Bis-(hydroxymethyl)-cyclobutyl-purines or pyrimidines and their pharmaceutically acceptable salts

 

(57) Abstract:

Usage: in medicine as a drug. The inventive product - bis-(hydroxymethyl)-cyclobutyl-purines or pyrimidines f-ly I, where R1is f-ly II. The structure of the compounds of formulas I and II are indicated in the text description.

The invention relates to novel purine and pyrimidine compounds exhibiting biological activity, namely the compounds represented by formula I, and their pharmaceutically acceptable salts with, for example, antiviral activity.

HOCH I

In the formula I and in the description of the symbols have the meanings defined below.

R1represents a group of the formula

where R3represents methyl or a group

< / BR>
Preferred compounds of formula I are compounds in which R1represents a group of the formula

< / BR>
< / BR>
< / BR>
The most preferred compounds of formula I are compounds, when R1< / BR>
.< / BR>
The compounds of formula I and their pharmaceutically acceptable salts are antiviral agents that can be used in the treatment of viral infections in mammals, such as the house of Compounds of formula I, where R1represents a group

< / BR>
< / BR>
are effective against one or more of the following viruses: herpes simplex virus 1 and 2, varicella zoster virus, vaccinia virus, the virus murine leukemia and human immunodeficiency virus. They are also active against other varieties DNA and retroviruses.

Examples of DNA viruses, in addition to the above, include other viruses (e.g., Epstein-Barr virus, the virus pseudoleskeella and the like), other se-viruses (e.g., monkey pox and fibroids), papovaviruses (e.g., papilloma virus), the virus serum hepatitis, and adenoviruses. Examples of retroviruses, in addition to the above, include viruses that affect humans, such as T-lymphocytes, lymphotropic viruses (V), and affecting animals, such as feline leukemia virus and equine virus infectious anemia.

The compound of formula I, where R1< / BR>
is active against various DNA and retroviruses described above, with the exception of herpes viruses 1 and 2, varicella zoster virus and virus cytomegalo.

The compounds of this invention can be applied parenteral (e.g. intravenous, intraperitoneal and intramuscular injection), orally or locally depending what internal infections connections can be used orally or parenterally in amounts sufficient to treat the infection. The dose depends on the severity of the infection, but the usual dose ranges from 1.0 to 50 mg/CC of body weight. The desired dose can be applied several times a day at appropriate intervals.

For infections of the eye or other external tissues, for example mouth and skin, the formulations can be applied locally on the affected part of the patient's body in the form of an ointment, paste, aerosol, gel, powder, lotion, suspension or solution (e.g., eye drops). The concentration of compounds in the filler will depend on the severity of infection, but is usually in the range from 0.1 to 7% by weight.

The compound of formula I, where R1< / BR>
,and R7and R8hydrogen can be obtained from the intermediate compounds of formula

where P is a protective group such as acyl, benzyl, silyl; and X leaving group such as chlorine, bromine, iodine or aryl - or alkylsulfonyl, well known in this field (e.g., pair-toluensulfonate or methansulfonate).

The term "acyl" refers to R9C-groups, where R9the lower alkyl group is branched or straight chain with 1-6 carbon atoms or phenyl group.

The term "silyl" refers to the well-known selectasynthesizer or triisopropylsilyl).

The reaction of the compound of formula 2 with a protected form of guanine, for example the compound of the formula

in the presence of such a base as potassium carbonate, sodium hydride or potassium hydride, in an aprotic polar solvent such as dimethylformamide, dimethylsulfoxide or sulfolane (tetramethylsilane), gives the corresponding compound of the formula

< / BR>
The reaction may not necessarily be performed in the presence formed with a metal chelate catalyst such as 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) or 15-crown-5 (1,4,7.10,13-pentachlorobenzene). The removal of the protective group from compounds of formula 4 gives compound of formula I, where R1< / BR>
.< / BR>
When the protective group R in the compound of formula 4 is the acyl group, the protective group R may be selectively removed using, for example, catalytic sodium methylate in methanol or methanolic ammonia. Subsequent removal of O-benzyl protective group on the purine fragment can be achieved by treatment of aqueous alcoholic mineral acid (e.g. aqueous-methanolic hydrochloric acid), sodium in liquid ammonia or by hydrogenolysis (for example, using palladium hydroxide on the on, and then acylamide group.

When the R group in the compound of formula 4 is a silyl protective group, removing it may be performed by using a fluoride ion (e.g., tetrabutylammonium fluoride in tetrahydrofuran). In this case, O-benzyl protective group of the purine can be removed aqueous alcoholic mineral acid or by hydrogenolysis. When the protective group R in the compound of formula 4 is benzyl, the benzyl remove all protective groups is carried out using either sodium in liquid ammonia, or hydrogenation (e.g., palladium hydroxide on coal in cyclohexane or ethanol). Alternative all of the benzyl protective group can be removed by reaction with trichloride boron in dichloromethane.

The reaction of the compound of formula 2 with the compound of the formula

in conditions similar to those used in obtaining the compounds of formula 4, gives compound of formula

NH2

Selective removal of the protective group R gives compound of formula I, where R1< / BR>
< / BR>
For example, when the protective group R in the compound of formula 6 is acyl, the R group may be selectively removed using, for example, catalytic methoxide (methyl who t be selectively removed by reaction with fluoride ion (e.g., fluoride tetrabutylammonium). When the protective group R in the compound of formula 6 is benzyl, the deletion of the R-group can be selectively carried out by reaction with trichloride boron.

Acid hydrolysis (for example, using hot water chlorotoluron the acid chloride group of the compounds of formula I, where R1-

gives compound of formula I, in which R1is a group

< / BR>
The compound of formula 2 can be obtained as follows.

The reaction of diethylfumarate, ketende - ethylacetate hot rubs. the butanol gives compound of formula 7 in the form of a racemic mixture (see K. C. Brannock, et al. J. Org. Chem, 29, 940 (1964)). The interaction of the compounds of formula 7 with a reducing agent such as a hydride methylamine in a solvent, for example diethyl ether or tetrahydrofuran, gives compound of formula 8. Hydroxyl groups can be protected with a protective group P is known in this area ways, giving the compound of formula 9. Demetalizarea the compounds of formula 9 by using, for example, para-toluensulfonate acid in acetone or aqueous sulfuric acid in acetonitrile gives compound of formula 10, which when processed by a reducing agent (e.g. sodium borohydride or zienab the power of the product, as well as the isomeric compound of formula 12 as the main product, which can be separated by chromatography. An alternative compound of formula 10 may be initially processed three-Deut.-butylbromide lithium or Tris-ISO-amiloride lithium in tetrahydrofuran, and then the aqueous hydrogen peroxide and sodium bicarbonate, giving the compound of formula 11 as the main product and the compound of formula 12 (if present) as a secondary substance, which can be separated (if necessary) chromatography. The compound of formula 11 can be converted to the compound of formula 2 by known methods. For example, the interaction of the compounds of formula 11 with paratoluenesulfonyl or methane - sulphonylchloride in pyridine gives compound of formula 2, where X pair-toluensulfonate or methansulfonate respectively. The compound of formula 2, where X pair-toluensulfonate or methansulfonate, can also be obtained from the isomeric compounds of formula 12 by engagement with a pair of toluensulfonate acid or methanesulfonic acid, respectively, in the presence of triethylamine, triphenylphosphine and diethyl - or aminobutiramida of azodicarboxylate in a solvent such as toluene, afia or halide methyltriphenylphosphonium (for example, chloride, bromide or iodide) in a solvent such as dimethylformamide, gives compound of formula 2, where X is chlorine, bromine or iodine. As another alternative, the compound of formula 2, where X is chlorine, bromine or iodine, can be obtained from compounds of formula 12 using triphenylphosphine, diethyl (or aminobutiramida)azodicarboxylate and a source of halide, such as methyliodide, bromide or dichloromethane, in accordance with the known method, Cm. for example, H. Loibner et al. Helv. Chim. Acta. 59, 2100 (1976).

