2-anilino-1,6-dihydro-6-oxo-5-pyrimidine-carboxylic acid derivatives, process for the preparation thereof, and antiallergic agent containing the same

The present invention relates to novel 2-anilino-1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acid derivatives, processes for the preparation thereof, and an antiallergic agent containing the same. More particularly, it relates to novel pyrimidinecarboxylic acid derivatives of the formula: ##STR2## wherein R.sup.1 and R.sup.2 are the same or different and are each hydrogen, an alkoxy, a tetrahydrofurylalkoxy, an alkyl, an alkoxycarbonyl, a halogen, a dialkylamino, hydroxy, trifluoromethyl, or nitro, and R.sup.3 is hydrogen or an alkyl. The present invention includes also any possible tautomers of the above compounds (I).
In the present specification, the term "alkoxy" denotes a straight or branched chain alkoxy having 1 to 7 carbon atoms, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, pentyloxy, hexyloxy, and heptyloxy. The "tetrahydrofurylalkoxy" denotes a (2,3,4,5-tetrahydrofuran-2-yl)alkoxy having 1 to 4 carbon atoms in the alkoxy moiety, such as (2,3,4,5-tetrahydrofuran-2-yl)methoxy. The "alkyl" denotes a straight or branched chain alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, n-butyl, sec-butyl, or tert.-butyl. The "alkoxycarbony" denotes an alkoxycarbonyl having 2 to 5 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, or butoxycarbonyl. The "halogen" denotes fluorine, chlorine, bromine, or iodine. The "dialkylamino" denotes a dialkylamino having 1 to 4 carbon atoms in each alkyl moiety, such as dimethylamino, or diethylamino.
The compounds of the present invention are novel and have excellent antiallergic activities, and are useful as an antiallergic agent. Particularly, the present compouds show sustained antiallergic activities for a long period of time, and hence, are useful for prophylaxis and treatment of allergic asthma.
Barth in U.S. Pat. Nos. 3,883,653, 3,917,835, 3,957,784, and 3,968,213 discloses various 5-carboxypyrimidine derivatives of the formula: ##STR3## wherein Ar is substituted or unsubstituted aryls (e.g. phenyl unsubstituted or substituted by methyl, methoxy, hydroxy, nitro, halogen, alkanoylamino, or di- or trialkoxyamino, or furyl), m is 0 or 1, or a dimer thereof, and mentions that these compounds have antiallergic activities and are useful particularly for allergic asthma. However, these known compounds are different from the compounds of the present invention in the point that the pyrimidine ring is bound to the aryl (e.g. phenyl) group directly or via methylene group instead of via imino group as in the present invention.
Juby et al. in U.S. Pat. No. 4,031,093 and in J. of Med. Chem., 1979, Vol. 22, No. 3, pages 263-269 disclose 1,6-dihydro-6-oxo-2-(ortho-substituted phenyl)pyrimidine-5-carboxylic acid derivatives of the formula: ##STR4## wherein Z.sup.a, Z.sup.b and Z.sup.c are each hydrogen or various substituents such as alkoxy, halogen, amino, substituted amino, alkoxycarbonyl, etc., and mention that these compounds have antiallergic activities and are useful as an antiallergic agent, but these compounds are different from the compounds of the present invention in the point that the pyrimidine ring is bound to the benzene ring directly instead of binding via imino group as in the present invention.
The following aminopyrimidine derivatives are disclosed in British Patent No. 1,189,188: ##STR5## wherein X is nitrogen atom in which case R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 may be the same or different represent hydrogen, halogen, trifluoromethyl, cyano, alkyl, mercapto, alkylthio, alkylsulphonyl, hydroxy, nitro, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl, amino, alkylamino, optionally substituted phenylamino, acrylamino, etc.; or x is CH group in which case R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above except that one of R.sup.1, R.sup.2 and R.sup.3 must represent amino, alkylamino, optionally substituted phenylamino or acylamino and if one of R.sup.1, R.sup.2 and R.sup.3 represents an amino group in the 4 position of the pyrimidine ring the remaining two of R.sup.1, R.sup.2 and R.sup.3 may be the same or different and may be any of the radicals or atoms defined above except H and methyl; R.sup.6 represents hydrogen or acyl, and this literature discloses that these compounds have antiphlogistic activity. The above general formula is too broadly defined but includes none of the compounds of the present invention. Besides, the pharmacological activity of this literature is different from the antiallergic activities of the present compounds.
Japanese Patent First Publication No. 30177/1979 discloses benzoic acid derivatives of the formula: ##STR6## wherein A is .dbd.C-- or .dbd.N--, R.sub.1 is (a) hydrogen, lower alkyl, lower alkoxy, condensed benzene ring, or (b) --CO-R.sub.4 at 4(or 5)-position, tetrazol-5-yl or cyano, R.sub.2 is --CO-R.sub.4, tetrazol-5-yl, cyano, or when R.sub.1 is the group as defined in (b), R.sub.2 may be further hydrogen, lower alkyl, lower alkoxy or condensed benzene ring, R.sub.3 is hydrogen or lower acyl, and R.sub.4 is hydroxy, amino, hydroxyamino, tetrazol-5-ylamino, or lower alkoxy, and this literature discloses that these compounds have anti-allergic activities and are useful as an anti-allergic agent for the prophylaxis and treatment of allergic diseases, such as asthma, etc. The compounds in this literature are different from the present compounds in the pyrimidine nucleus.
The compounds (I) of the present invention can be prepared by various processes, for example, by the process as shown in the following Reaction Scheme-I. ##STR7## wherein R.sup.1 and R.sup.2 are as defined above, R.sup.3 is an alkyl, and Me means methyl group.
That is, alkyl 2-(substituted or unsubstituted anilino)-1,6-dihydro-6-oxo-5-pyrimidinecarboxylates of the formula (Ia) are prepared by reacting alkyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate of the formula (III) which is disclosed by C. W. Todd et al. (cf. Journal of the American Chemical Society, 65, 350, 1943) with an aniline derivative of the formula (II). The reaction is easily carried out in a solvent or in the absence of a solvent. The used solvent is not specified unless it participates in the reaction. Suitable examples of the solvent are alcohols (e.g. methanol, ethanol, propanol, butanol, ethylene glycol, or ethylene glycol monomethyl ether), ethers (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether), pyridine, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), water, or a mixture of the above organic solvent and water. The reaction temperature is in the range of 50.degree. to 200.degree. C., preferably at a reflux temperature of the solvent. The reaction time is usually in the range of 1 to 72 hours. The amount ratio of the compound (II) to the compound (III) is selected from a wide range; the former is usually used in an amount of 1 to 5 moles, preferably 1 to 1.3 mole, to 1 mole of the latter. In case of using no solvent, the mixture of the compound (II) and the compound (III) is heated at a temperature of 80.degree. to 200.degree. C. for 30 minutes to 20 hours, preferably at a temperature of 100.degree. to 150.degree. C. for several hours, by which the desired compound (Ia) can be obtained in a high yield.
The compound (Ia) thus obtained is hydrolyzed with an alkali in a usual manner to give 2-anilino-1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acid derivative (Ib).
The compound (Ib) thus obtained can be changed into a pharmaceutically acceptable salt thereof, for example, by treating it with an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide), an alkali metal carbonate (e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate), or an organic amine (e.g. triethanolamine, trishydroxymethylaminomethane, lysine) to give an alkali metal or organic amine salt thereof.
Alternatively, the compounds (I) of the present invention can be prepared by a process as shown in the following Reaction Scheme-II. ##STR8## wherein R.sup.1 and R.sup.2 are as defined above, and X is an alkoxy or a dialkylamino, and R.sup.3 is an alkyl.
In the above reaction, the N-phenylguanidine derivative of the formula (IV) prepared by the reaction of an aniline derivative with cyanamide (as is disclosed in John L. Hughes et al., Journal of Medicinal Chemistry, 18, 1077, 1975) is reacted with the alkoxymethylenemalonic acid diester or dialkylaminomethylenemalonic acid diester of the formula (V) (cf. Arthur A. Santilli et al., Journal of Medicinal Chemistry, 7, 68, 1964). The reaction is carried out by heating the reactants in an inert solvent. The solvent is not specified, but suitable examples thereof are alcohols (e.g. ethanol, propanol, butanol, ethylene glycol), ethers (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether), aromatic hydrocarbons (e.g. benzene, toluene, xylene), pyridine, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or the like. The reaction temperature is usually in the range of 80.degree. to 200.degree. C. and the reaction time is usually in the range of 30 minutes to 48 hours. The reaction is advantageously carried out at a reflux temperature of the solvent for several hours.
