopropyl. This reaction can be generally carried out at temperatures from 0aboutWith up to room temperature for from several hours to several days. Connection with other4R5can in General be used in an amount of from ravnovesnogo to a large excess relative to the hydrolysate. In addition, each of 1-oxibendazole, N, N'-dicyclohexylcarbodiimide, N, N'-diisopropylcarbodiimide, 1,1'-carbonyldiimidazole can in General be used in ravnomyerno number relative to the hydrolysate.

The method of obtaining C: dehydrogenase

where R1/ R2/ R3and have indicated an appropriate solvent, to obtain this compound of General formula (Id). Examples dehydrogenation agents include palladium black, manganese dioxide, chloranil, 2,3-dichloro-5,6-diseaseprevention, etc., Examples of solvents include dichloromethane, dichloroethane, chloroform, dioxane, tetrahydrofuran, mixtures thereof, etc., This reaction can in General be carried out at a temperature in the region (-10)-80aboutWith in a few hours. This reaction in the preferred embodiment, is carried out in a mixture of tetrahydrofuran and chloroform at room temperature for approximately 1 h Dehydrogenase agent can be used in General in amounts of from ravnomernogo to a large excess relative to the compound of formula (Ic).

The method of obtaining D: isomerization

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where R1, R21, R3, R4, R5have the specified values.

The compound of formula (II) can interact with the compound of the formula (III) or (IV) in an organic acid such as acetic acid, propionic acid, butyl acid to obtain the connection formula (Va). This reaction can be generally carried out at a temperature of from room temperature to 100aboutWith in a few hours.

< what amidation (method get) with formation of a compound of the formula (Vb).

Compounds of the formulas (VA) and (Vb) can communicate with a base such as 1,8-diazabicyclo[5,4,0]-7-undecene, in an inert organic rastvoritele such as dichloromethane, chloroform, tetrahydrofuran, benzene or toluene, to obtain this connection formulas (Ie) and (If).

The parent compound of the above formula (II) are novel compounds and they can be obtained by using an appropriate combination of known procedures:

see Yakugaku Zasshi, 92, 465-470 (1972); Synthesis 138(1982); comp. rend., 249, 1367-1368 (1957), and Journal of Amer. Chem. Society, 66, 1883 (1944).

In the General case, the source compound of formula (II) can be obtained as follows.

______where R1, R3and have the specified values.

That is, the compound of formula (VI) can interact with pentasulfide phosphorus or reagents Losson in an inert organic solvent such as benzene, xylene, toluene, etc. at a temperature of 50-60aboutC for 1-3 h in order to obtain the compound of formula (II).

Procedures of its receipt will be described in detail in the examples of the links below.

The compounds of formula (I) can be applied either tematicheskim or parenterally way, Precambrian vary depending on age, diseases and body weight of the patient. In General it is recommended to use the compound of the formula (I) to an adult patient in a dose of 1-600 mg/day, in the preferred embodiment, 10-200 mg/day. The compounds of formula (I) can be included in various forms doses such as tablets, capsules, powders and granules together with the known additives (e.g., excipient, lubricant agent, binding agent), using a known pharmaceutical techniques.

The compounds of formula (I) demonstrate a significant effect improvements in experimental pecenicic disorders caused by the use of the rat D-galactosamine. In addition, the compounds of formula (I) can give improvement caused by complement necrosis of hepatocytes with intravenous administration of monoclonal antibodies relative to the cell membranes of the liver in rats (see Igaku but Aumi, 146, 3; S. 179-180 (1988)).

Thus, the connection of the present invention is extremely effective in the prevention or treatment of liver diseases such as chronic hepatitis, acute hepatitis and liver cirrhosis.

To further illustrate the invention the following are examples for reference, examples and sample tests.

the n-3-carboxylate add 200 ml of methylpropionate and 7.0 ml of tetraisopropyl titanium. The resulting mixture is heated to reflux distilled for three days. After distillation of the excess methylpropionate under reduced pressure the residue is added water and chloroform, and any insoluble materials are separated flitrate. The chloroform layer is washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After distillation of the chloroform, a simple ethyl ether added to the residue to crystallize.

Thus obtain 2.2 g of the compound of the header.

The temperature of the melting point: 104-105aboutC.

The NMR spectrum (CDCl3): to 1.22 (3H, doublet), 2,8-3,6 (3H, multiplet), of 3.95 (3H, singlet), 3.7 to 4.1 (1H, multiplet).

P R I m m e R 2 links. Isopropyl 4-methyl-2-dioxopyrimidine-3-carboxy - lat:

To 5.0 g ethyl-4-methyl-2-dioxopyrimidine-3-carboxylate add 300 ml of isopropyl alcohol 11.4 g of tetraisopropyl titanium. The resulting mixture is heated to reflux distilled at 24 h After distillation of the excess of isopropyl alcohol under reduced pressure, the residue is added water and chloroform, and any insoluble material is separated by filtration. The chloroform layer is washed with water and saturated aqueous sodium chloride, and dried over anhydrous su is the exercise: 41-44aboutC.

The NMR spectrum (CDCl3): 1.1 to 1.4 (M, multiplet), 2,7-4,0 (4H, multiplet), 5,11 (1H, multiplet).

Using the same procedure that was described in example for reference 2, get each of the following compounds of examples for references 3-5.

P R I m e R for reference 3. Secondary.-butyl 2-dioxopyrimidine-3-carboxylate:

The melting-point: 44-45oC.

The NMR spectrum (CDCl3): 0,9-1,4 (6N, multiplet), of 1.65 (2H, multiplet), to 2.55 (2H, multiplet), of 3.5-3.9 (3H, multiplet), 4,84 (1H, multiplet).

P R I m e R references 4.

Isopropyl 4-isopropyl-2-dioxopyrimidine-3-carboxylate:

The melting-point: 90-93oC.

The NMR spectrum (CDCl3): 0,92 (6N,doublet), of 1.28 (3H, doublet), of 1.34 (3H, doublet), of 1.5-2.0 (1H, multiplet), a 2.75 (1H, Quartet), the 3.2 to 3.9 (3H, multiplet), 5,13 (1H, multiplet).

P R I m e R references 5.

Isopropyl 4-phenyl-2-dioxopyrimidine-3-carboxylate:

The melting-point: 97-101aboutC.

The NMR spectrum (CDCl3): of 1.27 (3H, doublet), of 1.35 (3H, doublet), 3,6-4,3 (4H, multiplet), 5,16 (1H, multiplet) 7,30 (5H, singlet).

P R I m e R references 6.

Ethyl 4-methyl-2-dioxopyrimidine-3-carboxylate:

2.5 g of ethyl 4-methyl-2-SUP>C for 1 h After cooling, the undissolved material is separated by filtration, and the filtrate concentrated. The residue was subjected to purification on a chromatographic column of silica gel to obtain the result of 2.1 g of compound header example in the form of an oily product.

The NMR spectrum (CDCl3): of 1.23 (3H, doublet), of 1.34 (3H, triplet), 2,80-4,00 (4H, multiplet), 4,30 (2H, Quartet).

Using the same procedure that was described in example 6 links, get each of the following compounds of examples for references 7 and 8.

P R I m e R references 7.

Ethyl 4-isopropyl-2-dioxopyrimidine-3-carboxylate:

The melting-point: 68-69oC.

