POLYAZAHETEROCYCLIC DERIVATIVES, PROCESS FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITION

Abstract: Polyazaheterocyclic derivatives represented by the general formula (1), pharmaceutically acceptable salts there­ of process for their preparation, and pharmaceuticol com­ positions containing them. In the general formula, R repre­ sents hydrogen, lower alkyl, cycloalkyl, furyl, thienyl, pyridyl, or phenyl optionally having one to two substituents of halogen, lower alkyl, trifluoromethyl, alkoxy, aralkyloxy, alkylthio, aralkylthio, acyl, hydroxy, amino, nitro or cyano; R¹ represents hydrogen, cyano, carbamoyl, carboxyl, alkoxycar­ bonyl having optionally one to two substituents of alkoxy, cyano, -N(R a )(R b ) (wherein R a and R b each represent alkyl or aralkyl or, when taken together, represent a 5 to 7-­ membered heterocyclic ring), nitro, phenyl or heteroaryl, or alkanoyl; R² represents lower alkyl, hydroxyalkyl, acetoxyal­ kyl, haloalkyl, dihaloalkyl, trifluoromethyl, alkoxyalkyl, di­ alkoxymethyl, lower alkylcarbamoyloxyalkyl, lower alkyl­ thiocarbamoyloxyalkyl, formyl, hydroxyiminomethyl or cyano; and X, Y, and Z each represents a member of ring A and each represents N or CH. These compounds possess hypotensive, coronary vasodilating, cerebrovasodilating and cardiotonic effects, and an effect of preventing peroxidation of lipid, and are useful as agents for prevention and treatment of circulatory organ diseases.

Description: SPECIFICATION A polyazaheterocycle derivative, a method of preparing said compound and a pharmaceutical composition. Field of the Invention and Disclosure of the Invention The present invention relates to novel and pharmaceutically useful polyazaheterocycle derivatives of the formula: EMI1.1 or pharmaceutically acceptable salts thereof, methods of preparing said compounds and pharmaceutical compositions containing said compounds. In the above formula, each symbol is as defined below: R is a hydrogen atom, a lower alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertbutyl or pentyl), a cycloalkyl group¯(e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), a furyl group, a thienyl group, a pyridyl group, or a phenyl group which may be optionally substituted by one or two substituents selected from the group consisting of a halogen atom (fluorine, chlorine, bromine or iodine), a lower alkyl group (e.g. methyl, ethyl, propyl, isopropyl or butyl), a trifluoromethyl group, an alkoxy group (e.g. methoxy, ethoxy, propoxy or butoxy), an aralkyloxy group (e.g. benzyloxy, phenylethoxy or phenylpropoxy), an alkylthio group (e.g. methylthio,ethylthio, propylthio or butylthio), an aralkylthio group (e.g. benzylthio, phenylethylthio or phenylpropylthio), an acyl group (e.g. acetyl, propionyl, butyryl or benzoyl), a hydroxyl group, an amino group, a nitro group and a cyano group; R1 is a hydrogen atom, a cyano group, a carbamoyl group, a carboxyl group, an alkoxycarbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or tert-butoxycarbonyl) which may be optionally substituted in the alkoxy moiety by one or two substituents selected from the group consisting of an alkoxy group (e.g. methoxy, ethoxy, propoxy or isopropoxy), a cyano group, a group represent by the formula: : -N (Ra1) () [wherein each of Ra and ss is an alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl or tert butyll or an aralkyl group (e.g. benzyl, phenylethyl or phenylpropyl), or Ra and ss together with the adjacent nitrogen atom form a 5- to 7-membered heterocycle (e.g. pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine, N-(2-hydroxyethyl)piperazine, azepine or diazepnnei3, a nitro group, a phenyl group and a heteroaryl group (e.g. thienyl, furyl or pyridyl), or an alkanoyl group (e.g. acetyl, propionyl, butyryl, isobutyryl, valeryl, isovalery, pivaloyl or hexanoyl); ; R2 is a lower alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl), a hydroxyalkyl group (e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxybutyl), an acetoxyalkyl group (e.g. acetoxymethyl, acetoxyethyl, acetoxypropyl or acetoxybutyl), a haloalkyl group (e.g. fluoromethyl, chloromethyl, bromomethyl, iodomethyl, fluoroethyl, chloroethyl, fluoropropyl, chloropropyl, fluorobutyl or chlorobutyl), a dihaloalkyl group (e.g. dizlu oromethyl, dichloromethyl, dibromomethyl, difluoroethyl, dichloroethyl, difluoropropyl, dichloropropyl, difluorobutyl or dichlorobutyl), a trifluoromethyl group, an alkoxyalkyl group (e.g. methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, methoxybutyl or ethoxybutyl), a di-alkoxymethyl group (e.g. dimethoxymethyl, diethoxymethyl, dipropoxymethyl or dibutoxymethyl), a lower alkyl-carbamoyloxyalkyl group (e.g. methylcarbamoyloxymethyl, ethylcarbamoyloxymethyl, propylcarbamoyloxymethyl, butylcarbamoyloxymethyl, methylcarbamoyloxyethyl, ethylcarbamoyloxyethyl, methylcarbamoyloxypropyl, ethyl carbamoyloxypropyl, methylcarbamoyloxybutyl or ethylcarbamoyloxybutyl), a lower alkyl-thiocarbamoyloxyalkyl group (e.g. methylthiocarbamoyloxymethyl, ethylthiocarbamoyloxymethyl, propylthiocarbamoyloxymethyl, butylthiocarbamoyloxymethyl, methylthiocarbamoyloxyethyl, ethylthiocarbamoyloxyethyl, methylthiocarbamoyloxypropyl, ethylthiocarbamoyloxypropyl, methylthiocarbamoyloxybutyl or ethylthiocarbamoyloxybutyl), a formyl group, a hydroxyiminomethyl group or a cyano group; and Each of X, Y and Z is a member of the ring A, represents N or CH and forms tetrazolo-, triazolo-, imidazo- or pyrazoloring. The ring in the formula (I) and in the specification of the present invention represented by the formula: EMI4.1 means a 4,7-dihydrotetrazolo[1,5-a]pyrimidine of the formula (a): EMI4.2 a 4,7-dihydrotriazolo[1,5-a]pyrimidine of the formula (b): EMI4.3 a 5,8-dihydroimidaio[l,2-a]pyrimidine of the formula (c): EMI4.4 a 1,4-dihydroimidazo[l,5-a]pyrimidine of the formula (d): EMI5.1 or a 4,7-dihydropyrazolo[l,5-a]pyrimidine of the formula (e): EMI5.2 The compounds of formula (I) of the present invention can be, for example, prepared by the following methods. (1) A method which comprises subjecting a compound of the formula: EMI5.3 to dehydration condensation at room temperature or under heating in a suitable solvent or without it. (2) A method which comprises subjecting a compound of the formula: EMI5.4 to condensation with a compound of the formula: EMI6.1 at room temperature or under heating in a suitable solvent or without it. (3) A method which comprises