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    • 专利摘要:
    Cardiovascular activity is exhibited by compounds having the formula <CHEM> and pharmaceutically acceptable salts thereof wherein X is oxygen or sulfur; R is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R1 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclo, <CHEM> or halo substituted alkyl, or R and R1 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl or 1-pyrrolidinyl, 1-piperidinyl, or 1-azeipinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy; R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, <CHEM> or halo substituted alkyl; R3 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclo, <CHEM> or halo substituted alkyl; R4 is aryl or heterocyclo; R5 and R6 are each independently hydrogen, alkyl, -(CH2)q-aryl or -(CH2)q-cycloalkyl; Y1 is cycloalkyl, aryl, heterocyclo, hydroxyl, alkoxy, aryl-(CH2)m-O-, mercapto, alkylthio, aryl-(CH2)m-S-, amino, substituted amino, carbamoyl, (substituted amino)- @-, heterocyclo-(CH2)m- @-, carboxyl, alkoxycarbonyl, alkyl- @-, aryl-(CH2)m- @-, alkyl-@-O- or aryl-(CH2)m- @-O- Y2 is cycloalkyl, aryl, heterocyclo, carbamoyl, (substituted amino)- @-, carboxyl, alkoxycarbonyl, alkyl- @-, aryl-(CH2)m- @- or heterocyclo-(CH2)m- @-; Y3 is hydroxyl, alkoxy, aryl-(CH2)m-O-, mercapto, alkylthio, aryl-(CH2)m-S-, alkyl- @-O-, aryl-(CH2)m- @-O-, amino, or substituted amino; q is 0, 1, 2 or 3; m is 0 or an integer of 1 to 6; n is 0 or an integer of 1 to 5; and p is an integer of 1 to 5. 5
    公开号:SU1713437A3
    申请号:SU874202205
    申请日:1987-03-13
    公开日:1992-02-15
    发明作者:Сингх Атвал Карнейл；Чарльз Ровняк Джордж
    申请人:Е.Р. Сквибб Энд Санз, Инк, (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of pyrimidine derivatives or their pharmaceutically acceptable salts, new biologically active compounds that can be used in medicine. The purpose of the invention is a method for producing pyrimidine derivatives of low toxicity and having a higher antihypertensive activity.
    PRI and measures 1. Methyl ester 3- (ethylamine) carbonyl -1, 2, 3, 4-tetrahydro-6-methyl-4- (3-n itrophenyl) -2-thio xo-5-pyrimide incarboxylic acid .
    but. 3- (4-methoxymethyl) thiopseudomourea hydrochloride.
    A suspension of thiourea (38 g, 50.0 mmol) in dry tetrahydrofuran (40 ml) is cooled to 0 ° C in argon and 4-methoxybenzyl chloride (8.0 g, 50.0
    mmol). After that, the cooling bath is removed and the mixture is stirred for 2 hours at room temperature. It is then heated at a temperature of 60-65 ° C for 4 hours, after which a colorless voluminous precipitate is formed. The reaction was cooled to room temperature and diluted with anhydrous ether. The solid is filtered off and washed with anhydrous ether, and 10.92 g of 2- (4-methoxybenzyl) -2-thio-pseudourea are obtained, Hydrochloride with m.p. 161-163,5 ° C.
    Calculated,%: C 46.45; H 5.63; N 12.04; S 13.78; C1 15.23.
    C9H12N20S HCI
    Found%: C 46.48; H 5.64; N 12.25; S 13.74; Ch15.31.
    b. 1,4-Dihydr6-2-P14methoxyphenyl methyl thio-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid methyl ester.
    To a solution of 2- (3-nitrbphenyl) methylene-3-oxobutanoic acid methyl ester (5.0 g, 0.02 mol) in 20 ml of dimethylformamide in argon, at room temperature, add 5- (4-methoxybenzyl) thiopsevdomechanine hydrochloride (4 , 65 g, 0.02 mol) and sodium acetate (1.64 g, 0.02 mol). The mixture is then heated for 3 hours at 65 ± 5 ° C. After cooling, ethyl acetate is added and a small amount of solid is filtered. The filtrate is washed with water (twice), aqueous sodium biocarbonate and saturated brine. The aqueous washes were extracted with fresh ethyl acetate. The combined filtrate and washings were dried (magnesium sulfate) and concentrated in vacuo to obtain about 9 g of crude material. Crystallization from acetone-isopropyl ether gives 6.8 g of substance with m.p. 125-127.5C, thin layer chromatography, silica gel, ethyl acetate – hexane 1: 1, 48.
    Calculated,%: C 59.00; H, 4.95; N 9.83; S 7.50.
    C21H21N305S.
    Found,%: C 58.86; H 4.82; N 9.51; S 7.25.
    at. 1- (ethylamine) carbonyl -1, 6-dihydro-2- (4-methoxyphenyl) methyl thio-4-methyl-6 (3-nitrophenyl) -5-pyrimidinecarboxylic acid methyl ester.
    To a solution of 1,4-dihydro-2- (4-methoxyphenyl) methyl thio-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid methyl ester (1.5 g, 3.5 mol) in acetone in At room temperature, ethyl isocyanate (0.5 ml, 0.45 g, 6.3 mmol) and potassium carbonate powder (50 mg, 0.36 mmol) are added under argon at room temperature. Analysis of the reaction by thin layer chromatography (dichloromethane (methanol, 1: 1) showed a higher level of Rf, which did not increase after 1-2 hours. Volatile compounds were distilled off in vacuo and the residue was partitioned between ethyl acetate and water. The organic fraction was washed with water, 1 N. The hydrochloric acid, water and saturated brine. The aqueous fractions are again extracted with fresh ethyl acetate. The combined organic fractions are dried (magnesium sulfate) and concentrated in vacuo, after which 1.6 g of crude product are obtained.
    Instant chromatography on 250 ml of silica gel and dilution with dichloromethane - hexane (2: 1-3: 1) and dichloromethane - methanol (99.5: 0.5) gives 0.94 g of the intended product.
    Methyl ester 3- (ethylamine) carbonyl -1, 2, 3, 4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-thioxo-5-pyrimidinecarboxylic acid.
    5K methyl ester 1 - (ethylamine) carbonyl -1, 6-dihydro-2- (4-methoxyphenyl) methyl thio-4-methyl-6- (3-nitrophenyl) -5 pyrimidinecarboxylic acid (0.94 g, 1.89 mmol) in 10 ml of dry dichloromethane in argon at room temperature, trifluoroacetic acid (0.5 ml, 0.74 g, 6.5 mmol) and ethyl mercaptan (0.35 ml, 0.29 g, 4.67 mmol) are added and the mixture is stirred overnight.
    5 The volatile compounds are removed in vacuo, the residue after trituration with isopropyl ether gives 0.59 g of the expected product with an mp. 244-246 ° C.
    Calculated,%: C 50.79; H 4.79; N 14.81;
    0 38.47.
    Cl6Hl8N405S
    Found,%: C 50.82; H 4.86; N 14.54; S 8.54.
    P R.I m e p 2. 1-Methylether 5 3- (dimethylamine) carbonyl -1, 2, 3,4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5 pyrimidinecarboxylic acid
    a.1-Methylethyl 1,4-dihydro2-methoxy-6-methyl-4- (3-nitrophenyl) -5-pyr
    0 imidicarboxylic acid.
    A reacting mixture containing 2- (3-nitrophenyl) methylene 1-methyl ethyl ether-3-oxobutanoic acid (10.0 g, 36.0 mmol) sodium bicarbonate (8.40 g,
    5 108 mmol) and acidic sulfate 0-methyl-pseudourea (8.06 g, 46.8 mmol) in dimethylformamide is heated at 60 ° C in argon for about 2.5 days. The reaction mixture is then diluted with water and extracted with ethyl acetate. The organic phase is washed with water (six times) and saturated sodium chloride, dried (potassium carbonate) and evaporated. The residue is passed through a short silica gel.
    5 spacer and crystallize from isopropyl ether / hexane. The desired compound is obtained as yellow crystals (8.04 g).
    b.1-Methyl ethyl ester of 1- (dimethylamine) carbonyl -1,6-dihydro-2-methoxy-4-methyl 0 -6- (3-nitrophenyl) -pyrimidinecarboxylic acid.
    To a solution of 1,4-dihydro-2-methoxy-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methyl ethyl ester (3.34 g
    5 10.0 mmol) and distilled triethylamine (6.3 ml, 45 mmol) in dichloromethane (10 ml) in an ice-bath in argon are added dropwise with a syringe of 1.3 M phosgene in a solution of benzene (9.2 ml, 12 mmol) in 3-5 min. After
    Stirring at 0 ° C for 1.5 hours, 40% aqueous dimethylamine (3.3 ml, 15 mmol) was added to the reaction mixture, closed with a septum and stirred at room temperature for 2.5 days. It is then evaporated and partitioned between ethyl acetate and water. The organic phase is washed with saturated sodium chloride, dried (potassium carbonate) and evaporated to give the title compound (crude) as a brown oil (4.75 g).
    at. 1- Methyl ethyl ester 3- (dimethylamine) carbonyl 1,2,3,4-tetrahydro-6-methyl4, - (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid
    To a solution of 1- (dimethylamine) -carbonyl 1-methyl-ethyl ether -1,6-dihydro-2-methoxy-4-methyl-6- (3-nitrophenyl) -5-pyrimidinecarboxylic acid (2.27 g) in tetrahydrofuran - methanol (20 ml each) was added 5N. hydrochloric acid (3.0 ml, pH 1) and ne | 4mixed at room temperature for 1 hr. The mixture is then evaporated and partitioned between ethyl acetate and water. The organic phase is washed with saturated sodium chloride, dried (magnesium sulfate) and evaporated. The residue is crystallized from dichloromethane (isopropyl ether and get the target compound in the form of colorless crystals (1.55) Art. Square 165-1B6 ° C.
    Calculated,%; C 55.38; H5.68: N 14.35.
    C18H22N406
    Found,%: C 55.44; H 5.70; N 14.27.
    Froze 3- (dimethylamine) carbonyl -1, 2, 3, 4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-thioxo-5-pyrimidinecarboxylic acid ethyl ester,
    a. 1,4-Dihydro-2- (4-methoxyphenyl) methyl thio-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid ethyl ester.