The above is shown schematically below:

_____< / BR>
The reaction of the compound of formula 2 with the compound of the formula

by a method similar to the one used in obtaining the compounds of formula 4, and the subsequent removal of the protective groups R gives the corresponding compound of formula I, where

< / BR>
The alternative is a compound of the formula I can be obtained by reaction of compounds of formula

with a compound of formula 2 by methods similar to those used in the preparation of the compounds of formula 2. This gives the corresponding compound of the formula

(20) Treatment of compounds of formula 20 hot ammonia in alcohol, for example methanol or ethanol, and the simultaneous or subsequent removal of the protective groups R gives the corresponding connection form of the relevant compounds of formula

with the compound of the formula 2 in the presence of a base, for example potassium carbonate, sodium hydride or potassium hydride, in an aprotic polar solvent (e.g. dimethylformamide, dimethyl sulfoxide or sulfolane) when the optional presence of 18-crown-6 or 15-crown-5 and provides an intermediate compound of the formula

< / BR>
Removing the protective groups R gives the corresponding compound of formula 22. For example, when R acyl protective group can be removed by treatment with sodium methylate in methanol or methanol-ammonia, or, when R represents a silyl group, removal may be effected by fluoride ion. When P is benzyl group, removing the protection can be carried out by hydrogenolysis (for example using palladium hydroxide on carbon in cyclohexane and ethanol) or treatment trichloride boron.

The connection formulas

(27) where R3hydrogen, produced from the corresponding compounds of formula 24 (where R is, for example, the protective group is acyl) by known methods. See, for example, I. Wempner, et al. in "Synthetic Procedures in Nucleic Acid Chemistry", Vol. 1, W. W. Zorbach and R. S,Tipson, Eds. Interscience Publishers, N. Y. S. 299, 1968, T. S. Lin et al. J. Med. Chem. 26, 1691 (1983), P. Herdewijn et. al. J. Med. Chem. 28, 550 (1985). Remove protection using methanolic ammonia or SUB> hydrogen can be obtained by reaction of the corresponding compounds of formula

with the compound of the formula 2 in the presence of a base. such as potassium carbonate, sodium hydride or potassium hydride, in an aprotic solvent (e.g. dimethylformamide, dimethyl sulfoxide or sulfolane) when the optional presence of 18-crown-6 or 15-crown-5 with the subsequent removal of the protective groups. Not necessarily amino (-NH2)-group in the compound of formula 28 can be protected, for example, the acyl group. The removal of this protective group can be carried out using sodium methoxide in methanol or methanolic ammonia.

The compounds of formula 22 where R3iodine can be obtained from corresponding compounds of formula 22 where R3hydrogen by known methods. See, for example, Basic Principals in Nucleic Acid Chemistry, volume I, R. O. R. Ts'O, Ed. Academic Press. N. Y. S. 146, 1974; P. K. Chang in Nucleic Acid Chemistry, part 3, L. B. Townsend and R. S. Tipson, Eds. John Wiley and Sons, N. Y. C. 46, 1986.

The compounds of formula 22 where R3group

CC and R4bromine, can be obtained from corresponding compounds of formula 22 where R3iodine or HgCl, through palladium organic intermediate compounds. The compounds of formula 22 where R3HgCl, can be obtained from suitable), M. E. Perlman, et al. J. Med. Chem. 28, 741 (1985), P. Herdewijn et al. J. Med. Chem. 28, 550 (1985), D. E. Berhstrom, et al. J. Med. Chem. 27, 279 (1984).

The stereochemistry shown for compounds of the invention and intermediates, giving compounds of the present invention, a relative, not absolute. It is shown that in the compounds of the present invention, the base represented by R1is TRANS to the nearest-CH2HE is the Deputy, and CH2HE substituents are TRANS with respect to each other.

The compounds of formula I, where R1represents a group

,orcan form acid additive salts with organic or inorganic acids. Characteristic are halogenierte salt (e.g. hydrochloride or hydrobromide), alkyl sulphonates, sulphates, phosphates and carboxylates.

The compounds of formula I, where R1< / BR>
or , can form basic salts with inorganic and organic bases. Typical salts are alkali metal (e.g. sodium and potassium), alkaline earth metals (e.g. calcium and magnesium), ammonium and substituted ammonium.

P R I m e R 1. (1 ,2,3)-9-(203-bis)hydroxymethyl(coulometer)guanine

And Ketene Diethyl acetal.

To a solution of tert. butoxide potassium (28.5 g, 0,254 mol) in dry tert.butanol (150 ml, dried OVER molecular sieve) at the 50aboutWith the added bromoacetaldehyde diethylacetal (38,5 mo, 0,254 mol). A column Packed with glass spiral nozzles (h,4 cm) with partially removable head for full irrigation, placed on top of the reaction flask. The temperature of the oil bath was gradually raised to 100aboutC. After irrigation for 35 min drove tert. butanol for 16 h with a rate of 4.5 drops per minute with a ratio of irrigation in the cylinder 22:4,5. An oil bath was cooled to 20aboutAnd a column Packed with spiral nozzles, replaced by a distiller short passage. Distillation at 20-50aboutAnd 4 mm gave 26,96 g of a mixture containing 23,31 g getentitystate and 3,66 g of tert.butanol, as determined by IR-NMR integration. In) (TRANS)-3,3-diethoxy-1,3-cyclobutanecarbonyl acid, diethyl ether.

This compound was obtained by the modification method K. C. Brannock et al. J. Org. Chem. 29, 840 (1964).

To a solution of 25,27 g of the above mixture containing 21,63 g (0,186 mol) of getentitystate dry rubs. butanol (60 ml), was added diethylfumarate (28,28 ml, 0,173 mol). All this was heated at a temperature of 82about

Portion And chromatographically on Merck silica gel-60 (1.5 x 30 cm) in a mixture of hexane/ethyl acetate in a ratio of 19:1. The fractions containing the product were combined and concentrated. Received 567 mg

The portion was chromatographically twice on Merck silica gel-60 (35 x 5 cm) in the same solvent. The fractions containing the product were combined and concentrated. Got 10,43 g, the Total yield of the desired substance was 10,99,

(C) (TRANS)-3,3-diethoxy-1,2-cyclobutanediyl.

To a suspension of hydride methylalanine (2.38 g, 0,0627 mol) in dry tetrahydrofuran (50 ml) is slowly added (TRANS)-3,3-di ethoxy-1,2-cyclobutanecarbonyl acid, diethyl ether (of 11.29 g, 0,0392 mol) in tetrahydrofuran (25 ml) while maintaining a light irrigation. The mixture was heated at 55aboutC for 4 h, and then diluted with ether (100 ml). Lowered pH to 4 C M sulfuric acid. The suspension was extracted with ether (4 x 100 ml) and then with chloroform (3 x 100 ml). The ether extracts were combined, dried over sodium sulfate, filtered and concentrated. Got 5,613 g of the desired substance. Combined extracts of chloroform, dried over sodium sulfate, filtered and concentrated. Received 112 mg additional desired ingredient.

D) (Tranditonal (5.7 g, 0,028 mol) in dry pyridine (40 ml) under nitrogen atmosphere at 0aboutWith added during 5 min, benzoyl chloride (9,73 ml, 0,0838 mol), it was heated to room temperature, after which the Deposit formed. After 2 h was added water (20 ml) and the reaction mixture was stirred over night. The vacuum was removed solvents. The residue was dissolved in diethylacetal (400 ml) and washed with water (2 x 150 ml), 1 N. hydrochloric acid (2 x 150 ml) and saturated sodium bicarbonate (3x150 ml). The organic layer was dried over sodium sulfate, filtered and concentrated, giving 10,97 g of the target substance.

(E) (TRANS)-2,3-bis[(antilocks methyl]cyclobutanone.

To a solution of dibenzoates ether (TRANS)-3,3-diethoxy-1,2-CYCLOBUTANE - canola (10,87 g, 0,0263 mol) in acetone (200 ml) was added p-toluensulfonate acid (250 mg, 0,00132 mol). The reaction mixture was heated under reflux for 3 hours the Solution was concentrated in vacuum. The residue was dissolved in ethyl acetate (200 ml) and washed with saturated sodium bicarbonate (g ml). The aqueous layer was again extracted with ethyl acetate (50 ml). Combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo, which gave 8.7 g of impure product. is vorites for elution of hexane/ethyl acetate 5:1 ratio.

Were combined and concentrated the fractions containing the product. Received of 6.71 g of the target substance.

Alternative obtain (TRANS)-2,3-bis[(benzoyloxy)methyl]cyclobutanol.

