JPS61227584A - Polyaza heterocyclic ring derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R is H, lower alkyl, cyclic alkyl, furyl, thienyl; R<1> is H, cyano, carbamoyl, carboxyl; R<2> is lower alkyl, hydroxyalkyl, acetoxyalkyl, haloalkyl; X, Y, Z are members of ring A, being N, CH) and its pharmaceutically permissible salt. E X A M P L E:1-Phenyl-2-piperidinoethyl-5-methyl-7-(3-nitrophenyl)-4,7-dihydropyr azo-lo[1,5-a]pyrimi-dine-6 -carboxylate. USE:Preventive and remedy for diseases in circulation system, such as antihypertension, remedy for heart attack or cerebral circulation improver. PREPARATION:The dehydrative condensation reaction of a compound of formula I is effected in the presence or absence of an appropriate solvent at room temperature or under heating to give the compound of formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides a novel and pharmaceutically useful polyazaheterocyclic derivative represented by the general formula R or a pharmaceutically acceptable salt thereof, a method for producing the same, and the compound. The present invention relates to a pharmaceutical composition containing the present invention.

In the above formula, each symbol is as follows.

R is hydrogen, lower alkyl (methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, etc.), cyclic alkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), furyl, chenyl, pyridyl, or halogen as a substituent (fluorine, chlorine, bromine) , iodine), lower alkyl (methyl, ethyl, propyl, isopropyl, butyl, etc.), trifluoromethyl, alkoxy (methoxy, ethoxy, propoxy, butoxy, etc.), aralkyloxy (benzyloxy, phenylethoxy, phenylpropoxy, etc.), alkylthio (methylthio, ethylthio, propylthio, butylthio, etc.), aralkylthio (benzylthio, phenylethylthio, phenylpropylthio, etc.), acyl (acetyl, propionyl, butyryl, benzoyl, etc.), hydroxyl group, amino, nitro,
Indicates phenyl which may have 1 to 2 cyano atoms,
R1 is hydrogen, cyano, carbamoyl, carboxyl, alkoxy (methoxy, ethoxy, propoxy, isopropoxy, etc.) as a substituent on the alkoxy moiety, cyano, formula -N (methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, etc.) or aralkyl (benzyl, phenylethyl, phenylpropyl, etc.), but together with the adjacent nitrogen atom a 5- to 7-membered heterocycle (pyrrolidine, piperidine, Morpholine, piperazine, N-
methylpiperazine, N-(2-hydroxyethyl)piperazine, azepine, diazepine, etc.), a group represented by ], 1 or 2 of nitro, phenyl, heteroaryl (chenyl, furyl, pyridyl, etc.) Alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
tertiary butoxycarbonyl) or alkanoyl (such as tertiary butoxycarbonyl) or alkanoyl (
acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), and R2 is lower alkyl (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, etc.) , hydroxyalkyl (hydroxymethyl, hydroxyethyl, hydroxypropyl,
hydroxybutyl, etc.), acetoxyalkyl (acetoxymethyl, acetoxyethyl, acetoxypropyl,
acetoxybutyl, etc.), haloalkyl (fluoromethyl, chloromethyl, bromomethyl, iodomethyl, fluoroethyl, chloroethyl, fluoropropyl, chloropropyl, fluorobutyl, chlorobutyl, etc.), dihaloalkyl (difluoromethyl, dichloromethyl, dibromomethyl, difluoroethyl, dichloroethyl, difluoropropyl, dichloropropyl, difluorobutyl, dichlorobutyl, etc.), trifluoromethyl, alkoxyalkyl (methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl) , propoxypropyl, methoxybutyl, ethoxybutyl, etc.), dialkoxymethyl (dimethoxymethyl, jetoxymethyl, dipropoxymethyl,
dibutoxymethyl, etc.), (11m alkylcarbamoyloxyalkyl (methylcarbamoyloxymethyl, ethylcarbamoyloxymethyl, propylcarbamoyloxymethyl, butylcarbamoyloxymethyl,
methylcarbamoyloxyethyl, ethylcarbamoyloxyethyl, methylcarbamoyloxypropyl, ethylcarbamoyloxypropyl, methylcarbamoyloxybutyl, ethylcarbamoyloxybutyl, etc.)
, lower alkylthiocarbamoyloxyalkyl (methylthiocarbamoyloxymethyl, ethylthiocarbamoyloxydimethyl, propylthiocarbamoyloxymethyl, butylthiocarbamoyloxymethyl, methylthiocarbamoyloxyethyl, ethylthiocarbamoyloxyethyl, methylthiocarbamoyloxypropyl, ethylthio carbamoyloxypropyl, methylthiocarbamoyloxybutyl, ethylthiocarbamoyloxybutyl, etc.), formyl, hydroxyiminomethyl or cyano;
H represents a tetracylo, triazolo, imidazo or pyrazolo ring.