subjecting a compound of the formula: EMI6.2 to dehydration condensation with a compound of the formula: R-CHO (VI) at room temperature or under heating in a suitable solvent or without it, if necessary in the presence of a suitable acid catalyst, a base catalyst or both, and then subjecting the compound obtained to condensation with a compound of the formula (IV) at room temperature or under heating in a suitable solvent or without it. (4) A method which comprises reacting a compound of the formula: EMI6.3 with hydrogen gas in the presence of a suitable metal catalyst or a complex metal hydride (e.g. lithium aluminum hydride or sodium borohydride) at room temperature or under heating in a suitable solvent or without it. (5) A method which comprises converting the substituents R, R1 and R2 of the compound obtained by the above-mentioned methods (1)-(4) according to usual manners of organic chemical synthesis. Any inert solvent can be employed as a suitable solvent in the methods (1)-(4), and includes, for example, a lower alkanol (e.g. methanol, ethanol, propanol, isopropanol, butanol, tert-butanol or ethylene glycol), an aromatic hydrocarbon (e.g. benzene, toluene or xylene), an ether (e.g. diethyl ether, diisopropyl ether, dimethoxyethane,diethylene glycol dimethyl ether, tetrahydrofuran or dioxane), a halogenated lower alkane (e.g. dichloromethane, dichloroethane, chloroform or tetrachloromethane), an acid amide (e.g. dimethylformamide, N-methylpyrrolidone or hexamethylphosphoro triamide), a lower alkanecarboxylic acid or an ester thereof (e.g. formic acid, acetic acid, propionic acid, methyl acetate, ethyl acetate, butyl acetate or methyl propionate), a nitrated lower alkane (e.g. nitromethane or nitroethane), dimethylsulfoxide, sulsorane, water, or a mixture thereof. The reactions of the methods (1)-(4) perform at a temperature under 200 C, and preferably at a temperature of from room temperature to 150 C. The usual manners of organic chemical synthesis in the method (5) include, for example, formation of an aldehyde, a ketone, a carboxylic acid or an alcohol by hydrolysis of an acetal, a ketal or an ester in the presence of an acid or a base catalyst; formation of an aldehyde, a ketone, a carboxylic acid or an alcohol by removal of the protective group from the protected aldehyde, ketone, carboxylic acid or alcohol; formation of an oxime from an aldehyde or a ketone; reduction of an aldehyde or a nitro to an alcohol or an amine; formation of a nitrile by dehydration of an oxime or an amide; halogenation of an alkyl; acetoxylation of a haloalkyl; and formation of an urethane from an alcohol and an isocyanate. The compounds of formula (I) having an asymmetric carbon atom can be prepared as a racemate or an optically active isomer. The racemate can be devided into a desired optical isomer by means of a fractional recrystallization of a salt with an optically active acid. The compounds of formula (I) having at least two asymmetric carbon atoms can be prepared as an individual diastereomer or a mixture thereof. The individual diastereomer can be purified by means of fractional recrystallization or chromatography. In the compound (I) having an oxime of the present invention, syn- and anti-stereoisomers can exist. The compounds of the present invention also include the syn- and anti-forms. The compounds of formula (I), optical isomers thereof or diastereomers thereof can, if desired, be converted into acid addition salts thereof with an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid), an organic acid (e.g. acetic acid, propionic acid, glycollic acid, succinic acid,maleic acid, fumaric acid, malic acid, tartaric acid, oxalic acid, citric acid, benzoic acid, cinnamic acid, mandenic acid, salicylic acid, 2-acetoxybenzoic acid, nicotinic acid or isonicotinic acid), an organic sulfonic acid (e.g. methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalene-2-sulfonic acid), ascorbic acid, lysine or glutamic acid. Furthermore, the compounds (I) wherein R is a carboxyl group can also be converted into metal salts thereof (e.g. sodium salt, potassium salt oraluminum salt) or salts with amines (e.g. a salt with triethylamine). Since the compounds of the present invention exhibit antihypertensive, cardiovasodilative, cerebrovasodilative, cardiotonic and lipid peroxidation inhibiting activity as shown in the following pharmacological experiments, they are useful as drugs for the prophylaxis and the treatment of circulatory diseases such as antihypertensive agents, cardiotonics, drugs for the treatment of angina pectoris, heart failure or cardiac infarction, cerebral circulation improvers, prophylactics for the blood vessel, and so on. The following pharmacological experiments explain the effects of the compounds according to the present invention in more detail. The test compounds employed are as follows: Compound A : l-Phenyl-2-piperidinoethyl 7-methyl-5-(3 nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidne 6-carboxylate form of diastereomer) Compound B : l-Phenyl-2-piperidinoethyl 5-methyl-7-(3 nitrophenyl)-4,7-dihydropyrazolof1,5-a]- pyrimidine-6-carboxylate form of diastereomer) Compound C : 6-Ethoxycarbonyl-5-methyl-7- (2-trifluoromethyl- phenyl) -4, 7-dihydropyrazolo [1,5-a] pyrimidine Compound D : 6-Ethoxycarbonyl-5,7-dimethyl-5,8-dihydroimidazo [1,2-a]pyrimidine Pharmacological experiment 1 : Effect on hypertension Each of 30 mg/kg of test compound B was orally administered to five spontaneously hypertensive rats and the blood pressures were measured by tail cuff method. The mean blood pressure lowering value after 1 hour administration was 94 mmHg and that value after 5 hours administration was 47 mmHg. Pharmacological experiment 2 : Effect on coronary blood flow Adult mongrel dogs were anesthetized with sodium pentobarbital (30 mg/kg, i.v.). According to the method of Yago et al described in Folia Pharmacol. Japon, vol 57, 380 (1961), the left coronary artery was perfused and its blood flow was measured. Test compound was injected into the coronary artery at a volume of 10-30 p1. The effects of test compound on coronary blood flow were expressed as ED50 ( g), a dose required to increase the coronary blood flow by a half of the effects of 3 g of nifedipine (dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4dihydropyridine-3,5-dicarboxylate). Each of half-life (T 1/2, minute) was measured as the duration of effects. The results