The NMR spectrum (CDCl3): 0,90 (6N, doublet), of 1.32 (3H, triplet), of 1.75 (1H, multiplet), a 2.75 (1H, multiplet).

P R I m e R references 8.

Ethyl 4-phenyl-2-dioxopyrimidine-3-carboxylate:

The melting-point: 96-97oC.

The NMR spectrum (CDCl3): of 1.32 (3H, triplet), 4.26 deaths (1H, Quartet), 4,28 (1H, Quartet), 7.3 to 7.4 (5H, multiplet).

P R I m e R references 9.

Tration.-butyl-2-dioxopyrimidine-3-carboxylate:

1.7 g tration.-butyl-2-oxopyrrolidin-3-carboxylate and 1.8 g of reagent Losson dobavleny materials, the solvent is distilled off, and the obtained residue was subjected to purification on a chromatographic column of silica gel to obtain the result of 1.0 g of compound of the header.

The temperature of the melting point: 110-111aboutC.

The NMR spectrum (CDCl3) 1,50 (N, singlet), 2,3-2,7 (2H, multiplet) 3,4-4,0 (3H, multiplet).

P R I m e R 1.

Ethyl (7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate

4.9 g isopropyl 4-methyl-2-dioxopyrimidine-3-carboxylate are dissolved in 50 ml of ethanol and to the solution was added 3.0 g of anhydrous sodium acetate and 7.7 g of ester ethyl 4-bromocatechol acid. The resulting mixture was stirred at room temperature for 3.5 hours the Precipitated crystals thus collected by filtration, washed with water and dried. After recrystallization from a mixture of chloroform and ethanol and 3.3 g receive connections from the header.

The temperature of the melting point: 103-104oC.

Calculated, %: C 57,86; H To 6.80; N 4,50.

C15H21NO4S

Found, %: C 57,92; H Is 6.61; N 4,36.

NMR spectrum; (CDCl3): 1.1 to 1.4 (M, multiplet), 3,1-4,0 (3H, multiplet), 4,19 (2H, Quartet), was 4.76 (2H, doublet), 4,84 (1H, triplet), 5,07 (1H, multiplet).

Using the>/P>P R I m m e R 2. Ethyl /7-methoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate

The temperature of the melting point: 182-184aboutC.

The NMR spectrum (CDCl3): of 1.18 (3H, triplet), 2,9-3,2 (2H, multiplet), 3,61 (3H, singlet), 3,6-3,9 (2H, multiplet), Android 4.04 (2H, Quartet), 4,80 (2H, singlet), 4,91 (1H, triplet).

P R I m e R 3. Ethyl (7-etoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate

The temperature of the melting point: 148aboutC.

The NMR spectrum (CDCl3): of 1.27 (3H, triplet), of 1.29 (3H, triplet), 1,32 (3H, doublet), 3,20 (1H, multiplet), is 3.5-4.0 (2H, multiplet), 4,14 (2H, Quartet), 4,19 (2H, Quartet), of 4.77 (2H, doublet), is 4.85 (1H, triplet).

P R I m e R 4.

Ethyl /7-etoxycarbonyl-6-isopropyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate

The melting-point: 100oC.

The NMR spectrum (CDCl3): 0,78 (3H, doublet), were 0.94 (3H, doublet), of 1.29 (3H, triplet), is 1.31 (3H, triplet), 2,35 (1H, multiplet), 3,4-3,7 (3H, multiplet), 4,19 (2H, Quartet), are 4.24 (2H, Quartet), 4,82 (2H, singlet), 4,94 (1H, singlet).

P R I m e R 5.

Ethyl /7-isopropoxycarbonyl-6-isopropyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate

The melting point 70-72oC.

The NMR spectrum (CDCl3): of 0.75 (3H, doublet,singlet), 4,82 (1H, singlet), 5,00 (1H, multiplet).

P R I m e R 6.

Ethyl /7-etoxycarbonyl-6-phenyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate

The temperature of the melting point: 163-164aboutC.

The NMR spectrum (CDCl3): to 1.15 (3H, triplet), of 1.28 (3H, triplet), 3,5-4,8 (7H, multiplet), 4,90 (3H, singlet) 7,34 (5H, singlet).

P R I m e R 7.

Ethyl /7-isopropoxycarbonyl-6-phenyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate

The temperature of the melting point: 161-163oC.

The NMR spectrum (CDCl3): and 1.00 (3H, doublet), of 1.17 (3H, doublet), of 1.26 (3H, triplet), to 3.58 (1H, Quartet), of 4.00 (1H, doublet), 4,14 (2H, Quartet) and 4.65 (1H, Quartet), is 4.85 (3H, singlet), to 4.98 (1H, multiplet), 7,26 (5H, singlet).

P R I m e R 8.

Methyl /7-etoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate

The temperature of the melting point: 157-158aboutC.

NMR-spectrum (DCl3): of 1.31 (3H, triplet), of 1.34 (3H, doublet), 3,71 (3H, singlet), is 4.21 (2H, Quartet), 4,80 (2H, triplet), a 4.86 (1H, doublet).

P R I m e R 9. Ethyl /7-tration.-butoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate

The temperature of the melting point: 178-180oC.

The NMR spectrum (CDCl3: of 1.30 (3H, triplet), 1,50 (N, singlet), 3,0-3,3 (2H, multiple oxycarbonyl/-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate

The temperature of the melting point: 97-98oC.

The NMR spectrum (CDCl3): of 0.94 (3H, triplet), of 1.26 (3H, doublet), of 1.28 (3H, triplet), of 1.62 (2H, multiplet), 3,19 (2H, triplet), of 3.69 (2H, triplet), to 4.16 (2H, Quartet), 4,84 (3H, multiplet), of 4.95 (1H, multiplet).

P R I m e R 11.

4-nitrophenyl/7 isopropoxycarbonyl - Neil-6-methyl-2,3,5,6-tetrahydropyrrolo / 2, 1-b/a thiazol-3-ilidene/acetate

of 8.9 g of isopropyl 4-methyl-2-dioxopyrimidine-3-carboxylate are dissolved in 200 ml of benzene and the solution is added to 5.1 g of anhydrous sodium acetate and 16.7 g of 4-nitrophenyl 4-bromoacetate. The resulting mixture was stirred at room temperature for 8 hours Then add 500 ml of chloroform and the mixture is washed with water and saturated aqueous sodium chloride. After drying and removal of the solvent, the obtained residue was subjected to purification on a chromatographic column of silica gel. Faction elyuirovaniya dichloromethane, is subjected to crystallization from a mixture of simple ether and n-hexane. Thus, the gain of 11.9 g of compound of the header.

The temperature of the melting point: 182-183aboutC.

Calculated, %: C 56,43; H To 4.98; N 6,93.

C19H20N2O6S.

Found, %: C 56,41; H 4,96; N 6,85.