Besides, when the above reaction is carried out in the presence of a base in a mixed solvent of water and an organic solvent, the reaction proceeds rapidly and can give the desired compounds (I) in a high yield. Suitable examples of the organic solvent to be used in a mixture with water are ethanol, dioxane, tetrahydrofuran or ethylene glycol monomethyl ether, which are used in an appropriate mixed ratio with water, usually in a mixed ratio of equivalent amount or several times larger amount. Suitable examples of the base are potassium carbonate, sodium carbonate, which are used in an amount of 1 to 2 moles to 1 mole of the compound (IV). In the above reaction, the compound (IV) is preferably used in an excess amount, for example, about 1.2 mole to 1 mole of the compound (V). The compound (I) (R.sup.3 is an alkyl) thus obtained is optionally hydrolyzed like in Reaction Scheme-I.
The compounds of the present invention, as is disclosed hereinafter, have extremely low toxicity in a toxicity test in mice and have excellent pharmacological activities, i.e. excellent activity in passive cutaneous anaphylaxis (PCA) reaction and also remarkable anti-slow reacting substance of anaphylaxis (SRS-A) action in Magnus method using guinea pig smooth muscle. Accordingly, the compounds of the present invention are useful for the prophylaxis and treatment of asthma, e.g. allergic asthma. Moreover, the compounds are also useful for the prophylaxis and treatment of allergic dermatitis, allergic rhinitis and allergic conjunctivitis.
The compounds of the present invention are administered orally or parenterally in a daily dose of 5 to 2,000 mg, preferably 10 to 500 mg, in adult.
The compounds of the present invention are usually prepared in conventional preparations suitable for oral or parenteral administration, for example, solid preparations such as tablets, capsules, granules, fine granules, or powders, or liquid preparations such as suspensions, solutions, or emulsions. For the oral solid preparations, the compounds of the present invention are admixed with conventional pharmaceutically acceptable carriers or diluents, such as lactose, starches, crystalline cellulose, magnesium stearate, talc, or the like, and the mixture is formed into the desired preparation forms in a usual manner. For parenteral administration, the compounds of the present invention are prepared in the form of an injection by dissolving them in distilled water, wherein glucose, sodium chloride, etc. are usually incorporated in order to make it isotonic. For solution preparation including injection, a solubilizer (e.g. tween 80 and propylene glycol) may optionally be incorporated.
In the preparations, the compounds of the present invention are usually contained in an amount of 1.5 to 700 mg, preferably 3 to 170 mg, per a dosage unit.
The present invention is illustrated by the following Examples and Preparations, but should not be construed to be limited thereto.

EXAMPLE 1
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (5 g) and 2-methoxyaniline (3.4 g) are added to DMF (20 ml), and the mixture is refluxed with stirring for 8 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(2-methoxyanilino)-6-oxo-5-pyrimidinecarboxylate (5 g). M.p. 217.degree.-219.degree. C.
Elemental analysis for C.sub.14 H.sub.15 N.sub.3 O.sub.4 : Calcd. (%): C, 58.12; H, 5.23; N, 14.53. . Found (%): C, 58.17; H, 5.20; N, 14.52.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2700-3300 (NH), 1720 (C.dbd.O), 1660 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.24 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 3.86 (3H, s, OCH.sub.3), 4.17 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 7.04 (3H, m, Ar--H), 8.16 (1H, d, J-8 Hz, Ar--H), 8.42 (1H, s, C.sub.4 --H), 8.40-9.00 (1H, b, NH), 10.00-12.50 (1H, b, NH).
Mass m/e: 289 (M.sup.+).
EXAMPLE 2
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (8 g) and 2-ethoxyaniline (6.1 g) are added to ethanol (60 ml), and the mixture is refluxed with stirring for 48 hours. After cooling, the precipitate is collected by filtration, washed with ethanol and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-(2-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (7.5 g). M.p. 220.degree.-221.degree. C.
Elemental analysis for C.sub.15 H.sub.17 N.sub.3 O.sub.4 : Calcd. (%): C, 59.39; H, 5.65; N, 13.86. Found (%): C, 59.61; H, 5.56; N, 13.98.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 3000-3300 (NH), 1720 (C.dbd.O), 1600 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.30 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 1.36 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 4.20 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 4.23 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 6.90-7.24 (3H, m, Ar--H), 8.28 (1H, d, J-8 Hz, Ar--H), 8.52 (1H, s, C.sub.4 --H), 7.00-11.00 (1H, b, 2.times.NH).
Mass m/e: 303 (M.sup.+).
EXAMPLE 3
A mixture of ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (4.2 g) and 2-propoxyaniline (3.5 g) is heated with stirring without a solvent at 120.degree. C. for 1 hour. After cooling, methanol is added to the reaction mixture in order to pulverize the solid, and then the product is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-(2-propoxyanilino)-6-oxo-5-pyrimidinecarboxylate (4.5 g). M.p. 198.degree.-200.degree. C.
Elemental analysis for C.sub.16 H.sub.19 N.sub.3 O.sub.4 : Calcd. (%): C, 60.56; H, 6.03; N, 13.24. Found (%): C, 60.73; H, 6.12; N, 13.40.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 3000-3300 (NH), 1720 (C.dbd.O), 1600 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.00 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.2 CH.sub.3), 1.28 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 1.80 (2H, m, OCH.sub.2 CH.sub.2 CH.sub.3), 4.10 (2H, t, J=7 Hz, OCH.sub.2 CH.sub.2 CH.sub.3), 4.24 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 6.88-7.24 (3H, m, Ar--H), 8.23 (1H, d, J=8 Hz, Ar--H), 8.52 (1H, s, C.sub.4 --H), 7.80-14.00 (2H, b, 2.times.NH).
Mass m/e: 317 (M.sup.+).
EXAMPLE 4
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (15 g) and 2-(1-methylethoxy)aniline (11.5 g) are added to ethanol (100 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-[2-(1-methylethoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (8.5 g). M.p. 205.degree.-207.degree. C.
Elemental analysis for C.sub.16 H.sub.19 N.sub.3 O.sub.4 : Calcd. (%): C, 60.56; H, 6.03; N, 13.24. Found (%): C, 60.73; H, 6.12; N, 13.40.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 3000-3300 (NH), 1720 (C.dbd.O), 1600 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.34 (6H, d, J=7 Hz, OCH(CH.sub.3).sub.2), 1.30 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 4.26 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 4.73 (1H, m, OCH(CH.sub.3).sub.2), 6.86-7.30 (3H, m, Ar--H), 8.32 (1H, d, J-8 Hz, Ar--H), 8.53 (1H, s, C.sub.4 --H), 8.20-12.30 (2H, b, 2.times.NH).
Mass m/e: 317 (M.sup.+).
EXAMPLE 5
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (21.5 g) and 2-butoxyaniline (24 g) are added to pyridine (50 ml), and the mixture is refluxed with stirring for 18 hours. The reaction mixture is concentrated to dryness. The residue is recrystallized from DMF to give ethyl 1,6-dihydro-2-(2-butoxyanilino)-6-oxo-5-pyrimidinecarboxylate (20 g). M.p. 209.degree.-211.degree. C.
Elemental analysis for C.sub.17 H.sub.21 N.sub.3 O.sub.4 : Calcd. (%): C, 61.62; H, 6.39; N, 12.68. Found (%): C, 61.80; H, 6.31; N, 12.71.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2600-3200 (NH), 1720 (C.dbd.O), 1600 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 0.94 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 1.27 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 1.44 (2H, m, OCH.sub.2 CH.sub.2 CHH.sub.2 CH.sub.3), 1.72 (2H, m, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 4.12 (2H, t, J=7 Hz, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 4.29 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 6.90-7.36 (3H, m, Ar--H), 8.16 (1H, d, J-8 Hz, Ar--H), 8.50 (1H, s, C.sub.4 --H), 6.80-11.50 (2H, b, 2.times.NH).
Mass m/e: 331 (M.sup.+).
EXAMPLE 6
A mixture of ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (50 g) and 2-(2-methylpropoxy)aniline (45 g) is heated with stirring at 120.degree. C. for 2 hours. After cooling, ethanol (300 ml) is added to the reaction mixture and the solid is pulverized, and then the product is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (57 g). M.p. 188.degree.-190.degree. C.
Elemental analysis for C.sub.17 H.sub.21 N.sub.3 O.sub.4 : Calcd. (%): C, 61.62; H, 6.39; N, 12.68. Found (%): C, 61.51; H, 6.32; N, 12.81.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 3000-3300 (NH), 1720 (C.dbd.O), 1600 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.02 (6H, d, J=7 Hz, OCH.sub.2 CH(CH.sub.3).sub.2), 1.26 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 2.10 (1H, m, OCH.sub.2 CH(CH.sub.3).sub.2), 3.81 (2H, d, J=7 Hz, OCH.sub.2 CH(CH.sub.3).sub.2), 4.17 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 6.80-7.20 (3H, m, Ar--H), 8.07 (1H, d, J=8 Hz, Ar--H), 8.40 (1H, s, C.sub.4 --H), 8.46 (1H, b, NH), 11.86 (1H, b, NH).