are summarized in the Table 1. Table 1 EMI11.1 <tb> Test <SEP> Compound <SEP> ED50 <SEP> ( g, <SEP> in <SEP> artery) <SEP> T <SEP> 1/2 <SEP> (min.) <tb> <SEP> A <SEP> 10 <SEP> 5 <tb> <SEP> B <SEP> 1.7 <SEP> 1.5 <tb> Pharmacological experiment 3 : Effect on vertebral blood flow Adult mongrel dogs were anesthetized with sodium pentobarbital (25 mg/kg, i.v.). The right vertebral artery was perfused and the blood flow was measured. Test compound was injected in the vertebral artery. The percentage of maximum increase of blood flow by the injection of 100 g of papaverine hydrochloride (l-[(3,4-dimethoxyphenyl)methyl]-6, 7-dimethoxyisoquinoline hydrochloride) in vertebral artery was taken as 100%. The effects of test compound on vertebral artery were expressed as ED100 (g), a dose required to obtain 100% of the increase of blood flow. Each of half-life (T 1/2, minute) was measured as the duration of the effects. The results are summarized in the following Table 2. Table 2 EMI12.1 <tb> Test <SEP> Compound <SEP> ED100 <SEP> (pig, <SEP> in <SEP> artery) <SEP> T <SEP> 1/2 <SEP> (min.) <tb> <SEP> A <SEP> 3.5 <SEP> 0.9 <tb> <SEP> B <SEP> 1.0 <SEP> 3.0 <tb> Pharmacological experiment 4 : Effect on myocardial contractile force The papillary muscle of the rabbit right ventricle was isolated and suspended in Krebs-Henseleit solution (consisting of 117 mM sodium chloride, 4.7 mM potassium chloride, 2.6mM calcium chloride, 1.4 S-r magnesium sulfate, 1.2 mM potassium dihydrogenphosphate, 24.9 mM sodium hydrogencarbonate and 11 mM glucose). The solution was maintained at 350C and equilibrated with oxygen gas containing 5% of carbonic acid gas, and then the preparations were stimulated at frequency of 0.5 Hz. The developed tensions were measured with a force development transducer under a preload of 0.5 g. The results are summarized in the Table 3. Table 3 EMI13.1 <tb> Test <SEP> , <SEP> Number <SEP> of <SEP> Increase <SEP> in <tb> <SEP> Concentration <tb> Compound <SEP> (M) <SEP> animals <SEP> contractile <SEP> force <tb> <SEP> (%) <tb> <SEP> C <SEP> 10-5 <SEP> 4 <SEP> 54.2 <tb> <SEP> 10-4 <SEP> 4 <SEP> 132.5 <tb> <SEP> 10-5 <SEP> 3 <SEP> 21.7 <tb> <SEP> D <SEP> 10 <SEP> 4 <SEP> 86.0 <tb> Pharmacological experiment 5 : Effect on heart rate Adult mongrel dogs were anesthetized with sodium pentobarbital (i.v.). Heart rate was measured from electrocardiogram (lead II). Test compound was injected into the right coronary artery. The results are summarized in the Table 4. Table 4 EMI13.2 <tb> Test <SEP> - <SEP> Increase <SEP> in <tb> <SEP> Dose <SEP> ( g) <tb> Compound <SEP> heart <SEP> rate <SEP> (%) <tb> <SEP> 30 <SEP> -7.1 <SEP> <tb> <SEP> C <tb> <SEP> 100 <SEP> -10.5 <tb> Pharmacological experiment 6 : Effect on lipid peroxidation Male Sprague-Dawley rats weighing 300-350 g were used. According to the method of @@i et al described in Biochim. Biophys. Acta, vol. 572, (1670), the liver mitochnodria were isolated and ascorbic and revrous sulfate, potassium chloride and Tris-HCl buffer were ef. To the solution was added test compound dissolved in dimethylsulfoxide, and the mixture was incubated at 25 C for 30 minutes. The amount of malondialdehyde was determied by the thiobarbituric method. The 50% inhibitory concentration (IC50, mol) of test compound on the formation of malondialdehyde was 6 ijmol. Experiment of acute toxicity: Test compound C was orally or intraperitoneally administered to dry strain mice. All mice survived at the oral dose of 1,000 mg/kg and the intraperitoneal dose of 250 mg/ kg for five days after administration. The compounds of the present invention, when used as drugs, can be administered in the fars of powder, tablets, capsules, granules, injectable solutions, suppositories, ointments or the like by mixing with a suitable carrier, excipient, diluent or the like. The dose for human adults usually ranges from 10 mg to 500 mg, hut it may vary depending upon the age, body weight, and severity of the conditions to-be treated. Formulation Example 1 - Tables 25 mg tablets 50 mg tablets Compound (I) 25.0 mg 50.0 mg Lactose 59.5 67.0 25 mg tablets 50 mg tablets Corn starch 20.0 25.0 Crystalline cellulose 10.0 20.0 Methyl cellulose 1.0 1.5 Talc 4.0 6.0 Magnesium stearate 0.5 0.5 120.0 mg 170.0 mg Formulation Example 2 : 10 % Powder Compound (I) 10.0 E Lactose 59.5 Corn starch 30.0 Talc 0.5 100.0 % The present invention will be explained by the following examples in more detail, but these examples are not to be construed as limiting the present invention: Example 1 To l-phenyl-2-piperidinoethyl a-acetyl-3-nitrocinnamate prepared from 7.5 g of 3-nitrobenzaldehyde and 14.5 g of 1phenyl-2-piperidinoethyl acetoacetate is added a solution of 4.2 g of 3-aminopyrazole in ethanol, and then stirred at 500C for 3 hours. The mixture is concentrated at reduced pressure, and the residue is purified by column chromatography on silica gel with chloroform-ethyl acetate-ethanol eluents to give two forms of diastereomers. The initially eluated solution is concentrated and the residue is recrystallized from ethanol to give one form ( -form) of diastereomer of 1phenyl-2-piperidinoethyl 5-methyl-7-(3-nitrophenyl)-4,7dihydropyrazolo[1,5-a]pyrimidine-5-carboxylate, melting at 92-930C. Then, the subsequently eluated sol ion is con centrated and the residue ¯ recrytallized rom ethanol to give the other (ss-form) of diastereomer of 1-phenyl-2piperidinoethyl 5-methyl-7-(3-nitrophenyl)-4,7-dihydro [pyrazolo[1,5-a]pyrimidine-5-carboxylate, melting at 191-1920C. Example 2 Ethyl &alpha;-acetyl-ss-(3-aminopyrazol-2-yl)-ss-(2-trifluoro- methylphenyl)propionate (34.5 g) is dissolved in 200 ml of chloroform and heated under reflux for 6 hours. After the reaction mixture is washed with water, dried and concentrated, the residue is purified by column chromatography on silica gel with chloroform-methanol eluents to give 24 g of the product. The product is crystallized from isopropylether and further recrystallized from ethanol to give 6 ethoxycarbonyl-5-methyl-7 tr7Lluo-omethylphenyl)-4,7- dihydropyrazolo[1,5-a]pyrimidine, melting at 182-183 C. Ethyl &alpha;-acetyl-ss-(3-aminopyrazol-2-yl)-o 2-trifluoro methylphenylpropionate is synthesize by the following manner. Ethyl &alpha;-acetyl-2-trifluoromethylcinnamate (36 g) and 10.5 g of 3-aminopyrazole are dissolved in 200 ml of ethanol, and the mixture is stirred at rooE temperature for 5 hours. The precipitated white crystals are collected by