The ring system in general formula (1) and the specification of the present invention is 4,7-cyhydrotetrazolo [1°5-a
] Pyrimidine, tb1 formula.

4,7-cyhydrotriazolo[1°5-a
]Pyrimidine, 5,8-dihydroimidazo[1,2-a] represented by the formula +01
pyrimidine, 1,4-dihydroimidazo(1,5-a) represented by the formula
Pyrimidine, +81 4,7-cyclohydropyrazolo[l,5-a]
Indicates any pyrimidine.

The compound of general formula (1) of the present invention can be produced, for example, by the following method.

A method of dehydrating and condensing a compound represented by the above in a suitable solvent or without using it at room temperature or under heating.

iii) A method of addition-condensing a compound represented by the general formula with a compound represented by the general formula in a suitable solvent or without using it at room temperature or under heating.

(3) The compound represented by the general formula and the compound represented by the general formula R-CHO(Vl) are mixed in a suitable solvent or without using a suitable solvent at room temperature or under heating, optionally with a suitable acid catalyst, A method of dehydration condensation in the presence of a base catalyst or both, and addition condensation of the obtained compound and a compound of general formula (IV) in a suitable solvent or without using it at room temperature or under heating.

(4) The compound represented by the general formula is mixed with hydrogen gas or a complex metal hydride (e.g. lithium aluminum hydride, lithium hydride, A method of reacting with sodium boron, etc.).

(5) A method of converting the substituents R, R', R'' of the compounds obtained by the above methods (11 to (4)) by ordinary synthetic chemical techniques.

Suitable solvents in methods +1) to (4) may be any solvent as long as it is inert to the reaction, such as lower alkanols (methanol, ethanol, propatool, isopropyl, butanol, tertiary butanol,
ethylene glycol, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl ether, diisopropyl ether, dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), halogenated lower alkanes (dichloromethane, dichloroethane, chloroform, tetrahydrofuran, etc.), carbon chloride, etc.), acid amides (dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, etc.)
, lower alkane carboxylic acid or its ester (formic acid,
Acetic acid, propionic acid, methyl acetate, ethyl acetate, butyl acetate, methyl propionate, etc.), nitrated lower alkanes (nitromethane, nitroethane, etc.), dimethyl sulfoxide, sulfolane, water, etc., or a mixed solvent thereof can be used.

The upper limit of the reaction temperature in methods (1) to (4) is 200°C, preferably from room temperature to 150°C.

Common synthetic chemical methods in method (5) include hydrolysis of acetals, ketals, or esters under acid or base catalysts to produce aldehydes, ketones, carboxylic acids, or alcohols; protected aldehydes, ketones, Reactions for producing aldehydes, ketones, carboxylic acids, or alcohols by removing protective groups from carboxylic acids or alcohols; Oxime formation reactions for aldehydes or ketones; Reactions for producing alcohols or amines by reducing aldehydes or nitro; Dehydration of oximes or amides Examples include nitrile production reaction using alkyl; halogenation reaction of alkyl; acetoxylation reaction of haloalkyl; urethane production reaction using isocyanate of alcohol.

The compound of the present invention (when RI has an asymmetric carbon atom,
It can be obtained in the form of racemic mixtures or optical isomers. Racemic mixtures can be resolved into desired optical isomers, for example, by fractional recrystallization of salts with optically active acids. Furthermore, the compound (1) of the present invention having at least 2 asymmetric carbon atoms can be obtained as individual diastereomers or as a mixture thereof. can be separated by means. Furthermore, when the compound (1) of the present invention has an oxime, syn-anti stereoisomers exist, and the compound of the present invention also contains syn and anti stereoisomers.