    A mixture of 13.58 g of 2- (3-nitrophenyl) -methylene-3-oxobutanoic acid ethyl ester, 12.0 g of 5- (4-methoxyphenyl) -methyl-thiopsevido-urea hydrochloride, and 4.18 g (0.051 mol) of sodium acetate in 90 ml dimethylformamide is stirred and heated at 70 ° C for 4 hours. After cooling, ether is added, washed with water, sodium bicarbonate and brine. The dried solution is evaporated and an oil is obtained, to which 18.8 g of a creamy solid-colored solid 95-97 ° C are added.
    b. 1,6-Digidro-2- (4-methoxyphenyl) methyl thio-4-methyl-1- (dimeti-lamin) carbonyl-6- (3-nitrophenyl) -5-pyrimidinecarboxylic acid ethyl ester,
    To a solution of 1,4-dihydro-2- (4-methoxyphenyl) -methyl-1-thio-6-methyl-4- (3-nitrrphenyl) -5-pyrimidinecarboxylic acid ethyl ester (0.5 g, 1.1 mmol) in 10 ml dry
    tetrahydrofuran in argon at 0-5 ° C. pyridine (1.0 ml, 12.6 mmol), and then phosgene (1.16 ml, 12.5% in benzene, 1.47 mmol). After half an hour, dimethylamine (1 ml 40% excess) is added. The reaction was completed in half an hour. The mixture is diluted with ethyl acetate and washed with 1N. hydrochloric acid, water and saturated brine. The aqueous washes are re-extracted with fresh ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo, after which 0.6 g of a homogeneous substance was obtained.
    5 in. 3- (Dimethylamine) carbonyl -1, 2, 3, 4-tetrahydro-6-methyl-4- (3 nitrophenyl) -2-thioxo-5-pyrimidinecarboxylic acid ethyl ester.
    To a solution of 1,6-dihyd0ro-2-4-methoxyphenyl) methyl thio-4-methyl1- (dimethylamine) -carbonyl-6- (3-nitrophenyl) -5-, pyridinecarboxylic acid ethyl ester (1.26 g, 2.46 mmol) in dry dichloromethane in argon at room temperature is added
    5 Trifluoroacetic acid (0.55 ml, 0.82 g, 7.18 mmol) and ethyl mercaptan (0.36 ml, 0.30 g, 7.78 mmol). The reaction is completed after 2 hours. The volatiles are evaporated in vacuo and the residue, after trituration with hot isopropyl ether, gives 0.82 g of substance. Dissolving this substance in chloroform and filtering to remove some dark insoluble substances after final trituration with isopropyl ether gives 0.80 g of a homogeneous substance.
    Calculated,%: C 52.03; H 5.14; N 14.28; 58.17.
    C17H20N405S.
    0 Found,%: C 52.01; H 5.19; N 14.23; S 7.93.
    EXAMPLE 4 1-methyl ether 1, 2, 3, 4-tetrahydro-6-methyl-3-methyl (phenylmethyl) amine carbonyl-4- (3-nitropheny) 1) -25 oxo-5- pyrimidine carboxylic acid.
    but. 1-Methyl Ester 1,6-dihydro-1- | 1methyl (phenylmethyl) amine carbonyl 3-2-methoxy-4-methyl-6- (3-nitrophenyl) -5-pyrimidinecarboxylic acid.
    0 KpacjBOpy 1-methyl ethyl 1,4-dihydro-2-methoxy-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid (3.34 g, 10 mmol) (see Example 2A) and dry triethylamine (6.3 ml, 45 mmol) in dichloromethane (10 ml) in an ice-bath in argon is added dropwise through a syringe of 1.3 M phosgene in a solution of benzene (0.2 ml, 12 mmol). The mixture was stirred in a bath for 20 hours. After cooling to a fresh ice bath, benzylmethylamine (1.95 ml, 15 mmol) was added to the mixture at room temperature overnight. The mixture was then diluted with dichloromethane and washed with water, saturated chloride sodium, dried (potassium carbonate) and evaporated, the residue is passed through a short silica gel pad, diluted with 20% acetone - hexane. The fractions are combined, evaporated and triturated with isopropyl ether to give white crystals (4.11 g) with m. mp 145-146 ° C (size dry at 140 ° C)
    b. 1-Methylstil ether 1, 2, 3, 4-tetrahydro-6-methyl-3- (methyl (phenyl) amine carbonyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarbonyl acid.
    To a suspension of 1-methyl ethyl ester of 1,6-dihydro-1-methyl (phenylmethyl) bonyl} -2-methoxy-4-methyl-6- (3-nitrophenyl) 5-pyrimidinecarboxylic acid (1.81 g, 3.92 mmol ) in tetrahydrofuran-methanol (5 ml of each is added 5N hydrochloric acid (4.0 ml). The resulting solution is stirred at room temperature for 1.5 hours, partially evaporated and partitioned between saturated sodium bicarbonate and chloroform. Organic the phase is washed with a saturated solution of sodium chloride, dried (magnesium sulfate) and evaporated. The residue is crystallized from dichloromethane — isopr white ethers (1.648 g) are obtained, mp 159-161 ° C. Thin layer chromatography (7% methanol-dichloromethane) gives a single black spot, 54.
    Calculated,%: C, 61.79; H 5.62; N 12.01.
    C24H26N406
    Found,%: C 61.95; H 5.64; N 11.91.
    EXAMPLE 5 1-Methylethyl 1, 2, 3, 4-tetrahydro-6-methyl-3- (methylamine) carbonyl -4CH3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid.
    To a solution of 1,4-dihydro-2-methoxy-6-methyl-4- (3-nitrophenyl) 5-pyrimidinecarboxylic acid 1-methyl ethyl ester (5.00 g, 15.0 mmol (see Example 2A) and dry triethylamine (5 , 9 ml, 45 mmol in distilled dichloromethane (45 ml) at 0 ° C in argon is added dropwise through a syringe of 1.2 M phosgene in benzene (15.0 ml, 1 8.0 mmol). After stirring at 0 ° For 3.5 hours, 40% aqueous methylamine (1.94 ml, 22.5 mmol) was added to the reaction mixture. After 45 minutes, 1N hydrochloric acid (15 ml, pH 1) and partially evaporated. The remaining mixture is diluted with tetrahydrofuran (50 ml) and methanol (25 ml) and another 1N hydrochloric acid (15 ml) is added. After 2 hours of stirring at room temperature, the reaction mixture is partially evaporated. Then it is extracted with ethyl acetate, the combined organic phases are washed with saturated bicarbonate sodium, saturated with sodium chloride and evaporated. The organic residue is crystallized from warm ethyl acetate-hexane to give white crystals (3.47 g). This substance is crystallized from isopropyl ether dichloromethane to give colorless crystals (3.29 g) with a mp. 204-205 ° C. Recrystallization from ethyl acetate-hexane gives colorless crystals (2.588 g), m.p. 205-206 ° C. Thin layer chromatography (5% methanol - dichloromethane) gives a single spot, 45, visible with vanillin and heat.
    Calculated,%: C 54.25; H 5.35; N 14.89.
    C17H20N406
    Found,%: C 54.40; H 5.23; N 14.72.
    Example 6.1-Methyl 3- (aminocarbonyl) -1,2, 3,4-tetrahydro-6-methyl-4 (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid.
    a.1-Methyl ester of 1-carbimoyl-1,6-dihydro-2-methoxy-4-methyl-6- (3-nitrophenyl) -5-pyrimidinecarboxylic acid.
    To a solution of 1,4-dihydro-2-methoxy-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methyl ester (5.00 g, 15.0 mmol, see Example 2A) and triethylamine (5.88.45 mmol) in dichloromethane (45 ml) at 0 ° C in argon is added by syringing a 1.2 M solution of phosgene in benzene (15.0 ml, 18.0 mmol). After stirring at 0 ° C for 3.5 hours, concentrated ammonium hydroxide (1.52 ml, 22.5 mmol) was added to the reaction mixture.
    After 2 hours at room temperature, more concentrated ammonium hydroxide (0.5 ml, 7.5 mmol) is added to the reaction mixture and the mixture is stirred at room temperature overnight. The reaction mixture is diluted with dichloromethane and washed with water and saturated sodium chloride. The organic phase is concentrated and flash chromatographed to give the title compound as a yellow foam (2.83 g).
    b.1-Methyl ethyl ester of 3- (aminocarbonyl) -1, 2, 3, 4-tetrahydro-6-methyl-4- (3nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid.
    To a solution of 1-carbamoyl-1, 6-dihydro-2-methoxy-4-methyl-6- (3-nitrophenyl) -5-pyrimidinecarboxylic acid methyl ethyl ester (2.82, g, 7.49 mmol) in tetrahydrofuran (30 ml) and methanol (15 ml) was added 1N. hydrochloric acid (10 ml, pH 1) and stirred at room temperature for 2 hours; The reaction mixture is neutralized with saturated sodium bicarbonate and partially evaporated. The mixture is diluted with ethyl acetate, washed with water and saturated sodium chloride, dried (potassium carbonate) and evaporated. The residue is crystallized from ethyl acetate and colorless crystals (1.44 g) are obtained. Recrystallization from ethyl acetate does not remove impurities. Recrystallization from acetonitrile removes the contamination, but regeneration is weak (0.58 g). The compound is recombined and flash chromatographed using 15% acetone and dichloromethane. Trituration with ether gives the title compound as colorless crystals (1.242 g), mp. 206-207 ° C. Thin layer chromatography (15% acetone - dichloromethane) gives a single spot,, 50. Thin layer chromatography (methanol - dichloromethane) gives a single spot, 38.
    Calculated,%: C 53.04; H 5.01; N 15.46.
    Ci6Ht8N406
    Found,%: C 52.78, H 4.90; N 15.24.
    Note p7.1-methyl ethyl ester 1,2, 3, 4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2oxo-3- (1-piperidinylcarbonyl) -5-pyrim dinocarboxylic acid.