Mass m/e: 331 (M.sup.+).
EXAMPLE 7
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (10 g) and 3-methoxyaniline (8.5 g) are added to ethanol (150 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(3-methoxyanilino)-6-oxo-5-pyrimidinecarboxylate (4.3 g). M.p. 233.degree.-234.degree. C.
Elemental analysis for C.sub.14 H.sub.15 N.sub.3 O.sub.4 : Calcd. (%): C, 58.12; H, 5.23; N, 14.53. Found (%): C, 58.33; H, 5.13; N, 14.42.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2500-3200 (NH), 1690 (C.dbd.O), 1640 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.28 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 3.80 (3H, s, OCH.sub.3), 4.32 (2H, q, J=7 Hz, Ar--H), 7.30 (1H, s, Ar--H), 7.40 (2H, m, Ar--H), 8.63 (1H, s, C.sub.4 --H), 3.40-12.30 (2H, b, 2.times.NH).
EXAMPLE 8
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (10 g) and 4-ethoxyaniline (14.3 g) are added to ethanol (150 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(4-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (10 g). M.p. 263.degree.-265.degree. C.
Elemental analysis for C.sub.15 H.sub.17 N.sub.3 O.sub.4 : Calcd. (%): C, 59.39; H, 5.65; N, 13.86. Found (%): C, 59.02; H, 5.52; N, 13.88.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2500-3320 (NH), 1715 (C.dbd.O), 1645 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.27 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 1.34 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 4.07 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 4.24 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 6.95 (2H, d, J=8 Hz, Ar--H), 7.48 (2H, d, J=8 Hz, Ar--H), 8.47 (1H, s, C.sub.4 --H), 7.40-12.00 (2H, b, 2.times.NH).
Mass m/e: 303 (M.sup.+).
EXAMPLE 9
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (10 g) and 2,5-dimethoxyaniline (8.6 g) are added to ethanol (200 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-(2,5-dimethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (8.8 g). M.p. 221.degree.-223.degree. C.
Elemental analysis for C.sub.15 H.sub.17 N.sub.3 O.sub.5 : Calcd. (%): C, 56.42; H, 5.63; N, 13.16. Found (%): C, 56.21; H, 5.21; N, 13.05.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2600-3200 (NH), 1720 (C.dbd.O), 1605 (C.dbd.O). NMR (DMSO-d.sub.6) .delta.: 1.27 (3H, t, J=8 Hz, OCH.sub.2 CH.sub.3), 3.73 (3H, s, OCH.sub.3), 3.84 (3H, s, OCH.sub.3), 4.22 (2H, q, J=8 Hz, OCH.sub.2 CH.sub.3), 6.66 (1H, dd, J.sub.1 =8 Hz, J.sub.2 =4 Hz, Ar--H), 7.00 (1H, d, J=8 Hz, Ar--H), 8.48(1H, s, C.sub.4 --H), 7.00-11.86 (2H, b, 2.times.NH).
Mass m/e: 319 (M.sup.+).
In the same manne as described in Example 9, corresponding aniline derivatives are reacted with ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate to give the compounds of Examples 10 to 32. The compounds thus obtained and analytical data thereof are shown in Table 1.
TABLE 1__________________________________________________________________________Compounds ##STR9## R.sup.1 R.sup.2 IR NMREx. (binding (binding M.p. .nu. .sub.max.sup.nujol cm.sup.-1 Mass m/e (DMSO-d.sub.6)No. position) position) (.degree.C.) (c = 0) (M.sup.+) .delta.(C.sub.4H)__________________________________________________________________________10 H O(CH.sub.2).sub.4 CH.sub.3 170-172 1600, 1720 345 8.40 (2-position)11 H O(CH.sub.2).sub.2 CH(CH.sub.3).sub.2 178-180 1605, 1715 345 8.47 (2-position)12 H O(CH.sub.2).sub.5 CH.sub.3 168-170 1600, 1720 359 8.48 (2-position)13 H O(CH.sub.2).sub.6 CH.sub.3 150-152 1600, 1715 373 8.48 (2-position)14 H ##STR10## 165-167 1600, 1715 359 8.4615 H O(CH.sub.2).sub.2 CH.sub.3 184-186 1640, 1700 317 8.43 (3-position)16 H O(CH.sub.2).sub.3 CH.sub.3 181-183 1650, 1695 331 8.43 (3-position)17 H O(CH.sub.2).sub.4 CH.sub.3 183-185 1645, 1695 345 8.45 (3-position)18 H O(CH.sub.2).sub.2 CH.sub.3 258-260 1645, 1715 317 8.47 (4-position)19 H OCH(CH.sub.3).sub.2 248-250 1640, 1680 317 8.47 (4-position)20 H O(CH.sub.2).sub.3 CH.sub.3 238-240 1640, 1680 331 8.45 (4-position)21 H OCH.sub.2 CH(CH.sub.3).sub.2 251-253 1640, 1680 331 8.45 (4-position)22 H O(CH.sub.2).sub.4 CH.sub.3 242-244 1640, 1690 345 8.46 (4-position)23 H O(CH.sub.2).sub.2 CH(CH.sub.3).sub.2 231-232 1640, 1680 345 8.48 (4-position)24 H O(CH.sub.2).sub.5 CH.sub.3 229-231 1640, 1680 359 8.48 (4-position)25 OCH.sub.2 CH.sub.3 OCH.sub.2 CH.sub.3 227-229 1600, 1720 347 8.59 (2-position) (5-position)26 O(CH.sub.2).sub.2 CH.sub.3 O(CH.sub.2).sub.2 CH.sub.3 180-182 1610, 1720 375 8.08 (2-position) (5-position)27 O(CH.sub.2).sub.3 CH.sub.3 O(CH.sub.2).sub.3 CH.sub.3 160-162 1610, 1720 403 8.55 (2-position) (5-position)28 OCH(CH.sub.3).sub.2 OCH(CH.sub.3).sub.2 208-210 1615, 1720 375 8.55 (2-position) (5-position)29 OCH.sub.2 CH(CH.sub.3).sub.2 OCH.sub.2 CH(CH.sub.3).sub.2 166-168 1615, 1720 403 8.53 (2-position) (5-position)30 OCH.sub.2 CH.sub.3 OCH.sub.2 CH.sub.3 220-222 1615, 1720 347 8.53 (3-position) (4-position)31 O(CH.sub.2).sub.2 CH.sub.3 O(CH.sub.2).sub.2 CH.sub.3 145-147 1625, 1720 375 8.52 (3-position) (4-position)32 O(CH.sub.2).sub.3 CH.sub.3 O(CH.sub.2).sub.3 CH.sub.3 145-147 1620, 1720 403 8.56 (3-position) (4-position)__________________________________________________________________________
EXAMPLE 33
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5pyrimidinecarboxylate (10 g) and 2,5-dimethylaniline (8.5 g) are added to ethanol (150 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-6-oxo-2-(2,5-dimethylanilino)-5-pyrimidinecarboxylate (6.1 g). M.p. 252.degree.-254.degree. C.
Elemental analysis for C.sub.15 H.sub.17 N.sub.3 O.sub.3 : Calcd. (%): C, 62.70; H, 5.96; N, 14.63. Found (%): C, 62.49; H, 5.99; N, 14.71.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2500-3200 (NH), 1690 (C.dbd.O), 1640 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.25 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3),2.20 (3H, s, CH.sub.3), 2.30 (3H, s, CH.sub.3), 4.23 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 7.00 (1H, d, J=8 Hz, Ar--H), 7.12 (1H, d, J=8 Hz, Ar--H), 7.40 (1H, s, Ar--H), 8.40 (1H, s, C.sub.4 --H), 8.50-11.60 (2H, b, 2.times.NH).
Mass m/e: 287 (M.sup.+).
EXAMPLE 34
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (50 g) and 3-aminobenzotrifluoride (45.2 g) are added to ethanol (300 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylate (34.4 g). M.p. 229.degree.-230.degree. C.
Elemental analysis for C.sub.14 H.sub.12 N.sub.3 O.sub.3 F.sub.3 : Calcd. (%): C, 51.38; H, 3.67; N, 12.84. Found (%): C, 51.52; H, 3.76; N, 12.67.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2500-3400 (NH), 1720 (C.dbd.O), 1605 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.30 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 4.26 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 7.40-8.20 (4H, m, Ar--H), 8.60 (1H, s, C.sub.4 --H), 9.00-12.50 (2H, b, 2.times.NH).
Mass m/e: 327 (M.sup.+).