filtration to give 8.5 g of ethyl a-acetyl-ss-(3-aminopyrazol-2-ly)-ss- (2-trifluoromethylphenyl)propionate, melting at 136-1370C. Example 3 To the crude l-phenyl-2-piperidinoethyl a-acetyl-3 nitrocinamate, which was synthesized by reacting 30 g of 3-nitrobenzaldehyde with 67 g of l-phenyl-2-piperidinoethyl acetoacetate, is added 500 ml of ethanol solution of 2-aminoimidazole prepared from 26.4 g of 2-aminoimidazole sulfate and sodium hydroxide, and then stirred at 500C for 5 hours. After cooling, the precipitated crystals are collected by filtration and recrystallized from ethanol to give 9.7 g of l-phenyl-2-piperidinoethyl 7-methyl-5-(3-nitrophenyl)-5, 8-dihydroimidazo[1,2-agpyrimidine-6-carboxylate, melting at 205-2060C as one diastereomer (a-form). Then, the filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel with chloroform-ethyl acetate-ethanol eluents. The crystals thus obtained are recrystallized from a mixture of chloroform and ethanol to give 4.8 g of l-phenyl-2-piperidinoethyl 7-methyl 5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine-6- carboxylate, melting at 216-217 C with decomposition as the other diastereomer (form). Example 4 To a solution of 10.5 g of 2-aminoimidazole sulfate in 11 ml of water is added a sodium ethoxide solution prepared from 1.7 g of metal sodium and 200 ml of ethanol After the precipitated crystals are filtered off, to the filtrate is added 15.5 g of ethyl a-acetylcrotonate and then stirred at 500C for 3 hours and at 750C for 3 hours. After the ethanol is evaporated at reduced pressure, the residue is extracted by chloroform, washed with water and dried. The solvent is distilled off under reduced pressur to give white crystals. The crystals are recrystallized from ethanol to give 10.2 g of 6-ethOxyCarbonyl-5,7-dimethyl-5,8-dihydroimidazo[1,2-a]- pyrimidine, melting at 185-186.50C, Example 5 To 50 ml of ethanol are added 2.6 g of ethyl 3-nitroa-acetylcinnamate and 0.9 g of 5-aminotetrazole, and then heated under reflux for 16 hours. On cooling, 2 g of 6 ethoxyCarbonyl-5-methyl-7-(3-nitrophenyl)-4,7-dihydro- tetrazolo[1,5-a]pyrimidine, melting at 210-2120C, is obtained. Example 6 To 50 ml of ethanol are added 7.8 g of ethyl a-acetylcrotonate and 4.2 g of 3-amino-1,2,4-triazole, stirred at 500C for an hour and then heated under reflux for an hour. The ethanol is evaporated under reduced pressure, and the obtained crystals are recrystallized from ethyl to give 7 g of 6-ethoxyCarbonyl-5,7-dimethyl-4,7-dihydro-l,Z,4-triazolo- [1,5-a]pyrimidine, melting at l55-1570C. Example 7 A solution of 6.7 g of 6-ethoxycarbonyl-5,7-dimethyl-4, 7-dihydro-l,2,4-triazolo[l,5-a]pyrimidine in 40 ml of acetic acid is heated at 500C. To the reaction mixture is added dropwise a solution of 4.8 g of bromine in 20 ml of acetic acid for 10 minutes, and then the mixture is stirred at 50-60"C for an hour. The resulting mixture is poured into water, extracted with chloroform, washed with water and dried. The chloroform layer is purified by column chromatography on silica gel to give 0.5 g of 5-dibromomethyl-6 ethOxyCarbony'-7-methyl-4,7-dihydro-1,2,4-triazoloil,5-a]- pyrimidine, melting at 170-1710C with decomposition. Example 8 A mixture of 50 g of methyl 2-acetyl-3-(2-thienyl)acrylate, 20 g of 3-amino-1,2,4-triazole and 300 ml of ethanol is heated under reflux for 4 hours. The precipitated white crystals are collected by filtration to give 29.5 g of 6 methOxyCarbonyl-5-methyl-7-(2-thienyl)-4,7-dihydro-1,2,4- triazolo[l,5-alpyrimidine, melting at 239-2400C. Methyl 2-acetyl-3- (2-thienyl) acrylate was synthesized by the following manner. A mixture of 112 g of 2-thiophenecarbaldehyde, 116 g of methyl acetoacetate, 770 ml of benzene, 4 ml of acetic acid and 3 ml of piperidine is heated under reflux for 2.5 hours under the condition of azeotropic dehydration. The benzene is evaporated under reduced pressure and the residual solvent is distilled off to give 199 g of methyl 2-acetyl-3 (2-thienyl)acrylate, boiling at 130-1600C/0.2 mmHg. Example 9 In 300 ml of acetic acid is dissolved 29.5 g of 6 methOxyCarbonyl-5-methyl-7-(2-thienyl)-4,7-dihydro-1,2,4- triazolo[l,5-a]pyrimidine at 600C. To the solution is added dropwise a solution of 16 g of bromine in 50 ml of acetic acid for 20 minutes with stirring. After stirring at room temperature for an hour, the reaction mixture is poured into water, extracted with chloroform, washed with water and potassium carbonate solution, dried and the solvent is evaporated under reduced pressure. The obtained pale yellow crystals are recrystallized from ethanol to give 18 g of 5-bromomethyl-6-methoxycarbonyl-7-(2-thienyl)-4,7-dihydro-1, 2,4-triazolo[l,5-alpyrimidine, melting at 1550C with decomposition. Example 10 A mixture of 29.2 g of benzalacetone and 17.6 g of 3-amino-1,2,4-triazole is refluxed in 150 ml of dimethylformamide for 3 hours. On cooling at room temperature, crystals are precipitated and collected by filtration. The crystals are recrystallized from dimethylformamide to give 17 g of S-methyl-7-phenyl-4,7-dihydro-l,2 ,4-triazole [1,5-a]- pyrimidine, melting at 220-2220C. Example 11 To a solution of 41.3 g of 2-aminoimidazole sulfate in 50 ml of water are added 6.8 g of sodium hydroxide and 500 ml of methanol, and the mixture is stirred and dried over sodium sulfate. To the resulting solution is added 77.9 g of methyl a-acetyl-3-nitrocinnamate, stirred at 50 C for 2.5 hours and refluxed under heating for 1.5 hours. On cooling at room temperature, crystals are precipitated and collected by filtration to give 81.4 g of 6-methoxy carbonyl-7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]- pyrimidine, melting at 263-2640C with decomposition. Example 12 A mixture of 20.0 g of 6-methoxycarbonyl-7-methyl-5-(3 nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine, 200 ml of acetic acid and 3.0 g of 10 palladium-carbon is stirred at room temperature for 5 hours under hydrogen gas. After an insoluble material is filtered off, the filtrate is neutralized with sodium bicarbonate, and extracted with chloroform. The extract is dried and the solvent is distilled off under reduced pressure. The precipitated pale yellow crystals are collected by filtration and recrystallized from methanol to give 11.0 g of 5-(3-aminophenyl)-6-methoxycarbonyl-7-methyl- 5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 224-2250C. Example 13 To a solution of 4.0 g of 2-aminoimidazole sulfate in 10 ml of water