Derivatives dihydropyrimidine or their therapeutically acceptable salts accession acid with protivominniy and anti-inflammatory activity

 

(57) Abstract:

Usage: in medicine, as substances with protivominniy and anti-inflammatory activity. The inventive product is derived dihydropyrimidine f-ly I: where R1-C1-C6-alkoxy or phenylaminopropyl, R2-C1-C6-alkyl or phenyl, R3is hydrogen or 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, C1-C6-alkyl, C1-C6-alkoxy or hydroxy-group, or their therapeutically acceptable salts accession acid. Reagent 1: derivatives of 1,2,3,4-tetrahydro-2-pyrimidinethione f-ly II. 1 C.p. f-crystals, 4 PL.

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 can be Zam 6-dialkylamino,1-C6-alkyl, C1-C6-alkoxy and hydroxy-group, or their therapeutically acceptable salts accession acid with protivominniy and anti-inflammatory activity.

Known unsubstituted in the 7-position derivatives dihydropyrimidine reducing the intensity of the inflammation.

The purpose of the invention is the detection of the number of derivatives dihydropyrimidine new connections with a broader spectrum of activity and have higher anti-inflammatory activity.

This goal is achieved derivatives dihydropyrimidine formula I or their therapeutically acceptable salts accession acid with protivominniy and anti-inflammatory activity.

Preferred representatives of the compounds of formula (I) are those in which

R1means methoxy or ethoxy,

R2is methyl or phenyl,

R3is a hydrogen atom,

R4is methyl or phenyl, having one or more, identical or different substituents from among methoxy-, nitro group or halogen.

Compounds of General formula (I), as bases capable of forming salts accession/P> From a therapeutically acceptable salts are preferred salt galoidvodorodnykh acids, e.g. hydrochloric or Hydrobromic salt, carbonates, bicarbonates and sulfates, and acetates, fumarate, maleate, citrate and salts of ascorbic acid.

Derivatives dihydropyrimidine General formula (I) is produced by interaction of 4,5,6-translesanas 1,2,3,4-tetrahydro-2-pyrimidinethione General formula (II)

where R1, R2, R4have the specified values with dehalogenation General formula (III)

X-CHH-CH2-Y where R3has the specified values, and X and Y are halogen atom, and then, if desired, the compound obtained of General formula (I) transferred to salt accession acid or separated from salt accession acid in the form of free base or into another salt accession acid.

The reaction is preferably carried out in an inert organic solvent or mixture of solvents. As solvents it is possible to use aliphatic alcohols, for example isopropyl or ethyl alcohols, dialkylamide, preferably dimethylformamide, diallylsulfide, preferably dimethyl sulfoxide, chlorinated aliphatic measures benzene, toluene or xylene, aliphatic or alicyclic ethers, for example diethyl ether, tetrahydrofuran, or dioxane, aliphatic ketones, such as acetone or methyl ethyl ketone, or mixtures of these solvents. It is most preferable to conduct the reaction in a medium of dimethylformamide, or a mixture of dimethylformamide and methyl ethyl ketone, or dimethylformamide and acetone.

The reaction is carried out in the presence of kislorodsvyazyvayushchei funds. For this purpose it is preferable to use carbonates of alkali metals, e.g. sodium carbonate or potassium bicarbonates of alkali metals such as potassium bicarbonate or sodium hydroxides of alkali metals such as potassium hydroxide or sodium hydroxides of alkaline earth metals such as calcium hydroxide, or tertiary amines, for example pyridine, triethylamine or other trialkylamine. Preferably as kislorodsvyazyvayushchei tools to use potassium carbonate or sodium.

To accelerate the reaction it is possible to use a catalyst. As a catalyst, you can use the halides of the alkali or alkaline earth metals (e.g. potassium iodide, fluoride, potassium bromide, sodium or calcium chloride). Preferably the activity of the reactants the reaction can be conducted at a temperature from room temperature up to the boiling temperature of the reaction mixture. Preferably it at 70-80aboutC.

Duration of response depending on the reactivity of the starting reagents and the operating temperature is 5-36 h

The initial compounds of General formulas (II) and (III) can be taken in equimolecular quantities or to the reaction mixture, you can add not more than 0.5 mole excess dehalogenase derivative of General formula (III). Cyclotosaurus means you can take in equimolecular quantity or in excess of 1 mol.

The catalyst charge in the amount of 0.1 to 0.2 mole. Preferably the reaction is carried out in the presence of 0.1 mole of catalyst.

Further processing of the reaction mixture is carried out by known methods. To highlight the product is preferably separated solution from the drop-down sediment inorganic salts by filtration, the solvent is then distilled off in vacuum and the residue is recrystallized from water or an organic solvent. If necessary, the product was subjected to purification by known methods, for example by recrystallization or chromatographic separation.

Compounds of General formula (I) can also be selected as mentioned salts of joining therapeutically priea subsequent stage, to which they are subjected to interaction with the appropriate acid in an inert solvent. From the resulting salts of the base can be re-allocated in the free state and converted into another salt.

The initial compounds of General formula (III) are known and are produced by the industry.