EXAMPLE 35
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (20 g) and 4-(N,N-dimethylamino)aniline (19 g) are added to ethanol (200 ml), and the mixture is refluxed with stirring for 19 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-[4-(N,N-dimethylamino)anilino]-6-oxo-5-pyrimidinecarboxylate (15.7 g).
M.p. 246.degree.-248.degree. C.
Elemental analysis for C.sub.15 H.sub.18 N.sub.4 O.sub.3 : Calcd. (%): C, 59.59; H, 6.00; N, 18.53. Found (%): C, 59.46; H, 5.96; N, 18.69.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2400-3300 (NH), 1730 (C.dbd.O), 1640 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.25 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 2.88 (6H, s, N(CH.sub.3).sub.2), 4.22 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 6.74 (2H, d, J=8 Hz, Ar--H), 7.46 (2H, d, J=8 Hz, Ar--H), 8.45 (1H, s, C.sub.4 --H), 8.40-11.60 (2H, b, 2.times.NH).
Mass m/e: 302 (M.sup.+).
EXAMPLE 36
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (40 g) and 2-aminophenol (22.4 g) are added to DMF (80 ml), and the mixture is heated with stirring at 110.degree. C. for 18 hour. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(2-hydroxyanilino)-6-oxo-5-pyrimidinecarboxylate (29 g). M.p. 289.degree.-291.degree. C.
Elemental analysis for C.sub.13 H.sub.13 N.sub.3 O.sub.4 : Calcd. (%): C, 56.72; H, 4.76; N, 15.27. Found (%): C, 56.60; H, 4.74; N, 15.40.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2300-3400 (NH, OH), 1685 (C.dbd.O), 1650 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.26 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 4.24 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 6.80-7.10 (3H, m, Ar--H), 8.10 (1H, d, J=8 Hz, Ar--H), 8.50 (1H, s, C.sub.4 --H), 7.00-14.00 (3H, b, 2.times.NH, OH).
Mass m/e: 275 (M.sup.+).
EXAMPLE 37
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (20 g) and 2-fluoroaniline (15.6 g) are added to ethanol (200 ml), and the mixture is refluxed with stirring for 24 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(2-fluoroanilino)-6-oxo-5-pyrimidinecarboxylate (4.5 g). M.p. 250.degree.-252.degree. C.
Elemental analysis for C.sub.13 H.sub.12 N.sub.3 O.sub.3 F: Calcd. (%): C, 56.12; H, 4.33; N, 15.16. Found (%): C, 55.96; H, 4.28; N, 15.30.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2500-3300 (NH), 1695 (C.dbd.O), 1620 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.24 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 4.23 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 7.12-7.50 (3H, m, Ar--H), 8.50 (1H, s, C.sub.4 --H), 8.00-11.00 (2H, b, 2.times.NH).
Mass m/e: 277 (M.sup.+).
EXAMPLE 38
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (10 g) and butyl -4-aminobenzoate (10.8 g) are added to ethanol (100 ml), and the mixture is refluxed with stirring for 48 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-(4-butoxycarbonylanilino)-6-oxo-5-pyrimidinecarboxylate (7.0 g). M.p. 281.degree.-283.degree. C.
Elemental analysis for C.sub.18 H.sub.21 N.sub.3 O.sub.5 : Calcd. (%): C, 60.16; H, 5.89; N, 11.69. Found (%): C, 59.81; H, 5.87; N, 11.46.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2500-3300 (NH), 1725 (C.dbd.O), 1715 (C.dbd.O), 1650 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 0.98 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 1.31 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 1.50 (2H, m, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 1.70 (2H, m, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 4.31 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 4.33 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3) , 7.80-8.20 (4H, m, Ar--H), 8.64 (1H, s, C.sub.4 --H), 8.40-11.60 (2H, b, 2.times.NH).
Mass m/e: 359 (M.sup.+).
EXAMPLE 39
A mixture of ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyimidinecarboxylate (10 g) and 3-nitroaniline (7.7 g) is heated with stirring without solvent at 120.degree. C. for 1 hour. After cooling, methanol (50 ml) is added to the reaction mixture to pulverize solid. The resulting product is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(3-nitroanilino)-6-oxo-5-pyrimidinecarboxylate (8.5 g). M.p. 226.degree.-228.degree. C.
Elemental analysis for C.sub.13 H.sub.12 N.sub.4 O.sub.5 : Calcd. (%): C, 51.32; H, 3.95; N, 18.42. Found (%): C, 51.15; H, 3.92; N, 18.30.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2400-3340 (NH), 1730 (C.dbd.O), 1600 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.32 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 4.30 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 7.58 (1H, t, J=7 Hz, Ar--H), 7.80-8.12 (2H, m, Ar--H), 8.55 (1H, s, C.sub.4 --H), 8.60 (1H, m, Ar--H), 1.40-9.00 (2H, b, 2.times.NH).
Mass m/e: 304 (M.sup.+).
In the same manner as described in Examples 38 and 39, corresponding aniline derivatives are reacted with ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate to give the compounds of Examples 40 to 46. The compounds thus obtained and analytical data thereof are shown in Table 2.
TABLE 2______________________________________Compounds ##STR11## R.sup.1 (bind- ing R.sup.2 IR Mass NMREx. posi- (binding M.p. .nu. .sub.max.sup.nujol cm.sup.-1 m/e (DMSO-d.sub.6)No. tion) position) (.degree.C.) (c = 0) (M.sup.+ ) .delta.(C.sub.4H)______________________________________40 H (CH.sub.2).sub.3 CH.sub.3 248- 1640, 1690 315 8.47 (4-position) 25141 H CH.sub.2 CH.sub.3 265- 1650, 1685 287 8.44 (4-position) 26742 H F 290- 1640, 1690 277 8.64 (3-position) 29343 H F 300 1640, 1690 277 8.64 (4-position)44 H Br 300 1640, 1695 337 8.64 (2-position)45 H Cl 270- 1650, 1725 293 8.60 (3-position) 27246 H COOEt 221- 1675, 1715, 331 8.60 (3-position) 223 1730______________________________________
EXAMPLE 47
Ethyl 1,6-dihydro-2-(2-methoxyanilino)-6-oxo-5-pyrimidinecarboxylate (10 g) and sodium hydroxide (4 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the precipitate is collected by filtration and recrystallized from DMF to give 1,6-dihydro-2-(2-methoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (7 g). M.p. 251.degree.-253.degree. C.
Elemental analysis for C.sub.12 H.sub.11 N.sub.3 O.sub.4 : Calcd. (%): C, 55.17; H, 4.24; N, 16.09. Found (%): C, 55.20; H, 4.53; N, 16.03.
IR .nu..sub.max.sup.nujol cm.sup.-1 2200-3400 (NH, OH), 1720 (C.dbd.O), 1660 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 3.94 (3H, s, OCH.sub.3), 6.92-7.32 (3H, m, Ar--H), 8.16 (1H, d, J=8 Hz, Ar--H), 8.58 (1H, s, C.sub.4 --H), 8.00-13.80 (3H, b, 2.times.NH, OH).
Mass m/e: 261 (M.sup.+).
EXAMPLE 48
Ethyl 1,6-dihydro-2-(2-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (3.4 g) and sodium hydroxide (1 g) are added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate thus obtained is added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80.degree. C. under reduced pressure to give 1,6-dihydro-2-(2-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (2 g). M.p. 226.degree.-228.degree. C.
Elemental analysis for C.sub.13 H.sub.13 N.sub.3 O.sub.4 : Calcd. (%): C, 56.72; H, 4.76; N, 15.72. Found (%): C, 56.68; H, 4.66; N, 15.30.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2400-3300 (NH, OH), 1720 (C.dbd.O), 1630 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.38 (3H, t, J=7 L Hz, OCH.sub.2 CH.sub.3), 4.16 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 6.88-7.40 (3H, m, Ar--H), 8.15 (1H, d, J=8 Hz, Ar--H), 8.56 (1H, s, C.sub.4 --H), 8.40-14.00 (3H, b, 2.times.NH, OH).
Mass m/e: 275 (M.sup.+).
EXAMPLE 49
Ethyl 1,6-dihydro-2-(2-propoxyanilino)-6-oxo-5-pyrimidinecarboxylate (8 g) and sodium hydroxide (3 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the product is collected by filtration and dried at 80.degree. C. under reduced pressure to give 1,6-dihydro-2-(2-propoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (4.5 g). M.p. 202.degree.-204.degree. C.
Elemental analysis for C.sub.14 H.sub.15 N.sub.3 O.sub.4 : Calcd. (%): C, 58.13; H, 5.23; N, 14.53. Found (%): C, 58.04; H, 5.16; N, 14.42.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2200-3200 (NH, OH), 1720 (C.dbd.O), 1640 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.00 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.2 CH.sub.3), 1.32 (2H, m, OCH.sub.2 CHCH.sub.2 CH.sub.3), 4.07 (2H, t, J=7 Hz, OCH.sub.2 CH.sub.2 CH.sub.3), 6.90-7.34 (3H, m, Ar--H), 8.14 (1H, d, J=8 Hz, Ar--H), 8.59 (1H, s, C.sub.4 --H), 6.80-13.00 (3H, b, 2.times.NH, OH).