To a solution of dibenzoates ether (TRANS)-3,3-diethoxy-1,2-cyclobutanediyl - Nola (50 g, 0.12 mol) in 1.5 l of acetonitrile was added 570 ml of 0.5 M sulfuric acid in water. The reaction mixture was stirred under argon for 16 h at 25aboutC, and then diluted with 5 l of ethyl acetate. The mixture was washed with water (2x1 l), saturated sodium bicarbonate (2x1 l), water (2x1 l) and finally 1 l of brine. The organic phase was dried over sodium sulfate and concentrated to oil. Kneading the powder with hexane gave 34 g of crude product. Rubbing this crude solid with 300 ml diethyl ether gave 10 g of a target substance, so pl. 76-78aboutC. Cooling of the filtrate to -30aboutC for 4 h gave the second collect 12 g, so pl. 76-78aboutWith the same purity.

F) (1,2,3)-3-hydroxy-1,2-tulobuterol, ether 1,2-dibenzoate and (1,2,3)-3-hydroxy-1,2-cyclohepten - dimethanol, ether 1,2-dibenzoate.

To a solution of (TRANS)-2,3-bis[(benzoyloxy)methyl] cyclobutanone (2,46 g, 7,28 mol) in anhydrous methanol (40 ml) was added Lamborghini sodium (1.01 g, 16 mol).

Elution with hexane/ethyl acetate in a ratio of 7:3 gave 521 mg(1 ,2, 3)-3-hydroxy-1,2-cyclobutanediyl, ether 1,2-dibenzoate.

Elution with hexane/ethyl acetate in the ratio 6:3 gave 1.78 g(1 ,2, 3)-3-hydroxy-1,2-cyclobutanediyl, ether 1,2-dibenzoate.

Alternative receiving (1, 2,3)- 3-hydroxy-1,2-cyclobutanediyl, ether 1,2-dibenzoate and (1,2,3)-3-hydroxy-1,2-CYCLOBUTANE - methanol, ether 1,2-dibenzoate.

To a stirred solution of (TRANS)-2,3-bis[(benzoyloxy)methyl]cyclobutanone (12.0 g, 0,0355 mol) in anhydrous tetrahydrofuran at -78aboutWith nitrogen was added to 35.5 ml (0,0355 mol) 1M three-terbutyl of lithium borohydride in tetrahydrofuran for 3 minutes, the Reaction mixture was heated to room those% hydrogen peroxide (13,0 ml, to 0.127 mol) while maintaining the temperature at 30aboutWith the help of water ice baths. The reaction mixture was heated to room temperature, stirred for 30 min and was diluted with ethyl acetate (400 ml) and water (120 ml). Shared layers. The organic layer was extracted with water (100 ml). Formed emulsion, after which was added solid sodium chloride to separate the layers. Two water layers were combined and extracted with ethyl acetate. United all an ethyl acetate layers were dried over sodium sulfate, filtered and concentrated in vacuo to a residue (12.5 g). Part of this residue (7 g) was purified using preparative liquid chromatography high pressure on the two Waters Prep Pak 500 silicagel columns, using as solvent for elution of 30% ethyl acetate in hexane, at a speed of 250 ml/min (1,2,3)-3-hydroxy-1,2-CYCLOBUTANE - methanol, ether 1,2-dibenzoate was suirable through 14-22 min, and (1,2,3)-3-hydroxy-1,2-cyclobutanediyl, ether 1,2-dibenzoate was suirable through 23-34 minutes Similar chromatography remainder of 12.5 g of residue (in two stages, one using 25% ethyl acetate in hexane, and the second using 35% ethyl acetate in hexane) gave only 8,80 g (1,2, 1)-3-hydroxy-1,2-cyclobutanediyl, ether 1,2-dibenzo the 3-hydroxy-1,2-CYCLOBUTANE - methanol, ether 1,2-dibenzoate.

To a solution of (TRANS)-2,3-bis[(benzoyloxy)methyl] cyclobutanone (13,55 g, 0,0389 mol) in tetrahydrofuran (180 ml) at -78aboutWith nitrogen was added for 5 min for 38.9 ml (0,0389 mol) of 1M triazolylmethyl lithium in tetrahydrofuran. The reaction mixture was stirred 10 min and then was heated to room temperature. Was added saturated sodium bicarbonate (36,9 ml) and then slowly added 30% hydrogen peroxide (14,19 ml, was 0.138 mol), keeping the temperature 30aboutUsing ice baths. The mixture was diluted with water (120 ml) and was extracted with ethyl acetate (400 ml). The organic layer was washed with water (100 ml), dried over sodium sulfate and concentrated in vacuum, obtaining 17.8 g of crude desired product as a residue that does not contain detectable(1, 2, 3)- 3-hydroxy-1,2-cyclobutanediyl, ether 1,2-dibenzoate. The residue was purified preparative liquid chromatography high pressure on the two Waters Prep 500 silicagel columns, using as solvent for elution of 30% ethyl acetate in hexane, which gave 9,17 g (1,2,3)-3-hydroxy - 1,2-cyclobutanediyl, ether 1,2-dibenzoate.

Alternative crude product (42 g), obtained by reduction of 40.5 g (0.12 mol) of (TRANS)-2,3-bis[(benzoyloxy)methyl]qi(2/1) and put on a dry pillow 1.2 Marxisties-60. Pillow washed with 5 l of the same solvent, selecting 500 ml fractions. Containing the product fractions were combined and evaporated, giving of 39.8 g of the target substance in the form of colorless liquid, sufficiently pure for use in the next stage of the synthesis.

G) (1,2,3)-3-[(4-were)sulfonyl]-hydroxy-1,2-cyclobutanediyl, ether of dibenzoate.

To a solution of (1,2,3)-3-hydroxy-1,2-cyclobutanediyl, ether 1,2-dibenzoate (7,31 g, 0,0215 mol), previously dried by concentrating it from anhydrous pyridine (2x20 ml) in 36 ml of anhydrous pyridine was added para-toluene-sulphonylchloride (6,56 g, 0,0344 mol). The mixture was stirred for 16 h at 60aboutC in an atmosphere of nitrogen and pyridine was removed in vacuum. The remaining pyridine was removed by joint distillation with toluene (g ml). The residue was dissolved in ethyl acetate (480 ml) and washed with saturated potassium carbonate. Was dried over sodium sulfate the organic layer was filtered and concentrated in vacuo to a residue, which was purified by chromatography on a column of Merck silica gel-60 (1500 ml). The column was lirowaus 3000 ml of ethyl acetate and hexane in a ratio of 1: 5. The column was then suirable a mixture of ethyl acetate and hexane in a ratio of 1:3, collecting 50 ml fractions. The appropriate fractions obyedinyaet.

Alternative after heating (1,2,3)- 3-hydroxy-1,2-cyclobutanediyl, ether 1,2-dibenzoate (39,8 g, 117 mmol) of para-toluene-sulphonylchloride (24,65 g, 128,5 mmol) in 60 ml of pyridine at 60aboutC for 22 h, the temperature was lowered to 40aboutWith and added 2 ml of water. After 2 hours remove volatile compounds and the residue was distributed between ethyl acetate and water. The organic layer was washed with 3% sodium bicarbonate and dried over sodium sulfate. Obtained by concentration of the solvent the crude product is triturated with pentane, getting 39,4 g wet substances. This substance was dissolved in 120 ml of ethyl acetate under mild heating. The solution was cooled to room temperature and diluted with 120 ml of pentane. Settling in for several hours at +5aboutTo give crystals, which were filtered, dried, obtaining a 32.6 g of pure desired product.

Alternative preparation(1,2,3)-3-[[(4-were)sulfonyl] -oxy]-1,2-cyclobutanediyl, ether of dibenzoate.