The NMR spectrum (CDCl3< septet), 7,30 (2H, doublet), of 8.28 (2H, doublet),

P R I m e R 12. S-phenyl /7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/thioacetate:

In 15 ml of 70% aqueous methanol, which contains 470 mg hydroxide of sodium, add 3.0 g of ethyl/7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-5-ilidene/acetate. The resulting mixture was stirred at room temperature for 3 hours the Solvent is evaporated until dry. Then the mixture was added 50 ml of tetrahydrofuran and 1.8 ml of triethylamine. Next, add 1.6 ml of pivaloyloxy and the mixture is stirred for 2 hours Then add 1.1 ml of thiophenol and the mixture is stirred at room temperature for 24 hours Added to the reaction mixture in water, then extracted with dichloromethane. After washing with water, the extract is dried over anhydrous sodium sulfate and subjected to distillation. The residue was subjected to purification on a chromatographic column of silica gel. Thus, the gain of 2.6 g of the compound from preparation example in the form of pale yellow needles.

The melting-point: 216-220aboutC.

Calculated, %: C 59,81; H And 5.30; N 3,88.

C18H19NO3S2.

Found, %: C 60,00; H 5,44; N 3,97.

The NMR spectrum (CDCl3): 1,28 (6N, doublet), 3,20 (2 the.

S-phenyl /7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/thioacetate:

Using the same procedure that was described in example 12, receive a connection from header.

The temperature of the melting point: 153-154aboutC.

Calculated, %: C 60,77; H 5,64; N To 3.73.

C19H21NO3S2.

Found, %: C 60,67; H 5,70; N 3,71.

The NMR spectrum (CDCl3): 1,29 (6N, doublet), of 1.35 (3H, doublet), 3,2-4,0 (3H, multiplet), 4,74 (2H, doublet), to 5.08 (1H, septet), 5,32 (1H, triplet), 7,44 (5H, singlet).

P R I m e R 14.

N-methyl-/7-isopropoxycarbonyl-6 - methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide.

1.2 g of ethyl (7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetate are suspended in 25 ml of 40% aqueous solution of monomethylamine and stirred at room temperature for 24 hours the Precipitate is collected by filtration, washed with water and recrystallized from ethanol to get 1.2 g of the compound of the header.

The temperature of the melting point: 188-190aboutC.

Calculated, %: C 56,74; H To 6.80; N 9,45.

C14H20N2O3S.

Found, %: C 56,73; H 6,60; N Was 9.33.

NMR spectrum(1H, multiplet).

P R I m e R 15.

N-methyl-/7-isopropoxycarbonyl-6 - methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

2.0 g of N-methyl-/7-isopropoxycarbonyl-6-methyl-5,6-dihydropyrrolo /2,1-b/a thiazol-3-yl/ndimethylacetamide dissolved in a solvent mixture of 60 ml of chloroform and 6 ml of methanol. To the solution was added 0.3 g of 1,8-diazabicyclo /a 5.4.0/-7-undecene and the mixture is stirred at a temperature of 20aboutWith over 15 hours Later, the reaction mixture is washed with 20 ml of 5% aqueous solution of acetic acid, 0.5% aqueous solution of acid sodium carbonate and saturated aqueous sodium chloride. The chloroform layer is dried over anhydrous sodium sulfate. After distillation of the chloroform obtained crude crystals subjected to recrystallization from ethanol to obtain the result of 1.5 g of the compound of the header.

P R I m e R 16. N-methyl-/7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

Using the same procedure as described in example 14, receives each of the following compounds of examples 16-28.

The temperature of the melting point: 197-198aboutC.

Calculated, %: C 55,30; N To 6.43; N 9,92.

C13H18N2O3S.

Found, %: C 55,63; H Of 6.65; N 10 The), 4,96 (2H, singlet), 5,10 (1H, multiplet).

Thus obtained compound represented the following structural formula:

< / BR>
Nuclear Overhauser effect (hereinafter referred to as AAA) of the hydrogen atom at the 2'-or 5-position in the above formula were analyzed treated with deuterium chloroform. In the radiation of the hydrogen atom at the 2'-position receive a 7.5% increase AAO of a hydrogen atom in the 5-position, while the latter gave an 11.7% increase in AEA relative to the first.

P R I m e R 17. N-methyl-/7-methoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

The melting-point: 211-214aboutC.

Calculated, %: C51,95; H Of 5.55; N 11,02.

C11H14NO3S.

Found, %: C 52; H 5,80; N 10,98.

The NMR spectrum (CDCl3): 2,59 (3H, doublet), 3,03 (2H, triplet) and 3.59 (3H, singlet), the 3.65 (2H, triplet), 4,79 (2H, broad singlet), of 4.95 (1H, triplet).

P R I m e R 18. N-methyl-/7-etoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/-thiazole-3-ilidene/ndimethylacetamide;

The temperature of the melting point: 208-209aboutC.

Calculated, %: C 53,71; H 6,01; N 10,44.

C12H16N2O3S.

Found, %: C 53,96; H 6,17; N 10,30.

The NMR spectrum (CDCl3): 1,"ptx2">

P R I m e R 19.

N-methyl-/7-tration. -butoxycarbonyl - 2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide.

The melting-point: 200-203aboutC.

Calculated, %: C 56,71; H To 6.80; N 9,49.

C14H20N2O3S.

Found, %: C 56,65; N 6,86; N 9,40.

The NMR spectrum (CDCl3): 1,50 (N, singlet), and 2.83 (3H, doublet), 3,0-3,3 (2H, multiplet), 3,5-3,8 (2H, multiplet), 4,70 (1H, triplet), to 4.87 (2H, doublet).

P R I m e R 20. N-methyl-/7-secondary.-butoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide.

The temperature of the melting point: 187-188aboutC.

Calculated, %: 55,06; N 6,93; N 9,17.

C14H20N2O3S5H2O

Found, %: C 55,00; N 6,76; N 9,20.

The NMR spectrum (CDCl3): of 0.93 (3H, triplet), of 1.23 (3H, doublet), to 1.60 (2H, multiplet), and 2.83 (3H, doublet), 3,17 (2H, triplet), 3,62 (2H, triplet), 4,72 (1H, broad), 4,89 (2H, broad), 4,91 (1H, multiplet).

P R I m e R 21. N-methyl-/7-cyclohexyloxycarbonyl-6-methyl-2,3,5,6-tetrahed - reparole /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

The temperature of the melting point: 178-180aboutC.

Calculated, %: C 60,69; H 7,19; N 8,33.

WITH17H24N2O3S.

Found, %: 60,62; H 7,19; N By 8.22.

P R I m e R 22.

N-methyl-/7-etoxycarbonyl-6-methyl - 2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide.

The temperature of the melting point: 186-188oC.

Calculated, %: C 55,30; H To 6.43; N 9,92.

C13H18N2O3S.

Found, %: C 55,36; H 6,46; N 9,44.

The NMR spectrum (CDCl3): of 1.29 (2H, triplet), 1,32 (3H, doublet), 2,84 (3H, doublet), 3,1-3,9 (3H, multiplet), 4,19 (2H, Quartet), to 4.73 (2H, singlet), a 4.86 (2H, singlet).

P R I m e R 23. N-methyl-/7-etoxycarbonyl-6-isopropyl-2,3,5,6-tetrahydropyran - lo /2,1-b/thiazole-3-ilidene/ndimethylacetamide.

The temperature of the melting point: 180-182aboutC.

Elemental analysis for C15H22N2O3Sx x0,2 H2O.

Calculated, %: 57,37; H 7,19; N 8,92.

Found, %: C 57,60; H 7,30; N 8,82.