Mass m/e: 289 (M.sup.+).
EXAMPLE 50
Ethyl 1,6-dihydro-2-[2-(1-methylethoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (7.5 g) and sodium hydroxide (3 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (80 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80.degree. C. under reduced pressure to give 1,6-dihydro-2-[b 2-(1-methylethoxy)anilino]-6-oxo-5-pyrimidinecarboxylic acid (6.7 g). M.p. 202.degree.-204.degree. C.
Elemental analysis for C.sub.14 H.sub.15 N.sub.3 O.sub.4 : Calcd. (%): C, 58.13; H, 5.23; N, 14.53. Found (%): C, 57.96; H, 5.24; N, 14.34.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2400-3300 (NH, OH),1725 (C.dbd.O), 1650 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.30 (6H, d, J=7 Hz, OCH(CH.sub.3).sub.2), 4.86 (1H, m, OCH(CH.sub.3).sub.2), 6.88-7.28 (3H, m, Ar--H), 8.20 (1H, d, J=8 Hz, Ar--H), 8.60 (1H, s, C.sub.4 --H), 4.00-12.00 (3H, b, 2.times.NH, OH).
Mass m/e: 289 (M.sup.+).
EXAMPLE 51
Ethyl 1,6-dihydro-2-(2-butoxyanilino)-6-oxo-5-pyrimidinecarboxylate (12 g) and sodium hydroxide (3 g) are added to water (150 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate thus obtained is collected by filtration and added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80.degree. C. under reduced pressure to give 1,6-dihydro-2-(2-butoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (8 g). M.p. 212.degree.-214.degree. C.
Elemental analysis for C.sub.15 H.sub.17 N.sub.3 O.sub.4 : Calcd. (%): C, 59.39; H, 5.65; N, 13.86. Found (%): C, 59.25; H, 5.84; N, 14.00.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2400-3300 (NH, OH), 1720 (C.dbd.O), 1630 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 0.92 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 1.44 (2H, m, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 1.73 (2H, m, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 4.10 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 6.88-7.36 (3H, m, Ar--H), 8.59 (1H, s, C.sub.5 --H), 6.80-12.00 (3H, b, 2.times.NH, OH).
Mass m/e: 303 (M.sup.+).
EXAMPLE 52
Ethyl 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (7.5 g) and sodium hydroxide (3 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80.degree. C. under reduced pressure to give 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylic acid (4.3 g). M.p. 213.degree.-215.degree. C.
Elemental analysis for C.sub.15 H.sub.17 N.sub.3 O.sub.4 : Calcd. (%): C, 59.39; H, 5.65; N, 13.86. Found (%): C, 58.99; H, 5.68; N, 13.48.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2400-3200 (NH, OH), 1720 (C.dbd.O), 1630 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 0.98 (6H, d, J=7 Hz, OCH.sub.2 CH(CH.sub.3).sub.2), 2.09 (1H, m, OCH.sub.2 CH(CH.sub.3).sub.2), 3.86 (2H, d, J=7 Hz, OCH.sub.2 CH(CH.sub.3).sub.2), 6.88-7.32 (3H, m, Ar--H), 8.01 (1H, d, J=8 Hz, Ar--H), 8.59 (1H, s, C.sub.4 --H), 6.60-12.00 (3H, b, 2.times.NH, OH).
Mass m/e: 303 (M.sup.+).
EXAMPLE 53
Ethyl 1,6-dihydro-2-(3-methoxyanilino)-6-oxo-5-pyrimidinecarboxylate (3 g) and sodium hydroxide (1 g) are added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (60 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80.degree. C. under reduced pressure to give 1,6-dihydro-2-(3-methoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (1.8 g). M.p. 247.degree.-249.degree. C.
Elemental analysis for C.sub.12 H.sub.11 N.sub.3 O.sub.4 : Calcd. (%): C, 55.17; H, 4.24; N, 16.09. Found (%): C, 54.84; H, 4.09; N, 15.79.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2400-3200 (NH, OH), 1670 (C.dbd.O), 1630 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 3.84 (3H, s, OCH.sub.3), 6.80 (1H, dd, J.sub.1 =8 Hz, J.sub.2 =4 Hz, Ar--H), 7.06-7.48 (3H, m, Ar--H), 8.56 (1H, s, C.sub.4 --H), 3.60-10.20 (3H, b, 2.times.NH, OH).
Mass m/e: 261 (M.sup.+).
EXAMPLE 54
Ethyl 1,6-dihydro-2-(4-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (10 g) and sodium hydroxide (3 g) are added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80.degree. C. under reduced pressure to give 1,6-dihydro-2-(4-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (5 g). M.p. 250.degree.-252.degree. C.
Elemental analysis for C.sub.13 H.sub.13 N.sub.3 O.sub.4 : Calcd. (%): C, 56.72; H, 4.76; N, 15.27. Found (%): C, 56.82; H, 4.63; N, 15.17.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2400-3200 (NH, OH), 1700 (C.dbd.O), 1660 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.32 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 4.04 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 6.94 (2H, d, J=8 Hz, Ar--H), 7.42 (2H, d, J=8 Hz, Ar--H), 8.40 (1H, s, C.sub.4 --H), 3.60-11.40 (3H, b, 2.times.NH, OH).
Mass m/e: 275 (M.sup.+).
EXAMPLE 55
Ethyl 1,6-dihydro-2-(2,5-dimethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (6 g) and sodium hydroxide (2 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80.degree. C. under reduced pressure to give 1,6-dihydro-2-(2,5-dimethoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (3.7 g). M.p. 260.degree.-262.degree. C.
Elemental analysis for C.sub.13 H.sub.13 N.sub.3 O.sub.5 : Calcd. (%): C, 53.61; H, 4.50; N, 14.43. Found (%): C, 53.61; H, 4.41; N, 14.21.
IR.sub.max.sup.nujol cm.sup.-1 : 2400-3300 (NH, OH), 1715 (C.dbd.O), 1630 (C.dbd.O).
NMR (DMSO-d.sub.6): 3.76 (3H, 3, OCH.sub.3), 3.88 (3H, 3, OCH.sub.3), 6.72 (1H, dd, J.sub.1 =8 Hz, J.sub.2 =4 Hz, Ar--H), 7.04 (1H, d, J=8 Hz, Ar--H), 7.94 (1H, d, J=4 Hz, Ar--H), 8.60 (1H, s, C.sub.4 --H), 5.00-11.00 (3H, b, 2.times.NH, OH).
Mass m/e: 291 (M.sup.+).
EXAMPLE 56
Ethyl 1,6-dihydro-2-(3,4-diethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (5 g) and sodium hydroxide (2 g) are added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (40 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80.degree. C. under reduced pressure to give 1,6-dihydro-2-(3,4-diethoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (3 g). M.p. 243.degree.-245.degree. C.
Elemental analysis for C.sub.15 H.sub.17 N.sub.3 O.sub.5 : Calcd. (%): C, 56.42; H, 5.37; N, 13.16. Found (%): C, 56.66; H, 5.36; N, 13.15.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2400-3400 (NH, OH), 1720 (C.dbd.O), 1660 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.36 (6H, t=7 Hz, OCH.sub.2 CH.sub.3), 4.08 (4H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 6.96-7.20 (3H, m, Ar--H), 8.56 (1H, s, C.sub.4 --H), 5.00-11.80 (3H, b, 2.times.NH, OH).
Mass m/e: 319 (M.sup.+).
EXAMPLE 57
Ethyl 1,6-dihydro-2-(2,5-dimethylanilino)-6-oxo-5-pyrimidinecarboxylate (10 g) and sodium hydroxide (4 g) are added to water (200 ml), and the mixture is refluxed with stirring for 2 hours. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80.degree. C. under reduced pressure to give 1,6-dihydro-2-(2,5-dimethylanilino)-6-oxo-5-pyrimidinecarboxylic acid (7 g). M.p. 242.degree.-244.degree. C.
Elemental analysis for C.sub.13 H.sub.13 N.sub.3 O.sub.3 : Calcd. (%): C, 59.76; H, 5.79; N, 16.08. Found (%): C, 59.88; H, 5.68; N, 16.30.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2400-3300 (NH, OH), 1715 (C.dbd.O), 1630 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 2.22 (3H, s, CH.sub.3), 2.31 (3H, s, CH.sub.3), 7.05 (1H, d, J=8 Hz, Ar--H), 7.22 (1H, d, J=8 Hz, Ar--H), 8.52 (1H, s, C.sub.4 --H), 9.40-11.20 (3H, b, 2.times.NH, OH).