4,5,6-Transnistria derivatives of General formula (II) in which R4means unsubstituted or substituted phenyl, are known. They can be obtained, for example, using the methods described in Japanese laid out the application N 59.190.974 or European application N ER 202654.

The compounds of formula (II), where R4means1-C11-alkyl, are novel.

Derivatives tetrahydropyrimidines acid of General formula (III), where

R4means1-C11-alkyl,

R1- C1-6-alkoxy-, amino - or phenylaminopropyl;

R2- C1-6-alkyl or phenyl, are new compounds.

The method of obtaining compounds of General formula (II) is that the aldehyde of General formula (IV)

R4- CHO, where R4means1-11-alkyl, are subjected to interaction with the derived-Methocarbamol what urbanizam.

The above reaction can be carried out in an inert organic solvent or mixture of solvents. So, for this purpose it is possible to use aliphatic alcohols, for example isopropyl or ethyl alcohols, dialkylamide, dimethylsulfoxide, chlorinated aliphatic hydrocarbons, such as chloroform, carbon tetrachloride, dichloromethane, aromatic hydrocarbons such as benzene, toluene or xylene, aliphatic or alicyclic ethers, for example diethyl ether, tetrahydrofuran or dioxane, or mixtures of these solvents.

To accelerate the reaction it is possible to use a catalyst, preferably a solution of gaseous hydrogen chloride in an anhydrous organic solvent, in particular, a solution of hydrogen chloride in isopropanol.

The reaction is carried out at 10-50aboutC, preferably at room temperature. Duration of response depending on the reactivity of the starting compounds is in the range 3-35 hours of starting compound of the General formula (IV) and (V) and thiocarbamide preferable to take in equimolecular quantities. You can however take the thiocarbamide in excess of 0.1-1 mol. The catalyst can be taken in a number 1-7, the preferred is m follows. The resulting target product can be isolated from the reaction mixture by simple filtration. Alternatively, after removal of the solvent the residue is crystallized from water or an organic solvent and filtering the resulting suspension. Compounds of General formula (IV) are known and are produced by the industry.

P R I m e R 1. Getting ethyl-(6-phenyl-8-methyl-3,4-dihydro-2H,6N-pyrimido-[2,1-b] [1,3] thiazin-7-carboxylate) and its Hydrobromic and hydrochloric salt.

of 27.6 g (0.1 mole) of ethyl-(4-phenyl-6-methyl-1,2,3,4-tetrahydro-2-pyrimidinethione-5-carboxylate and 30.3 grams (0.15 mole) of 1,3-dibromopropane in the presence of 27.6 g (0.2 mole) of potassium carbonate and 2.0 g (0,012 mol) is boiled for 15 hours under reflux in a mixture of 500 ml of methyl ethyl ketone and 50 ml of dimethylformamide. Then the reaction mixture is cooled to room temperature, filtered and the filtrate evaporated. The residue is crystallized from ethyl acetate, the crystals are filtered and dried. The result of 25.8 g (65%) Hydrobromic salt of the target compound. Melting point 192-194aboutC.

The receiving base. Received Hydrobromic salt is dissolved in 530 ml of water and with sodium bicarbonate set the gain of 19.5 g (95%) of the target base connection. The pace. plvl. 110-112aboutC.

Getting hydrochloric salt. The base is dissolved in 225 ml of ethyl acetate and added dropwise to the prepared solution dropwise ethyl alcohol containing equimolecular the number of hydrogen chloride. After stirring for 1 h, the suspension is cooled to 50aboutWith, the solid is filtered off, washed with ethyl acetate and dried. The result of 21.3 g of the target compound.

Brutto-formula: C17H20N2O2S HCl; mol.m. : 352,879.

Calculated, %: C 57,68; H 6,0; N 7,94; S Remaining 9.08; Cl-of 10.05

Found, %: C 58,87; H 6,17; N 7,87; S 9,18; Cl-of 10.25.

P R I m m e R 2. Getting ethyl-[6-(2-fluoro-6-chlorophenyl)8-methyl-3,4-dihydro-2H,6N - pyrimido [2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between of 32.9 g (0.1 mole) ethyl-4-(2-fluoro-6-chlorophenyl)-6-methyl-1,2,3,4-tetrahydro - 2-pyrimidinethione-5-carboxylate and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 20 h in the same manner as described in example 1. The residue is crystallized from water, drop the crystals are filtered and dried. The result is a 35 g (94,9%) of target compound.

Sothe Plava.: 129-131oC.

Brutto-formula: C17H18ClSN2O2, mol.m: 368,855

In the tion ethyl-[6-(3,4-dichlorophenyl)-8-methyl-3,4-dihydro-2H, 6N-pyrimido [2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between of 34.5 g (0.1 mole) of ethyl-[4-(3,4-dichlorophenyl)-6-methyl-1,2,3,4-tetrahydro - 2-pyrimidine-5-carboxylate] and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 26 h in the same conditions as in the case of example 1. The residue is crystallized from water, drop the crystals are filtered and dried. The result is 37 g (97,0%) of target compound.

Solawl.: 116-118oC.

Brutto-formula: C17H18Cl2N2O2S, mol.m: 385,315.