are added 1.2 g of sodium hydroxide and 200 ml of methanol, and the mixture is dried over sodium sulfate. To the resulting solution is added 9.5 g of 2-methoxyethyl a-acetyl-2-trifluoromethylcinnamate and stirred at 500C for 3 hours. After stirring under reflux for 3.5 hours, the solvent is distilled off and the precipitated crystals are collected by filtration. The crystals are recrystallized from a mixture of methanol and chloroform to give 5.5 g of 6- (2-methoxyethoxycarbonyl) -7-methyl-5- (2-trifluoromethyl- phenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 181-182"C. 2-Methoxyethyl a -acetyl-2-trifluoromethylcinnamate is synthesized by the following manner. A mixture of 12.2 g of 2-trifluoromethylbenzaldehyde, 11.2 g of 2-methoxyethyl acetoacetate, 1 ml of piperidine, 2 ml of acetic acid and 150 ml of benzene is refluxed under the condition of azeotropic dehydration for 3.5 hours. The solvent is distilled off under reduced pressure to give red brown oil. The oil is distilled under reduced pressure to give 15.5 g of 2-methoxyethyl a-acetyl-2-trifluoromethylcinnamate, boiling at 145-1510C/0.5 mmHg. Example 14 Crystals are obtained by reacting 6.8 g of 2-aminoimidazole sulfate with 10.5 g of methyl 2-acetyl-3-cyclohexylacrylate in a similar manner as described in Example 13. Recrystallization from methanol gives 4.8 g of 5-cyclohexyl 6-methOxyCarbonyl-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 1780C. Example 15 To 100 ml of benzene are added 10.7 g of 2-pyridinecarbaldehyde and 13 g of methyl acetoacetate, and maintained at 30-400C for 2 hours in the presence of 0.5 ml of acetic acid and 0.25 ml of piperidine. The mixture is washed with sodium chloride solution, dried and the solvent is distilled off. To the residue is added 150 ml of isopropanol solution containing 2-aminoimidazole prepared from 10.5 g of 2-aminoimidazole sulfate and 2.9 g of sodium hydroxide, and then refluxed under heating for 2 hours. The reaction mixture is passed through silica gel column, and the solvent of the eluate is distilled off. Crystallization from methanol gives 2.5 g of 6-methoxycarbonyl-7-methyl-5-(2-pyridyl)-5, 8-dihydroimidazo[1,2-a]pyrimidine, melting at 224-2260C with decomposition. Example 16 2-N,N-diethylaminoethyl 5-(3-nitrophenyl)-7-methyl-5, 8-dihydroimidazo[1,2-a]pyrimidine-6-carboxylate (1.6 g), melting at 119-1210C is obtained as crystals by reacting 7.6 g of 3-nitrobenzaldehyde with 10.1 g of 2-N,N-diethylaminoethyl acetoacetate and 4.5 g of 2-aminoimidazole sulfate in a similar manner as described in Example 15. Example 17 In a mixture of 50 ml of acetone, 30 ml of methanol and 20 ml of water is dissolved 1.8 g of 5-[3-(2-methyl-1, 3-dioxolan-2-yl) phenyl] -6-methoxycarbonyl-7-methyl-S , 8- dihydroimidazo[l,2-a]pyrimidine. The mixture is adjusted to pH 1 with p-toluenesulfonic acid and then heated at 600C for 3 hours. The solvent is distilled off and the residue is neutralized with sodium bicarbonate solution. The resulting white precipitations are collected by filtration and recrystallized from a mixture of ethanol and acetone to give 1.1 g of 5-(3-acetylphenyl)-6-methoxycarbonyl-7 methyl-5,8-dihydroimidazo[1,2-appyrimidine, melting at 227-2290C. 5-[3-(2-methyl-1,3-dioxolan-2-yl)phenyl]-6-methOxy- carbonyl-7-methyl-5 , 8-dihydroimidazo [l,2-a]pyrimidine is synthesized according to the following manner 5-[3-(2-methyl-1,3-dioxolan-2-yl)phenyl]-6-methOxy- carbonyl-7-methyl-5, 8-dihydroimidazo [l,2-a]pyrimidine (9 g), melting at 199-2010C, is obtained by reacting 11 g of 3-(2 methyl-1,3-dioxolan-2-yl)benzaldehyde with 7.3 g of methyl acetoacetate and 9 g of 2-aminoimidazole sulfate in a similar manner as described in Example 15. Example 18 To an isopropanol solution of 2-aminoimidazole, which is prepared from 7.9 g of 2-aminoimidazole sulfate and 2.2 g sodium hydroxide, is added 11.7 g of a-acetyl-3-nitrocrotonamide and heated under reflux for 5 hours. After cooling, the precipitated crystals are collected by filtration to give 12 g of 6-carbamoyl-7-methyl-5-(3-nitrophenyl)-5,8- dihydroimidazo[l,2-a] pyrimidine, melting at 238-2400C. a-Acetyl-3-nitrocrotonamide is synthesized by the following manner. A mixture of 10 g of acetoacetamide and 15 g of 3 nitrobenzaldehyde in 100 ml of isopropanol is stirred at 350C for 4 hours in the presence of 0.3 ml of piperidine and 0.5 ml of acetic acid. The precipitated yellow crystals are collected by filtration to give 20 g of a-acetyl-3nitrocrotonamide, melting at 159-1610C. Example 19 1.5 ml of thionyl chloride is added dropwise to a solution of 3 g of 6-carbamoyl-7-methyl-5-(3-nitrophenyl)-5, 8-dihydroimidazo[1,2-a]pyrimidine in 30 ml of dimethylformamide. After stirring for an hour, the mixture is poured into chloroform and washed with sodium bicarbonate solution followed by passing the mixture through a column containing 50 g of silica gel with a mixture of dichloromethane and ethanol as an eluent. Upon allowing the eluates to stand, crystals are precipitated and collected by filtration to give 1.1 g of 6-cyano-7-methyl-5-(3-nitrophenyl)-5, 8-dihydroimidazo [1,2-a]pyrimidine, melting at 278-2800C with decomposition. Example 20 50 ml of ethanol is added to a solution of 4.5 g of 2-aminoimidazole sulfate and 1.3 g of sodium hydroxide in 11 ml of water and dried over sodium sulfate. To the solution is added 10 g of ethyl 4,4-dimethoxy-2-(3-nitrobenzylidene)3-oxobutylate. The resulting mixture is stirred at 500C for 30 minutes and further refluxed under heating for 6 hours. After cooling, the precipitated yellow crystals are collected by filtration, purified by column chromatography on silica gel with chloroform-methanol eluents, and then recrystallized from methanol to give 6 g of 7-dimethoxymethyl-6-ethoxy carbonyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-appyrimidine, melting at 190-1910C with decomposition. Ethyl 4, 4-dimethoxy-2- (3-nitrobenzylidene)-3-oxobutylate is synthesized by the following manner. A solution of 24 g of 3-nitrobenzaldehyde, 30 g of ethyl 4,4-dimethoxy-3-oxobutylate, 0.5 ml of piperidine and 1 ml of acetic acid in 200 ml of benzene is refluxed under heating for 4 hours under the condition of azeotropic dehydration. rl'he solvent is distilled off and evaporated under reduced pressure to give 36 g of ethyl 4,4-dimethoxy-2-(3-nitrobenzylidene)-3-oxobutylate, boiling at 195-2100C/0.2 mmHg. Example 21 10 ml of 6N hydrochloric acid is added to a solution of 4.4 