Mass m/e: 259 (M.sup.+).
EXAMPLE 58
Ethyl 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylate (34.4 g) and sodium hydroxide (10 g) are added to water (300 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (300 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80.degree. C. under reduced pressure to give 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylic acid (21.5 g). M.p. 252.degree.-254.degree. C.
Elemental analysis for C.sub.12 H.sub.8 N.sub.3 O.sub.3 F.sub.3 : Calcd. (%): C, 48.16; H, 2.68; N, 14.05. Found (%): C, 48.15; H, 2.86; N, 14.28.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2200-3400 (NH, OH), 1725 (C.dbd.O), 1650 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 7.40-8.00 (3H, m, Ar--H), 8.12 (1H, s, Ar--H), 8.58 (1H, s, C.sub.4 --H), 6.00-12.00 (3H, b, 2.times.NH, OH).
Mass m/e: 299 (M.sup.+).
EXAMPLE 59
Ethyl 1,6-dihydro-2-[4-(N,N-dimethylamino)anilino]-6-oxo-5-pyrimidinecarboxylate (7.5 g) and sodium hydroxide (3.0 g) are added to water (150 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80.degree. C. under reduced pressure to give 1,6-dihydro-2-[4-(N,N-dimethylamino)anilino]-6-oxo-5-pyrimidinecarboxylic acid (5 g). M.p. 261.degree.-263.degree. C.
Elemental analysis for C.sub.13 H.sub.14 N.sub.4 O.sub.3 : Calcd. (%): C, 56.93; H, 5.13; N, 20.43. Found (%): C, 57.20; H, 5.17; N, 20.68.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2400-3300 (NH, OH), 1710 (C.dbd.O), 1620 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 2.96 (6H, s, N(CH.sub.3).sub.2), 6.84 (2H, d, J=8 Hz, Ar--H), 7.40 (2H, d, J=8 Hz, Ar--H), 8.52 (1H, s, C.sub.4 --H), 4.40-12.00 (3H, b, 2.times.NH, OH).
Mass m/e: 274 (M.sup.+).
EXAMPLE 60
Ethyl 1,6-dihydro-2-(2-hydroxyanilino)-6-oxo-5-pyrimidinecarboxylate (5 g) and sodium hydroxide (2 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80.degree. C. under reduced pressure to give 1,6-dihydro-2-(2-hydroxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (3 g). M.p. 254.degree.-256.degree. C.
Elemental analysis for C.sub.11 H.sub.9 N.sub.3 O.sub.4 : Calcd. (%): C, 53.44; H, 3.69; N, 17.00. Found (%): C, 53.52; H, 3.55; N, 17.00.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2200-3400 (NH, OH), 1720 (C.dbd.O), 1650 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 6.70-7.16 (3H, m, Ar--H), 8.02 (1H, d, J=7 Hz, Ar--H), 8.53 (1H, s, C.sub.4 --H), 8.60-10.00 (3H, b, 2.times.NH, OH).
Mass m/e: 247 (M.sup.+).
EXAMPLE 61
Ethyl 1,6-dihydro-2-(2-fluoroanilino)-6-oxo-5-pyrimidinecarboxylate (5 g) and sodium hydroxide (2 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic aicd, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (70 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80.degree. C. under reduced pressure to give 1,6-dihydro-2-(2-fluoroanilino)-6-oxo-5-pyrimidinecarboxylic acid (3.1 g). M.p. 300.degree. C.
Elemental analysis for C.sub.11 H.sub.18 N.sub.3 O.sub.3 F: Calcd. (%): C, 53.10; H, 3.21; N, 16.87. Found (%): C, 52.87; H, 3.31; N, 16.68.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2400-3300 (NH, OH), 1680 (C.dbd.O), 1620 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 7.04-7.44 (3H, m, Ar--H), 7.96-8.20 (1H, m, Ar--H), 8.61 (1H, s, C.sub.4 --H), 9.00-10.08 (3H, b, 2.times.NH, OH).
Mass m/e: 249 (M.sup.+).
In the same manner as described in Example 61, ethyl 1,6-dihydro-2-anilino-6-oxo-5-pyrimidinecarboxylate derivatives are hydrolyzed with an alkali to give the corresponding compounds of Examples 62 to 88. The compounds thus obtained and analytical data thereof are shown in Table 3.
TABLE 3__________________________________________________________________________Compounds ##STR12## R.sup.1 R.sup.2 IR NMREx. (binding (binding M.p. .nu. .sub.max.sup.nujol cm.sup.-1 Mass m/e (DMSO-d.sub.6)No. position) position) (.degree.C.) (c = 0) (M.sup.+) .delta.(C.sub.4H)__________________________________________________________________________62 H O(CH.sub.2).sub.4 CH.sub.3 198-200 1630, 1720 317 8.54 (2-position)63 H O(CH.sub.2).sub.2 CH(CH.sub.3).sub.2 215-216 1650, 1710 317 8.59 (2-position)64 H O(CH.sub.2).sub.5 CH.sub.3 186-188 1640, 1720 331 8.59 (2-position)65 H O(CH.sub.2).sub.6 CH.sub.3 167-169 1600, 1715 345 8.54 (2-position)66 H O(CH.sub.2).sub.2 CH.sub.3 186-188 1660, 1720 286 8.50 (3-position)67 H O(CH.sub.2).sub.3 CH.sub.3 183-185 1660, 1705 303 8.50 (3-position)68 H O(CH.sub.2).sub.4 CH.sub.3 169-170 1660, 1705 317 8.52 (3-position)69 H O(CH.sub.2).sub.2 CH.sub.3 249-250 1630, 1700 289 8.52 (4-position)70 H OCH(CH.sub.3).sub.2 248-250 1660, 1700 289 8.48 (4-position)71 H O(CH.sub.2).sub.3 CH.sub.3 246-248 1660, 1705 303 8.48 (4-position)72 H OCH.sub.2 CH(CH.sub.3).sub.2 248-250 1660, 1700 303 8.47 (4-position)73 H O(CH.sub.2).sub.4 CH.sub.3 243-245 1670, 1705 317 8.47 (4-position)74 H O(CH.sub.2).sub.2 CH(CH.sub.3).sub.2 240-242 1660, 1705 317 8.48 (4-position)75 H O(CH.sub.2).sub.5 CH.sub.3 228-230 1670, 1705 331 8.48 (4-position)76 OCH.sub.2 CH.sub.3 OCH.sub.2 CH.sub.3 251-253 1620, 1700 319 8.63 (2-position) (5-position)77 O(CH.sub.2).sub.2 CH.sub.3 O(CH.sub.2).sub.2 CH.sub.3 228-230 1630, 1715 347 8.64 (2-position) (5-position)78 OCH(CH.sub.3).sub.2 OCH(CH.sub.3).sub.2 206-208 1640, 1720 347 8.64 (2-position) (5-position)79 O(CH.sub.2).sub.3 CH.sub.3 O(CH.sub.2).sub.3 CH.sub.3 180-182 1620, 1710 375 8.58 (2-position) (5-position)80 OCH.sub.2 CH(CH.sub.3).sub.2 OCH.sub.2 CH(CH.sub.3).sub.2 206-208 1620, 1700 375 8.64 (2-position) (5-position)81 O(CH.sub.2).sub.2 CH.sub.3 O(CH.sub.2).sub.2 CH.sub.3 229-231 1670, 1720 347 8.59 (3-position) (4-position)82 O(CH.sub.2).sub.3 CH.sub.3 O(CH.sub.2).sub.3 CH.sub.3 226-228 1650, 1700 375 8.54 (3-position) (4-position)83 H (CH.sub.2).sub.3 CH.sub.3 212-214 1640, 1680 287 8.52 (4-position)84 H CH.sub.2 CH.sub.3 248-250 1630, 1720 259 8.48 (4-position)85 CH.sub.3 CH.sub.3 249-251 1630, 1720 259 8.48 (2-position) (3-position)86 H F 270-272 1640, 1680 249 8.54 (3-position)87 H Br 247-248 1640, 1680 309 8.62 (4-position)88 H ##STR13## 220-222 1640, 1725 331 8.48__________________________________________________________________________
EXAMPLE 89
A mixture of ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (5 g) and aniline (2.6 g) is heated without solvent at 130.degree. C. for 1 hour. After cooling, the resulting solid is pulverized and recrystallized from DMSO to give ethyl 2-anilino-1,6-dihydro-6-oxo-5-pyrimidinecarboxylate (3.7 g). M.p. 267.degree.-269.degree. C.