The NMR spectrum (CDCl3): 0,80 (3H, doublet), were 0.94 (3H, doublet), of 1.32 (3H, triplet), a 2.36 (1H, multiplet), 2,89 (3H, doublet), 3,3-3,7 (3H, multiplet), 4,32 (2H, Quartet), a 4.83 (1H, singlet), to 4.92 (2H, singlet).

P R I m e R 24.

N-methyl-/7-isopropoxycarbonyl-6 - isopropyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

The temperature of the melting point: 149-153oC.

Calculated, %: C 59,23; H 7,46; N 8,63.3
): of 0.77 (3H, doublet), of 0.90 (3H, doublet), 1.27mm (6N, doublet), 2,1-2,6 (1H, multiplet), 2,80 (3H, doublet) 3,2-3,6 (3H, multiplet), 4,80 (3H, singlet), to 4.98 (1H, multiplet).

P R I m e R 25.

N-methyl-/7-etoxycarbonyl-6-phenyl-2, 3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

The melting-point: 168-171aboutC.

Calculated, %: C 62,77; H Of 5.85; N 8,13.

C18H20N2O3S.

Found, %: C 62,77; H 5,94; N 7,86.

The NMR spectrum (CDCl3): of 1.13 (3H, triplet), and 2.83 (3H, doublet), 3,4-5,8 (6N, multiplet), to 4.92 (2H, singlet), 7,26 (5H, singlet).

P R I m e R 26.

N-methyl-/7-isopropoxycarbonyl-6 - phenyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

The temperature of the melting point: 143-146aboutC.

Calculated, %: C 63,66; H Is 6.19; N 7,81.

C19H22N2O3S.

Found, %: C 63,52; H 6,32; N 7,95.

The NMR spectrum (CDCl3): a 1.01 (3H, doublet), of 1.17 (3H, doublet), of 2.81 (3H, doublet), 3,50 (1H, Quartet), 3,98 (1H, triplet), 4,5-5,1 (2H, multiplet), to 4.73 (1H, singlet), of 4.90 (2H, doublet), and 7.1 to 7.4 (5H, multiplet).

P R I m e R 27.

/7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

The temperature of the melting point: 204-207aboutC.

The P CLASS="ptx2">

The NMR spectrum (CDCl3): of 1.28 (6H, doublet), 1,32 (3H, doublet), 3,0-3,3 (1H, multiplet), 3,4-3,9 (2H, multiplet), 4,82 (2H, singlet), of 4.90 (1H, singlet), 5,02 (1H, multiplet).

P R I m e R 28. N-ethyl-/7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyran - role /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

The melting-point: 116-119aboutC.

Calculated, %: C 58,04; H 7,14; N 9,02.

C15H22N2O3S.

Found, %: C 58,17; H 7,32; N 8,76.

The NMR spectrum (CDCl3): to 1.15 (3H, triplet), 1.27mm (6N, doublet), is 1.31 (3H, doublet), 3,1-4,0 (5H, multiplet), 4,72 (1H, triplet), is 4.85 (2H, doublet), of 5.05 (1H, multiplet).

P R I m e R 29. /7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetylpiperidine:

1.0 g of S-phenyl/7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/thioacetate and 1.2 g of piperidine are suspended in 40 ml of tetrahydrofuran, and the suspension is added 740 mg trifenatate silver with stirring at room temperature. After 2 h undissolved material is separated by filtration, and the filtrate concentrated. The residue was subjected to purification using chromatographic column on silica gel and recrystallization from ethanol. Thus, the gain of 0.65 g of compound of the header.

N2O3S.

Found, %: C 60,39; H 7,30; N Compared To 8.26.

The NMR spectrum (CDCl3): 1,29 (6N, doublet), 1,65 (6N, multiplet), 3,18 (2H, triplet), 3,50 (4H, multiplet), 3,68 (2H, triplet), the 4.90 (2H, singlet), 5,09 (1H, septet), 5,13 (1H, singlet).

Using the same procedure that was described in example 29, receives each of the following compounds of examples 30 and 31.

P R I m e R 30. /7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetylmorpholine:

The temperature of the melting point: 186-187aboutC.

Calculated, %: 56.78 Has; H 6,55; N 8,28.

C16H22N2O4S.

Found, % C 56,48; H To 6.57; N 8,14.

The NMR spectrum (CDCl3): 1,28 (6N, doublet), 3,19 (2H, triplet), 3.5 to 3.8 (10H, multiplet), 4,91 (2H, singlet), is 5.06 (1H, singlet), 5,07 (1H, septet).

P R I m e R 31. /7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetylmorpholine:

The temperature of the melting point: 183-185aboutC.

Calculated, %: C 54,21; H Of 6.26; N Of 7.90.

C16H22N2O3S2.

Found, %: C 53,97; H 6,28; N 7,74.

The NMR spectrum (CDCl3): 1,29 (6N, doublet), to 2.66 (4H, triplet), up 3.22 (2H, triplet), and 3.72 (2H, triplet), 3,88 (4H, triplet), 4,94 (2H, singlet), to 5.08 (1H, septet), 5,10 (1H, singlet).

g S-phenyl/7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/thioacetate suspended in 10 ml of 40% aqueous dimethylamine and stirred at room temperature for 1 h After distillation of the excess dimethylamine obtained crude crystals subjected to recrystallization from isopropyl alcohol. Thus obtain 0.7 g of soedinenii header example in the form of crystals.

The temperature of the melting point: 159-160aboutC.

Calculated, %: C 54,73; H 6,90; N 9,12.

C14H20N2O3S0,6H2O.

Found, %: C 54,80; H 7,05; N 8,95.

The NMR spectrum (CDCl3): 1,30 (6N, doublet), 3,06 (6N, singlet), 3,21 (2H, triplet), and 3.72 (2H, triplet), of 4.95 (2H, singlet), 5,11 (1H, septet), 5,13 (1H, singlet).

Using the same procedure as described in example 32, receives each of the following compounds of examples 33 and 34.

P R I m e R 33. /7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetylpiperidine:

The temperature of the melting point: 155-158aboutC.

Calculated, %: C 61,69; H Of 7.48; N 7,99.

C18H26N2O3S.

Found, %: C 61,56; H 7,44; N 7,80.

The NMR spectrum (CDCl3): 1,27 (6N, doublet), of 1.33 (3H, doublet), 2,5-2,8 (6N, multiplet), a 3.2 to 3.8 (7H, multiplet), is 4.85 (2H, doublet), is 5.06 (1H, septet), 5,13 (1H, triplet).

P R I m e R 34.

/7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo- /2,1-b/thiazole-3-ilidene/is 2">

C17H24N2O4S.

Found, %: C 57,76; H 6,90; N 7,80.

The NMR spectrum (CDCl3): 1,27 (6N, doublet), of 1.33 (3H, doublet), 3.1 to 3.4 (1H, multiplet), 3,4-3,9 (10H, multiplet), is 4.85 (2H, doublet), of 5.05 (1H, triplet), 5,13 (1H, septet).

P R I m e R 35.

N, N-dimethyl-/7-isopropoxycarbonyl - 6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

In 1.50 g of 4-nitrophenyl /7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo - lo /2,1-b/thiazole-3-ilidene/acetate add 40 ml of 25% aqueous dimethylamine and the mixture is stirred at room temperature for 3 days. The mixture was added 40 ml of water and the resulting thus precipitate is collected by filtration, washed with water and dissolved in chloroform. After drying and removal of the solvent thus obtained crude crystals subjected to recrystallization from a solvent mixture of simple ether and n-hexane. Thus obtain 0.6 g of the compound of the header.