The compound (■) of the present invention, its optical isomer or diastereomer, may optionally be prepared with an inorganic salt (hydrochloric acid, hydrobromic acid,
sulfuric acid, phosphoric acid, etc.), organic carboxylic acids (acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, oxalic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid) , 2-acetoxybenzoic acid, nicotinic acid, isonicotinic acid, etc.), organic sulfonic acids (methanesulfonic acid, ethanesulfonic acid, 2-
Hydroxyethanesulfonic acid, benzenesulfone M, p
-toluenesulfonic acid, naphthalene-2-sulfonic acid, etc.) or acid addition salts with ascorbic acid, lysine, glutamic acid, etc. Also, compound (1)
In, when R1 is a carboxyl group, a metal salt (sodium salt, potassium salt, aluminum salt, etc.)
, it can also be converted into an amine salt (such as triethylamine salt).

As is clear from the following pharmacological experiments, the compound of the present invention has antihypertensive effects, coronary vasodilator effects, cerebral vasodilator effects, cardiotonic effects, and lipid peroxidation inhibitory effects, and is an antihypertensive drug and a treatment for angina pectoris. It is useful as a preventive/therapeutic agent for cardiovascular diseases, such as a cardiotonic agent, a heart failure treatment agent, a myocardial infarction treatment agent, a cerebral circulation improving agent, and a vasoprotective agent.

Next, the effects of the compounds of the present invention will be specifically explained through pharmacological experiments. The test compounds used are as follows.

Test compound A: 1-phenyl-2-piperidinoethyl
β-diastereomer of 7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo(1,2-a)pyrididine-6-carpoxylate Test compound B: l-phenyl-2-piperidinoethyl.
β of 5-methyl-7-(3-nitrophenyl)-4,7-cihydropyrazolo(1,5-a)pyrididine-6-carpoxylate One diastereomer Test compound C; 6-nitoxycarbonyl-5-methyl-
7-(2-Trifluoromethylphenyl)-4,7-dihydrovirazolo(1,5-a)pyrimidine Test compound D: 6-ethoxycarbonyl-5,7-dimethyl-5,8-dihydroimidazo(1,2-a) ) Pyrimidine Pharmacology Experiment Example 1 Antihypertensive Effect Test compound 830 was administered to 5 spontaneously hypertensive rats in 1 group.
When mg/kg was orally administered and blood pressure was measured 1 hour and 5 hours after administration using the tail cuff method, the blood pressure reduction value after 1 hour was 94 + smHg, and the blood pressure reduction value 5 hours later was 47 + wnHg. .

Pharmacological Experiment Example 2 Effect on Coronary Blood Flow An adult mongrel was anesthetized by intravenously administering 30 kg of bentoparbital sodium (body weight) using the method described above [Japanese Pharmacological Journal, Vol. 57, p. 380 (1961)] ], the left coronary artery was perfused and its blood flow was measured. Test compounds 10-30P1 were administered intracoronarily. The effect of the test compound on coronary blood flow was determined by nifedipine [dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-
The dose required to increase coronary blood flow to half the effect of intracoronary administration of dicarboxilade]3N is
D.S.

(n) and the results are summarized in Table 1.

In addition, the half-life (T'A, minutes) is the duration of the effect.
I also asked for

Table 1 Pharmacological Experiment Example 3 Effect on vertebral artery blood flow A mongrel adult was anesthetized by intravenously administering 251 Ig/kl [r body weight of sodium bentoparbital], the right vertebral artery was perfused, and the blood flow was measured. Test compounds were administered into the vertebral artery.

Papaverine hydrochloride (1-((3,4-dimethoxyphenyl)methyl)-6,7-simethoxyisoquinoline hydrochloride)
When 100 Pg is administered to the vertebral artery, the maximum rate of increase in blood flow is set as 100%, and the effect of the test compound is that the rate of increase in blood flow is 1
The dose required to achieve 00% is E D +s+a(p
g) and the results are summarized in Table 2. The half-life (T'A, minutes) was also determined as the duration of the effect.

Table 2 Pharmacological Experiment Example 4 Effect on myocardial contractile force The papillary muscle of the right ventricle of a rabbit was removed, and Taleb-Henseleit solution (composition: sodium dichloride 1175M, potassium chloride 4.7a+M, calcium chloride 2.6+wM, magnesium sulfate) 1.4s
+ M, potassium dihydrogen phosphate 1.21, sodium bicarbonate 24.9 + nM and glucose 11 mM), kept at 35°C, equilibrated with oxygen gas containing 5% carbon dioxide, and at a frequency of 0.5 Hz. electrically stimulated. Contraction force was measured using a tensile quadrant juicer under a static tension of 0.5 g.