    To a solution of 1,4-dihydro-2-methoxy-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methyl ethyl ester (3.50 g,
    10.5 mmol, see example 2A) and triethylamine (4.39 ml, 31.5 mmol) in dichloromethane (33 ml) at 0 ° C in argon are added by syringing a 1.2 M solution of phosgene in benzene (10.5 ml,
    12.6 mmol). After stirring at 0 ° C for 3.5 hours, piperidine (1.56 ml, 15.7 mmol) was added to the reaction and stirred at room temperature in argon overnight. The reaction mixture is then diluted with dichloromethane, washed with water and evaporated. The residue is subjected to instant chromatography and the desired intermediate is obtained as a yellow foam (4.94 g). This foam was dissolved in tetrahydrofuran (50 ml) and methanol (30 ml) and 1N hydrochloric acid (15 ml, pH 1) was added. After stirring at room temperature for 2.5 hours, the reaction mixture was partially evaporated. The residue is diluted with ethyl acetate and washed with saturated sodium bicarbonate, saturated sodium chloride, dried (magnesium sulfate) and evaporated. The residue is crystallized from dichloromethane-isopropyl ether to obtain a pale yellow solid (4.12 g). This substance is subjected to recrystallization and get the target compound in the form of colorless crystals.
    The title compound is in the form of colorless crystals (2.75 t), m.p. 164-165 ° C. Thin layer chromatography (15% acetone dichloromethane gives a single spot,, 45.
    Calculated,%: C 58.60: H 6.09; N 13.02
    C21H26N406
    Found,%: C 58.61; H 6.00; N 12.91. PRI me R 8. 1-Methyl ester 1,
    2, 3, 4-tetrahydro-6-methyl-3 (methylstil) amine carbonyl-4- (3-nitrophenyl) -2-oxo-5 pyrimidinecarboxylic acid.
    To a solution of 1,4-digiAro-2-methoxy-6-methyl-4- (3-nitrophenyl) 1-methyl ester
    -5-pyrimidinecarboxylic acid (2.10 g, 6.3 mmol, see Example 2A) and triethylamine (2.64 ml, 19 mmol) in dichloromethane (19 ml) at 0 ° C in argon are added by syringing 1.2 M solution of phosgene in benzene (6.3 ml,
    7.6 mmol). After moving at 0 ° C for 3.5 hours, isrpropylamine (0.81 ml, 9.5 mmol) is added to the reaction mixture and stirred at room temperature in argon overnight. It is then diluted with dichloromethane, washed with water and saturated sodium chloride, and evaporated. The residue was dissolved in tetrahydrofuran-methanol (18 ml each), 1N was added. hydrochloric acid (10 ml, pH 1) and stirred at room temperature for 2 hours. The reaction mixture is then partially evaporated and partitioned between ethyl acetate and water. Wash the organic phase with saturated sodium bicarbonate, saturated
    sodium chloride, dried (magnesium sulfate) and evaporated. The residue is crystallized from isopropyl ether - hexane and get yellow crystals (2.16 g, 85%). This substance is recrystallized from isopropyl ether from dichloromethane and colorless crystals (1.759 g) are obtained, m.p. 145-146 ° C. Thin layer chromatography (5% ethyl acetate - dichloromethane) gives a single spot,, 49.
    Calculated,%: With 56,43; H 5.98; N 13.85.
    C19H24N406
    Found,%; C 56.18: H 5.89; N 13.45.
    PRI me R 9. 1-Methylethyl 1, 2, 3, 4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-3- (phenylmethyl) amine carbonyl-5-pyrimidinecarboxylic acid .
    but. 1,6-dihydro-2methoxy-4-methyl-6- (3-nitrophenyl) -1 - (phenylmethyl) amine carbonyl - 5-pyrimidinecarboxylic acid 1-methyl ethyl ester ..
    To a solution of 1,4-dihydro-2-methoxy-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methyl ester (5.00 g of 15.0 mmol; see Example 2A) and dry triethylamine ( 6.27 ml, 45 mmol) in dichloromethane (45 ml) in an ice bath in argon was added a 1.2 M solution of phosgene in benzene (15.0 ml, 18.0 mmol) by spriting. After stirring for 4 hours at 0 ° C, benzylamine (2.46 ml, 22.5 mmol) was added to the reaction mixture and stirred at ambient temperature overnight. The mixture is treated with water and saturated sodium chloride. The organic phase is evaporated and subjected to instant chromatography (3% ethyl acetate in dichloromethane) and the desired compound is obtained as a yellow foam (6.20 g), thin layer chromatography (5% ethyl acetate - dichloromethane) gives the main spot,, 70
    b. 1-1U1-ethyl ethyl 1, 2, 3, 4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-3 - (phenylmethyl) amine carbonyl - 5-pyrimidinecarboxylic acid.
    To a solution of 1,6-dihydro-2-methoxy-4-methyl-6-: (3-nitrophenyl) -1- (phenylmethyl) amine 1-methyl ethyl ester carbonyl-5-pyrimidinecarboxylic acid (3.00 g, 6.45 mmol ) in tetrahydrofuran (50 ml) (methanol (25 ml), 1N hydrochloric acid (6.0 ml, pH 1) is added and stirred at room temperature for 1 h. The reaction mixture is neutralized with saturated sodium bicarbonate and partially evaporated. The residue is separated between chloroform and water. The organic phase is washed with saturated sodium chloride, dried (magnesium sulfate) and evaporated. The residue is crystallized from dich ormethane - isopropyl ether. The precipitated solids are recrystallized and the title compound is obtained as a colorless electrostatic solid (1.84 g), mp 184-185 ° C. Thin layer chromatography (5% ethyl acetate - dichloromethane) gives a single spot, 39 .
    Calculated,%: C 61.05; H 5.35; N 12.38.
    S23N24M40b
    Found,%: C 60.97; H 5.36; N 12.33. I'll try it on. 1-Methyl l-about you and the ester 3- (ethylamine) carbonyl -1, 2, 3, 4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid.
    To a solution of 1,4-dihydro-2-methoxy-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methyl ethyl ester (2 g, 6 mmol, see example 2A) and triethylamine (2.5 ml , 18.0 mmol) in acetonitrile (18 ml) in an ice bath in argon are added by sprinkling a 1.3 M solution of phosgene in toluene. The reaction mixture was stirred at 0 ° C for 3 hours and then treated with 70% aqueous ethylamine solution (0.36 ml, 9.0 mmol). After stirring in an ice bath for 3 hours, the mixture was evaporated. The residue was dissolved in tetrahydrofuran-methanol (24 ml each) and added 9N 5N. hydrochloric acid (4.0 ml). After stirring for 1 hour at ambient temperature, the mixture is partially evaporated and neutralized with saturated sodium bicarbonate. The aqueous phase is extracted with ethyl acetate and washed with saturated sodium chloride. Instant chromatography (5% ethyl acetate in dichloromethane) and crystallization from dichloromethane-isopropyl ether gave colorless crystals (1.22 g), m.p. 153155 C. Thin layer chromatography (5% ethyl acetate-dichloromethane) gives a single spot,, 26.
    Calculated,%: C 55.37; H 5.68; N 14.35.
    C18H22N406
    Found: C 55.33; H 5.66; N 14.31.
    EXAMPLE 3- (Dimethylamine) carbonyl -1, 2, 3, 4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid.
    a.t-Butyl ester 1,4-dihydro-2-methoxy-6-methyl-4- (3-n-itrofen and l) -5-n and rimide dinocarboxylic acid.
    A mixture of 2- (3-nitrophenyl) methylene-3-oxobutanoic acid t-butyl ester (6.80 g, 23.3 mmol), 0-methylisourea acid sulfate (5.22 g, 30.3 mmol), and sodium bicarbonate (5.87 g, 69.9 mmol) in dimethylformamide (35 ml) was stirred at room temperature overnight in argon. After being kept at room temperature for 23 hours, the mixture is heated at 60 ° C (oil bath) for 5.5 hours. Then it is partitioned between ethyl acetate and 5% sodium bicarbonate. The organic phase is washed several times with water, washed with saturated sodium chloride, dried with Kap6oHatOM potassium. Evaporated. The crude title compound is obtained as a light brown oil (9.93 g).
    B. t-Butyl ether 3- (dimethylamine) carbonyl -1,2; 3; 4-tetrahydro-6-methyl4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid.
    To a solution of 1,4-dihydro-2-methoxy-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid t-butyl ester (1.30 g, 3.05 mmol) and dry triethylamine (1.27 ml, 9.15 mmol) in dichloromethane (10 ml) in an ice bath in argon, a 1.2 M solution of phosgene in benzene (3.05 ml, 3.66 mmol) is added by syringing. After stirring overnight, the reaction mixture is cooled to and treated with 40% aqueous dimethylamine (0.40 ml, 4.57 mmol). Remove the bath and stir the mixture for 3 hours at room temperature. The mixture is diluted.
    dichloromethane, washed with water, saturated sodium chloride and evaporated. Instant chromatography (3% ethyl acetate-dichloromethane) gives the desired intermediate compound as a yellow foam (0.50 g). This compound was dissolved in a mixture of tetrahydrofuran and methanol (6 ml each) and 1N was added. hydrochloric acid (2 ml, pH). The mixture is stirred for 2 hours at ambient temperature and then evaporated. The residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate, saturated sodium chloride, dried (magnesium sulfate) and evaporated. The residue is crystallized from a mixture of isopropyl ether and dichloromethane and get the target compound in the form of colorless crystals (265 mg), t. Pl. 187188 ° C. .
    at. 3- (Dimethylamine) carbonyl -1, 2, 3, 4 tetrahydro-6-methyl-4- (3-nitro, enyl) -2-oxo-5-pyrimidinecarboxylic acid.
    To a solution of t-butyl ether-3- (dimethylamine) carbonyl -1, 2, 3, 4-tetrahydro-6methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimide-incarboxylic acid (230 kg, 0, 59 mmol) in chloroform (4.0 ml) was added trifluoroacetic acid (1.2 ml) at ambient temperature in argon. After stirring for 2.5 hours, the mixture is evaporated, co-evaporated with toluene and crystallized from a mixture of ethanol and ether, and the title compound is obtained as colorless crystals (134 mg), m.p. 193195 ° C. Thin layer chromatography (5% methanol - dichloromethane) gives a single spot, 21.
    Calculated,%: C 51.72; H 4.63; N 16.08.
    Ci5Hi6N406
    Found,%: C 51.41; H 4.57; N 15.73.
    EXAMPLE 12 3- (aminocarbonyl} -1, 2, 3, 4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid ethyl ester
    but. 1,4-Dihydro-2-methoxy-6-methyl-4- (3-nitrophenyl) -5-pyrimidine carboxylic acid ethyl ester.