g of 7-dimethoxymethyl-6-ethoxycarbonyl-5-(3-nitro- phenyl) -5,8-dihydroimidazo [l,2-a]pyrimidine in mixture of 10 ml of acetone and 10 ml of water and the mixture is stirred at room temperature for an hour, and then allowed to stand overnight. The solvent is distilled off under reduced pressure below 40"C to give 4 g of 6-ethoxycarbonyl7-formyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine hydrochloride, melting at 2280C with decomposition. Example 22 To a solution of 6-ethoxycarbonyl-7-formyl-5-(3-nitro phenyl)-5,8-dihydroimidazo[l,2-a]pyrimidine hydrochloride in a mixture of 20 ml of ethanol and 20 ml of dimethylformamide are added 0.88 g of hydroxylamine hydrochloride and 1.22 g of sodium carbonate and the mixture is stirred at 50"C for 1.5 hours. The solvent is distilled off under reduced pressure and water is added to the residue, then precipitated crystals are collected by filtration. The crystals are recrystallized from a mixture of chloroform and methanol to give 2.0 g of 6-ethoxycarbonyl-7-hydroxy iminomethyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]- pyrimidine, melting at 229-2300C with decomposition. Example 23 A solution of 6-ethoxycarbonyl-7-hydroxyiminomethyl 5-(3-nitrophenyl)-5,8-dihydroimidazo[l,2-a]pyrimidine (1.25 g), 0.29 g of sodium acetate and 0.4 ml of acetic anhydride in 15 ml of acetic acid is stirred with heating at 80-900C for 30 minutes. The reaction solution is poured into water and precipitated crystals are collected by filtration. Recrystallization from a mixture of chloroform and ethanol gives 0.5 g of 7-cyano-6-ethoxycarbonyl-5-(3-nitrophenyl)-S, 8-dihydroimidazo[l,2-a]pyrimidine, melting at 260-2610C with decomposition. Example 24 12 g of 8-carboxy-3-ethoxycarbonyl-2-methyl-4-(3 nitrophenyl)-1,4-dihydroimidazo[1,5-a]pyrimidine is heated at 2150C for 20 minutes and purified by column chromatography on silica gel with chloroform eluent. The yellow crystals obtained are recrystallized from ethanol to give 1.5 g of 3-ethOxyCarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydro- imidazo[l,5-a]pyrimidine, melting at 196-1970C. 8-Carboxy-3-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1, 4-dihydroimidazo [1, 5-a]pyrimidine is synthesized by the following manner. 0.17 g of potassium hydroxide in 1.7 ml of water is added to a solution of 1.0 g of 3,8-diethoxycarbonyl-2-methyl 4- (3-nitrophenyl)-l,4-dihydroimidazo[l,5-a]pyrimidine in 20 ml of ethanol, and gradually heated followed by stirring at 700C for 10 hours. The ethanol is distilled off under reduced pressure, chloroform is added to the resulting oil and extracted with potassium carbonate solution. The water layer is washed with chloroform and adjusted to pH 5-6 with acetic acid. The precipitated crystals are collected by filtration and recrystallized from ethanol to give 0.32 g of 8-carboxy-3-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-l, 4-dihydroimidazo[l,5-a]pyrimidine, melting at 2220C with decomposition. 3,8-Diethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1, 4-dihydroimidazo !l,S-a]pyrimidine is synthesized by the following manner. A solution of 2 g of 5-amino-4-ethoxycarbonylimidazole and 3.4 g of ethyl a-acetyl-3-nitrocinnamate in 50 ml of ethanol is refluxed under heating for 7 hours under a nitrogen atmosphere. The ethanol is removed under reduced pressure, the resulting oil is purified by column chromatography on silica gel with a mixture of chloroform and methanol as eluent. Recrystallization from a mixture of isopropyl alcohol and isopropyl ether gives 2.5 g of 3,8-diethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydroimidazo[l, 5-a]pyrimidine, melting at 160-1620C. Example 25 16 mg of sodium borohydride is added gradually to a solution of 17 ing of 6-methoxycarbonyl-5-methyl-7-(2-tri fluoromethylphenyl)pyrazolotl,5-a]pyrimidine in 1 ml of methanol with stirring and heating at 60 C. The reaction mixture is poured into water, extracted with ethyl acetate and dried. The solvent is removed and the residue is recrystallized from methanol to give 6-methoxycarbonyl-5methyl-7-(2-trifluoromethylphenyl)-4,7-dihydropyrazolo[l, 5-a]pyrimidine, melting at 209-2100C. The following compounds can also be, for example, prepared in a similar manner as the above examples. (26) 6-Ethoxycarbonyl-S-methyl-7- (3-nitrophenyl)-4,7- dihydropyrazolo[l,5-a]pyrimidine, melting at 157-1590C with decomposition (27) 6-Ethoxycarbonyl-7-methyl-5 (3-nitrophenyl) -5,8 dihydroimidazo[l,2-a]pyrimidine, melting at 242-2430C (28) 7-Chloromethyl-6-ethoxycarbonyl-5-(3-nitrophenyl)-5,8- dihydroimidazo[l,2-a]pyrimidine, melting at 190-1920C with decomposition (29) 6-tert-Butoxycarbonyl-7-methyl-5-(3-nitrophenyl)-5, 8-dihydroimidazo[l,2-a]pyrimidine, melting at 219-222 C with decomposition (30) 6-(2-Cyanoethoxycarbonyl)-7-methyl-5-(3-nitrophenyl)-5, 8-dihydroimidazo[l,2-a]pyrimidine, melting at 230-2370C (31) 6-EthOxycarbonyl-7-N-methylcarbamoyloxymethyl-5-(3- nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 207-2080C with decomposition (32) 6-EthOxycarbonyl-7-hydroxymethyl-5-(3-nitrophenyl)-5, 8-dihydroimidazo[1,2-a]pyrimidine, melting at 196-1970C with decomposition (33) 6-Ethoxycarbonyl-5- (3-nitrophenyl)-7-trifluoromethyl-5, 8-dihydroimidazo[l,2-a]pyrimidine, melting at 240-2420C with decomposition (34) 6-Benzyloxycarbonyl-7-methyl-5-(3-nitrophenyl)-5, 8-dihydroimidazo[l,2-a]pyrimidine, melting at 2050C (35) 6-(2-MethOxyethoxycarbonyl)-7-methyl-5-(3-nitrophenyl)- 5,8-dihydroimidazo[l,2-a]pyrimidine, melting at 18S-1860C (36) 3-N,N-Dimethylaminopropyl 7-methyl-5-(3-nitrophenyl) 5,8-dihydroimidazo[1,2-a]pyrimidine-6-carboxylate (37) 6-Ethoxycarbonyl-5-(3-nitrophenyl)-7-propyl-5,8- dihydroimidazo[1,2-a]pyrimidine (38) 6-Carboxy-7-fOrmyl-5-(3-nitrophenyl)-5,8-dihydro- imidazo[1,2-a]pyrimidine hydrochloride, melting at above 3500C (39) 7-Methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 194-1960C with decomposition (40) 6-Ethoxycarbonyl-7-methyl-5-(2-nitrophenyl)-5,8dihydroimidazo[l,2-a]pyrimidine, melting at 253-2540C with decomposition (41) 6-Methoxycarbonyl-7-methyl-5-(2-nitrophenyl)-5,8dihydroimidazo[l,2-a]pyrimidine, melting at 256-2580C with decomposition (42) 6-Methoxycarbonyl-7-methyl-5-(4-nitrophenyl)-5,8dihydroimidazo[1,2-a]pyrimidine, melting at 2490C with decomposition (43) 6-Ethoxycarbonyl-7-methyl-5- (2-trifluoromethylphenyl) - 5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 2760C (44) 