Calculated, %: C 52,99; H 4,71; N 7,27; S 8,32; Cl Is 18.40.

Found, %: C 52,71; H 4,71; N 7,27; S 8,32; Cl Is 18.40.

P R I m e R 4. Obtaining methyl-[6-(3-nitrophenyl)-8-methyl-3,4-dihydro-2H,6N-Piri - Mido-[2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between a 30.7 g (0.1 mole) of methyl-[4-(3-nitrophenyl)-6-methyl-1,2,3,4-Tetra - hydro-2-pyrimidinethione-5-carboxylate] and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 13 h under the same conditions as in the case of example 1. The residue is crystallized from water, drop the crystals are filtered and dried. The result 29,2 g (84%) of target compound.

Sothe melt.: 178-180aboutC.

Brutto-formula: C16H17N3O4S, mol.m.: 347,391

Calculated,Il-3,4-dihydro-2H,6N-pyrimido-[2,1-b] [1,3] thiazin-7-carboxylic acid and its hydrochloride.

Conduct the reaction between and 32.3 g (0.1 mole) of anilide 4-phenyl-6-methyl-1,2,3,4-Tetra hydro-2-pyrimidinethione-5-carboxylic acid and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 6 h in the same conditions as in the case of example 1. The residue is crystallized from ethyl alcohol, a drop-down crystals are filtered and dried. The result is 21.8 g (60%) of target compound in the form of free base. Getting hydrochloric salt.

of 18.2 g (0.05 mol) of the obtained base is suspended in 170 ml of ethyl acetate and then added to the suspension dropwise ethyl alcohol containing equimolecular the number of hydrogen chloride. After stirring for 1 h, the suspension is cooled to 5aboutC, filtered, the filter residue is washed and dried. The result is to 17.6 g (88%) of target compound.

Sothe Plava.: 206-209oC.

Brutto-formula: C21H21N3O5SHCl, mol.m.: 399,938.

Calculated, %: C 63,07; H 5,54; N 10,51; S 8,02; Cl-8,86.

Found, %: C 62,59; H 5,69; N 10,20; S 7,84; Cl-8,75.

P R I m e R 6. Getting anilide 6-[3-fluoro-6-chlorophenyl)-8-methyl-3,4-dihydro-2H, 6N-pyrimido[2,1-b] [1,3] thiazin-7-carboxylic acid.

of 37.6 g (0.1 mole) of anilide 4-(2-fluoro-6-chlorophenyl)-6-methyl-1,2, g (0,115 mole) of 1,3-dibromopropane in the presence of 13.8 g (0.1 mole) of potassium carbonate in 200 ml of dimethylformamide. Then the reaction mixture is cooled to room temperature, filtered and the filtrate evaporated in vacuum. The residue is crystallized from water, drop the crystals are filtered and dried. The result of 40.3 g (97%) of target compound.

Melting point: 210-215oC.

Brutto-formula: C21H19ClFN2OS, mol.m.: 415,914.

Calculated, %: C 60,65; H 4,60; N 10,10; S 7,71; Cl Charged 8.52.

Found, %: C 59,68; H 4,59; N 9,94; S 7,71, Cl 8,49.

P R I m e R 7. Getting ethyl-[8-methyl-6-(4-methoxyphenyl)-3,4-dihydro-2H,6N-PI - imido[2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between 30.6 g (0.1 mol) of ethyl-[6-methyl-4-(4-methoxyphenyl)-1,2,3,4-tetrahydro-2-pyrimidinethione - 6-carboxylate] and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 13 h under the same conditions as in example 1. The residue is crystallized from isopropyl alcohol, drop-down, the crystals are filtered and dried. The result is 18 g (52%) of target compound.

Soplvl.: 148-150aboutC.

Brutto-formula: C18H22N2O3S, mol.m.: 346,447.

Calculated, %: C 62,40; H 6,40; N 8,09; S 9,25.

Found, %: C 62,33; H 6,33; N 8,13; S 9,10.

P R I m e R 8. Obtaining methyl-[6-(4-chloro-3-nitrophenyl)-3,4-dihydro-2H, 6N-Enyl)-6-methyl-1,2,3,4-tetrahydro-2-pyrimidinethione - 5-carboxylate] and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 13 h under the same conditions as in example 1. The residue is crystallized from water, drop the crystals are filtered and dried. The result is 37.4 g (98%) of target compound.

Melting point: 146-148aboutC.

Brutto-formula: C16H16ClN3O4S, mol.m.: 381,834.

Calculated, %: C 50,33; H 4,22; N 11,0; Cl 9.28 Are; S 8,40.

Found, %: C 49,00; H 4,33; N 10,78; Cl To 9.32; S 8,07.

P R I m e R 9. Obtaining methyl-[3,8-dimethyl-6-(4-chloro-3-nitrophenyl)-3,4-dihydro-2H-6N-pyrimido [2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between a 34.2 g (0.1 mole) of methyl-[4-(4-chloro-3-nitrofen)-6-methyl-1,2,3,4-tetrahydro-2 - pyrimidinethione-5-carboxylate] and 19.7 g (0,115 mole) of 2-methyl-1,3-chloropropane for 16 h, under the same conditions as in example 6. The residue is crystallized from water, drop the crystals are filtered and dried. The result was 29.7 g (75%) of target compound.