    A mixture of ethyl 2- (3-nitrophenyl) methylene-3-oxobutanoic acid (16.46 g, 62.6 mmol) of acid sulphate 0-methylisourea (14 g, 81.4 mmol) and sodium bicarbonate (15.8 g, 18.8 mmol) in dimethylformamide (9.4 ml) is heated at 70 ° C (oil per bath) in argon overnight. The cooled mixture is diluted with water and extracted with ethyl acetate. The organic phase is washed several times with water, washed with saturated sodium chloride, dried (potassium carbonate) and evaporated. The residue is passed through
    silica gel pad, crystallized from isopropyl ether-hexane mixture and then triturated with 60% n-isopropyl ether / hexane mixture (50 ml) to obtain these 1,4-dihydro-2-methoxy-6-methyl ether -four-; (3-nitrophenyl) -5pyrimidine carboxylic acid as pale yellow crystals (12.32 g), so pl. 101-103 C.
    at. 3- {aminocarbonyl) -1,2, 3,4-tetrahydro-draw-6-methyl-4- (3-n -thophenyl) -2oxo-5-pyrimidinecarboxylic acid ethyl ester;
    To a solution of 1,4-dihydro-2-methoxy-6-methyl-4- (3-nitrophenyl) -5 pyrimidinecarboxylic acid ethyl ester (19.8 mmol) and dry triethylamine (11.2 ml, 80 mmol) in acetonitrile (40 ml) in an ice bath in argon, a 1.2 M solution of phosgene in toluene (20 ml, 24 mmol) is added by syringing. After stirring for 2 hours, a 0.7 M solution of ammonia in tetrahydrofuran (46 ml, 32 mmol) was added to the mixture, and then stirred for 1.3 hours at 0 ° C. Nitrogen was bubbled through the mixture and then partially evaporated. The residue was diluted with tetrahydrofuran (100 ml) and methanol (50 ml) and 1N was added. hydrochloric acid (40 ml, pH 1). After stirring for 1 hour, the reaction mixture is neutralized with saturated sodium bicarbonate. The organic extracts are washed with saturated sodium chloride, dried (magnesium sulfate) and evaporated. The residue is crystallized from a mixture of dichloromethane and isopropyl ether to obtain yellow crystals (2.7 g). This solid is thoroughly triturated with acetonitrile and the title compound is obtained as colorless crystals (2.254 g), mp. 213-215 ° C.
    Thin-layer chromatography (40% acetone-hexane) will give a single spot,, 42. . Calculated,%: C 51.72; H 4.63; N 16.08
    Ci5Hi6N406
    Found,%: C 51.78; H 4.67; N 15.95.
    EXAMPLE 13 3- (aminocarbonyl) -1, 2, 3, 4-tetrahydro-6-methyl-2oxo-4- 2- (trifluoromethyl) phenyl-5-pyrimidinecarboxylic acid ethyl ester.
    but. 1,4-Dihydro-2-methoxy-6-methyl-4 (2-trifluoromethyl) phenyl-5-pyridinecarboxylic acid ethyl ester.
    To a solution of ethyl ether. 2-2 trifluoromethyl) phenylmethylene-3-oxobutanoic acid (2.86 g, 10.0 mmol) in dry dimethylformamide (10 ml) in argon is added with acidic sulfate 0-methylisourea (2.10 g , 12.2 mmol) and sodium acetate (2 g, 12.2 mmol). The resulting suspension is stirred at room temperature overnight, and
    the mixture is then heated overnight for 6 hours and then heated at 55 ° C for 6 hours. The mixture is diluted with ethyl acetate, filtered and the filtrate is washed with water, sodium bicarbonate and brine. After drying with anhydrous magnesium sulfate, the solvent is distilled off and a yellow foam is obtained. It is purified by flash chromatography (5% ethyl acetate in methylene chloride) to give the title compound (2.17 g) as a colorless thick oil, which solidifies quickly. This product is used in the next reaction without further purification.
    b. 3- (Amincarbynyl) -1, 2, 3, 4-tetrahydro-6-methyl-2-oxo-4-2 (trifluoromethyl) phenyl-5-pyrimidinecarboxylic acid ethyl ester.
    To a solution of 1,4-dihydro-2g methoxy-6-methyl-4- (2-trifluoromethyl) phenyl-5-pyrimidinecarboxylic acid ethyl ester (2.85 g, 8.63 mmol) and dry triethylamine (4.81 ml, 34.5 mmol) in acetonitrile (20 ml) at 0 ° C. A 1.2 M solution of phosgene in toluene (8.6 ml, 10.3 mmol) is added by syringing with argon. After stirring at 0 ° C for 2 hours, 0.7 M ammonia in tetrahydrofuran (19.7 ml, 13.8 mmol) is added to the reaction mixture and stirred at 0 ° C for 1.5 hours. Nitrogen is bubbled through the mixture and it is partially evaporated. The residue was diluted with tetrahydrofuran (40 ml) and methanol (20 ml) and 1N was added. hydrochloric acid (20 ml, pH 1). After stirring for 1.5 hours, the reaction mixture is neutralized with saturated sodium bicarbonate and partially evaporated. The aqueous phase is extracted with ethyl acetate. The combined organic layers are washed with saturated sodium chloride and evaporated. The product is subjected to flash chromatography (5-15% acetone - dichloromethane) and powdered with ether (twice) to give the title compound as colorless crystals (790 mg). The crystals dry out in the range of 105-115 ° C and then slowly melt at 155-160 ° C. Thin layer chromatography (3% acetone) gives a single spot,, 61.
    Calculated,%: C, 51.75; H 4.34; N 11.32; F 15.35.
    Ci6Hi6F3N404
    Found,%: C 52.05; H 4, N 10.99; F 15.64.
    Example14. Isomers A and B of 1-methyl ethyl ester 3 (S) -1,2, 3,4-tetrahydro-6methyl-4- (3-nitrophenyl) -2-oxo-3- (1-phenyl-ethyl) amine carbonyl-5- pyrimidine carboxylic acid.
    A solution of 1,4-dihydro-2-methoxy-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methyl ethyl ester (2.0 g, 6.0 mmol, see Example 2A) in dichloromethane
    (10 ml) and triethylamine (4.2 ml) is cooled to 0 ° C in argon and a solution of phosgene in toluene (6 ml of a 1.3 M solution) is added dropwise. A thick, colorless precipitate was obtained, the reaction was stirred at 0 ° C for
    30 minutes and then (S) - (-) a-methylbenzylamine (800 mg, 6.6 mmol) is added dropwise. Remove the ice bath and stir the mixture for 3 hours at room temperature. The solvent is distilled off, the precipitate
    dissolved in methanol-tetrahydrofuran (10 ml of the mixture in a 1: 1 ratio); To the resulting solution was added 2N hydrochloric acid (2 ml) and stirred at room temperature for 1 hour. The solvent was distilled off and the residue was extracted with dichloromethane. The combined extracts are washed with water, sodium bicarbonate and brine. After drying with anhydrous magnesium sulfate, the solvent is distilled off and the residue is passed through a short silica gel column (ethyl acetate – dichloromethane in a ratio of 5/95). The substance is crystallized from dichloromethane - isopropyl ether, which gives a colorless solid (isomer B; 619 mg).
    Recrystallization from the same solvent gives the analytically pure isomer B, mp. 197.5-198.5 ° C, and about + 139 ° (1% chloroform). The mother liquor from the first crystallization is evaporated and the residue is again subjected to crystallization from dichloromethane - isopropyl ether and get a mixture of isomers A and B (301 mg). The resulting mother liquor is subjected to concentration and crystallization from ether - hexane, which gives the pure isomer A (501 mg) so pl. 94-97 ° C, ab -232 ° (1%, chloroform). C 61.79 H 5.62 N 12.01 Calculated,% (isomer A); C, 61.94; H
    5.54; N 11.97
    C24H26N406
    Found,% (isomer B): C 61.90; H 5.57; N 11.99. ,
    Example 15. Isomers a and b 1-methyl ethyl ester 3 (R) -1, 2, 3, 4-tetragus Dro-6methyl-4- (3-n1 (trofenyl) -2-oxo-3 (1-phenyl-ethyl) amine carbonyl-5-pyrimidinecarboxylic acid.