Elemental analysis for C.sub.13 H.sub.13 N.sub.3 O.sub.3 : Calcd. (%): C, 60.23; H, 5.05; N, 16.21. Found (%): C, 59.99; H, 5.09; N, 15.89.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2400-3350 (NH), 1710 (C.dbd.O), 1660 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.28 (3H, t, J=8 Hz, OCH.sub.2 CH.sub.3), 4.26 (2H, q, J=8 Hz, OCH.sub.2 CH.sub.3), 7.00-7.74 (5H, m, Ar--H), 8.10 (2H, b, 2.times.NH) 8.48 (1H, s, C.sub.4 --H).
EXAMPLE 90
Sodium hydrogen carbonate (0.82 g) is dissolved in water (50 ml), and thereto is added 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylic acid (3 g), and the mixture is heated. After foaming is finished, ethanol is added to the reaction mixture, and the solution is allowed to stand overnight. The precipitate is collected by filtration and recrystallized from a mixture of methanol and water to give sodium 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylate (2.4 g). M.p. 256.degree.-259.degree. C.
Elemental analysis for C.sub.12 H.sub.7 N.sub.3 O.sub.3 F.sub.3 Na.H.sub.2 O: Calcd. (%): C, 42.48; H, 2.65; N, 12.39. Found (%): C, 42.43; H, 2.68; N, 12.22.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2800-3400 (NH), 1680 (C.dbd.O), 1610 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 3.50 (1H, b, NH), 7.21 (1H, d, J=8 Hz, Ar--H), 7.50 (1H, t, J=8 Hz, Ar--H), 8.05 (1H, d, J=8 Hz, Ar--H), 8.34 (1H, s, Ar--H), 8.52 (1H, s, C.sub.4 --H), 9.51 (1H, bs, NH).
EXAMPLE 91
A mixture of 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylic acid (20 g) and sodium carbonate (7.0 g) in ethanol (100 ml) and water (100 ml) is heated until the solution is completed. After allowing to stand the solution overnight, the precipitate is collected by filtration, washed with water and dried to give sodium 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (12.4 g). M.p. 231.degree.-233.degree. C.
Elemental analysis for C.sub.15 H.sub.16 N.sub.3 O.sub.4 Na: Calcd. (%): C, 55.38; H, 4.96; N, 12.92. Found (%): C, 55.14; H, 4.93; N, 12.77.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2400-3400 (NH), 1665 (C.dbd.O), 1625 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.04 (6H, d, J=7 Hz, OCH.sub.2 CH(CH.sub.3).sub.2), 2.16 (1H, m, OCH.sub.2 CH(CH.sub.3).sub.2), 3.84 (2H, d, J=7 Hz, OCH.sub.2 CH(CH.sub.3).sub.2), 6.94 (3H, m, Ar--H), 7.59 (1H, b, NH), 8.44 (1H, s, C.sub.4 --H), 8.50 (1H, m, Ar--H), 12.20-12.80 (1H, b, NH). Mass m/e: 327 (M.sup.+).
EXAMPLE 92
To a solution of N-(2-propoxyphenyl)guanidine (9.1 g) in dioxane (30 ml) is added dropwise diethyl ethoxymethylenemalonate (10.2 g), and the mixture is refluxed with stirring for 5 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-6-oxo-2-(2-propoxyanilino)-5-pyrimidinecarboxylate (11.7 g). M.p. 198.degree.-200.degree. C.
Elemental analysis for C.sub.16 H.sub.19 N.sub.3 O.sub.4 : Calcd. (%): C, 60.56; H, 6.03; N, 13.29. Found (%): C, 60.81; H, 5.97; N, 13.48.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 3000-3300 (NH), 1720 (C.dbd.O), 1600 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.00 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.2 CH.sub.3), 1.28 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 1.80 (2H, m, OCH.sub.2 CH.sub.2 CH.sub.3), 4.10 (2H, t, J=7 Hz, OCH.sub.2 CH.sub.2 CH.sub.3), 4.25 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 6.80-7.30 (3H, m, Ar--H), 8.23 (1H, d, J=8 Hz, Ar--H), 8.52 (1H, s, C.sub.4 --H), 7.90-14.00 (2H, b, 2.times.NH).
Mass m/e: 317 (M.sup.+).
EXAMPLE 93
A mixture of N-(2-butoxyphenyl)guanidine (11.6 g) and diethyl ethoxymethylenemalonate (12.1 g) in DMF (70 ml) is heated at 100.degree. C. for 9 hours. After cooling, water (50 ml) is added to the reaction mixture, and the precipitate is collected by filtration, washed with ethanol and recrystallized from a mixture of DMF and water to give ethyl 2-(2-butoxyanilino)-1,6-dihydro-6-oxo-5-pyrimidinecarboxylate (16.1 g). M.p. 211.degree.-213.degree. C.
Elemental analysis for C.sub.17 H.sub.21 N.sub.3 O.sub.4 : Calcd. (%): C, 61.62; H, 6.39; N, 12.68. Found (%): C, 61.39; H, 6.45; N, 12.73.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2600-3200 (NH), 1720 (C.dbd.O), 1600 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 0.94 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 1.27 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 1.46 (2H, m, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 1.72 (2H, m, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 4.12 (2H, t, J=7 Hz, OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 4.30 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 6.90-7.40 (3H, m, Ar--H), 8.16 (1H, d, J=8 Hz, Ar--H), 8.50 (1H, s, C.sub.4 --H), 6.80-11.70 (2H, b, 2.times.NH).
Mass m/e: 331 (M.sup.+).
EXAMPLE 94
Diethyl morpholinomethylenemalonate (20.0 g) is added to a solution of N-[2-(2-methylpropoxy)phenyl]guanidine (16.1 g) and potassium carbonate (21.5 g) in ethanol (40 ml) and water (40 ml), and the mixture is heated with stirring at 60.degree. C. for 3 hours. After the reaction is completed, water (100 ml) is added to the reaction mixture with stirring under water-cooling, and the mixture is acidified to pH 3 with 10% aqueous HCl. The resulting precipitate is collected by filtration and dissolved in chloroform (300 ml). The chloroform layer is washed with water twice, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue is recrystallized from DMF to give ethyl 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (16.0 g). M.p. 175.degree.-177.degree. C.
Elemental analysis for C.sub.17 H.sub.21 N.sub.3 O.sub.4 : Calcd. (%): C, 61.62; H, 6.39; N, 12.68. Found (%): C, 61.96; H, 6.35; N, 12.44.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2600-3300 (NH), 1730 (C.dbd.O), 1620 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.03 (6H, d, J=7 Hz, OCH.sub.2 CH(CH.sub.3).sub.2), 1.28 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 2.10 (1H, m, OCH.sub.2 CH(CH.sub.3).sub.2), 3.81 (2H, d, J=7 Hz, OCH.sub.2 CH(CH.sub.3).sub.2), 4.18 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 6.80-7.22 (3H, m, Ar--H), 8.10 (1H, d, J=8 Hz, Ar--H), 8.40 (1H, s, C.sub.4 --H), 8.50-12.50 (2H, b, 2.times.NH).
Mass m/e: 331 (M.sup.+).
This product has polymorphic forms as is shown in the following example, and hence, even though they are the same substance, they are somewhat different in some physical properties such as the melting point, IR spectrum or the like.
EXAMPLE 95
To a solution of N-[2-(2-methylpropoxy)phenyl]guanidine (89 g) in denatured alcohol (300 ml) is added dropwise diethyl ethoxymethylenemalonate (93 g), and the mixture is refluxed with stirring for 3 hours. After cooling, the precipitate is collected by filtration, washed with denatured alcohol and petroleum ether and dried to give ethyl 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (94 g). M.p. 188.degree.-190.degree. C.
Elemental analysis for C.sub.17 H.sub.21 N.sub.3 O.sub.4 : Calcd. (%): C, 61.62; H, 6.39; N, 12.68. Found (%): C, 61.45; H, 6.33; N, 12.70.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2600-3240 (NH), 1705 (C.dbd.O), 1650 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.05 (6H, d, J=7 Hz, OCH.sub.2 CH(CH.sub.3).sub.2), 2.10 (1H, m, OCH.sub.2 CH(CH.sub.3).sub.2), 3.81 (2H, d, J=7 Hz, OCH.sub.2 CH(CH.sub.3).sub.2), 4.18 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 6.81-7.25 (3H, m, Ar--H), 8.10 (1H, d, J=8 Hz, Ar--H), 8.42 (1H, s, C.sub.4 --H), 8.50-12.50 (2H, b, 2.times.NH).
Mass m/e: 331 (M.sup.+).
EXAMPLE 96
A mixture of N-(3-trifluoromethylphenyl)guanidine (10 g), diethyl N,N-diethylaminomalonate (11.8 g) and potassium carbonate (13.4 g) in water (100 ml) and ethanol (100 ml) is refluxed with stirring for 7 hours. After cooling, the mixture is acidified to pH 3 with 10% aqueous HCl. The precipitate is collected by filtration, washed with water and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylate (13.4 g). M.p. 229.degree.-231.degree. C.