To a solution of (1,2,3)-3-hydroxy-1,2-cyclobutanediyl, ether of dibenzoate (3,096 g, 9,10 mol) in anhydrous toluene (25 ml) was added monohydrate para-toluenesulfonic acid (2,08 g, 10.9 mmol), triethylamine (1,51 ml, 10.9 mmol), triphenylphosphine (3,81 g, 14.6 mmol) and diisopropyl is still after 3 h was added triphenylphosphine (1.90 g, 7,3 mmol) and aminobutiramida azodicarboxylate (1,43 ml, 7,3 mmol). Even after 3 h of heating was added an additional amount of triphenylphosphine (0.95 g, 3.65 mmol) and diisopropyl of azodicarboxylate (0,717 ml 3.65 mmol). The reaction mixture continued to heat for another 1 h, cooled to room temperature and filtered. The precipitate was washed with toluene (20 ml), the filtrate and wash water were combined and concentrated in vacuo to a residue, which was dissolved in ethyl acetate (100 ml). The ethyl acetate solution was washed with water (I ml), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by chromatography on Merck silica gel-60 (300 ml) using a mixture of hexane and ethyl acetate in the ratio of 5:1, and the appropriate fractions were combined and concentrated to 20 ml of This concentrate was diluted with 30 ml of hexane and left overnight at room temperature. Filtering the collected crystals were washed with hexane and dried, which gave 2,18 g (portion 1) of pure desired product. Uterine fluids from the portion 1 was concentrated to 40 ml and left overnight at room temperature.

Filtered to collect crystals (portion 2), dried in vacuo and subjected to chromatography on Merck silica gel-60 (300 ml) with 2% who have adversely chromatography on Merck silica gel-60 (300 ml) using 2% ethyl acetate in toluene, that gave 187 mg (portion 4) impure desired product.

Combined portions 3 and 4, recrystallized from hexane/ethyl acetate, which gave additional 770 mg of pure desired product. The total net output of the target product was 2.95 g

N) (1,2,3)-3-[2-amino-6-(phenylmethoxy)-N-pyridin-9-yl]-1,2-cyclobutanediyl Nol,ether 1,2-dibenzoate.

To a solution of(1,2,3)-3-[[(4-were)sulfonyl]oxy]-1,2-CYCLOBUTANE - canola, dibenzoate (1,072 g, 2,17 mmol) in dimethylformamide (20 ml) was added 2-amino-6-(phenylmethoxy)-N-purine (784 mg, 3.25 mmol), 18-crown-6 (573 mg, 2,17 mmol) and potassium carbonate (600 mg, 4,34 mmol). The reaction mixture was stirred in nitrogen atmosphere at 110aboutC for 24 h In vacuum was removed, the solvent and the residue was chromatographically on Merck silica gel-60 (h cm) using a mixture of ethyl acetate in the ratio 3:1, which gave 400 mg of pure desired product. The other fraction containing the target product with impurities, United and once again chromatographically on Merck silica gel-60 (1.5 x 30 cm) using a mixture of ethyl acetate and hexane in a ratio of 2:1, which gave additional 52 mg of the target product, and the total output amounted to 452 mg.

I) (1, 2,3)-3-[2-amino-6-(phenylmethoxy)-N-purine-9-yl]-1,2-cyclobe 1,2-dibenzoate (452 mg, 0,803 mmol) in anhydrous methanol (12 ml) was added a 25% solution of sodium methoxide in methanol (109 ml, 0,482 ml). The reaction mixture was stirred in a stream of nitrogen for 1 h at 40aboutC. In a vacuum solvent was removed and added water (10 ml). With the help of 1H. HCl was lowered pH to 7. Was removed in vacuum, the solvent and the residue triturated with ether (2x20 ml) and dried, which gave 358 mg of crude desired product, which is then used in the next stage.

J) (1,2,3)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine.

To a suspension of (1,2,3)-3-[2-amine-6-(phenylmethoxy)-N-purine-9-yl]-1,2-cyclo - butadiene (358 mg, 1.0 mmol) in methanol (5 ml) was added 3n. HCl (2.5 ml). The mixture was stirred 4 h at 45aboutC. In vacuum to remove the solvents and the residue was dissolved in water (20 ml). Using 1 N. COHN raised the pH to 7. Selected 10% sample and solvents were removed in vacuum. The residue was concentrated from methanol (3x4 ml) and ethyl acetate (2x4 ml). The residue was dissolved in water (4 ml) when heated and placed in a column of CHP-20P resin (1,h cm), Mitsubishi chemical industries Ltd. (75-150 μm). Elution with water, a mixture of 2% acetonitrile/water and 4% acetonitrile/water gave 11 mg of the target product.

The remaining 90% of the mixture was concentrated in vacuo, and then was concentrated from methanol is th (2,h cm). Elution with water, mixtures of 2% acetonitrile/water, 4% acetonitrile/water and 10% acetonitrile/water gave additional 111 mg (1,2,3)- 9-[2,3-bis(hydroxymethyl)CEC - libutil]guanine with a melting point > 220aboutC.

Calculated: C11H15N5O31,43 3H2O:

C 45,40; H 6,18; N 24,08; H2O 8,83.

Found: C 45,66; H 5,95; N 23,82; H2O 8,83.

P R I m e R 2. (1,2,3)-3-(6-Amin-N-purine-9-yl)-1,2-cyclobutadiene

A) (1, 2, 3)-3-[6-Amin-N-purine-9-yl] -1,2-cyclobutanediyl, ether of dibenzoate.

To a solution of(1, 2,3)-3-[[(4-were)sulfonyl]oxy]-1,2-CYCLOBUTANE - canola, ether of dibenzoate (988 mg, 2 mmol) in anhydrous dimethylformamide (20 ml) in a stream of nitrogen was added adenine (405 mg, 33 mmol), 18-crown-6 (538 mg, 2 mmol) and potassium carbonate (276 mg, 2 mmol). The reaction mixture was heated at 110aboutWith 16 h, and then the vacuum was removed, the solvent gave a residue that was purified by chromatography on a column of Merck silica gel-60 (400 ml). Elution of 0.1, 0.5, 5 and 10% methanol in ethyl acetate to give 522 mg of the target product with impurities. Chromatography on a column of this substance on Merck silica gel-60 (400 ml) using a mixture of dichloromethane/methanol in a ratio of 20: 1 gave 400 mg of pure (1,2,3)-3-(6-Amin-N-purine-9-yl)-1,2-ሺ="ptx2">

To a suspension of (1,2,3)-3-(6-Amin-N-purine-9-yl)-1,2-cyclobutanediyl, ether of dibenzoate (400 mg, 0,899 mmol) in anhydrous methanol (20 ml) was added a 25% solution of sodium methoxide in methanol (123 ml, 0,539 mmol). The mixture was stirred 45 min at 40aboutWith, and then removed in vacuum solvent.

The residue is suspended in water (20 ml) with 1 N. Hcl pH was brought to 7.0 and remove volatile substances. The residue was purified by chromatography on a column of CHP-20P resin. Elution with water, gradient from 0 to 20% methanol in water, and then 20% and 30% methanol in water gave 128 mg (1,2,3)-3-(6-amino-N-purine-9-yl)-1,2-CYCLOBUTANE - dimethanol as a solid substance with a melting point 181-183aboutC.

Calculated for C11H15N2O50,1 H2O:

C 52,63; H 6,10; N 27,90

Found: 52,64; H 6,10; N 28,00.

P R I m e R 3. (1,2,3)-1-[2,3-bis(hydroxymethyl)cyclobutyl]-5-methyl-2,4-(1H, 3H)-pyrimidinedione.

And) (1,2,3)-1-[2,3-bis[(benzoyloxy)methyl]cyclobutyl]-5-methyl-2,4(1H, 3H)-pyrimidinedione.

The mixture(1,2,3)-3-[[(4-were-sulfonyl]oxy]-1,2-cyclobutadiene - La, ether of dibenzoate (1,245 g, 2,52 mmol), thymine (625 mg, 4,96 mmol), potassium carbonate (1.39 g, 10.1 mmol) in anhydrous dimethylformamide (12.5 ml) under argon with stirring nagavalli) and continued heating at 125aboutWith another 2 h reaction mixture was cooled and filtered, the insoluble matter was washed with dimethylformamide. The filtrates of dimethylformamide were combined and evaporated to a residue which is triturated with ethyl acetate. Solids were removed by filtration, the filtrate is evaporated to a residue. This residue was dissolved in a small amount of ethyl acetate-hexane (1:1) and placed in a column of Merck silica gel-60 (5x11,5 cm) in hexane. Elution with ethyl acetate and hexane (4:1) and then ethyl acetate to give 219 mg of partially purified target product. Chromatography of this substance on a column of Merck silica gel-60 (dichloroethane) at the elution 10, 20, 30 and 50% ethyl acetate in dichloromethane gave 166 mg of pure(1,2, 3)-1-[2,2-bis[benzoyloxy/methyl] -cyclobutyl]-5-methyl-2,4(1H,3H)-Piri mydiv the form of a white solid.