    A solution of 1, 4-dihydro-2-methoxy-6-methyl- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1 methyl ester (2 g, 6.0 mmol, see example 2A) in dichloromethane (10 ml) and triethylamine (4.2 ml) is cooled to 0 ° C in argon and added dropwise with a solution of 17 17134 phosgene in toluene (6 ml of a 1.3 M solution). A colorless thick precipitate is obtained. The mixture is stirred for 30 minutes at 0 ° C, and then (P) - (+ "-methylbenzyl rank (800 mg, 6.6 mmol) is added dropwise. The 5" ice bath is removed and stirred for 3 hours at room temperature. temperature. The solvent was evaporated and the residue was dissolved in methanol-tetrahydrofuran (10 ml of a 1: 1 mixture). To the resulting solution was added 2N hydrochloric acid (2 ml) and stirred for 1 hour at room temperature. The solvent was removed and the residue is extracted with dichloromethane.15 The combined extracts are washed with water, sodium bicarbonate and brine. After drying with anhydrous magnesium sulfate, the solvent was evaporated and the residue was passed through a short silica gel column (ethyl acetate: dichloromethane ratio 5:95). The product crystallized from dichloromethane-isopropyl ether to give a colorless solid (isomer B: 530 mg) .25 Recrystallization from the same solvent gives analytically pure isomer B (380 mg), mp 187-188 ° C AB -125 ° (1%, chloroform). The mother liquor is evaporated from 30 the first crystallization and the residue is recrystallized from dichloromethane- isopropyl ether and semi ayut mixture of isomers A and B (380 mg). The mother liquor obtained is concentrated and crystallized from a mixture of iso-35 propyl ether-hexane to give isomer A (325 mg), mp. 145-149 C ab + 236 ° (1%, chloroform) Calculated,%: C 61.79: H 5.62; N12.02. Q j 1U1 Q 40 Found,% (isomer A): C 61.84; H 5.53; N1200 Found,% (isomer B): C 61; 90; H 5.57; . Example 16. 1- Methyl ethyl ester 3- (aminecarbonylI- (2. 1, 3-benzoxadiazol4-yl) -1, 2, 3, 4-tetrahydro-6-methyl-2-oxo-5 pyrimidinecarboxylic acid a. 1-Methyl ethyl ester 442, 1, 3-benzoxadiazol-4-yl) -1,4-dihydro-2-methoxy-6 0 -methyl-5-pyrimidinecarboxylic acid. A mixture of 1- methylethyl ester of 2- (2, 1, 3-benzoxadiazol-4-yl) methylene 3-oxobanoyl acid (2.04 g, 7.43 mmol), bicar-sodium bonate (1.87 g , 22.3 mmol) and acidic 5-methyl sulfonyl urea sulfate (1.66 g, 3.66 mmol) in dimethylformamide (7.5 ml) are heated at 65 ° C (oil per bath) overnight in argon. The mixture is then diluted with ethyl acetate, washed 718 several times with water, washed with saturated sodium chloride, dried (potassium carbonate) and evaporated. The residue is subjected to flash chromatography over Merck silica gel (400 ml), a 10% mixture of ethyl acetate-dichloromethane is used as a diluent to give 1. „ethyl ethyl effect p 4- (2.1,3-benzoxadiazol yl) -1.4-dimethyl 2-methoxy 6-methyl-5-pi. rimidinecarboxylic acid as a dark solid (0.60 g, 24%). Thin-layer chromatography (10% ethyl acetate - dichloro; tan) gives a single spot, 17. b. 5- (1-Methylethyl), 3- (4-nitrophenyl) ether 4- (2, 1, 3-benzoxadiazol-4-yl) -1, 2, 3, 4-tetrahydro-6-methyl-2-oxo- 3,5-pyrimidinecarboxylic acid, To a solution of 4- (2, 1, 3-benzoxadiazol-4-yl) -1,4-dihydro-2-me xy-b-methyl-5-pyrimidinecarboxylic acid 1-methyl ethyl ester (0, 60 g, 1.82 mmol) and pyridine (0.88 "l, 0.9 mmol) in dichloromethane (10 ml) in an ice bath in argon are added dropwise 4Nt-phenyl chloroformate (403 mg , 2.00 mmol) in dichloromethane (10 ml). Then the mixture is stirred for 1 h at 0 ° C and evaporated. The residue was then dissolved in tetrahydrofuran, (2 ° m) methanol (10 ml) and 3 was added; n The surrounding HG mixture is evaporated to near dryness, cooled in an ice bath, and dissolved in a saturated sodium bicarbonate solution. The mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride, dried (potassium carbonate), evaporated and get 5- (1-methylethyl), 3- (4-nitrophenyl) ether 4- (2, 1, 3-benzoxadiazol-4-yl 1, 2, 3, 4-tetrahydro-6-methyl-2-oxo-3,5-pyrimidinecarboxylic acid as a brown solid (0.63 g, 74%). Thin-layer chromatography {40% acetone hexane) gives the main SPOT,, 33. - ,, “1-Methyl ester of 3-aminocarbonyl) 3-benzoxadiazol-4-yl) -1, 2, 3, 4-tetrahydro-6-methyl-2-oxo-5-pyrimidinecarbo. acid. , o / v,. To a solution of 5 1-methylethyl), 3- 4-nitrophenyl) ester 4- {2, 1, 3-benzoxadiazol-1, 2, 3, 4-tetrahydro-6-methyl-2-oxo-3 5-pyrimidinecarboxylic acid (0.63 gI.35 mmol) in distilled tetrahydrofuran (14 ml of an ice bath in argon was added a 0.7 M solution of ammonia in tetrahydrofuran (2.5 ml, 1.75 mmol) and stirred for 1 hour at - Then the mixture was evaporated and subjected to instant chromatography over Merck silica gel (150 ml), diluted with 40% mixture of lilacetate and hexane, a yellow foam (109 mg) is obtained. Crystallization from isopropyl ether-dichloromethane gives 1-methyl ethyl ether 3- ( aminocarbonyl) -4- (2,1, 3-benzoxadiazol-4-yl) -1, 2, 3, 4-tetrahydro-6-methyl-3-oxo-5-pyrimidinecarboxylic acid as a yellow solid (141 mg, 37%), mp 207-20 8 C. Thin-layer chromatography (4% methanol - dichloromethane) gives a single spot,, 27.
    Example 7. Hydrochloride, (5) -1-methyl2-methyl (phenyl) 1methyl) amine ethyl ester 1, 2, 3, 4-tetrahydro-6-methyl-3-1 (1-methylethyl) -amine carbonyl -4CH3- nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid.
    A- (3) -1-Methyl-2-methyl (phenylmethyl) amine 1,4-dihydro-2-methoxy-6-methyl-4- (3-n itrophe n and l) ethyl ester ri and dincarboxylic acid.
    A mixture of (5) -1-methyl-2-methyl (phenylmethyl) amine 2-3-nitrophenylmethylene-3-oxobitanoic acid ethyl ester (7.4 g, 18.8 mmol), 0-methylisourea acid sulfate (3.88 g, 22.5 mmol) and sodium bicarbonate (7.89 g, 94 mmol) in dimethylformamide (19 ml) in argon are heated at 65 ° C (oil per bath) overnight. The mixture is then partitioned between ether and water. The organic phase is washed several times with water and then washed with saturated sodium chloride, dried (potassium carbonate) and evaporated. A thick red residue no; t is cast on instant Merck silica over Merck silica, diluted with a 520% mixture of acetone and dichloromethane, to give (5) -1-methyl-2-methyl (phenylmethyl) amine 1,4-dihydro-2 ethyl ester -methoxy-6-methyl-4- (3-nitrophenyl) -5-pyrim and dincarboxylic acid as a thick dark oil (3.77 g, 44%). Thin layer chromatography (20% acetone - dichloromethane) gives two spots, R 0.34 and 0.47.
    B. 5 (5) -1-Methyl-2-methyl (phenylmethyl) amine ethyl 3- (4-nitrophenyl) ether 3, 4 dihydro-6-methyl-4- (3-nitrophenyl) -2-oxo-3 , 5-pyrimidinecarboxylic acid.
    To a solution of (8) -1-methyl-2-methyl (phenylmethyl) amine 1 4-dihydro-2methoxy-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid ethyl ester (2.20 g, 4, 87 mmol) and pyridine (2.36 ml, 29.2 mmol) in dichloromethane (20 ml) in an ice bath in argon, a solution of 4-nitrophenyl chloroformate (1.08 g, 3.36 mmol) in dichloromethane is added via an additional funnel . The mixture is then stirred in an ice bath for 15 minutes and evaporated. The residue is treated with toluene and evaporated to remove pyridine. Then, the residue was dissolved in tetrahydrofuran (50 ml) and methanol (25 ml) and 3N was added. hydrochloric acid (5.0 ml, pH 1). After
    stirring for 1.5 hours at ambient temperature, the mixture is poured into cold (ice on a bath) saturated sodium bicarbonate. After evaporation almost to dryness, the mixture is extracted with ethyl acetate. The combined organic phase is washed with saturated sodium chloride, dried (potassium carbonate), evaporated to give 5 (5) -1-methyl-2-methyl (phenylmethyl) amine-ethyl, 3 4-nitro-6-phenyl) ether 3, 4-dihydro-methyl -4- {3-nitrophenyl) -2-oxo-3,5-pyrimidinecarboxylic acid as a brown solid (2.38 g, 83%). Thin layer chromatography (10% acetone-dichloromethane) gave two main points,, 25 and 0.39.
    at. Hydrochloride (5) -1-methyl-2-methyl (phenylmethyl) amine ethyl ester 1, 2, 3, 4-tetrahydro-6-methyl-3-1-methylethyl-amine carbonyl -4- (3-nitrophenyl) 2 - oxo-5-pyrimi0 dincarboxylic acid.
    A mixture of 5 (5) -1-methyl-2-methyl (phenylmethyl) amine-ethyl, 3 (4-nitrophenyl) ether 3, 4-dihydr-6-methyl-4- (3-nitrophenyl) -2-oxo-3, 5 pyrimidinecarboxylic acid (2.38 g,
    5 4.04 mmol) and isoprplamine (0.34 ml, 4.04 mmol) in acetonitrile (8 ml) are stirred at ambient temperature overnight in argon. The reaction mixture is diluted with ethyl acetate, washed with saturated sodium bicarbonate (three times) and saturated sodium chloride, dried (potassium carbonate) and evaporated. Instant chromatography on Merck silica gel (300 ml) diluted with 5% mixture
    5 acetone and dichloromethane gives a yellow foam (0.84 g). The foam is dissolved in ether and pactBop ether hydrogen chloride is added to give (5) -1-methyl-2-methyl (Fe NIL-methyl) and hydrochloride ethyl ester 1,2,3,
    0 4-tetrahydro-6-methyl-3- (1-methyl-ethyl) amide carbonyl-4 (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid in the form of electrostatic yellow crystals (672 mg, 30%), m.p. 110-130 ° C (decomposed). Thin layer chromatography (10% acetone - dichloromethane) gives two spots,, 38 and 0.46.
    EXAMPLE 18.1-Methylether 1, 2, 3, 4-tetrahydro-3-Shch5) 2-ethoxy-2-oxo-1 (phenylmethyl) ethyl amine carbonyl-6-methyl0 4- (3-nitrophenyl ) -2-oxo-5-pyrimidinecarboxylic acid.
    To a mixture of 1,4-dihydro-2-methoxy-6-methyl-4- (3-nitrophenyl) -5 methyl methyl ethyl ester of pyrimidinecarboxylic acid (4.00 g,
    5 12.0 mmol, see Example 2A) and triethylamine (6.69 ml, 48.0 mmol) in an ice bath, under the action of argon in acetonitrile (48 ml), is added dropwise by syringing a 1.3 M solution of phosgene in toluene (12.0 ml, 15.6 mmol). After stirring for 1 hour at 0 ° C, L-phenylalanine ethyl ether hydrochloride (3.31 g, 14.4 mmol) is added to the reaction mixture, stirred for 1 hour at ambient temperature. The mixture was then diluted with lutetetrahydrofuran-methanol (100 ml each) and 3N was added. hydrochloric acid 15 ml, 45 mmol). After stirring at ambient temperature for 1 hour, the reaction mixture is cooled in an ice bath and neutralized with a saturated sodium bicarbonate solution. The resulting mixture was partially evaporated and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride, dried (magnesium sulfate) and evaporated.