Elemental analysis for C.sub.14 H.sub.12 N.sub.3 O.sub.3 F.sub.3 : Calcd. (%): C, 51.38; H, 3.67; N, 12.84. Found (%): C, 51.22; H, 3.83; N, 12.97.
IR .nu..sub.max.sup.nujol cm.sup.-1 : 2500-3400 (NH), 1720 (C.dbd.O), 1605 (C.dbd.O).
NMR (DMSO-d.sub.6) .delta.: 1.30 (3H, t, J=7 Hz, OCH.sub.2 CH.sub.3), 4.26 (2H, q, J=7 Hz, OCH.sub.2 CH.sub.3), 7.40-8.20 (4H, m, Ar--H), 8.60 (1H, s, C.sub.4 --H), 9.00-12.50 (2H, b, 2.times.NH).
Mass m/e: 327 (M.sup.+).
EXAMPLES 97 TO 103
In the same manner as described in Example 92, the corresponding N-substituted phenylguanidine and diethyl ethoxymethylenemalonate are reacted to give the compounds as shown in Table 4.
TABLE 4__________________________________________________________________________Compounds ##STR14## IR NMREx. M.p. .nu. .sub.max.sup.nujol cm.sup.-1 Mass m/e (DMSO-d.sub.6)No. R.sup.1 R.sup.2 (.degree.C.) (c = 0) (M.sup.+) .delta.(C.sub.4H)__________________________________________________________________________ 97 H 2-CH.sub.3 O 217-219 1660, 1720 289 8.42 98 H 2-(CH.sub.3).sub.2 CHO 206-208 1600, 1720 317 8.54 99 H 4-CH.sub.3 CH.sub.2 265-267 1650, 1680 287 8.43100 H 3-Cl 270-272 1650, 1720 293 8.59101 H 4-(CH.sub.3).sub.2 N 246-248 1640, 1730 302 8.45102 2-CH.sub.3 5-CH.sub.3 252-254 1640, 1690 287 8.40103 2-CH.sub.3 O 5-CH.sub.3 O 221-223 1605, 1720 319 8.48__________________________________________________________________________
______________________________________Preparation 1______________________________________1,6-Dihydro-2-[2-(2-methylpropoxy)anilino]- 50 mg6-oxo-5-pyrmidinecarboxylic acidLactose 190 mgCrystalline cellulose 50 mgMagnesium stearate 10 mg______________________________________
A mixture of the above components is tabletted in a usual manner to give tablets containing the active ingredient of 50 mg per each tablet.
______________________________________Preparation 2______________________________________1,6-Dihydro-2-(2-propoxyanilino)-6-oxo- 25 mg5-pyrmidinecarboxylic acidMagnesium stearate 5 mgLactose 135 mgPotato starch 50 mgTalc 35 mg______________________________________
A mixture of the above components is granulated in a usual manner to give granules containing 10% of the active ingredient.
Preparation 3
The granules obtained in Preparation 2 are packed into 1# hard capsules to give capsules containing the active ingredient of 25 mg per each capsule.
______________________________________Preparation 4______________________________________Sodium 1,6-dihydro-6-oxo-2-(3-trifluoromethyl- 25 mganilino)-5-pyrmidinecarboxylateSolubilizer (if necessary) q.s.Sodium chloride (if necessary) q.s.Distilled water for injection 1 mlTotally 1 ml______________________________________
The active ingredient, solubilizer and sodium chloride are dissolved in the distilled water, and the solution is entered into an ampoule, which is sterilized to give an injection ampoule.
______________________________________Preparation 5______________________________________Sodium 1,6-dihydro-2-[2-(2-methylpropoxy)- 50 mganilino]-6-oxo-5-pyrmidinecarboxylateLactose 190 mgCrystalline cellulose 50 mgMagnesium stearate 10 mg______________________________________
A mixture of the above components is tabletted in a usual manner to give tablets containing the active ingredient of 50 mg per each tablet.
______________________________________Preparation 6______________________________________Sodium 1,6-dihydro-2-[2-(2-methylpropoxy)- 5 mganilino]-6-oxo-5-pyrmidinecarboxylateSolubilizer (if necessary) q.s.Sodium chloride (if necessary) q.s.Distilled water for injection 1 mlTotally 1 ml______________________________________
The active ingredient, solubilizer and sodium chloride are dissolved in the distilled water, and the solution is entered into an ampoule, which is sterilized to give an injection ampoule.
Pharmacological Test
[1] PCA response in rats:
Wistar male rats weighing 190-220 g were used. A diluted anti-dinitrophenyl-Ascalis (DNP-As) rat serum (each 0.1 ml) was intracutaneously injected into the back of the animals, by which the animals were passively sensitized. After 48 hours, Evans blue liquid (1.0 ml) containing DNP-As (20 mg, as a protein) was intravenously injected to the animals to induce PCA.
After 30 minutes, rats were killed, and the skin at the response region was peeled off, and the amount of color was measured spectrophotometrically. Test compounds were administered 30 minutes (in case of intraperitoneal injection) or one hour (in case of oral administration) before the challenge with the antigen.
The 50% inhibiting dose (ED.sub.50) of representative compounds in the rat PCA is shown in Table 5. The data of the references: disodium chromoglycate (SDCG) and Tranilast are also shown therein.
TABLE 5______________________________________Compound ##STR15##Ex. No. of ED.sub.50 (mg/kg)compound R i.p. p.o.______________________________________48 CH.sub.2 CH.sub.3 20.2 98.049 CH.sub.2 CH.sub.2 CH.sub.3 11.0 22.250 CH(CH.sub.3).sub.2 13.0 7551 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 10.7 9252 CH.sub.2 CH(CH.sub.3).sub.2 4.7 39DSCG 3.3 >200Tranilast 40 110______________________________________
[2] Anti-SRS-A action:
The anti-SRS-A activity of the compounds of the present invention was measured by Magnus method using the isolated guinea pig ileum. An extracted ileum of guinea pig was hung within a Magnus vessel which was maintained at 31.+-.1.degree. C. and then pre-treated with mepiramine to remove any effect by histamine. Test compound was administered in a dose of 3.times.10.sup.-5 to 10.sup.-3 M, and after 3 minutes, a previously prepared crude SRS-A was acted thereto, and then, the shrink rate (%) of the ileum was measured. The results as to the representative compounds are shown in Table 6. The data as to the references: DSCG and Tranilast are also shown in the table.
TABLE 6______________________________________Compound ##STR16## Concen- Inhibi- 50% in- tration of tion hibitionEx. No. of test compd. rate concentra-compound R (M) (%) tion (M)______________________________________49 CH.sub.2 CH.sub.2 CH.sub.3 10.sup.-4 8.1 4.87 .times. 10.sup.-4 3 .times. 10.sup.-4 17.9 10.sup.-3 97.352 CH.sub.2 CH(CH.sub.3).sub.2 3 .times. 10.sup.-5 12.2 1.54 .times. 10.sup.-4 10.sup.-4 26.2 3 .times. 10.sup.-4 87.9Tranilast 10.sup.-4 23.5 >10.sup.-3 3 .times. 10.sup.-4 32.4 10.sup.-3 48.2DSCG 10.sup.-3 6 >10.sup.-3______________________________________
Toxicity Test
The test compound was suspended in 0.5% carboxymethylcellulose solution, and the suspension was intraperitoneally administered to ddY male mice (weighing 20-25 g, one group: 10 mice). Based on the total mortality during 7 days after the administration of the test compound, the 50% lethal dose (LD.sub.50) was calculated by Litchfield-Wilcoxon method. The results of the representative compounds are shown in Table 7. The data of reference (Tranilast) are also shown therein.
TABLE 7______________________________________Compound ##STR17##Ex. No. of LD.sub.50 (mg/kg)compound R i.p. p.o.______________________________________48 CH.sub.2 CH.sub.3 >500 >300049 CH.sub.2 CH.sub.2 CH.sub.3 1160 >300051 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 1230 >300052 CH.sub.2 CH(CH.sub.3).sub.2 780 >3000Tranilast 430 780______________________________________

Number	Name	Date
3883653	Barth	May 1975
3917835	Barth	Dec 1975
3957784	Barth	May 1976
3968213	Barth	Jul 1976
4031093	Juby	Jun 1977

Number	Date	Country
30177	Jun 1979	JPX
376115	May 1964	CHX
859716	Jan 1961	GBX
1189188	Apr 1970	GBX

2-anilino-1,6-dihydro-6-oxo-5-pyrimidine-carboxylic acid derivatives, process for the preparation thereof, and antiallergic agent containing the same

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Juby, et al., Journal of Medicinal Chemistry, 22, 1979, pp. 263-269.
Chemical Abstracts, 54, 11038e (1960) Shirakawa and Zasshi.