6-MethOxyCarbonyl-7-methyl-5-(2-trifluoromethylphenyl)- 5,8-dihydroimidazo[1,2-alpyrimidine, melting at 285-2860C with decomposition (45) 7-Acetoxymethyl-6-ethoxycarbonyl-5-(2-trifluorometh phenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 174-176 C (46) 2-Piperidinoethyl 7-methyl-5-(2-trifluoromethylphenyl) 5,8-dihydroimidazol1,2-a]pyrimidine-6-carboxylate, melting at 205-2070C with decomposition (47) 6-Ethoxycarbonyl-7-methyl-5- (3-trifluoromethylphenyl) - 5,8-dihydroimidazo[l,2-a]pyrimidine, melting at 193-1940C (48) 7-Methyl-6-(2-nitroethoxycarbonyl)-5-(2-trifluoro methylphenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine (49) 5-(2-Benzylthiophenyl)-6-methoxycarbonyl-7-methyl-5, 8-dihydroimidazo[1,2-a]pyrimidine, melting at 196-1980C (50) 5-(2-Chlorophenyl)-6-methoxycarbonyl-7-methyl-5, 8-dihydroimidazo[l,2-a]pyrimidine, melting at 257-2580C with decomposition (51) 6-Ethoxycarbonyl-7-methyl-5-phenyl-5,8-dihydro- imidazo[l,2-a]pyrimidine, melting at 183-1840C (52) 6-Ethoxycarbonyl-7-methyl-5-(2-methylphenyl)-5,8 dihydroimidazo[l,2-a]pyrimidine, melting at 2150C (53) 5- (2-Cyanophenyl) -6-methoxycarbonyl-7-methyl-5, 8-dihydroimidazo[l,2-a]pyrimidine, melting at 2680C with decomposition (54) 6-Methoxycarbonyl-7-methyl-5- (2-methylthiophenyl)-5, 8-dihydroimidazoll,2-a]pyrimidine, melting at 259-2600C with decomposition (55) 5-(4-Aminophenyl)-6-methoxycarbonyl-7-methyl-5,8dihydroimidazo[l,2-a]pyrimidine, pale yellow crystals (56) 6-Methoxycarbonyl-5-(2-methoxyphenyl)-7-methyl-5, 8-dihydroimidazo[1,2-a]pyrimidine, melting at 242-2450C with decomposition (57) 6-Ethoxycarbonyl-7-methyl-5-propyl-5,8-dihydroimidazo [1,2-a]pyrimidine, melting at 144-1450C (58) 6-Methoxycarbonyl-7-methyl-5 (2-thienyl) -S ,8-dihydro- imidazo[1,2-a]pyrimidine, melting at 230-2320C with decomposition (59) 5-(2-Furyl)-6-methoxycarbonyl-7-methyl-5,8-dihydro imidazo[l,2-a]pyrimidine (60) 6-EthOxycarbonyl-7-methyl-5,8-dihydroimidazo[1,2-a]- pyrimidine, melting at 248-2490C (61) 7-Methyl-5-phenyl-5,8-dihydroimidazo[1,2-a]pyrimidine (62) 6-Ethoxycarbonyl-5-methyl-7-(3-nitrophenyl)-4,7- dihydro-1,2,4-triazololl,5-a]pyrimidine, melting at 222-2240C (63) 5-Acetoxymethyl-6-ethoxycarbonyl-7- (3-nitrophenyl) -4, 7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine, melting at 169171 C (64) 6-Methoxycarbonyl-7-(3,4-dimethoxyphenyl)-5-methyl-4, 7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine, melting at 2112130C (65) 7-(2-Chloropheynl)-6-methoxycarbonyl-5-methyl-4, 7-dihydro-l,2,4-triazolo[l,5-a]pyrimidine, melting at 268 2710C with decomposition (66) 6-Methoxycarbonyl-5-methyl-7- (2-trifluoromethylphenyl) - 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine, melting at 2420C (67) 5-Bromomethyl-6-methoxycarbonyl-7-(2-trifluoromethyl- phenyl)-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine, melting at 160-1700C (68) 5-Chloromethyl-7-(4-hydroxyphenyl)-6-methoxycarbonyl-4, 7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine, melting at 2900C with decomposition (69) 6-EthOxyCarbonyl-5-methyl-7-(3-pyridyl)-4,7-dihydro-1, 2,4-triazolo[l,S-a]pyrimidine, melting at 221-2230C (70) 5-tert-Butyl-7-(3-pyridyl)-4,7-dihydro-1,2,4-triazolo [1,5-a]pyrimidine, melting at 179-1810C (71) l-Phenyl-2-N,N-dibutylaminoethyl 7-methyl-5-(3-nitro phenyl) -5, 8-dihydroimidazo [1,2-a] pyrimidine-6-carboxylate, a-form: melting at 146-1470C, form: melting at 174-1750C (72) 1- (2-Thienyl)-2-piperidinoethyl 7-methyl-5-(3-nitro phenyl) -5, 8-dihydroimidazo [1,2-a] pyrimidine-6-carboxylate, a-form: melting at 204-2060C, form: melting at 182-1830C (73) l-Phenyl-2-(N-methyl-N-benzylamino)ethyl 7-methyl-5 (3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine-6carboxylate, a-form: melting at 193-194 C, ss -form: melting at 188-1900C (74) 1- (2-Furyl) -2-piperidinoethyl 7-methyl-5-(3-nitro phenyl) -5,8-dihydroimidazo [l,2-a]pyrimidine-6-carboxylate, a-form: melting at 199-2000C with decomposition, form: melting at 186-1870C with decomposition (75) 6-Carbamoyl-7-methyl-5-(2-trifluoromethylphenyl)-5, 8-dihydroimidazo[1,2-a]pyrimidine, melting at 254-2550C (76) 6-Cyano-7-methyl-5-(2-trifluoromethylphenyl)-5,8 dihydroimidazo[1,2-a]pyrimidine hydrochloride, melting at 275-278 0C (77) 6-Ethoxyearbonyl-5,7-dimethyl-4,7-dihydropyrazolov {1,5-a]pyrimidine, melting at 168-1700C (78) 2-Methoxy-l-phenylethyl 7-methyl-5-(3-nitrophenyl)-5, 8-dihydroimidazo[1,2-a]pyrimidine-6-carboxylate, &alpha;-form: melting at 194-195 C, form: : melting at 1840C (79) 6-Methoxycarbonyl-5-methyl-7-(3,4-dihydroxyphenyl)-4, 7-dihydropyrazolo[l,5-a]pyrimidine, melting at 253-2550C (80) 5-Acetoxymethyl-6-ethoxycarbonyl-7- (2-trifluoromethyl- phenyl)-4,7-dihydropyrazolo[1,2-a]pyrimidine, melting at 166-167 0C (81) 6-EthOxyearbonyl-5-hydroxymethyl-7-(2-trifluoromethyl- phenyl)-4,7-dihydropyrazolo[1,2-a]pyrimidine, melting at 229-230 C (82) 5-MethOxycerbonyl-5-methyl-7-(3-pyridyl)-4,7-dihydro- pyrazolo[1,2-a]pyrimidine, melting at 222-2230C (83) 6-EthOxycarbonyl-5-propyl-7-(2-thienyl)-4,7-dihydro- pyrazolo[1,2-a]pyrimidine, melting at 169-1700C (84) 6-Ethoxycarbonyl-5-methyl-7-(2-chlorophenyl)-4, 7-dihydropyrazolo[1,2-a]pyrimidine, melting at 176-1780C (85) 6-Butoxycarbonyl-5-methyl-7-(2-trifluoromethylphenyl)-4, 7-dihydropyrazolo[l,5-a]pyrimidine, melting at 134-1360C (86) 6-Methoxycarbonyl-5-methyl-7-(2-hydroxyphenyl)-4, 7-dihydropyrazolo[1,2-a]pyrimidine, melting at 218-2200C (87) 5-Chloromethyl-6-ethoxycarbonyl-i-(2-trifluoro methylphenyl)-4,7-dihydropyrazolofl,5-a]pyrimidine, melting at 147-1490C (88) 6-EthOxycarbonyl-5-fluoromethyl-7-(2-trifluoromethyl- phenyl)-4,7-dihydropyrazolo[1,2-a]pyrimidine (89) 6-Acetyl-5-methyl-7-(3-nitrophenyl)-4,7-dihydropyrazolo [l,5-a]pyrimidine, melting at 190-1920C (90) 6-Benzyloxycarbonyl-5-methyl-7-(2-trifluoromethylphenyl)-4,7-dihydropyrazolo[1,2-a]pyrimidine, melting at 164-1660C (91) 6-Carboxy-5-methyl-7-(2-trifluoromethylphenyl)-4, 7-dihydropyrazolo[1,5-a]pyrimidine, melting at 172-1730C with decomposition (92) 6-EthOxyCarbonyl-5-methyl-7-(3-trifluoromethylphenyl)- 4,7-dihydropyrazolo[1,5-a]pyrimidine, melting at 189-1900C (93) 6-Ethoxycarbonyl-5-methyl-7-(2-methylphenyl)-4, 7-dihydropyrazolo[1,2-a]pyrimidine, melting at 186-1870C Although the present invention has been adequately discussed in the foregoing specification and examples included therein, one readily recognizes that various changes and modifications may be made without departing from the spirit and scope thereof.