The temperature of the melting point: 126-128aboutC.

Calculated, %: C 58,04; H 7,14; N 9,02.

C15H22N2O3S.

Found, %: C 58,28; H 7,15; N Remaining 9.08.

The NMR spectrum (CDCl3): 1,24 (6N, doublet), of 1.33 (3H, doublet), to 3.02 (6N, singlet), 3,1-3,3 (1H, mult is isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/acetylthiocholine:

Using the same procedure that was described in example 35, receive a connection from header.

The melting point 164-165aboutC.

Calculated, %: 55,41; N 6,56; N 7,60.

C17H24N2O3S2.

Found, %: C 55,23; H 6,56; N 7,38.

The NMR spectrum (CDCl3): 1,27 (6N, doublet), of 1.33 (3H, doublet), of 2.5-2.8 (4H, multiplet), 3,21 (1H, double doublet), 3,6-4,0 (6N, multiplet), is 4.85 (2H, doublet), 5,07 (1H, singlet), 5,13 (1H, septet).

P R I m e R 37.

N-methyl-/7-isopropoxycarbonyl-6 - methyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

15.3 g of N-methyl-/7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo- /2,1-b/thiazole-3-ilidene/ndimethylacetamide dissolved in a solvent mixture containing 300 ml of chloroform and 120 ml of tetrahydrofuran. Then the solution is added to 11.7 g of 2,3-dichloro-5,6-diseaseprevention under stirring and cooling with cold water. After 0.5 h the mixture was added saturated aqueous solution of acid sodium carbonate. After stirring the undissolved material is separated by filtration using celite, and the filtrate is extracted with chloroform, the chloroform phase is washed with water and saturated sodium chloride solution and dried. After distillation, rastvoritelyami header.

The temperature of the melting point: 173-175aboutC.

Calculated, %: C 57,12; H 6,16; N 9,52.

C14H18N2O3S.

Found, %: C 57,06; H 6,12; N 9,48.

The NMR spectrum (CDCl3): 1,35 (6N, doublet), and 2.27 (3H, singlet), 2,90 (3H, doublet), 4,91 (2H, doublet), 5,16 (1H, multiplet), 5,6 (1H, multiplet), of 5.68 (1H, triplet), to 6.67 (1H, singlet).

Thus obtained compound represented the following structural formula

< / BR>
AEO hydrogen atom at the 2'- or 5'-position in the above formula analyze in dimethyl sulfoxide (DMSO-dt). In the radiation of the hydrogen atom at the 2'-position receive a 10% increase in AEA of a hydrogen atom in the 5-position, while the latter gave a 6% increase of AEO relative to the first.

Using the procedure described in example 37, receives each of the following compounds of examples 38-49.

P R I m e R 38.

N-methyl-/7-isopropoxycarbonyl-2,3 - dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

The temperature of the melting point: 191-192oC.

Calculated, %: C 55,70; H Of 5.75; N 9,99.

WITH13H16N2O3S.

Found, %: C 55,67; H 5,86; N 10,00.

The NMR spectrum (CDCl3): 1,33 (6N, doublet), 2,89 (3H, doublet), to 4.98 (2H, dustprotector-6-isopropyl-2,3-dihydrospiro - lo /2,1-b/thiazole-3-ilidene/ndimethylacetamide.

The temperature of the melting point: 175-177aboutC.

Calculated, %: C 59,62; H 6,56; N 8,70.

C16H22N2O3S.

Found, %: C 59,50; H 6,62; N 8,83.

The NMR spectrum (CDCl3): 1,20 (6N, doublet), 1,33 (6N, doublet), 2,87 (3H, doublet), 3,32 (1H, multiplet), is 4.85 (2H, doublet), 5,10 (1H, multiplet), of 5.68 (1H, triplet), 6,60 (1H, singlet).

P R I m e R 40, N-methyl-/7-isopropoxycarbonyl-6-phenyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

The melting-point: 155-159aboutC.

Calculated, %: C PHP 64.00; H 5,66; N 7,86.

C19H20N2O3S.

Found, %: C63,79; H 5,64; N Of 7.90.

The NMR spectrum (CDCl3): of 1.26 (6H, doublet), is 2.88 (3H, doublet), to 4.92 (2H, doublet), is 5.18 (1H, multiplet), of 5.75 (1H, triplet), 6,85 (1H, singlet), and 7.3 to 7.7 (5H, multiplet).

P R I m e R 41. N-methyl-/7-etoxycarbonyl-6-methyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

The temperature of the melting point: 177-178aboutC.

Calculated, %: C 55,69; H Of 5.75; N 9,99.

C13H16N2O3S.

Found, %: C 55,37; H 5,73; N 9,94.

The NMR spectrum (CDCl3): of 1.31 (3H, triplet), 2,22 (3H, doublet), 4,22 (2H, Quartet), 4,84 (2H, doublet), 5,88 (1H, triplet), 6,72 (1H, doublet), 7,10 (1H, singlet).

P R I m e R 42. /7-isoprop-180aboutC.

Calculated, %: C 55,70; H Of 5.75; N 9,99.

C13H16N2O3S.

Found, %: C 55,73; H 5,71; N 10,06.

The NMR spectrum (CDCl3): 1,27 (6N, doublet), of 2.20 (3H, doublet), 4,82 (2H, doublet), free 5.01 (1H, multiplet), 6,04 (1H, triplet), 6,97 (1H, Quartet).

P R I m e R 43. N-ethyl-/7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo- /2,1-b/thiazole-3-ilidene/ndimethylacetamide.

The temperature of the melting point: 139-140aboutC.

Calculated, %: C 58,42; H Is 6.54; N Remaining 9.08.

C15H20N2O3S.

Found, %: C 58,25; H 6,33; N 9,25.

The NMR spectrum (CDCl3): to 1.15 (3H, triplet), 1.27mm (6N, doublet), of 2.28 (3H, singlet), 3,1-3,6 (2H, multiplet), of 4.90 (2H, doublet), of 5.15 (1H, multiplet), of 5.68 (1H, triplet), of 6.65 (1H, singlet).

P R I m e R 44. /7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/acetylmorpholine.

The temperature of the melting point: 156-158aboutC.

Calculated, %: C 58,27; H 6,33; N 7,99.

C17H22N2O4S.

Found, %: C 58,45; H 6,32; N Of 7.90.

The NMR spectrum (CDCl3): 1,33 (6N, doublet), 2,28 (3H, doublet), 3,4-3,9 (8H, multiplet), to 4.87 (2H, doublet), of 5.15 (1H, septet), the 6.06 (1H, triplet), 6,74 (1H, broad singlet).

P R I m e R 45. /7-isopropoxycarbonyl-6-methyl-2,3-ASS="ptx2">

Calculated, %: C 55,71; H Equal To 6.05; N Of 7.64.

C17H22N2O3S2.

Found, %: C 55,55; H Of 5.99; N Of 7.48.

The NMR spectrum (CDCl3): 1,33 (6N, doublet), 2,28 (3H, doublet), 2,6-2,8 (4H, multiplet), 3.7 to 4.1 (4H, multiplet), a 4.86 (2H, doublet), is 5.18 (1H, septet), the 6.06 (1H, triplet), 6,77 (1H, doublet).