    The residue was flash chromatographed over Merck silica gel (600 ml), diluted with a 5% mixture of ethyl acetate and dichloromethane. A mixture of two isomers is obtained, as well as a slow isomer (2.5 g), each as a yellow foam. The slow isomer (B) is crystallized from dichloromethane — isopropyl ether and slightly bronze white crystals are obtained (1.30 g, mp 132-133 ° C). The mother liquor was combined with a mixture of two isomers and recrystallization from dichloromethane — isopropyl ether and an additional slow isomer (0.60 g) was obtained as colorless crystals. The filtrate is partially evaporated and two substances (2.45 and 1.39 g) of the fast isomer (A) are obtained. These two substances are combined, recrystallized, and a fast isomer is obtained in the form of light, electrostatic needles (1.34 g, 21%), mp. 122-124 ° C. Thin layer chromatography (10% ethyl acetate dichloromethane) single spot,, 59. ci: D + 165 ° (1% chloroform). The corresponding parts of the slow isomer (B) are combined and recrystallized. They give off colorless slightly electrostatic needles (1.57 g, 24%), mp. 134-135 ° C. Thin layer chromatography (10% ethyl acetate dichloromethane) yields a single spot,, 43.
     (1% chloroform)
    Calculated,%: G 60.21; H 5.61; N 10.41.
    C27H30N408
    Found,% (fast isomer): C 60.24; H5.66; N 10.37.
    Found,% (slow isomer): C 60.17; H 5.60; N 10.34.
    Example t9. 1-Methyl ethyl ester 1, 2, 3, 4-tetrahydro-6-methyl-3- 2-methyl (phenylmethyl) carbonyl-4- (3 nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid.
    To a solution of 1-methyl ethyl ether, 4-dihydro-2-methoxy-6-methyl-4- (3-nitrophenyl) -6-pyrimidinecarboxylic acid (2 g, 6.0 mmol, see Example 2A) and triethylamine (1, 25 ml, 9.0 mmol) in acetonitrile (18 ml) in an ice bath in argon, a 1.3 M solution of phosgene in toluene (6 ml, 7.8 mmol) is added by syringe. After stirring for 3 hours at 0 ° C, a solution of triztilamine (1.25 ml, 9.0 mmol) and M-benzyl-N-methyl-aminethylamine (1.523 g,
    0 9.0 mmol) in dry tetrahydrofuran (12 ml) under the action of argon by douching. The mixture was stirred for 1.5 hours at 0 ° C, diluted with tetrahydrofuran (24 ml) and methanol (24 ml) and 1N was added. salt
    5 acid (30 ml, pH 1). The SateM reaction mixture is stirred at room temperature for 2 hours and neutralized with a saturated sodium bicarbonate solution. The resulting mixture is partially evaporated and extracted with
    0 using ethyl acetate. The combined organic phases are washed with saturated sodium chloride, dried (magnesium sulfate) and evaporated to give a yellow foam (3.12 g). This substance is subjected to instant chromatography (2% methanol - dichloromethane), crystallized from ether - isopropyl ether and get a colorless solid (1.64 g, 54%), so pl. 133-135 ° C. Thin layer chromatography (2% methanol 0 dichloromethane) gives a single spot,, 17.
    Calculated,%: C, 61.28; H 6.13; N 13.74.
    CaeHsiNsOe
    Found,%: C 61.33; H 6.19; N 13.49.
    five
    Example 20. (-) - 3- (Dimethylamine) carbonyl 1, 2, 3, 4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic 1-methyl ethyl ether
    0 acid.
    A. 5- (1-Methylethyl) ether, 3- 1-1-dimethylethoxy-carbonyl-5 (3) - (methoxycarbonyl) -3 (P) -pyrrolidinyl ether 3,4-dihydro-2-14 methoxyphenyl) methyl thio - 6-methyl-4- (3-nit5rophenyl) -3,5-pyrimidine dicarboxylic acid. lots.
    To a solution of 1,4-dihydro-2- (4-methoxyphenyl) methyl thio-6-methyl-4- (3-nitrofeiyl) -5-pyrimidinecarboxylic acid in pure pyridine (44 ml) at room temperature in nitrogen toluene (1.3 M, 1; Zekv, 22 ml). The mixture is stirred for 2 hours, and then a solution of methyl 15 (1,1-dimethylethoxy) carbonyl -4- (trans-hydroxy) -broline (8.6 g, 35.2 mmol) in pure pyridine is added dropwise. (2.0 ml).
    After stirring for 24 hours at room temperature using thin layer chromatography (1: 2 ethyl acetate
    - Hexane) set the end of the reaction. An additional amount of methyl 1- (1,1-dimethylethoxy) carbonyl-4-trans-hydroxy) -1-proline (5.4 g, 22 mmol) is added as a solution in pyridine (15 ml) and the reaction is continued for 24 hours. Dilute with ethyl acetate (100 ml), the organic layer is separated and washed with a solution of saturated sodium bicarbonate (2 x 50 ml), secondary sodium hydrogen phosphate (2 x 50 ml) and water (2 x 50 ml) dried over magnesium sulfate, filtered, evaporated in vacuo, get the foam. Instant chromatography on 1000 g of silica (1: 2 ethyl acetate-hexane) gives a yellow foam of 9.3 g (58).
    B. 5- (1-Methylethyl) ether, (5) -methoxycarbonyl) -3 (H) -pyrrolidinyl ether 1, 2, 3, 4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-thioxo-3 , 5- pyrimidinecarboxylic acid.
    5- (1-Methylethyl) ether,, 1-dimethylethoxy (carbonyl) -5- (5) methoxycarbonyl) -3 (H) -pyrrolidine ether. 3, 4-dihydro-2 4-methoxyphenyl) methyl} hyo-6- methyl 4- (3nitrophenyl) -3,5-pyrimidine dicarbric acid (9.3 g, 12.8 mmol) as a solution in dichloromethane (11 ml) is added dropwise to a mixture of trifluoroacetic acid (26 ml) and anisole (2 , 6 ml) at 0 ° C in nitrogen,
    The mixture is stirred for 90 minutes at 0 ° C and the trifluoroacetic acid is evaporated in vacuo. The yellow residue was dissolved in dichloromethane (100 ml) and the organic layer was washed with water (50 ml), saturated sodium bicarbonate (2 CBL ml), dried over magnesium sulfate, filtered, evaporated in vacuo to give an oil. The oil is dissolved in a mixture of hexane-methanol acetate (80: 20: 1), cooled to -78 ° C and treated with ethereal hydrochloric acid (1 eq.). The pale yellow solid is collected by filtration and dried in vacuo. A mixture of diastereoisomers is obtained (b g, 86%). The free base of this mixture is freed before separation by chromatography by exposure to a solution of dichloromethane with sodium hydroxide and the organic layer is absorbed into celite. Instant chromatography on 1000 g of silica with a mixture of ethyl acetate - hexane - methanol in a ratio of 60: 40: 1 and followed by treatment with the same solvent in a ratio of 80: 20: 1 gives two isomers A and B. All fractions are acidified with ethereal hydrochloric acid as they are received. Isomer A, 2.01 g (57%). Isomer B, 2.04 g (58%).
    B. 1-methylethyl ester of (-) -, 2, 3, 4 tetrahydro-6-methyl-4- (3-nitrophenyl) -2-thioxo-5-pyrimidinecarboxylic acid.
    Sodium methylate in methanol (2 eq.) Is added to a solution of the A-5- (1-methylethyl) -ether isomer, 3 - {(8) 5-methoxycarbonyl-3-pyrrolidinyl ester 1,2,3,4-tetrahydrop-6- methyl 4-3-nitrophenyl-2-thioxp-3, 5-pyrimidine carboxylic acid (2.01 g, 3.7 mmol) in me-.
     Thanol (4 ml). The reaction is stirred at room temperature. After 16 hours of stirring, the pH is adjusted to 2 with ethereal hydrochloric acid and the mixture
    10 is cooled to -78 ° C. A solid is obtained by filtration. From the mother liquor there are substances that, when combined, give 1 g (79%) ..
     , 1 (, dimethylsulfo.xide).
    5 g. (-) - 1,4-Dihydro-2- {(4-methoxyphenyl) methyl thio-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methyl ethyl ester.
    (-) - 1, 2, 3, 4-tet0 rahydro-B1-methyl-4- (3-nitrophenyl) -2-thioxo-pyrimidinecarboxylic acid (2.6 mmol, 884 mg) was dissolved in dry tetragi drofu wound and cooled to 0 ° C. 4-methoxybenzyl chloride is added dropwise (1.1 eq 32.9
    5 mmol, 393 ml). The bath is then removed and the reaction mixture is stirred for 2 hours at room temperature. The mixture is then heated for 16 hours at 65 ° C. Using thin-layer chromatography in a mixture of acetone 0 hexane in a ratio of 35:65, it was established that the reaction was not completed, an additional portion of 4-methoxybenzyl chloride was added to the reaction mixture (1.1 eq, 1.3 mmol, 393 ml). After heating for 7 hours at 65 ° C, the mixture is cooled to room temperature and diluted with ether. After cooling the mixture to 0 ° C, a white solid is obtained. The solid is collected by suction, washed
    0 ester, and 1,4-dihydro-2- (4methoxyphenyl) methyl thio-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methyl-ethyl ester hydrochloride is obtained and prepared; 636 mg (49%).
    with D. 1-Methyl ethyl ester of (-) - 3,4-dihydro-3- (dimethylamine) carbonyl -2- (4-methoxyphenyl) methyl thio - 6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid .
    The 1,4-dihydro-2- | 1 (4-methoxyphenyl) methyl thio-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methylethyl ester hydrochloride free base was prepared by washing the dichloromethane solution with sodium bicarbonate. The organic layer is dried, filtered, reduced under vacuum, and a green foam is obtained. The foam (1.66 mmol, 754 mg) was dissolved in dry dichloromethane (8.3 ml) and triethylamine (5 eq, 8.3 mmol, 1.2 ml) was added. Phosgene in toluene (1.6 eq.,
    2.66 mmol, 2.0 ml) at 0 ° C. After the addition, the bath is removed and the mixture is stirred at room temperature. After 30 minutes, dimethylamine (excess 1.66 ml) was added and the mixture was stirred for an additional 30 minutes. The reaction mixture was diluted with ethyl acetate (50 ml) and diluted with 1N. hydrochloric acid (2X) and on, saturated with sodium bicarbonate (2X). The organic layer is dried over magnesium sulfate, filtered, reduced in vacuo, and an oil, 586 mg, is obtained. Instant chromatography on 40 g of silica (1: 2; ethyl acetate: hexane) gives the pure product as an oil, 355 mg (41%).