Melting point: 139-142aboutC.

Brutto-formula: C17H18ClN3O4S, mol.m.: 395,861.

Calculated, %: C 52,58; H 4,58; N 10,61; S 8,10; Cl 8,96.

Found, %: C 51,12; H 4,46; N 10,61; S 8,06; Cl 8,97.

P R I m e R 10. Obtaining methyl-[3,8-dimethyl-(0,1 mole) of methyl-[4-(3-nitrophenyl)-6-methyl-1,2,3,4-tetrahydro-2 - pyrimidinethione-5-carboxylate] and 19.7 g (0,115 mole) of 2-methyl-1,3-chloropropane within 24 h PIaboutWith, in the same conditions as in example 6. The residue is crystallized from water. Drop down the crystals are filtered and dried. The result of 31.4 g (87,1%) of target compound.

Melting point: 145-150oC.

Brutto-formula: C17H18N3O4S, mol.m.: 360,411.

Calculated, %: C 56,65; H To 5.03; N 11,66; S 8,89.

Found, %: C, 56.78 Has; H Of 5.34; N 11,54; S 9,06.

P R I m e R 11. Getting ethyl-[6-(4-bromophenyl)-8-methyl-3,4-dihydro-2H, 6N-pyrimido[2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between 35.5 g (0,1 mole) of ethyl-[4-(4-bromophenyl)-6-methyl-1,2,3,4-tetrahydro-2-pyrimidinethione - 5-carboxylate] and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 13 h under the same conditions as in example 1. The residue is crystallized from water, drop the crystals are filtered and dried. The result of 28.2 g (71,3%) of target compound.

Melting point: 150-153oC.

Brutto-formula: C17H19BrN2O2S, mol.m.: 395,393.

Calculated, %: C 15,65; H 4,84, N 7,09; Br 20,21; S 8,11

Found, %: C 52,00; H is 4.93; N 7,42; Br grade of 20.06; S 7,94

P R I m e R 12. Getting ethyl-[8-phenyl-6-(2-fluoro-6-chlorophenyl)3,4-dihydro-2H,6N-pyrimido [2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between dibromopropane for 5 h in the same conditions, as in example 6. The residue is crystallized from water, drop the crystals are filtered and dried. The result was 39.6 g (92%) of target compound.

Melting point: 168-170aboutC.

Brutto-formula: C22H20ClFN2O2S, mol.m.: 430,926.

Calculated, %: C 61,32; H To 4.68; N 6,50; S 7,44; Cl 8,23.

Found, %: C 60,40; H With 4.64; N Of 6.49; S 7,44; Cl 8,12.

P R I m e p 13. Getting ethyl-[8-phenyl-6-(4-nitrophenyl)-3,4-dihydro-2H,6N-Piri - Mido [2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between 38,3 g (0.1 mole) of ethyl-[6-phenyl-4-(4-nitrophenyl)-1,2,3,4-tetrahydro-2-pyrimidinethione - 5-carboxylate] and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 6 h, under the same conditions as in the case of example 1. The residue is crystallized from water, drop the crystals are filtered, the crystals are filtered and dried. The result of 19.1 g (45%) of target compound.

Melting point: 190-192oC.

Brutto-formula: C22H21N3O4S, mol.m.: 423,49.

Calculated, %: C 62,40; H 5,0; N 9,92; S 7,54.

Found, %: C 62,77; H Is 5.06; N 9,73; S 7,47.

P R I m e R 14. Obtaining methyl-[6,8-dimethyl-3,4-dihydro-2H,6N-pyrimido [2,1-b] [1,3] thiazin-7-carboxylate].

to 20.0 g (0.1 mole) Meteora for 32 h at the boiling temperature in the presence of 27.6 g (0.2 mole) of potassium carbonate and 2.0 g (0,012 mol) of potassium iodide in a mixture of 500 ml of acetone and 50 ml of dimethylformamide. After that the reaction mixture is cooled to room temperature, filtered and the filtrate evaporated. The residue is crystallized from water, drop the crystals are filtered and dried. The result of 19.2 g (80%) of target compound.

Melting point: 92-94aboutC.

Brutto-formula: C11H16N2O2S, mol.m.: 240,323.

Calculated, %: C 54,98; H Of 6.71; N 11,66; S 13,34.

Found, %: C 55,37; H Is 6.78; N 11,35; S 13,22.

P R I m e R 15. Obtaining methyl-[8-methyl-6-(4-methoxyphenyl)-3,4-dihydro-2H,6N - pyrimido [2,1-b] [1,3] thiazin-7-carboxylate]

Conduct the reaction between the 29.2 g (0.1 mole) of methyl-[6-methyl-4-(4-methoxyphenyl)-1,2,3,4-tetrahydro-2-pyrimidinethione - 5-carboxylate] and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 36 h under the same conditions as in example 14. The residue is crystallized from isopropanol, drop-down, the crystals are filtered and dried. The result 27.9 g (83,9%) of target compound.

Melting point: 185-186aboutC.