In) (1,2,3)-1-[2,3-bis(hydroxymethyl)cyclobutyl]-5-methyl-2,4(1H,3H)-Piri - medindie.

25% solution of sodium methoxide in methanol (44,7 ml, 0,196 mmol) was added to a stirred suspension(1,2,3)-1-[2,3,-bis[(benzoyloxy/methyl)cyclobutyl] 5-methyl-2,4(1H,3H)-pyrimidinedione (146 mg, 0,326 mmol) in anhydrous methanol (4.9 ml) in argon at 40aboutC. After 4 h the clear solution was cooled to room temperature and concentrated in Vacu the lot, and the solution was placed in a column (1,h cm) CHP-20P resin in water. Elution with water, 2, 4, and 10% acetonitrile in water gave after wyprasowanie and subsequent lyophilization from water 58 mg(1, 2, 3)-1-[2,3-bis(hydroxymethyl)CEC - libutil]-5-methyl-2,4 (1H, 3H)-pyrimidinedione as rasplivcego solid.

Proton NMR (270 MHz, CD3--CD3, tetramethylsilane was) 11, 11, (broad singlet, 1H), to 7.64 (doublet, I 1,1 Hz, 1H), 4,56 (multiplet, 2H), 4,47 (multiplet, 2H), 4,47 (multiplet, 1H), 3,44 (multiplet, 4H) 2,5 (multiplet, CD3--CD3solvent +1H), 1,85 (multiplet, 1H), 1,84 (multiplet, 1H), 1,79 (doublet, I 1,1 Hz, 3H).

P R I m e R 4. (1,2,3)-4-amino-1-[2,3-bis(hydroxymethyl)-cyclobutyl] -2(1H)- pyrimidinone

(A) (1,2,3)-4-amino-1-[2,3-bis(benzoyloxy)methyl/cyclobutyl]-2(1H)-pyrimi - dine.

The mixture(1, 2,3)-3-[[(4-were)sulfonyl]oxy]-1,2-CYCLOBUTANE - canola, ether of dibenzoate (1.51 g of 3.05 mmol), cytosine (6.78 mg, 6,10 mmol), potassium carbonate (1,69 g 12.2 mmol) and 18-crown-6 (804 mg, 3.04 from mmol) 12.5 anhydrous dimethyl sulfoxide was stirred in argon 112aboutWith over 4.5 hours the Reaction mixture was cooled to room temperature and neutralized by addition of glacial acetic acid (0.7 ml, 12.2 mmol). The solvent was removed in vacuo, the residue sconce the initial filtrate was concentrated to residue, which was dissolved in toluene and placed in a column of Merck silica gel-60 in toluene. Elution with isopropanol in toluene gave 156 mg of the target substance.

In) (1,2,3)-4-amino-1-[2,3-bis(hydroxymethyl)cyclobutyl]-2(1H)-pyrimido - non.

25% solution of sodium methoxide in methanol (48 ml, 0,209 mmol) was added to a solution of (1,2,3)-4-amino-1-[2,3-bis[(benzoyloxy)methyl]cyclobutyl]-2(1H)-pyrimidine (151, 3mm mg, 0,349 mmol) in 5.25 ml of anhydrous methanol. The reaction mixture was stirred for 75 min at 40aboutC and cooled to room temperature. In vacuum solvent was removed, the residue was dissolved in water. Using 1 N. Hcl brought the pH up to 7. The aqueous solution was passed through a column of CHP-20P resin in water, the column was washed with 50 ml water and was suirable gradient of 0-50% acetonitrile in water. Combining the appropriate fractions and removal of solvent in vacuo gave the desired product in the form of transparent glass (52 mg).

Proton NMR (270 MHz, CD3--CD3, tetramethylsilane was) : 7,69 (doublet, I 7 Hz, 1H), 6,98 (broad singlet, 2H), 5,71 (doublet, I and 7.6 Hz, 1H) and 4.65 (broad multiplet, 2H), 4,37 (multiplet, 1H), 3.43 points (multiplet, 4H), 2,43 (multiplet, 1H), 2,31 (multiplet, 1H), 2,20 (multiplet, 1H), 1.77 in (multiplet, 1H).

P R I m e R 5. [1 (E), ,2,3-1-[2,3-bis(hydroxym the l]-2,4(1H,3H)-pyrimi - dindin.

To a solution of uracil (1.26 g, 11,23 mmol), dried for 16 h at 50aboutC, and 18-crown-6 (1.98 g, 7,49 mmol) in dimethyl sulfoxide (9 ml) at 50aboutWith added potassium carbonate (2,07 g, 14,98 mmol) and(1,2,3)-3-[[(4-were)sulfonyl] oxy]-1,2-cyclobutanediyl, air dibenzoate (3.7 g, 7,49 mmol), When heated at 100aboutWith nitrogen formed emulsion. Was added dimethyl sulfoxide (3 ml) and the mixture was stirred at 100aboutC for 24 h In a vacuum removed the solvents and received a residue that was purified by chromatography on Merck silica gel-60 (700 ml) using a gradient of toluene to 3% of isopropyl alcohol in toluene. Combined appropriate fractions and received 850 ml of pure target product. The fraction containing the target product with impurities, were combined and concentrated to a residue, which was dissolved in toluene (1 ml). Collected the obtained crystals were dried, and received 35 mg additional pure target product.

In) (1,2,3)-1-[2,3-bis(hydroxymethyl)cyclobutyl]-2,4(1H,3H)-pyrimidinedione.

To the suspension(1, 2,3)-1-[2,3-bis[(benzoyloxy)methyl]cyclobutyl]-2,4- (1H, 3H)-pyrimidinedione (885 mg, 2.04 mmol) in anhydrous methanol (25 ml) was added a 25% solution of sodium methoxide in methanol (264 ml, 1,22 mmol). The mixture naked is whether the pH to 7 using 1 N. HCl, and the solution was left overnight at 0aboutC. the precipitate and pop-up substance was purified on a column of CHP-20P resin (200 ml) using a step gradient of water, a mixture of 2% acetonitrile/water and 4% acetonitrile/water, and received 423 mg of the target product.

With) (1 ,2,3)-1-[2,3-bis[(hydroxymethyl)cyclobutyl]-5-iodine-2,4(1H,3H)-pyrimi - dindin.

To the suspension(1, 2,3)-1-[2,3-bis(hydroxymethyl)cyclobutyl]-2,4,(1H, 3H)-pyrimidinedione (3423 mg of 1.87 mmol) in dioxane (38 ml), purified on basic alumina, was added iodine (950 mg, 3.75 mmol) and 0.8 M nitric acid (2.5 ml, 2 mmol). This solution was stirred 90 min at 95aboutC, and then cooled to room temperature. Solution was added saturated aqueous sodium thiosulfate until then, until he got red. The reaction mixture was concentrated in vacuo and obtained a slightly yellowish residue. This substance was purified by chromatography on CHP-20P resin (150 ml) using a gradient of water to 50% acetonitrile in water, which gave 557 mg of the target product.

D) [1 (E), 2,3]-3-[1-[2,3-bis(hydroxymethyl)cyclobutyl]-1,2,3,4-tetrahydro-2,4 - dioxo-5-pyrimidinyl]-2-Papanova acid, methyl ester.

A suspension of palladium (II) acetate (17.5 mg, 0,078 mmol), triphenylphosphine (of 40.9 mg, 0.15 mmol) in at 85aboutIn nitrogen atmosphere, and then was added a solution of (1,2,3)-1-[2,3-bis(hydroxymethyl)cyclobutyl] -5-iodine - 2,4(1H,DD)-pyrimidinedione (457 mg, 1.3 mmol) and methyl acrylate (468 ml, 5.2 mmol) in dioxane (310 ml). The reaction mixture was heated at 85aboutWith in a stream of nitrogen. After 4 h was added the methyl acrylate (234 ml, 2.7 mmol). After further heating for 2 h, the reaction was still not complete. Added celite (300 mg) and warm the reaction mixture was filtered. The vacuum was removed solvents. The residue was dried by concentration of the anhydrous dioxane (2x10 ml) and the residue was subjected to the following reaction conditions.