    E. 1-Methyl ester C) -3- (dimethylamine) carbonyl -1,2,3,4 tetrahydro-6-methyl4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid,
    To a solution of (-) (3, 4-dihydro-3- (dimethylamine) carbonyl} -2 4-methoxyphenyl-methyl thio-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methyl ethyl ester in dry dichloromethane (6.7 ml) was added 3-chloroperoxybenzoic acid (3 SQV, 2 mmol, 349 mg) at 0 ° C under a nitrogen atmosphere. The mixture was stirred overnight, after which a precipitate formed. The mixture was diluted with 15% (15%). ml) and washed with 1N hydrochloric acid (twice), 1N, sodium hydroxide (twice) and water. The combined organic layers are dried over magnesium sulfate, filtered, and reduced in vacuo and 390 mg of oil is obtained. Instant chromatography on 39 g of silica gel (2: 1 ethyl acetate-hexane) gives the product as an oil. The oil is left for 48 hours under the action of ether, and then triturated to give a white crystalline substance, 144 mg (55%), t, pl, 152-153 ° C,
     , 6 (, 2, chloroform).
    Calculated,%: C 55.38: H 5.68; N 14.35,
    C18H22N406
    Found,%: C 55.41; H 5.68; N 14.17,
    PR and m e p 21, 1-Methyl ethyl ester (+) - 3- (dimethylamine) carbonyl -1, 2, 3, 4gtetrahydro-6-methylg4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid,
    A, (+) -1, 2, 3, 4-tetrahydro-6-methyl-4-3-nitrophenyl-2-tioc 1-methyl ester of co-5-pyrimidinecarboxylic acid,
    To the solution of isomer B (described in Example 20B) 5- (1-methylethyl) ether, 3- (S) -5methoxycarbonyl-3-pyrrolidinyl ether 1, 2, 3, 4-tetrahydro-6-methyl-4- (3 -nitrophenyl) -2-thioxo-3, 5-pyrimidinecarboxylic acid (2.04 g, 3.7 mmol) in methanol (18 ml) was added methylate sodium e methanol (1.6 ml, 7.5 mmol, 2 eq ). The reaction is stirred at room temperature. After 16 h, the pH was adjusted to 2 with ethereal hydrochloric acid and the mixture was cooled to 0 ° C for 6 h. The resulting solid was isolated by filtration. Three substances are obtained from the mother liquor, which, when combined, yield 1.12 g (89%).
    and (, 5, dimethyl sulfoxide).
    B, (+) - 1,4-dihydro-2- (4-methoxy-phenyl) methyl thio-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methyl-ethyl ester.
    (+) -1, 2, 3, 4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-thioxo-5-pyrimidinecarboxylic acid 1-methyl ethyl ester (2.6 mmol, 884 mg) is dissolved in dry tetrahydrofuran and cooled to 0 ° C. 4-methoxybenzyl chloride (1.1 eq 32.9 mmol 393 l) is added dropwise. The bath is removed and the reaction mixture is stirred for 2 hours at room temperature. The mixture is then heated 16 hours at 65 ° C. Thin-layer chromatography with a mixture of acetone-hexane in a ratio of 35:65 indicates that the reaction is not complete, so an additional amount of 4-methoxybenzyl chloride is added to the mixture (0.5 eq, 1.3 mmol 176 ml). After 7 hours at 65 ° C, the mixture is cooled to room temperature and diluted with ether. After cooling to 0 ° C, a white solid is obtained. The solid is collected by filtration, washed with ether, dried and get (1) methyl ethyl ether (+) - 1,4-dihydro-2- {1 (4-meth6xyphenyl) methyl thio-6-methyl-4- (3- nitrophenyl) -5-pyrydimidinecarboxylic acid, 493 mg (38%),
    B, (+) - 3, 4-dihydro-3- {(dimethylaminecarbonyl -2- (4-methoxyphenyl) methyl thio-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid, 1 + methyl ether
    The free base of (+) - 1,4-digidro-2- (4methoxyphenyl-methyl-thio-6-methyl-4- (3-nitrophenyl) -B-pyrimidinecarboxylic acid 1-methylethyl ester hydrochloride ester is obtained by washing the solution of dichloromethane with sodium bicarbonate. The organic layer is dried, filtered, reduced in vacuo to give a green foam. The foam (0.95 mmol, 431 mg) was dissolved in dry dichloromethane (4.8 ml) and triethylamine (5 eq., 4.75 mmol) was added. 1.3 M phosgene in toluene (1.6 eq, 1.5 mmol, 662 ml) at 0 ° C. The bath is then removed and the mixture is stirred at room temperature. es 30 min was added dimethylamine (excess, 0.95 mL) and the mixture was stirred for 30 min., reaction mixture was diluted with ethyl acetate (50 mL) and washed with hydrochloric acid (twice), saturated sodium bicarbonate (twice). The organic layer was dried
    over magnesium sulfate, filtered and reduced in vacuo to give an oil. Instant chromatography on 40 g of silica gel (1; 2 ethyl acetate - hexane) gives the pure product as an oil, 431 mg (86%).
    G. 1-Methyl ethyl ester (+) - 3 - {(dimethylamine) carbonyl -1, 2, 3, 4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidine carboxylic acid.
    To a solution of (+) 3, 4-dihydro-3- (dimethylamine) carbonyl -2 (4-methoxyphenyl) methyl thio-bmethyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methylethyl ester (+) 3 (8 , 2 ml) at 0 ° C under nitrogen atmosphere are added 3-chloroperoxybenzoic acid (3 eq, 2.5 mmol, 424 mg). The reaction mixture is stirred overnight at room temperature, a precipitate forms. The mixture is diluted with ethyl acetate (15 ml) and washed with 1 and. hydrochloric acid (twice), 1 n, sodium hydroxide (twice) and water. The combined organic layers are dried over magnesium sulphate, filtered, reduced in vacuo to give an oil, 390 mg.
    Instant chromatography on 39 g silica gel (2: 1 ethyl acetate-hexane) gives the product as an oil (433 mg). The oil is left for 48 hours under ether, triturated to give a white crystalline solid, 254 mg (67%), m.p. 153-155 ° C.
     a, 5 (, 1, chloroform).
    Calculated,%: C 55.38; H 5.68; N 14.35;
    C18H22N406
    Found,%; C 55.32; H 5.76; N 14.00.
    Example 22. (+) - Isomer of 1- methylethyl ester 3- (aminecarbonyl) -1,2,3,4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5pyrimidinecarboxylic acid.
    Isomers of 1 (3) -1, 2, 3, 4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-3- (1-phenylethyl) 1-methyl ethyl ester 3 (S) -1, 2, 3, (1-phenylethyl) amine carbonyl-5- Pyrimidine carboxylic acid (1.7 g, 3.65 mmol, as in Example 14) in trifluoroacetic acid (10 ml) is heated for 4 hours at 75 ° C. Then the reaction mixture is cooled to room temperature and the solvent is evaporated. The residue is dissolved in ethyl acetate, washed with water, sodium bicarbonate and brine. Dried over magnesium sulfate, evaporated, a yellow foam is obtained. Upon crystallization from isopropyl ether, a colorless solid (1.12 g) is obtained. Recrystallization from isopropyl ether of dichloromethane gives the analytically pure (+) - isomer of 1- methyl ethyl ester 3- (aminecarbonyl) -1,2,3,4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo
    -5-pyrimidinecarboxylic acid (870 mg), so pl. 160-161 ° C.
     a 0 -153 ° (1% in methanol).
    Calculated,%; C 53.03; H 5.01; N 15.47. CieHieN Oe
    Found,%; C 53.06; H 5.01; N 15.47.
    EXAMPLE 23 (-) - 3- (Amincarbonyl) -1,2,3,4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5 1-methyl ethyl ester isomer -py0 rimidicarboxylic acid.
    A solution of isomer A of 1-methylethyliogr ester 3 (S) -1,2, 3, 4-tetrahydro-6-methyl-4- (3 nitrophenyl) -2-oxo-3- (1-phenylethyl) amine carbonyl-5-pyrimidinecarboxylic acid (60 mg, 0.13 mmol, as in Example 14) in trifluoroacetic acid (10 ml) is heated for 4 hours at 75 ° C. The reaction mixture is cooled to room temperature, then the solvent is evaporated. The residue is dissolved in ethyl acetate and washed with water, sodium bicarbonate and brine. Dry over magnesium sulfate and evaporate, dissolve in dichloromethane (-) - isomer of 1-methyl ethyl ester 3 - (- amincarbonyl) -1, 2, 3, 4-tetra5 hydro-6-methyl-4- (3-nitrophenyl) - 2-oxo-5-pyrimidinecarboxylic acid (27 mg), so pl. 160-161 ° C a (1% in methanol).
    Calculated,%: C 53.03; H 5.01; N 15.47.
    Ci6Hi8N406 0Found%; C 53.20; H 5.12; N 15.11.
    Biological tests of the compounds obtained under the conditions of the proposed method were carried out.
    Male New Zealand rabbits weighing 1.9-2.4 kg were killed by injection of sodium pentobarbital (50 mg / kg) into the marginal ear vein. The thoracic aorta is removed and placed in a Petri dish containing cold Krebs solution or physiological saline solution. The Krebs solution had the following composition, mg-mole; NaCl 111; KCI 5; KH2P04 1; MgSO 1,2; CaCIa 1.25; D glucose 11.5; NaHCOa 25. The composition of saline, mg-mol; 140 NaCI, KCI 4.7; NaHP04, 1.2; MOPS 2 (pH 7.4); CaCl2 1.6; MgS04, 1.2; D-glucose 5.6 and Naa EDTA 0.02. Excess fat and tissues are removed and rings of approximately 3 mm wide are cut, which are broken to obtain strips approximately 1 cm long from the circumference. The strips are suspended in a muscle chamber with double walls with a volume of 20 ml 5 under a preload of 4 g, which is stored in during the equilibration period of not less than 1 hour. The temperature in the bath is maintained at 37 ° C, the Krebs solution is flushed
    with a mixture of 95% 02 and 5% CO2, to obtain a pH value of 7.35. Saline is flushed with pure oxygen (100% Oa). The strips are stimulated with 100,110 ml mol KCI (equimolar replacement of NaCl). After achieving a stable stress in a flat state, cumulative or non-cumulative concentration effects are obtained. The force retained in the presence of the compound was normalized with respect to the registered initial voltage. ICso values are determined using a quadratic approximation for a logistic transformation of the concentration effect curves. The compounds are dissolved in a 95% ethanol solution and added to muscular chambers in such quantities that the ethanol concentration in them does not exceed 0.01%. In such concentrations, ethanol does not affect the strength of the reduction in this experiment.