P R I m e R 46. /7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/acetylpiperidine.

The temperature of the melting point: 122-123oC.

Calculated, %: C 62,04; H 6,94; N 8,04.

C18H24N2O3S.

Found, %: C 61,80, H 6,98, N 7,88.

The NMR spectrum (CDCl3): 1,33 (6N, doublet), 1,5-1,8 (6N, multiplet), 2,28 (3H, doublet), 3,4-3,7 (4H, multiplet), to 4.87 (2H, doublet), of 5.15 (1H, septet), 6,13 (1H, triplet), 6,76 (1H, doublet).

P R I m e R 47. N,N-dimethyl-/7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide.

The temperature of the melting point: 132-135aboutC.

Calculated, %: 58,40; H Is 6.54; N Is 9.09.

C15H20N2O3S.

Found, %: C 58,37; H 6,50; N 8,96.

NMR-spectrum (DCl3): 1,33 (6N, doublet), to 2.29 (3H, doublet), 3,07 (6N, singlet), 4,88 (2H, doublet), of 5.15 (1H, septet), 6,10 (1H, trilat), to 6.75 (1H, doublet).

P R I m e R 48. N-methyl-/7-cyclohexyl) - Rev. P>oC.

Calculated, %: C 61,05; H 6,63; N Scored 8.38.

C17H22N2O3S.

Found, %: C 61,02; H Of 6.68; N 8,20.

The NMR spectrum (CDCl3): 1,1-2,2 (1H, multiplet), and 2.27 (3H, doublet), 2,89 (3H, doublet), 4,91 (2H, doublet), 4,9-5,1 (1H, multiplet), 5,69 (1H, triplet), of 6.65 (1H, Quartet).

P R I m e R 49. N-methyl-/6-ethyl-7-isopropoxycarbonyl-2,3-dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide:

The melting-point: 179-182aboutC.

Calculated, %: C 58,42; H Is 6.54; N Remaining 9.08.

C15H20N2O3S.

Found, %: C 58,41; H Of 6.49; N 9,12.

The NMR spectrum (CDCl3): to 1.19 (3H, triplet), 1,33 (6N, doublet), 2,73 (2H, Quartet), 2,89 (3H, doublet), of 4.90 (2H, doublet), of 5.15 (1H, septet), 5,71 (1H, triplet), 6,60 (1H, singlet).

P R I m e R 50. Methyl/7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/a thiazol-3-yl/acetate.

4.0 g isopropyl 4-methyl-2-dioxopyrimidine-3-carboxylate, 4.7 g of methyl 4-bromocrotonate and 2.1 g of anhydrous sodium acetate are suspended in 100 ml of ethanol and stirred at a temperature of 60-70aboutC for 3 hours. After removal of the solvent under reduced pressure the residue is dissolved in ethyl acetate, washed with saturated aqueous sodium chloride and dried over anhydrous sulfate is some column of silica gel. So get a connection from header example (4.5 g) in the form of a pale yellow oily product.

The NMR spectrum (CDCl3): of 1.1-1.3 (3H, multiplet), 1,25 (6N, doublet), 2,2-3,8 (8H, multiplet), and 3.72 (3H, singlet), to 5.03 (1H, septet.

P R I m e R 51. Methyl /7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/a thiazol-3-yl/acetate.

Using the same procedure as described in example 50, receive a connection from header.

Calculated, %: C 54,72; H Of 6.71; N 4,91.

C13H19NO4S.

Found,% : C 54,71; H 6,64; N 4,74.

The NMR spectrum (CDCl3): 1,25 (6N, doublet), 2,5-3,8 (N, multiplet), and 3.72 (3H, singlet), to 5.03 (1H, septet).

P R I m e R 52. N-methyl-/7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetradehydro - role /2,1-b/a thiazol-3-yl/ndimethylacetamide.

4.5 g of methyl /7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/a thiazol-3-yl/acetate was added 100 ml of 40% aqueous solution of monomethylamine. The mixture is stirred at room temperature for 20 hours. After distillation, monomethylamine the residue is extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After distillation of the solvent to obtain 4.1 g joint is S="ptx2">

NMR-range, (CDCl3): 1,25 (N, doublet), 1,8-3,9 (8H, multiplet), of 2.81 (3H, doublet), free 5.01 (1H, septet).

P R I m e R 53. N-methyl-/7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo /2,1-b/a thiazol-3-yl/ndimethylacetamide.

Using the same procedure as described in example 52, receive a connection from header.

The melting-point: 79-95oC.

Calculated, %: 54,91; H To 7.09; N 9,85.

C13H20N2O3S.

Found, %: C 54,86; H 7,05; N To 9.91.

NMR-range, (CDCl3): 1,25 (6N, doublet), 2,3-3,8 (N, multiplet), of 2.81 (3H, doublet), 5,00 (1H, septet).

P R I m e R 54. N-methyl-/7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo- /2,1-b/a thiazol-3-yl/ndimethylacetamide.

4.1 g of N-methyl-/7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/a thiazol-3-yl/ndimethylacetamide dissolved in 150 ml of chloroform and 3.9 g of 2,3-dicyano-5,6-di-chloro-parabenzoquinone add in the semi-obtained solution under cooling with ice and stirring. The mixture is stirred at room temperature for 1 h After removal of the undissolved materials, the chloroform layer washed sequentially with a saturated aqueous solution of acid sodium carbonate and saturated aqueous sodium chloride. After drying over anhydrous sulfate agile. Thereby obtaining 2.0 g of the compound of the header.

The temperature of the melting point: 108-109aboutC.

Calculated, %: C 56,73; H To 6.80; N 9,45.

WITH14H20N2O3S.

Found, %: C 56,71; H 6,83; N 9,49.

The NMR spectrum (CDCl3): 1,30 (6N, doublet), to 2.18 (3H, doublet), 2,3-2,7 (2H, multiplet), 2,80 (3H, doublet), 3,32 (1H, double doublet), with 3.89 (1H, double doublet), 4,7-5,0 (1H, multiplet), to 5.08 (1H, multiplet), 6,38 (1H, doublet).

P R I m e R 55. N-methyl-/7-isopropoxycarbonyl-2,3-dihydropyrrolo /2,1-b/a thiazol-3-yl/ndimethylacetamide.

Using the same procedure as described in example 54, to receive a connection from header.

The temperature of the melting point: 117-119aboutC.

Calculated, %: C 55,30; H To 6.43; N 9,92.

C13H18N2O3S.

Found, %: C 55,27; H 6,38; N 9,86.

The NMR spectrum (CDCl3): 1,30 (6N, doublet), to 2.57 (1H, singlet), of 2.64 (1H, singlet), 2,80 (3H, doublet), to 3.38 (1H, double doublet), 3,99 (1H, double doublet), is 4.93 (1H, triplet of double doublets), 5,10 (1H, septet), 6,53 (1H, doublet), 6,56 (1H, doublet).

P R I m e R 56. /7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo /2,1-b/a thiazol-3-yl/acetylmorpholine.

1.54 g /7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo /2,1-b under ice cooling and stirring, 1.44 g of N,N-dicyclohexylcarbodiimide. The mixture is then stirred at room temperature for 9 days. After separation by filtration of undissolved materials, the solvent is distilled off. Oily residue, thus obtained, was subjected to purification on a chromatographic column of silica gel. After crystallization from a mixture of simple ether/n-hexane gain of 1.05 g of compound of the header.