Brutto-formula: C17H20N2O3S, mol.m.: 332,42

Calculated, %: C 61,42; H The 6.06; N 8,43; S For 9.64.

Found, %: C Of 61.95; H 6,30; N 8,40; S 9,46.

P R I m e R 16. Obtaining methyl-[6-(3,4-dichlorophenyl)-8-methyl-3,4-dihydro-2H,6N-pyrimido [2,1-is,4-tetrahydro-2-pyrimidinethione - 5-carboxylate and 30.3 grams (0.15 mol) of 1,3-dibromopropane for 23 h, in the same conditions as in example 14. The residue is crystallized from water, drop the crystals are filtered and dried. The result was 35.3 g (95%) of target compound.

Melting point: 151-152aboutC.

Brutto-formula: C16H16Cl2N2O2S, mol.m.: 371,288.

Calculated, %: C 51,76, H 4,34, N 7,54, S 8,63, Cl 19,10.

Found, %: C 52,02; H 4,43; N 7.62mm; S 8,71; Cl 18,38.

P R I m e R 17. Getting ethyl-[8-methyl-6-(3-nitrophenyl)-3,4-dihydro-2H,6N-pyrimido [2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between 32,1 g (0.1 mole) of ethyl-[6-methyl-4-(3-nitrophenyl)-1,2,3-tetrahydro-2-pyrimidinethione - 5-carboxylate] and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 30 h under the same conditions as in example 14. The residue is crystallized from water, drop the crystals are filtered and dried. The result of 33.6 g (93%) of target compound.

Melting point: 163-165aboutC.

Brutto-formula: C17H19N3O4S, mol.m.: 361, 419.

Calculated, %: C 56,49; H And 5.30; N 11,63; S 8,86.

Found, %: C 56,89; H Of 5.05; N 11,48; S 8,76.

P R I m e R 18. Obtaining methyl-[8-methyl-6-(3,4,5-trimethoxyphenyl)-3,4-dihydro-2H,6N-pyrimido [2,1-b] [1,3] thiazin-7-carboxylate].

Premlata] and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 32 h under the same conditions, as in example 14. The residue is filtered off and dried. The result of 19.6 g (50%) of target compound.

Melting point: 137-138aboutC.

Brutto-formula: C19H24N2O5S, mol.m.: 392,473.

Calculated, %: C 58,15; H 6,16; N 7,14; S 8,17.

Found, %: C 57,28; H 5,96; N 7,02; S 8,01.

P R I m e R 19. Getting ethyl-[8-phenyl-6-(4-methoxyphenyl)-3,4-dihydro-2H,6N-PI - imido [2,1-b] [1,3] thiazin-7-carboxylate]

Conduct the reaction between 36,8 g (0.1 mole) of ethyl-[6-phenyl-4-(4-methoxyphenyl)-1,2,3,4-tetrahydro-2-pyrimidinethione-5-carboxylate] and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 9 h under the same conditions as in example 1. Drop the resulting crystals are filtered, washed with isopropyl alcohol and dried. The result was 32.7 g (80%) of target compound.

Melting point: 180-182oC.

Brutto-formula: C23H24N2O3S, mol.m.: 408,518.

Calculated, %: C 67,62; H of 5.92; N 6,86; S A 7.85

Found, %: C 67,33; H 5,90; N 6,93; S 7,69.

P R I m e R 20. Obtaining methyl-[8-methyl-6-(4-were)-3,4-dihydro-2H,6N - pyrimido [2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between of 27.6 g (0.1 mole) of methyl-[6-methyl-4-(4-were)-1,2,3,4-tetrahydro-2-pyrim the current washed with a small amount of acetone, filtered and dried. The result of 24.7 g (78%) of target compound.

Melting point: 184-186aboutC.

Brutto-formula: C17H29N2O2S, mol.m.: 316,404.

Calculated, %: C 64,53; H 6,37; N Cent To 8.85; S 10,13.

Found, %: C 64,67; H 6,46; N 8,89; S 10,11.

P R I m e R 21. Getting ethyl-[8-methyl-6-(3,4,5-trimethoxyphenyl)-3,4-dihydro-2H,6N-pyrimido [2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between of 36.6 g (0.1 mol) of ethyl-[6-methyl-4-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-2 - pyrimidinethione-5-carboxylate] and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 28 h under the same conditions as in example 14. The residue is crystallized from water, drop the crystals are filtered and dried. The result is 34 g (83.6 percent) of target compound.

Melting point: 104-105aboutC.

Brutto-formula: C20H26N2O5S, mol.m: 404,480.

Calculated, %: C 59,09; H 6,45; N 6,89; S 7,88.

Found, %: C 58,94; H 6,50; N 6,82; S 7,76.

P R I m e R 22. Getting ethyl-[6-(4-dimethylaminophenyl)-8-methyl-3,4-dihydro - 2H,6N-pyrimido [2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between to 31.9 g (0.1 mol) of ethyl-[4(-dimethylaminophenyl)-6-methyl-1,2,3,4-tetrahydro-2-pyrimidinethione - 5 is result of water, drop down the crystals are filtered and dried. The result of 31.3 g (87,1%) of target compound.

Melting point: 128-130oC.