The reaction was repeated, but this time removed the oxygen from dioxane, passing bubbles of argon through the solvent. After heating the suspension of palladium (II) acetate (17.5 mg, 0,078 mmol), triphenylphosphine (of 40.9 mg, 0.15 mmol) and triethylamine (290 ml of 2.08 mmol) in dioxane (20 ml) for 15 min at 85aboutWith nitrogen was added a solution of the above residue and methyl acrylate (468 ml, 5.2 mmol) in dioxane (10 ml). The mixture was heated 3 h at 85aboutC. was Added celite (300 mg), warm the reaction mixture was filtered, cooled to room temperature and concentrated in vacuum. The residue was placed in a column of Merck silica gel-60 (150 ml in chloroform) and acii and concentrated, that gave 310 mg of the target substance that has been contaminated by salts of triethylamine. The mixture was dissolved in water (5 ml) and ethyl acetate (50 ml). Separated layers, the water layer was extracted with ethyl acetate (CH ml). Layers of ethyl acetate were combined, dried over sodium sulfate, filtered and concentrated, giving 230 mg of the target substance.

E) [1(E), 2,3]-3-[1-[2,3-bis(hydroxymethyl)cyclobutyl]-1,2,3,4-tetrahydro - 2,4-dioxy - 5-pyrimidinyl]-2-Papanova acid.

A solution of methyl ester [1(E), 2, 3] -3-[1-[2,3-bis(hydroxide - Tyl)cyclobutyl] -1,2,3,4-tetrahydro-2,4-di - oxo-5-pyrimidinyl]-2-propanolol acid (230 mg, 0,742 mmol) in 2M sodium hydroxide (3,7 ml, 7,42 mmol) was stirred 1.5 h at room temperature, the mixture was cooled to 4aboutC. Lowered the pH to 2 with 2 N. Hcl and left for 1 h at 4aboutC. filtering the collected precipitate was washed with water and dried over P2ABOUT5in vacuum for 16 h, which gave 120 mg of the target substance. Royal solutions and rinse waters were concentrated to 3 ml and left for 16 h at 4oC. was Collected crystals were washed with water, dried over R2ABOUT5in vacuum for 4 h, and was obtained 7 G. more target substances.

F) [1(E),2,3]-3-[1-[2,3-bis(hydroxymethyl)cyclobutyl]-5-(2-bromanil)-2, is ioxo-5-pyrimidinyl] -2-Pro - benovoy acid (127 mg, 0,429 mmol, dried by evaporation of dimethylformamide, 2x3 ml) in dimethylformamide (2 ml) was added potassium bicarbonate (129 mg, 1,29 mmol). Solution was added N-bromosuccinimide (76 mg, 0,429 mmol) in dimethylformamide (1 ml), the mixture was stirred 2.5 h at room temperature. The reaction mixture was filtered and concentrated in vacuum. The residue was concentrated from water (2x5 ml) and was chromatographically on CHP-20P resin (110 ml) using a gradient of water up to 30% acetonitrile in water, which gave, after concentration in vacuo 99 mg of [1(E),2,3]-1-[2,3-bis(hydroxymethyl-cyclobutyl]-5- (2-bromanil)-2,4(1H,3H)-pyrimidinedione with a melting point 155-157aboutC.

Calculated for C12H15N2O4Br 0,31 H2O:

C 42,79; H 4,69; N 8,32.

Found: C 42,85; H 4,69; N Compared To 8.26.

P R I m e R 6. (1,2,3)-1-[2,3-bis(hydroxymethyl)cyclobutyl]-5-iodine-2,4- (1H,3H)-pyrimidinedione.

And) (1,2,3)-1-[2,3-bis(benzoyloxy)methylcyclobutene]-2,4(1H,3H)-pyrimi - dindin.

The mixture(1, 2,3)-3-[[(4-were - sulfonyl]oxy]-1,2-cyclobutadiene - La, ether of dibenzoate (1,25 g 5,07 mmol), uracil (0,567 g 5,07 mmol), potassium carbonate (1.40 g, 1.12 mmol) and 18-crown-6 (670 mg, 2.54 mmol) in anhydrous dimethylsulfoxide (12.5 ml) was heated for 4.5 hours at 110aboutC. In a vacuum removed the floating top layers were concentrated to small volume it was diluted with equal volumes of hexane and applied on a column of Merck silica gel-60 (2.5 x 25 cm) in hexane. The column was suirable a mixture of ethyl acetate and hexane in a ratio of 1:4 and 1:1, then ethyl acetate, and got partially purified target product (250 mg). Chromatography of this substance on silicagel column (1,h,5 cm) in methylene chloride using as eluent a mixture of ethyl acetate and methylene chloride in the ratio of 1:4 and 1:1, then ethyl acetate did not ensure the removal of impurities. Subsequent chromatography on silicagel column (1,h cm) in toluene and elution with a mixture of isopropanol and toluene in the ratio of 4:96 gave the target net product (56,5 mg), and the target product with impurities. Recrystallization from toluene the target product with impurities gave additional target substance (86,3 mg, total yield 143 mg).

In) (1,2,3)-1-[2,3-bis(hydroxymethyl)cyclobutyl]-2,4(1H,3H)-pyrimidine - dione.

The mixture(1, 2,3)-1-[2,3-bis(benzoyloxy)methylcyclobutene]-2,4(1H,3H)-Piri - medindia (142,9 mg, 0,329 mmol), 45 ml of 25% aqueous solution of sodium methoxide in methanol and 4.9 ml of anhydrous methanol was stirred at 40aboutWith argon for 8.5 hours the Mixture was cooled to room temperature and was removed in vacuum solvent. Sticky OST what LOTOS and sodium bicarbonate. Solution (7-8 ml) was applied on a column of SN-20P resin (1,h,5 cm) in water. After elution with water ( 50 ml) column was suirable water acetonitrile (2% to 4% and 10%) and got to 55.8 mg of the target substance in the form of a solid substance.

With) (1,2,3)-1-[2,3-bis(hydroxymethyl)cyclobutyl]-5-iodine-2,4(1H,3H)-pyrimi - dindin.

Solution (1,2,3)-1-[2,3-bis(hydroxymethyl)cyclobutyl]-2,4(1H,3H)-pyrimi - Indiana (54,7 mg, 0,242 mmol), iodine (123 mg, 0,484 mmol) and aqueous nitric acid (0,8 N. 0,256 mmol) in 5 ml of dioxane was stirred at 105aboutWith 85 minutes After cooling to room temperature the mixture was decolorized aqueous sodium thiosulfate and concentrated in vacuo to solids. The solid was taken in water and concentrated in vacuum (3 times). The obtained solid was partially dissolved in water and applied on a column of CHP-20P resin (1,5x20 cm) in water. After elution with water (50 ml) column was suirable continuous gradient of water to 50% acetonitrile in water and got to 67.3 mg (1,2,3)-1-[2,3-bis(hydroxymethyl)CEC - libutil]-5-iodine-2,4(1H,3H)-pyrimidinedione in the form of a solid substance with a melting point 170-171aboutC.

Calculated for C10H13IN2O40,27 H2O:

C 33,65; H 3,82; N A 7.85.

Found: C 33,68; H Of 3.77; N Of 7.82.

Abbreviations:

HSV-1 (herpes type 1);

HSV-2 (herpes type 2);

VZV (varicella zoster virus);

HCMV (human cytomegalovirus);

MuLV virus (murine leukemia).

Analyses of cell culture.

Virus (herpes 1, herpes 2, cytomegalovirus, varicella) adsorbiroval in WI-38 single-layer cell cultures in the cups with the culture with 6 cells (Costar, Cambridge, MA) for 1 h before being added to a nutrient medium containing twofold dilutions of the test compounds. Inhibition of development of plaques was assessed on fixed and stained monolayers after 4-day incubation at 37aboutFor HSV-1 and HSV-2 and after 6-7 days of incubation at 37aboutFor HCMV and VZV.

ID50value was determined by the concentration of the drug, which could provide at least a 50% reduction of plaques compared to control viruses.