The temperature of the melting point: 97-99aboutC.

Calculated, %: C 57,93; H 6,86; N 7,95.

C17H24N2O4S.

Found, %: C 57,99; H 6,91; N Of 7.90.

The NMR spectrum (CDCl3): 1,32 (6N, doublet), 2,22 (3H, singlet), of 2.5-2.8 (2H, multiplet), 3,2-3,5 (3H, multiplet), 3,4-3,7 (6N, multiplet), of 4.00 (1H, double doublet), 4,7-5,1 (1H, multiplet), 5,13 (1H, septet), 6.42 per (1H, singlet).

P R I m e R 57. /7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo /2,1-b/a thiazol-3-yl/ndimethylacetamide.

1.0 g of methyl /7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo /2,1-b/a thiazol-3-yl/acetate dissolved in 30 ml of methanol and to the solution was added 30 ml of concentrated aqueous ammonia. The resulting mixture was stirred at room temperature for 6 days. After the distillation of the ammonia, the residue is extracted with chloroform. The chloroform layer was washed with saturated aqueous anisty the residue is crystallized from a mixture of simple ether/n-hexane. Thus obtain 0.3 g of the compound of the header.

The temperature of the melting point: 143-146oC.

Calculated, %: C 55,30; H To 6.43; N 9,92.

C13H18N2O3S.

Found, %: C 55,20; H 6,47; N 9,71.

The NMR spectrum (CDCl3): 1,31 (6N, doublet), of 2.21 (3H, doublet), 2,6-2,8 (2H, multiplet), to 3.34 (1H, double doublet), of 3.94 (1H, double doublet), 4,7-5,0 (1H, multiplet), 5,12 (1H, septet), to 6.43 (1H, doublet).

P R I m e R 58.

1) Ethyl /7-isopropoxycarbonyl-6-methyl-5,6-dihydropyrrolo /2,1-b/a thiazol-3-yl/acetate.

2.0 g isopropyl 4-methyl-2-dioxopyrimidine-3-carboxylate are dissolved in 30 ml of acetic acid and the solution is added to 4.2 g of ethyl 4-bromoacetate. The mixture is stirred at 20aboutC for 1 h After the distillation of acetic acid under reduced pressure, add 50 ml of water and chloroform, and the aqueous layer was collected. The aqueous layer was converted into alkaline using acidic sodium carbonate, extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. After distillation of the chloroform obtain 1.5 g of the compound of header example in the form of an oily product.

The NMR spectrum (CDCl3): 1,26 (6N, doublet), of 1.28 (3H, triplet), of 1.30 (3H, doublet), 3,37 (2H, singlet), 3,3-3,8 (2H, m is oxycarbonyl-6-methyl-5,6-dihydropyrrolo /2,1-b/thiazole-3/ndimethylacetamide.

3.3 grams ethyl /7-isopropoxycarbonyl-6-methyl-5,6-dihydropyrrolo /2,1-b/a thiazol-3-yl/acetate added to 60 ml of 40% aqueous solution of monomethylamine and stirred at a temperature of 20aboutC for 24 h, the Residue is collected by filtration, washed with water, dried and subjected to recrystallization from ethanol.

Thus, the gain of 2.2 g of compound of the header.

The temperature of the melting point: 203-205oC.

Calculated, %: C 56,71; H To 6.80; N 9,49.

C14H20N2O3S.

Found, %: C 57,03; H 6,95; N 9,65.

The NMR spectrum (CDCl3): 1,23 (6N, doublet), of 1.27 (3H, doublet), 2,71 (3H, doublet), 3,30 (2H, singlet), 3,4-3,8 (2H, multiplet), 4,17 (1H, multiplet), 4,96 (1H, multiplet), of 5.92 (1H, singlet).

3) N-methyl-/7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide.

2.0 g of N-methyl-/7-isopropoxycarbonyl-6-methyl-5,6-dihydropyrrolo /2,1-b/thiazole-3-ilidene/ndimethylacetamide dissolved in 60 ml of chloroform and to the solution was added 0.3 g of 1,8-diazabicyclo /5.4.0/-7-undecene. The resulting mixture was stirred at room temperature overnight. Then the chloroform phase is successively washed with 20 ml of 5% aqueous solution of acetic acid and 10 ml of water. The chloroform phase consequently the Oia, and dried over anhydrous sodium sulfate. After removal of the solvent the crude crystals subjected to recrystallization from ethanol. Thus obtained 1.2 g of the compound of the header.

Thus obtained compound was identical to the compound of example 14 in regard to the temperature of the melting point, and a variety of spectrometric data.

P R I m e R test 1.

The impact on the model of hepatitis induced by D-galactosamine:

Test animal: male SD rats weighing 170 to 200 g

Use the test connection:

Each test compound suspended in 1% aqueous solution of methylcellulose and used tematicheskim way at a dose of 400 mg/kg for 1 h before induction of hepatic disease.

Induction of Hepatology by galactosamine (hepatitis):

Hydrochloride D-galactosamine dose of 800 mg/kg was used (by subcutaneous way) to rats to induce hepatitis. Animals were not fed after applying D-galactosamine. After 24 h took samples of blood from the Vena cava under ether anesthesia and as indicators of hepatic disorders were measured concentration GPT (alanine aminotransferase) and GOT (aspartamine and GOT the serum in the test group is significantly lower compared to values in the control group of diseases. Thus, the compounds of the present invention provide high efficiency, the improvement or prophylaxis of hepatitis caused by the use of hydrochloride D-galactosamine.

P R I m e R test 2.

The compound from example 16 or 37 suspended in 1% aqueous solution of methylcellulose and used tematicheskim way to SD rats (males) at a dose of 400 mg/kg the result is not killed a single animal.

Although the present invention has been described in detail and with reference to specific embodiment, it is obvious to any expert in this field of technology that can implement various changes and modifications without leaving the field covered by the present invention.

Tests for acute toxicity in rats.

(Methods).

Test samples.

Each of the compounds of examples 16 and 37 suspended in 1% solution of methylcellulose.

Experimental animals.

In our experiments we used 80 male rats Slc-SD at the age of five weeks (group RO with the introduction connections oral; rat weight from 114 to 135 g; group IP introduction - intraperitoneal; rats weighing between 128 to entam. In particular, individuals RO-group before assigning them of the tested compounds was kept without food (16 h only on the water). From each group of animals used in experiments 4 individuals.

Dose:

in the RO-group test was carried out at two different doses (2000 mg/kg and 4000 mg/kg or 1 ml/100 g and 2 ml/100 g), and in the IP group at three different doses (500 mg/kg 750 mg/kg and 1000 mg/kg or of 0.66 and 1.33 ml/100 g). The test compound was administered to receive in the form of single (single) dose.

Observable signs:

Common symptoms, mortality, body weight and pathological changes of the organs (at the time of autopsy).

Period of observation:

Observation of experimental animals was carried out for 7 days including the day of reception of the tested compounds. After observing the surviving animals were killed under ether anesthesia by lowering blood from the veins of the abdomen and visually studied the condition of various organs.

The results are shown in table.2.

DERIVATIVES PYRROLO(2,1-b)THIAZOLE AND DERIVATIVES of 2-DIOXOPYRIMIDINE AS intermediates FOR OBTAINING DERIVATIVES PYRROLO(2,1-b)THIAZOLE.