Brutto-formula: C19H24N3O2S, mol.weight: 358,335.

Calculated, %: C 63,48; H 7,01; N Of 11.69; S 8,92.

Found, %: C 63,91; H 6,97; N Of 11.69; S 8,80.

P R I m e R 23. Getting ethyl-[6-ethyl-8-phenyl-3,4-dihydro-2H,6N-pyrimido-[2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between 29 g (0.1 mole) of ethyl-(4-ethyl-6-phenyl-1,2,3,4-tetrahydro-2-pyrimidinethione-5-carboxylate) and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 28 h under the same conditions as in example 14. The residue is crystallized from water, drop the crystals are filtered and dried. The result is 27 g (81,7%) of target compound.

Melting point: 74-76aboutC.

Brutto-formula: C18H22N2O2S, mol.m.: 330,448.

Calculated, %: C 65,43; H Of 6.71; N 8,48; S 9,70.

Found, %: C 64,11; H Is 6.61; N 8,33; S 9,41.

P R I m e R 24. Obtaining methyl-[6-phenyl-8-methyl-3,4-dihydro-2H,6N-pyrimido-[2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between 26,2 g (0.1 mole) of methyl-[4-phenyl-6-methyl-1,2,3,4-tetrahydro-2-pyrimidinethione-5-carboxylate] and 30.3 grams (0.15 mole) of 1,3-tally filtered off and dried. The result is 19 g (62,8%) of target compound.

Melting point: 194-195oC.

Brutto-formula: C16H18N2O3S, mol.m.: 302,393.

Calculated, %: C 62,55; H 6,00; N 9,26; S OR 10.60

Found, %: C 62,98; H 5,91; N 9,02; S Of 10.25.

P R I m e R 25. Obtaining methyl-[8-methyl-6-(2-methoxyphenyl)-3,4-dihydro-2H,6N - pyrimido [2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between of 29.3 g (0.1 mole) of methyl-[6-methyl-4-(2-methoxyphenyl)-1,2,3,4-tetrahydro-2-pyrimidinethione-5-carboxylate] and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 15 h under the same conditions as in example 1. After evaporation of the drop down, the crystals are filtered, washed with a small amount of ether and dried. The result of 20.9 g (62,9%) of target compound.

Melting point: 133-135aboutC.

Brutto-formula: C17H20N2O3S, mol.m.: 332,42.

Calculated, %: C 61,42; H The 6.06; N 8,43; S For 9.64.

Found, %: C 62,12; H 6,20; N To 8.34; S 9,48.

P R I m e R 26. Getting ethyl-[3,8-dimethyl-6-(3-nitrophenyl)-3,4-dihydro-2H,6N - pyrimido [2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between 32,1 g (0.1 mole) of ethyl-[6-methyl-4-(3-nitrophenyl)-1,2,3,4-tetrahydro-2-pyrimidinethione - 5-carboxylate] and 19.7 g (0,115 Miz water, drop down the crystals are filtered and dried. The result of 19.5 g (51,9%) of target compound.

Melting point: 124-126aboutC.

Brutto-formula: C18H21N3O4S, mol.m.: 375,446.

Calculated, %: C 57,58; H 5,64; N 11,19; S 8,54;

Found, %: C 56,48; H 5,73; N 11,18; S 8,73.

P R I m e R 27. Obtaining methyl-[6-(4-dimethylaminophenyl)-8-methyl-3,4-dihydro - 2H,6N-pyrimido [2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between of 30.5 g (0.1 mol) of methyl-[4-(4-dimethylaminophenyl)-6-methyl-1,2,3,4-tetrahydro-2 - pyrimidinethione-5-carboxylate] and 30.3, grams (0.15 mole) of 1,3-dibromopropane for 32 hours under the same conditions as in the case of example 14. The residue is crystallized from water, drop the crystals are filtered and dried. The result of 26.6 g (77%) of target compound.

Melting point: 128-130aboutC.

Brutto-formula: C18H23N3O2S, mol.m.: 345,463.

Calculated, %: C 62,58; H Of 6.71; N 12,16; S 9.28 Are.

Found, %: C 62,50; H 6,76; N 12,11; S 9,14.

P R I m e R 28. Getting ethyl-[6-(4-chloro-3-nitrophenyl)-8-methyl-3,4-dihydro-2H,6N - pyrimido [2,1-b] [1,3] thiazin-7-carboxylate].

Conduct the reaction between 35,6 g (0.1 mole) of ethyl-[4-(4-chloro-3-nitrophenyl)-6-methyl who, as in example 14. The residue is crystallized from water, drop the crystals are filtered and dried. The result of 36.4 g (92%) of target compound.

Melting point: 126-128oC.

Brutto-formula:C17H18ClN3O4S, mol.m.: 395,861.

Calculated, %: C 52,58; H 4,58; N 10,61; Cl 8,96; S 8,10.

Found, %: C 52,08; H 4,65; N 10,32; Cl 8,95; S 8,00.

P R I m e R 29. Obtaining methyl-[6-(3-hydroxy-4-methoxyphenyl)-8-methyl-3,4-dihydro-2H,6N-pyrimido [2,1-b] [1-3)thiazin-7-carboxylate].