Antiviral assays MuLV was performed with modifications as described by Rowe et al. and Shannon et al. SC-1 cells were placed in the amount of approximately 2x105cells to a cell in nie 1 h at 37aboutUsing the DEAE-Dextran, washed and inoculable MuLV. In the culture of the newly added environment for the growth, containing different concentrations of experimental compound. After 3 days at 37aboutWith the culture of the newly added fresh environment and experienced compounds and incubated at 37aboutWith 3 more days. The culture was then washed to remove medium was irradiated with UV light and placed in the environment for the growth of cells containing the appropriate concentration experienced connection, in the amount of approximately 5x105XC cells in the cell. Then the culture was incubated for another 4 days with the addition on the second day environment of growth, containing experienced a connection with the subsequent imposition of XC cells. Then the cultures were rinsed, stained and counted plaques.

To the product of example 1 (100 mg, 0,358 mmol) was added to 20 ml of distilled pair of water (degassed in vacuum for 20 min, and then 0.1 N. sodium hydroxide (3.6 ml). The resulting mixture was stirred in nitrogen atmosphere for 5 minutes, adding additional water (5 ml) and stirring was continued for 1 h, the Insoluble portion was removed, and the resulting clear solution liofilizirovanny to obtain 79 mg of granulated monosodium salt (1, 2, UB>14N5O3Na 2H2O

Calculated: C 40,87; H 5,61; N 21,66.

Found: C 41,21; H 5,46; N 21,61.

Comparative tests.

Antiviral activity and activity inhibition of cell growth was determined as follows.

Antivirus experience in cell culture.

The virus Herpes Simplex type 1(HSV-1) strain Schooler, strain HSV-2-186 were prepared in the form of extracts from cell cultures infected vero. Strain AD169 of cymatosaurus person (HCMV) and Ellen strain of the virus stays zoster (VZV) were prepared in the form of a suspension of cells infected WI-38. Cells WI-38 was grown in minimal integral environment Eagles with salt Eagles (EMEM) with the addition of 2 mm glutamine, 100 units/ml penicillin, 11 μg/ml streptomycin and 10% embryonic bovine serum (Gibco the laboratories, Grand island, NY).

Viruses were analyzed on monolayers of cells WI-38. The virus was absorbed on the cell monolayers in 6-mesh plates for culture (Costar, Cambridge, MA) for 1-2 h before adding the environment to sustain (EMEM plus supplements, 1% carboxymethyl cellulose, 2.5% of embryonic (fetal) bovine serum drug) containing two-fold dilutions of the test compounds. UB>50was determined by the concentration of the drug, which provided a 50% reduction in the number of plaques compared to virus controls. All titrations were performed in two iterations and was expressed as an interval in repeated tests.

The data are given in table.2-4.

Inhibition of cell growth.

Cells WI-38 was applied in the amount of 1x105cells/ml in 12-mesh plates for cell culture, Costar. After 24 h in cell culture was re-added environment for growth, containing anti-virus connection with a series of dilutions. At intervals of 24 h culture of cells at each concentration with a fourfold repetition of the re-suspendibility with trypsinization, was made count of viable and dead cells using the exclusion criteria (exclusion) tripan blue. The control culture was evaluated in the same way and during the 96-hour period increased by 3-5 times. Indicator ID50for each compound was calculated as the concentration that inhibited growth by 50% compared to control cell cultures.

Bis-(hydroxymethyl-cyclobutyl-purines or pyrimidines of General formula

< / BR>
where R1group four

 

Same patents:

The invention relates to a process for the preparation of 9-substituted derivatives of guanine General formula

(l) where R is a C1-C4-alkyl, optionally substituted by one or more hydroxyl groups, or R is

a benzyl, ribosom, 2-deoxyribosyl or (CH2)n-OR SIG1where n is 1 or 2, and R1is CH2CH2HE or CHor their salts

The invention relates to a derivative of propionic acid, useful as fungicides, to fungicidal compositions containing them and to methods used to combat fungi, especially fungal infections of plants

The invention relates to organic synthesis and concerns a method for obtaining substituted falicov and heterocyclic falicov General formula

(I) where ring a is selected from the group comprising residues:

a) phenyl,

b) pyridyl,

b) five-membered heteroaromatic ring containing oxygen, sulfur or nitrogen as a heteroatom;

R cyano, formyl, ketonuria group, carboxyl group, which may be in the form of the free acid, ester or salt, carnemolla group or mono - or disubstituted carnemolla group or ring

Z

Y1, Y2and Y3attached to carbon atoms and are independently hydrogen, halogen, hydroxyl, C1-8-alkyl, C2-8-alkenyl,2-8-quinil,1-8-alkoxy, C2-8-alkenylamine,2-8-alkyloxy,1-8-alkylsulfonate, each of which may be substituted by 1 to 6 halogen atoms and conjugated WITH1-8-alkoxyl,2-8-acyl, phenyl WITH1-8-alkoxyl, phenylthio, each of which can be substituted one or three halogen atoms;

Y1and Y2>W3, W4and W5independently is CH, CR3or N;

Z is a bridge consisting of elements selected from the group of methylene, substituted methylene, -C(O)-;

R1and R2each independently hydrogen, halogen, C1-8-alkyl, C1-8-alkoxy, C2-8-alkenylamine,2-8-alkyloxy, each of which may be substituted by 1 to 6 halogen atoms, 5 - or 6-membered heterocycle-C1-8-alkoxy, phenyloxy or phenyl-C1-8-alkoxy, each of which may be substituted by 1-3 substituents selected from halogen or1-8-alkyl; R2WITH1-8-alkyl, phenyl-C1-8-alkoxy or phenyl;

X and Y each independently hydrogen, hydroxyl, halogen, cyano, C1-8-alkyl, C1-8-alkoxy, C1-8-alkoxycarbonyl,2-8-acyloxy, carbamoylated,1-8-alkylthio, phenyloxy, phenyl S, each of which may be substituted by 1-3 halogen atoms, or together they predstavljaet,S,NH,NOR12илиCR13R14;

or X and R together may form a bridge having the formula-C(O)-O - or-C(O)-NR2where the carbonyl is attached to A; with the proviso that when R carboxyl in free ether or salt and X and Y together javlautsa, one of the rings a and b contains a heteroatom

The invention relates to a method for obtaining new pyrimidine derivatives possessing valuable fungicidal properties, which can find application in agriculture

The invention relates to pyrimidine derivative of the General formula I:

where R1- alkyl-(C1-C4), O-alkyl-(C1-C4), halogen;

R2- alkyl-(C1-C4), O-alkyl-(C1-C4);

n = 3-5;

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where R1- alkyl-(C1-C4), O-alkyl-(C1-C4), halogen;

R2- alkyl-(C1-C4), O-alkyl(C1-C4);

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The invention relates to methods of producing derivatives of 2-anilinopyrimidines or acid additive salts of novel biologically active compounds, which can find application in agriculture

FIELD: organic chemistry, agriculture.

SUBSTANCE: method involves carrying out a seasonal single treatment of plant leaves with asymmetrical derivative of 4,6-bis-(aryloxy)pyrimidine of the formula: wherein X means chlorine atom (Cl), nitro- or cyano-group. Invention provides enhancing the long-term time of plants protection.

EFFECT: enhanced effectiveness and valuable properties of compounds.

6 cl, 6 tbl

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a novel method that can be used in industry for synthesis of substituted aniline compound represented by the following general formula (6):

wherein in the general formula (6) each R1, R2 and R3 means independently alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group, alkylcarboxamide group, nitro-group, aryl group, arylalkyl group, aryloxy-group, halogen atom or hydrogen atom; each X and Y means independently hydrogen atom, alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group or halogen atom. Method involves oxidation of substituted indole compound represented by the following general formula (3):

(wherein values R1, R2, R, X and Y are given above) resulting to opening indole ring to yield acetanilide compound represented by the following general formula (4):

(wherein values R1, R2, R3, X and Y are given above) and Ac means acetyl group, and treatment of this compound by reduction and deacetylation. Also, invention relates to novel intermediate compounds. Proposed compound (6) can be used as intermediate substance for production of chemicals for agriculture and as medicinal agents.

EFFECT: improved method of synthesis.

20 cl, 1 sch, 3 tbl, 31 ex

FIELD: organic chemistry, herbicides, chemical technology.