1. Derivatives pyrrolo(2,1-b)thiazole of General formula

< / BR>
alkoxygroup, the amino, lower mono - or dialkylamino or cyclic amino group, which may also contain as ring atoms oxygen atom or sulfur, phenylthio - or 4-nitrophenylacetate;

R3is hydrogen, lower branched or unbranched alkyl, or phenyl;

- simple or double bond.

2. Derivatives of 2-dioxopyrimidine General formula

< / BR>
where R1the lower branched or unbranched alkyl;

R3is hydrogen, lower branched or unbranched alkyl or phenyl;

as intermediates for obtaining derivatives pyrrolo(2,1-b)thiazole.

 

Same patents:

The invention relates to new biologically active chemical compounds, specifically to derived dihydropyrimidine formula I

where R1- C1-C6-alkoxy or phenylaminopropyl,

R2- C1-C6-alkyl or phenyl,

R3is a hydrogen atom or a C1-C6-alkyl,

R4- C1-C6-alkyl or phenyl which may be substituted by one or more identical or different substituents from the group halogen, nitro, C1-C6-dialkylamino,1-C6-alkyl, C1-C6-alkoxy and hydroxy-group, or their therapeutically acceptable salts accession acid with protivominniy and anti-inflammatory activity

The invention relates to the first new derivatives of 1,2,5-thiadiazolo[3,4-h] quinoline General formula 1

NNAlK where Alk is methyl or ethyl, with improved anthelminthic activity

The invention relates to new derivatives of 2-methyl-3-etoxycarbonyl-5-(2'-cyano-3'-aminopropyl-2'-enylidene)pyrrolin - 2-it-4 or 2-(2'-cyano-3'-aminopropyl-2'-enylidene)indolinone-3 of the General formula 1

< / BR>
where, if R = COOC2H5, R1= CH3, R2+ R3= (CH2)5(a) R2+ R3= CH2CH2OCH2CH2(b) R2= H, R3= CH2C6H5(C) R2= H, R3= CH2C6H4OCH3-4 (g) R2= H, R3= CH2C6H3(OCH3)-3,4 (d) R + R1= CH = CH-CH = CH R2= R3= H (e) R2= H, R3= (CH2)6(W) R2= H, R3= CH2CH2N(C2H5)2(C) R2= H, R3= CH2CH(OH)CH2OH and R2+ R3= CH2CH2OCH2CH2(K) R2+ R3= CH2CH2N(CH3)CH2CH2(l) R2+R3=CH2CH2= H, R3= CH2C6H4OCH3-4 (o) R2= H, R3= CH2C6H3(OCH3)-3,4 (p) R2= H, R3= CH(CH3)C6H5(p) R2= H, R3= CH2CH2C6H5(c) R2= H, R3= CH2CH2C6H3(OCH3)-3,4 (t) R2= H, R3= CH(CH3)CH2C6H5(u) R2= H, R3= C6H5(f) R2= H, R3= C6H4OCH3-4 (x) with antihypertensive activity
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 a new di-tert-butylaniline derivative used for the treatment of inflammatory processes, as well as caused by ischemia cell damage

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

FIELD: medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a solid composition eliciting with an anti-ulcer activity and to a method for its preparing. Pharmaceutical composition consists of a core containing famotidine as an active component and starch, aerosil, stearic acid salt as accessory inert substances wherein a core is covered by polymeric envelope. Core comprises glucose and stearic acid as an accessory inert substance and magnesium stearate as a stearic acid salt. Polymeric envelope comprises oxypropylmethylcellulose, propylene glycol, castor oil, talc and titanium dioxide taken in the definite ratio of all components in the composition. Method for preparing pharmaceutical composition involves preparing raw, mixing therapeutically effective amount of famotidine with glucose and starch, moistening the mixture with starch paste, granulation, drying wetted granulate, repeated granulation, powdering dry granules, tableting and applying polymeric envelope containing oxypropylmethylcellulose on prepared cores with addition of titanium dioxide, propylene glycol, castor oil and talc. Invention provides enhancement of degradability, solubility and stability in storing.

EFFECT: improved method for preparing, valuable pharmaceutical properties of composition.

3 cl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to methods for treatment of diseases or syndromes associated with metabolism of fatty acids and glucose and to new compounds and their pharmaceutically acceptable salts. Invention relates to applying new compounds and pharmaceutical compositions for treatment of cardiovascular diseases, diabetes mellitus, cancer diseases, acidosis and obesity by inhibition of activity of enzyme malonyl-CoA-decarboxylase. Indicated compounds correspond to formulae (I) and (II) wherein Y, C, R1, R2, R6 and R7 have values given in the invention claim.

EFFECT: valuable medicinal and biochemical properties of azoles.

27 cl, 8 tbl

FIELD: medicine, therapy, gastroenterology.

SUBSTANCE: method involves preliminary assay of the disorder type in gallbladder motor contraction and bile-excretion ways followed by prescribing thermal low-mineralized hydrocarbonate-sodium-sulfate-calcium-magnesium mineral water in the dose by 200-300 ml, 3 times per a day, 1 h before eating, tubages № 3 with mineral water, bathes and shower with mineral water every day for 10-14 days. In the hypotonic type of motor activity method involves mineral water at temperature 25-30°C, and in the hypertonic type - at temperature 38-40°C. Method provides accelerating in scars formation of ulcers and epithelization of erosions in gastroduodenal system, to prevent frequent exacerbations and to reduce activity of Chelicobacter-induced inflammation.

EFFECT: improved therapy method.

4 tbl, 2 ex

FIELD: medicine, endocrinology.

SUBSTANCE: invention relates to treatment of diabetes mellitus in mammals. Invention proposes applying inhibitors of enzyme dipeptidyl peptidase IV as an active component in manufacturing a medicinal agent, and in a method for treatment of diabetes mellitus. Invention provides enhancing the functional activity of insulin-producing cells in animal and differentiation of epithelial cells of the pancreas.

EFFECT: improved method for insulin producing and diabetes treatment.

20 cl, 5 dwg, 2 tbl, 2 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to lyophilized composition comprising epotilone in the effective amount and mannitol or cyclodextrin. The second variant of the lyophilized composition involves epotilone and hydroxypropyl-beta-cyclodextrin. The preferable content of epotilone in the lyophilized composition is from 0.1% to 1.5%, and cyclodextrin - from 90% to 99% as measured for the total mass of solid components. Epotilone-containing lyophilized compositions can be used fro preparing an anti-tumor medicinal agent useful for parenteral administration and the lyophilized composition can be reduced preferably before administration directly. Epotilone-containing lyophilized compositions show improved indices of epotilone solubility and can retain stability for 24-36 months at temperature from 2°C to 30°C being without change of the solubility index.

EFFECT: improved and valuable properties of composition.

10 cl, 4 tbl, 14 ex

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

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: medicine.

SUBSTANCE: method involves using dipeptidyl peptidase IV (DP IV or CD 26) or DP IV-like enzyme for producing drug for treating stress or anxiety cases. Inhibitors are usable in combination with neuropeptides Y. The inhibitors are transported in physiologically compatible carriers. The inhibitors are also produced as prodrugs.

EFFECT: enhanced effectiveness of treatment.

6 cl, 11 dwg, 2 tbl

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