    The results of biological tests confirming the vasodilating effect of the compounds of the proposed method are presented in Table. one.
    In the tested doses, the proposed compounds showed no signs of toxicity, they can be classified as low-toxic.
    The tests carried out showed that the proposed compounds of the invention are low toxic and have a vasodilating effect.
    In addition, the effect of the proposed compounds on mean arterial pressure was determined.
    h
    Test compounds were applied to groups of 5 rats with spontaneous hypertension induced by oral administration. Such a test predicted anti-hypertensive activity in humans. Arterial blood pressure was measured 24 hours after dosing. The drug was administered at a dose of 135 µmol / kg, in cases marked with an asterisk (Table 2), a lower dose was used - 45 µmol / kg.
    The results are shown in Table. 2
    The data are presented in the form of the greatest decrease in blood pressure.
    which is noted for a group of rats for four consecutive six-hour observation intervals.
    The tests carried out showed that the compounds obtained under the conditions of the proposed method are of low toxicity, possess high antihypertonic activity, lowering blood pressure to a greater extent than diltiazol. 0 o rmul a and 30 bret and
    The method of producing pyrimidine derivatives of the general formula
    about
     loR,
    .RRjN-C.
    .
    where X is oxygen or sulfur;
    R is hydrogen, C1-C4-alkyl, C1-C 1-phenylalkyl;
    RI is hydrogen, C1-C4-alkyl, alkoxy (C1C4) carbonyl- (phenyl) alkyl (C1-C4)
    or R and RI, taken together with the nitrogen to which they are attached, form piperidinyl, R2-C1-C4-alkyl: Hz-C1-C4-alkyl;
    R4 is phenyl substituted by a nitro group or a trifluoromethyl group, benzoxadiazole,
    or their pharmaceutically acceptable salts, characterized in that the compound of the general formula
    Rh
    .G
    RR.N
    where R-R4 has the indicated values, Y-OCHN or -S-CH2-- © -OCHNz,
    protective groups are cleaved off.
    Priority on the grounds of 14.03.86 with R-H, C1-C4-alkyl; Ri-CiC4 alkyl; Rz-C1-C4-alkyl; R4-3-nitrophenyl;
    X-oxygen or sulfur;
    09/10/86 with R-H, C 1 -C 4 alkyl; Ri-H, C1-C4-alkyl Ci-C4 or R and Ri together piperidinyl; X is oxygen; R2 is C1-C4-alkyl, Ra-
    C1-C4 alkyl; R43-nitrophenyl, trifluoromethylphenyl;
    09.02.87 when R-H, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl; alkoxy (C1-C4) carbonyl (phenyl) alkyl (Ci-C4), X is oxygen; R2 is Ci-C4 alkyl; Ra is C1-C4 alkyl; R4 - 3-nitrophenyl, benzoxadiazole.
    Compound
    Example
    3- (Ethylamino) carbonyl -1,2,3,4-tetrahydro-6-methyl-4 (3-nitrophenyl) -2-thioxo-5-pyrimidinecarboxylic acid, methyl ester
    3- (Dimethylamino) carbonyl -1,2,3,4-tetrahydro-6-methyl4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid, 1-methyl ethyl ester
    3- CTC-methylamino) carbonyl -1,2,3,4-tetrahydro-6-methyl4- (3-nitrophenyl) -2-thioxo-5-pyrimidinecarboxylic acid, ethyl ester
    1,2,3,4-Tetra hydro-6-methyl-3 methyl (phenyl methyl) a m and n about carbonyl -4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid, 1 - methyl ethyl ether
    1,2,3,4-Tetrahydro-6-methyl-3- (methyl-amino) carbonyl-4 (3-nitrophenyl) -oxo-5-pyrimidinecarboxylic acid, 1-methyl ethyl ester
    3- (Aminocarbonyl) -1,2,3,4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid, 1-methyl ethyl ester
    1,2,3,4-Tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-3 (1-piperidinylcarbonyl) -5-pyrimidinocarboxylic acid, 1-methyl ethyl ether
    1,2,3,4-Tetrahydro-6-methyl-3- | 1 (1-methyl-ethyl) amino-carbonyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid, 1-methyl ethyl ester
    1,2,3,4-Tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo 3 (phenylmethyl) amino carbonyl-5-pyrimidinecarboxylic acid, 1-methyl ethyl ester
    3- (Ethylamino) carbonyl -1,2,3,4-tetrahydro-6-methyl-40 (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid, 1-methyl ethyl ester
    3- (Dimethylamino) carbonyl -1,2,3,4-tetrahydro-6-methyl
    1-4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid
    3- (Aminocarbonyl) -1,2,3,4-tetrahydro-6-methyl-4- (3-nit2rophenyl) -2-oxo-5-pyrimidinecarboxylic acid, ethyl ester
    3- (Aminocarbonyl) -1,2,3,4-tetrahydro-6-methyl-2-oxo-43 2- (trifluoromethyl) phenyl-5-pyrimidinecarboxylic acid, ethyl ester
    3 (5) -1,2,3,4-Tetrahydro-6-methyl-4- (3-nitrophenyl) -2-ok4 co-3 (1-phenylethyl) -amino-carbonyl-5-pyrimidinecarboxylic acid, 1- methyl ethyl ether
    Table 1
    1С50
    (nanomolar)
    3
    Not tested
    3000
    175
    723
    sixteen
    at
    551
    60
    13
    Not tested
    ten
    Isomer B 12 Isomer A 1000
    权利要求:
    Claims (2)
    [1]
    1 2 3 fifteen [3 (K)] - 1,2,3,4-Tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo3 - [[1-phenylethyl) amino] carbonyl] -5-pyrimidinecarboxylic acid, 1 -methyl ethyl ether, isomers A and B Isomer B 313Isomer A 2770 16 3- (Aminocarbonyl) -4- (2,1,3-benzoxadiazol-4-yl) -1,2,3,4tetrahydro-6-methyl-2-oxo-5-pyrimidinecarboxylic acid. 1-methyl ethyl ether 82  17 1,2,3,4-Tetrahydro-6-methyl-3 [[(1-methyl-ethyl) amino] carbonyl] -4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid, (5) - 1-methyl-2- [methyl (phenylmethyl) amino] ethyl ether 164 18 1,2,3,4-Tetrahydro-3 ~ III (5) -2-ethoxy-2-oxo-1- (phenylmethyl) ethyl l] amine o] carboxyl yl] -6-methyl-4- (3 -n ytrofe n and l) -2-o kso-5pyrimidinecarboxylic acid, 1-methylethyl ether Fast isomer> 1000 Slow isomer 58 19 1,2,3,4-Tetrahydro-6-methyl-ZZ [2- [methyl- (phenylmethyl) amino] ethyl] amino] carbonyl] -4 (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid, 1 methyl ethyl ether 2 20 (-) - 3 - [(Dimethylamino) carbonyl] -1,2,3,4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid, 1-methylethyl ether 1630 21 (+) - 3 - [(Dimethylamino) carbonyl] -1,2,3,4-tetrahydro-6-methyl4- (3-nitrophenyl) -2-oxo-5 ~ pyrimidinecarboxylic acid, 1-methylethyl ether 3470 22 3- (Aminocarbonyl) -1,2,3,4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid, 1-methylethyl ether, (+) - isomer 1000 23 3- (Am and n ocarbonyl) -1,2,3,4-tetrahydride po-6-methyl l-4- (3-nitro-phenyl) -2-oxo-5-pyrimidinecarboxylic acid, 1-methylethyl ether, (~) -isomer. 10
    Table
    [2]
    2 Continuation of the table. 2
    Example SHP (%) with reduced B P (at a dose of 135 μmol / kg) Maximum effect 5 1 2 eleven12thirteen Not tested -16.4 -25.1 1 214 -17.1 1 -14.3fifteen -17.2 2 -46.3 10 16 -36.5 * 3 -18.017 -11.6 * . 4 -28.618 Not tested 5 -42.719 -29.5 * 6 -46.420 -42.4 * 7 -15.3 * fifteen 21 -11.4 * 8 -39.8 *22 -49.6 * 9 -7.223 -8.2 * 10 -17.8 *Diltiazole -14 I
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    同族专利:
    公开号 | 公开日
    FI871087A0|1987-03-12|
    HUT43832A|1987-12-28|
    PL264629A1|1988-07-21|
    PL153727B1|1991-05-31|
    PT84479B|1990-08-31|
    JPH0819113B2|1996-02-28|
    FI871087A|1987-09-15|
    PT84479A|1987-04-01|
    CA1337655C|1995-11-28|
    ES2039234T3|1993-09-16|
    NO871044D0|1987-03-13|
    JPS62265271A|1987-11-18|
    HU206091B|1992-08-28|
    PH27052A|1993-02-01|
    EP0237347B1|1991-06-12|
    IE60114B1|1994-06-01|
    KR870008856A|1987-10-21|
    DK131887A|1987-09-15|
    IL81800D0|1987-10-20|
    KR900005014B1|1990-07-16|
    DE3770661D1|1991-07-18|
    NO871044L|1987-09-15|
    IE870633L|1987-09-14|
    DK169031B1|1994-08-01|
    FI96683C|1996-08-12|
    EP0237347A2|1987-09-16|
    EP0237347A3|1988-11-02|
    FI96683B|1996-04-30|
    GR3002715T3|1993-01-25|
    DK131887D0|1987-03-13|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US83976786A| true| 1986-03-14|1986-03-14|
    US91734986A| true| 1986-10-09|1986-10-09|
    US07/008,037|US4855301A|1986-10-09|1987-02-09|1,2,3,4-Tetrahydro-6-substituted-4-aryl-3-carbonyl)-2-thioxo -5-pyrimidinecarboxylic acids and esters|
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