SUBSTANCE: invention relates to derivatives of substituted sulfonylaminomethylbenzoic acid of the general formula (I): wherein R1 means hydrogen atom (H) or (C1-C8)-alkyl; R2 and R3 mean H; R4 and R5 mean H; R6 means H or (C1-C8)-alkyl; R7 means (C1-C8)-alkyl; R8 is similar or different and means (C1-C4)-alkyl or (C1-C4)-alkoxy-group; n means 0 or 1. Compounds of the formula (I) are intermediate substances in synthesis of biologically active compounds possessing the herbicide activity, in particular, in synthesis of sulfonylureas. Also, invention describes methods for synthesis of compounds of the formula (I) and their derivatives.

EFFECT: improved method of synthesis.

27 cl, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new method of producing formerly unknown 1-(pyrimidine-2-il)propane-2-on of the general formula wherein R designates every time the C1-C10 alkyl group. The method consists in that the reaction of malone diimidate is carried out with the general formula , wherein R has the above-stated magnitudes, with dikenete of the formula . It is preferable to use malone diimidate (II) produced in situ from is appropriate salt and base. Here, the salt of used malone diimidate (II) is dihydrochloride, and tertiary amine. The preferable malone diimidate of the formula (II) is dimethyl malone diimidate.

EFFECT: new compounds feature useful biological properties.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the new methylcetone pyrimidine -2 of the formula (I) and to the new method of their preparation. The compounds of the invention are intermediate products for synthesis of agronomical active effectors. The method of preparation of methylcetone pyrimidine -2 of general formula in which R1 and R2 define C1-C10 alkyl group in each case is that reaction malondiimidate of the general formula (II) , in which R1 has above mentioned value with β-ketoester of the general formula (III) , in which R2 has above mentioned value and R3 define C1-C10 alkyl group. Usually, water appeared during reaction are taken away from the reactor feed. Basic malondiimidate(II) can be derived in situ from the conforming salt and base. Preferably, used salt of malondiimidate (II) is dihydrochloride and used malondiimidate (II) is dimethylmalondiimidate. Preferably used β-ketoester (III) is acetacetic ester, 3-oxopentane ester.

EFFECT: method of the compound preparation is improved.

9 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new sulphamines with general formula (I) , where R1 represents (low) alkyl-O-(CH2)n-; R2 represents Ra-Y-(CH2)m-; R3 represents phenyl, which can be replaced by such substitutes as halogen, (low) alkyl or (low)alkoxy; R4 represents hydrogen; R6 represents hydrogen; X represents oxygen or a bond; Y represents a bond of -O-; n is equal to 2; m is equal to 2; Ra represents heteroaryl, in form of a 6-member aromatic ring, containing two nitrogen atoms, which can be substituted with such substitutes as halogen, thio(low)alkyl or (low)alkoxy; and their pharmaceutical salts. The invention also pertains to related objects, including the method of obtaining the following compounds formula II , formula III , formula IV , formula V , where radicals assume values indicated above or in the description.

EFFECT: invented compounds can be used as active ingredients for obtaining pharmaceutical compositions, which have inhibiting effect to endothelial receptors.

13 cl, 4 ex, 3 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing azoxystrobin by reacting a compound of formula (II): with 2-cyanophenol or a salt thereof in the presence of 2.5-40 mol. % 1,4-diazabicyclo[2,2,2]octane and an acid acceptor, where W is a methyl(E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3. 1,4-diazabicyclo[2,2,2]octane is mixed with a compound of formula (II) only in the presence of 2-cyanophenol or when conditions are such that the compound of formula (II) and 1,4-diazabicyclo[2,2,2]octane are not capable of reacting with each other.

EFFECT: method enables to obtain a product with high output using a certain order of adding components.

12 c, 18 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compositions having herbicidal activity, which contain a compound of formula (I) which is mixed with one or more known herbicide products, optionally stabilised by adding at least one inorganic or organic base, and the corresponding application for weed control in crops.

EFFECT: obtaining compositions having herbicidal activity.

20 cl, 1 tbl, 5 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention proposes the novel derivatives of phenylalanine of the formula (I) and (II) possessing with antagonistic activity with respect to α4-integrin. Derivatives of phenylalanine are used as therapeutic agents in different diseases associated with α4-integrin.

EFFECT: valuable medicinal properties of compounds.

37 cl, 30 tbl, 215 ex

FIELD: chemistry.

SUBSTANCE: in formula (I') , R5 is any group selected from a group comprising C1-C6 alkoxy group, which can be substituted with one group selected from a group of β substitutes, phenyloxy group which can be substituted with one group selected from a group of γ substitutes, C1-C6 halogenalkoxy group and C3-C6 cycloalkyloxy group; R6 is a substitute in a benzene ring which is selected from a group of α substitutes; R7 is a hydrogen atom, C1-C6 halogenalkyl group, C1-C6 hydroxyalkyl group which can be substituted with a hydroxy-protective group, C1-C6 alkyl group which can be substituted with one group selected from a group of β substitutes, or a phenyl group which can be substituted with one hydroxy group; m equals 1; n equals 1 or 2; numbers in each benzene ring denote the number of the position of each substitute; the group of substitutes includes hydroxyl groups, nitro groups, cyano groups, C1-C6 dialkylamino groups, acetamide groups, halogen atoms, C1-C6 alkyl groups, which can be substituted with one group selected from a group of β substitutes, C1-C6 halogen alkyl groups, C3-C10 cycloalkyl groups, 6-member heterocyclic groups with an N atom or O atom as a heteroatom, C3-C6 cycloalkenyl groups, phenyl group which can be substituted with one group selected from a group of γ substitutes, 5-6-member heteroaryl groups with 1-3 N atoms as heteroatoms which can be substituted wit one or more groups selected from a group of γ substitutes, C1-C6 alkoxy groups, C1-C6 halogenalkoxy groups, C3-C10 cycloalkoxy groups, phenyloxy group, C1-C6 alkylthio groups, C1-C6 halogenalkylthio groups, C1-C6 alkylsulphonyl groups and C1-C6 alkylcarbonyl groups; the group of β substitutes includes C1-C6 alkoxycarbonyl groups, C3-C10 cycloalkyl groups which can be substituted with one group selected from a group of γ substitutes, C3-C6 cycloalkenyl groups, C6-C10 aryl groups which can be substituted with one or more groups selected from a group of γ substitutes, 5-6-member heteroaryl groups with one N, O or S heteroatom, 9-member heteroaryl groups with two heteroatoms selected from N and S, C1-C6 alkoxy group and C6-C10 aryloxy group; and the group of γ substitutes include cyano groups, C1-C6 dialkylamino groups, C1-C6 cyclic amino groups, halogen atoms, C1-C6 alkyl groups, C3-C10 cycloalkyl grous, C1-C6 halogenalkyl groups, C1-C6 alkoxy groups and C1-C6 alkylenedioxy groups. The invention also relates to compounds or pharmaceutically acceptable salts thereof, selected from: 4-(2-cyclopropylethoxy)-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide, 4-(2-cyclopropylethoxy)-N-(2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide, 4-(2-cyclopropylethoxy)-N-(2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}-vinyl)-benzamide. Other compounds are given in the formula of invention. The invention also relates to a pharmaceutical composition which can inhibit bone resorption, which contains the disclosed compound, to use of the disclosed compound as a medicinal agent for inhibiting bone resorption, for preparing a medicinal agent for lowering concentration of calcium in the blood, for preparing a medicinal agent for inhibiting reduction of bone mass, to a medicinal agent for inhibiting bone resorption in form of the disclosed compound, to a method of inhibiting bone resorption, a method of lowering concentration of calcium in the blood, a method of inhibiting reduction of bond mass, involving addition of an effective amount of the disclosed compound.

EFFECT: more effective use of the compounds.

22 cl, 6 tbl, 116 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 1H-quinazoline-2,4-diones of formula and to their pharmaceutically acceptable salts where R1 and R2 have the values specified in cl. 1 of the patent claim. The specified compounds exhibit antagonistic activity with respect to the AMPA receptor.

EFFECT: reception of a pharmaceutical composition for preparing a preparation used for treating a condition mediated by the AMPA receptor and first of all for treating epilepsy or schizophrenia.

8 cl, 81 ex

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