Conduct the reaction between 30,8 g (0.1 mole) of methyl-[4-(3-hydroxy-4-methoxyphenyl)6-methyl-1,2,3,4-tetrahydro-2 - pyrimidinethione-5-carboxylate] and 30.3 grams (0.15 mole) of 1,3-dibromopropane for 30 h under the same conditions as in example 14. Then the reaction mixture is cooled, filtered, the falling crystals, washed with water and dried. The result of 21.9 g (65,1%) of target compound.

Melting point: 275-277aboutC.

Brutto-formula: C16H20N2O4S, mol.m.: 336,408.

Calculated, %; C 57,13; H Of 5.99; N 8,33; S At 9.53.

Found, %: C 56,98; H Equal To 6.05; N 8,28; S 9,45.

P R I m e R 30. Obtaining methyl-(4,6-dimethyl-1,2,3,4-tetrahydro-2-pyrimidinethione - carboxylate).

Conduct the reaction in technologo ester of acetoacetic acid in the environment 100 ml of 15% aqueous solution of hydrogen chloride in isopropyl alcohol. After the reaction, the suspension is cooled, filtered, the filter residue is washed with isopropyl alcohol and dried. The result is 30 g (50%) of target compound.

Melting point: 203-206oC.

Gross formula: C8H12N2O2S, mol.m.: 200,257.

Calculated, %: C 47,98; H the 6.06; N 13,99; S 16,0

Found, %: C 48,05; H 5,98; N 13,87; S 15,59.

P R I m e R 31. Obtaining methyl-[4-ethyl-6-methyl-1,2,3,4-tetrahydro-2-pyrimidine - he-5-carboxylate].

Conduct the reaction between 17,4 g (0,3 mol) of propionic aldehyde, 22,8 g (0,3 mol) of thiourea and 34.8 g (0,3 mol) of methyl ester of acetoacetic acid for 35 h, under the same conditions as in example 30. After cooling, filtration and washing obtain 12.8 g of target compound.

Melting point: 180-182aboutC.

Brutto-formula: C9H14N2O2S, mol.m.: 214,284.

Calculated, %: C 50,45; H To 6.58; N 13,07; S 14,96.

Found, %: C 50,52; H For 6.81; N Is 12.85; S 14,94.

P R I m e R 32. Getting ethyl-(4,6-dimethyl-1,2,3,4-tetrahydro-2-pyrimidinethione-5 - carboxylate).

Conduct the reaction between 13,22 g (0,3 mol) of acetaldehyde, and 22.8 g (0,3 mol) of thiourea and 39 g (0,3 mol) of ethyl ester of acetoacetic cyclotella connection.

Melting point: 198-200oC.

Brutto-formula: C9H14N2O2S, mol.m.: 214,284.

Calculated, %: C 50,45; H is 6.54; N 13,07; S 14,96

Found, %: C 50,52; H For 6.81; N Is 12.85; S 14,95.

P R I m e R 33. Getting ethyl-(4-ethyl-6-methyl-1,2,3,4-tetrahydro-2-pyrimidinethione - 5-carboxylate).

Conduct the reaction for 35 h between 17,4 g (0,3 mol) of propionic aldehyde; and 22.8 g (0,3 mol) of thiourea and 39 g (0,3 mol) of ethyl ester of acetoacetic acid in the environment 400 ml of 15% aqueous solution of hydrogen chloride in isopropyl alcohol. The solution is then evaporated in vacuum, the residue is crystallized from water, drop the crystals are filtered and dried. The result of 20.5 g (30%) of target compound.

Melting point: 143-145oC.

Brutto-formula: C10H16N2O2S, mol.m.: 228,212.

Calculated, %: C 50,45; H To 6.58; N 13,07; S 14,98.

Found, %: C 50,45; H To 6.58; N 13,10; S 14,80.

P R I m e R 34. Getting ethyl-(4-methyl-6-phenyl-1,2,3,4-tetrahydro-2-pyrimidinethione-5-carboxylate).

Conduct the reaction between 13,2 g (0,3 mol) of acetaldehyde, and 22.8 g (0,3 mol) of thiourea and 57.7 g (0,3 mol) of ethyl ether benzooxazol acid for 30 h under the same conditions as in the example of the population: 220-235oC.

Brutto-formula: C14H16N2O2S mol.m.: 276,356.

Calculated, %: C 52,9; H 7,07; N 12,50; S 14,37.

Found, %: C 52,61; H 7,06; N 12,27; S 14,04.

P R I m e R 35. Getting ethyl-[4-ethyl-6-phenyl-1,2,3,4-tetrahydro-2-pyrimidinethione - 5-carboxylate].

Conduct the reaction between 17,4 g (0,3 mol) of propionic aldehyde, 22,8 g (0,3 mol) of thiourea and 57.7 g (0,3 mol) of ethyl ether benzisoxazol acid for 30 h under the same conditions as in example 30. After cooling, filtration and washing obtain 30.5 g (35%) of target compound.

Melting point: 219-221aboutC.

Brutto-formula: C15H18N2O2S, mol.m.: 290,382.

Calculated, %: C 60,85; H Of 5.83; N 10,14; S 11,60.