Claims: What is claimed is: 1. A polyazaheterocycle derivative of the formula: EMI37.1 or a pharmaceutically acceptable salt thereof. In the above formula, each symbol is as defined below. R is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a furyl group, a thienyl group, a pyridyl group or a phenyl group which may be optionally substituted by one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, a trifluoromethyl group, an alkoxy group, an aralkyloxy group, an alkylthio group, an aralkylthio group, an acyl group, a hydroxyl group, an amino group, a nitro group and a cyano group; R1 is a hydrogen atom, a cyano group, a carbamoyl group, a carboxyl group, an alkoxycarbonyl group which may be optionally substituted in the alkoxy moiety by one or two substituents selected from the group consisting of an alkoxy group, a cyano group, a group represented by the formula: : -N( (Rf) (wherein each of R and RA is an alkyl group or an aralkyl group, or Ra and RA together with the adjacent nitrogen atom form a 5- to 7-membered heterocycle), a nitro group, a phenyl group and a heteroaryl group, or an alkanoyl group; Rê is a lower alkyl group, a hydroxyalkyl group, an acetoxyalkyl group, a haloalkyl group, a dihaloalkyl group, a trifluoromethyl group, an alkoxyalkyl group, a di-alkoxymethyl group, a lower alkyl-carbamoyloxyalkyl group, a lower alkyl-thiocarbamoyloxyalkyl group, a formyl group, a hydroxyiminomethyl group or a cyano group; and Each of X, Y and Z is a member of the ring A and represents N or CH. 2. The compound of claim 1 represented by the formula: EMI38.1 or a pharmaceutically acceptable salt thereof. In the above formula, each symbol is as defined below. R is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a furyl group, a thienyl group, a pyridyl group or a phenyl group which may be optionally substituted by one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, a trifluoromethyl group, an alkoxy group, an aralkyloxy group, an alkylthio group, an aralkylthio group, an acyl group, a hydroxyl group, an amino group, a nitro group and a cyano group; R1 is a hydrogen atom, a cyano group, a carbamoyl group, a carboxyl group, an alkoxycarbonyl group which may be optionally substituted in the alkoxy moiety by one or two substituents selected from the group consisting of an alkoxy group, a cyano group, a group represented by the formula: : -N(Ra)(ss)(wherein each of Ra and ss is an alkyl group or an aralkyl group, or Ra and ss together with the adjacent nitrogen atom form a 5- to 7-membered heterocycle), a nitro group, a phenyl group and a heteroaryl group, or an alkanoyl group; and Rê is a lower alkyl group, a hydroxyalkyl group, an acetoxyalkyl group, a haloalkyl group, a dihaloalkyl group, a trifluoromethyl group, an alkoxyalkyl group, a di-alkoxymethyl group, a lower alkyl-carbamoyloxyalkyl group, a lower alkyl-thiocarbamoyloxyalkyl group, a formyl group, a hydroxyiminomethyl group or a cyano group. 3. The compound of claim 1 represented by the formula: EMI39.1 or a pharmaceutically acceptable salt thereof. In the above formula, each symbol is as defined below. R is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a furyl group, a thienyl group, a pyridyl group or a phenyl group which may be optionally substituted by one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, a trifluoromethyl group, an alkoxy group, an aralkyloxy group, an alkylthio group, an aralkylthio group, an acyl group, a hydroxyl group, an amino group, a nitro group and a cyano group; R1 is a hydrogen atom, a cyano group, a carbamoyl group, a carboxyl group, an alkoxycarbonyl group which may be optionally substituted in the alkoxy moiety by one or two substituents selected from the group consisting of an alkoxy group, a cyano group, a group represented by the formula: : 1 1 1 1 -N(Ra)(Rb) (wherein each of Ra and Rb is an alkyl group or an aralkyl group, or Ra and RA together with the adjacent nitrogen atom form a 5- to 7-membered heterocycle), a nitro group, a phenyl group and a heteroaryl group, or an alkanoyl group; and R2 is a lower alkyl group, a hydroxyalkyl group, an acetoxyalkyl group, a haloalkyl group, a dihaloalkyl group, a trifluoromethyl group, an alkoxyalkyl group, a di-alkoxymethyl group, a lower alkyl-carbamoyloxyalkyl group, a lower alkyl-thiocarbamoyloxyalkyl group, a formyl group, a hydroxyiminomethyl group or a cyano group. 4. The compound of claim 1 represented by the formula: EMI40.1 or a pharmaceutically acceptable salt thereof. In the above formula, each symbol is as defined below. R is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a furyl group, a thienyl group, a pyridyl group or a phenyl group which may be optionally substituted by one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, a trifluoromethyl group, an alkoxy group, an aralkyloxy group, an alkylthio group, an aralkylthio group, an acyl group, a hydroxyl group, an amino group, a nitro group and a cyano group; R1 is a hydrogen atom, a cyano group, a carbamoyl group, a carboxyl group, an alkoxycarbonyl group which may be optionally substituted in the alkoxy moiety by one or two substituents selected from the group consisting of an alkoxy group, a cyano, a group represented by the formula: : 1 1 1 1 -N(Ra)(Rb) (wherein each of Ra and Rb is an alkyl group or an aralkyl group, or Rg and -i together with the adjacent nitrogen atom form a 5- to 7-membered heterocycle), a nitro group, a phenyl group and a heteroaryl group, or an alkanoyl group; and Rê is a lower alkyl group, a hydroxyalkyl group, an acetoxyalkyl group, a haloalkyl group, a dihaloalkyl group, a trifluoromethyl group, an alkoxyalkyl group, a di-alkoxymethyl group, a lower alkyl-carbamoyloxyalkyl group, a lower alkyl-thiocarbamoyloxyalkyl group, a formyl group, a hydroxyiminomethyl group or a cyano group. 5. The compound of claim 1: l-phenyl-2-piperidinoethyl 5-methyl-7-(3-nitrophenyl)-4, 7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxylate and diastereomer thereof. 6. The compound of claim 1: 6-ethOxyCarbonyl-5-methyl-7-(2-trifluoromethylphenyl)-4, 7-dihydropyrazolo [1,5-a] pyrimidine. 7. The compound of the formula: l-phenyl-2-piperidinoethyl 7-methyl-5-(3-nitrophenyl)-5, 8-dihydroimidazo[1,2-a]pyrimidine-6-carboxylate and diastereomer thereof. 8. The compound claim 1: 6-ethoxyCarbonyl-5,7-dimethyl-5,8-dihydroimidazo[1,2-a]- pyrimidine. 9. A method of preparing a polyazaheterocycle derivative of the formula: EMI42.1 or a pharmaceutically acceptable salt thereof, which comprises (a) subjecting a compound of the formula: EMI42.2 to dehydration condensation, (b) subjecting a compound of the formula: EMI43.1 to condensation with a compound of the formula: EMI43.2 (c) subjecting a compound of the formula: EMI43.3 to dehydration condensation with a compound of the formula: R-CHO, and then subjecting the compound obtained to condensation with a compound of the formula: EMI43.4 (d) reacting a compound of the formula: EMI43.5 with hydrogen gas or a complex metal hydride, or (e) if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt or a metal salt. In the above formulas,each symbol is as defined below. R is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a furyl group, a thienyl group, a pyridyl group or a phenyl group which may be optionally substituted by one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, a trifluoromethyl group, an alkoxy group, an aralkyloxy group, an alkylthio group, an aralkylthio group, an acyl group, a hydroxyl group, an amino group, a nitro group and a cyano group; R1 is a hydrogen atom, a cyano group, a carbamoyl group, a carboxyl group, an alkoxycarbonyl group which may be optionally substituted in the alkoxy moiety by one or two substituents selected from the group consisting of an alkoxy group, a cyano group represented by the formula: : 1 1 1 1 -N(Ra)(Rb) (wherein each of Ra and Rb is an alkyl group or an aralkyl group, or Ra and RA together with the adjacent nitrogen atom form a 5- to 7-membered heterocycle), a nitro group, a phenyl group and a heteroaryl group, or an alkanoyl group; R2 is a lower alkyl group, a hydroxyalkyl group, an acetoxyalkyl group, a haloalkyl group, a dihaloalkyl group, a trifluoromethyl group, an alkoxyalkyl group, a di-alkoxymethyl group, a lower alkyl-carbamoyloxyalkyl group, a lower alkyl-thiocarbamoyloxyalkyl group, a formyl group, a hydroxyiminomethyl group or a cyano group; and Each of X, Y and Z is a member of the ring A and represents N or CH. 10. A pharmaceutical composition for the prophylaxis and treatment of circulatory diseases comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier thereof.

Inventors: ARAKI, KAZUHIKO 1212-4, AZA-AZEMA, INUI, JUN, MISHINA, TADASHI, NAKAMURA, TADAO, OBATA, MINORU, TSUDA, YOSHINAO
Applicants: YOSHITOMI PHARMACEUTICAL INDUSTRIES, LTD.
Application year: 1985
Main classification: C07D487
IPC codes: A61P9, A61K31, C07D487