Found, %: C 60,47; H 5,76; N 10,11; S 11,72.

P R I m e R 36. Getting anilide 4-undecyl-6-methyl-1,2,3,4-tetrahydro-2-pyrim - edition-5-carboxylic acid.

Conduct the reaction between of 55.3 g (0,3 mol) of the aldehyde laurinovoj acid, 228 g (0,3 mol) of thiourea and 53.2 g (0,3 mol) anilide acetoacetic acid for 30 h under the same conditions as in example 30. After cooling, filtration and washing obtain 29 g (24,1%) of target compound.

Melting point: 158-160oC.

Found, %: C 67,46; H To 8.94; N 10,12; S Of 7.82.

Compounds of General formula (I) in accordance with the present invention along with the ability to reduce the intensity of inflammation also have valuable property to provide protivojazvennoe action, additional diuretic action and the action on the Central nervous system (Tranquillo-sedative and/or antidepressant, anticonvulsant activity), and in the case of some compounds and weak positive inotropic and inhibiting the secretion of hydrochloric acid by the action.

Compounds of General formula (I) proved to be the most effective in tests on protivojazvennoe action and to reduce the intensity of inflammation. This action in the case of compounds of General formula (I) is well complemented by action on the Central nervous system and diuretic action. If to consider that at angineh diseases often occurs when they play the role of factors of nervous origin, or they occur in patients who have already developed painful retention of urine, calming or uplifting effect in combination with diuretic provide comprehensive therapeutic effect. Compounds of General formula (II) also have protivojazvennoe action is s carried out by the known methods.

Test compounds of General formula (I) acute toxicity in mice.

Method. The tests were carried out on white CFLP mice of both sexes weighing 18-22 g Each dose was tested on 10 animals. Compound was administered orally in the amount of 20 ml/kg, after which the animals were observed for 14 days. For this they were placed in a plastic box with a litter of wood shavings in the room, which was maintained at room temperature. Animals were given plenty of tap water and standard food. Toxicity was determined by the method of Lichtfield. - Wilcoxon. The test results are given in table. 1.

The test compounds of the General formulas (I) and (II) on protivojazvennoe effect on the rats.

Method. The tests were carried out on rats weighing 180-220 g Animals were narcoticyou chlororesorcinol and using needle electrodes were removed ECG in the second standard allocation. Protivojazvennoe action was determined by the modified method Ncesshultz. Coronary insufficiency caused by intravenous vasopressin (1 is 1E/kg). Measured the height of the T wave on the ECG before and after injection of vasopressin in experimental animals and animals of the control group. The compounds were administered intravenously over 2 min the higher activity, than prenilamin.

The test derived dihydropyrimidine to reduce acute inflammation in rats, which caused swelling with karagina.

Method. In the sole of the hind paws of rats weighing 150-180 g were injected 0.1 ml of 1% aqueous solution of karagina. Starving for 12 h animals (the bird feeders all the time was water) for 1 h before drug administration was hydrational. Experimental animals orally was administered to test the connection and control of inert basis in the amount of 10 ml/kg, and after 1 h gave them the means causing inflammation. Before and 3 h after injection of irritating tools measured the amount of paws with plethysmometer, which was read on the millimeter scale moving fluid, which characterizes the change in volume. Compared the change in the volume of the paws of animals, which were injected compound, and the animals of the control group. The dose which causes a 30% inhibition (LD30) development of inflammation was determined by regression line. The results are given in table. 3.

The investigated compounds are superior used in the treatment of comparative means and terms of absolute dose, and from the point of view of therapeutic index (TI).

The test with bodily on groups, consisting of 6 mice. After 1 h after oral drug administration animals as the control group and those who were administered the compounds in accordance with the present invention, were euthanized by an intravenous injection of 40 mg/kg hexobarbital.

Animals, the duration of sleep which was 2.5 times higher than the average duration of sleep in animals of the control group, took over the animals, giving a positive reaction. Using transformed thus values expected values U50(modified method Kaergaard et al.) The results are given in table. 4

The compounds of formula (I) is superior to the sedative effect of the comparative compound as from the point of view of the absolute dose, and from the point of view of therapeutic spectrum. In addition to strengthening the anesthesia they have a less pronounced inhibitory effect on the motility.

1. Derivatives dihydropyrimidine General formula

< / BR>
where R1-C1-C6-alkoxy - or phenylaminopropyl;

R2-C1-C6-alkyl or phenyl;

R3is hydrogen or C1- C6-alkyl;

R4-C1-C6-alkyl or phenyl which may be substituted by one or more SUB>-alkyl, C1-C6-alkoxy or hydroxy-group,

or their therapeutically acceptable salts accession acid with protivominniy and anti-inflammatory activity.

2. Derivatives dihydropyrimidine under item 1, where R1- methoxy or ethoxy; R2is methyl or phenyl; R3is hydrogen, R4is methyl or phenyl which may be substituted with halogen, methoxy or nitro-group.

 

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FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

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wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

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EFFECT: improved preparing methods.

27 cl, 3 dwg, 16 ex

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EFFECT: valuable properties of agent.

3 tbl, 6 dwg, 4 ex

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