The results are shown in Table 3.

Table 3 Pharmacological Experiment Example 5 Effect on heart rate An adult mongrel was anesthetized by intravenous administration of bentoparbital sodium, and heart rate was measured by second lead electrocardiogram. The test compound was administered into the right coronary artery. The results are shown in Table 4.

Table 4 Pharmacology Experiment Example 6 Effect on lipid peroxidation prevention Male Spr
ague-Dae+ley rats (body weight 300-35
using the method of Shimada et al. (Biochim, Bi
ophys.

^eta, No. 572S, page 531 (1979)]
Therefore, liver mitochondria are prepared and ascorbic acid, ferrous sulfate, potassium chloride and Tris-HCl buffer are added thereto. A test compound dissolved in dimethyl sulfoxide was added to this solution and reacted at 25° C. for 30 minutes, and the amount of malondialdehyde produced was determined by the thiobarbic acid method.

50% of test compound A for malondialdehyde formation
The inhibitory concentration was 6 μmol.

Acute toxicity experiment When test compound C was orally and intraperitoneally administered to ddY mice and observed for 5 days, no deaths were observed with oral administration of 1000 μg/kg and intraperitoneal administration of 250 mg/kg.

When the compound of the present invention is used as a medicine, a suitable carrier,
It can be mixed with excipients, diluents, etc., and administered in the form of powders, tablets, capsules, granules, injections, suppositories, ointments, etc. Although the dosage may vary depending on the patient's symptoms, weight, age, etc., 10 to 500 mg per dose is usually appropriate for adults.

Formulation Example 1: Tablet (25mg tablet) Compound (1) 25.0mg Lactose 59.5 Corn Starch 20.0 Crystalline Cellulose
10.0 Methylcellulose
1.0 Talc 4.0 Magnesium stearate 0.5120.0■
g (50mg tablet) Compound (1) 50.0mg lactose 67.0 corn starch 25.0 crystalline cellulose
20.0 Methylcellulose
1.5 Talc 6.0 Magnesium stearate 0.5170.0m
g Pharmaceutical formulation example 2: 10% powder compound (1) 10.0% milk I!
59.5 Corn starch 30.0 Talc
0.5100.0% The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.

Example 1 3-nitrobenzaldehyde 7.5 g (!: 1-
Phenyl-2-piperidinoethyl acetoacetate 14
．． An ethanol solution of 4.2 g of 3-aminopyrazole was added to 1-phenyl-2-piperidinoethyl α-acetyl-3-nitrosinnamate prepared from 5 g, and the mixture was heated at 50°C.
, stir for 3 hours. The reaction solution was concentrated under reduced pressure and subjected to silica gel chromatography using a mixed solvent of chloroform, ethyl acetate and ethanol as an eluent.
Separate and purify the two diastereomers. When the first eluate is concentrated and recrystallized from ethanol, 1-
Phenyl-2-piperidinoethyl 5-methyl-7-(
3-nitrophenyl)-4,7-cyhydropyrazolo(1
, 5-a) Obtain one diastereomer (α form, melting point 92-93°C) of pyrimidine-6-carpoxylate.

In addition, when the next eluate is concentrated and recrystallized from ethanol, l-phenyl-2-piperidinoethyl
The other diastereomer (β form, melting point 19
1-192°C).

Example 2 Ethyl α-acetyl-β-(3-aminopyrazole-
2-yl)-β-(2-trifluoromethylphenyl)
34.5 g of propionate was added to chloroform 20 (1+
The reaction solution was washed with water, dried and concentrated, and purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent to obtain 24 g of a product. This was crystallized from isopropyl ether and then recrystallized from ethanol, resulting in 6-nitoxycarbonyl-5-methyl-7-(2-
trifluoromethylphenyl)-4,7-cihydropyrazolo(1,5-a)pyrimidine (melting point 182-183°C
).

Ethyl α-acetyl-β-(3-aminopyrazole-
2-yl)-β-(2-trifluoromethylphenyl)
Propionate was synthesized as follows.

36 g of ethyl α-acetyl-2-trifluoromethyl cinnamate and 10.5 g of 3-aminopyrazole were dissolved in 200 ml of ethanol and stirred at room temperature for 5 hours. When the precipitated white crystals were collected by filtration, 8.5 g of ethyl α-
Acetyl-β-(3-aminopyrazol-2-yl)-
β-(2-trifluoromethylphenyl)propionate (melting point 136-137°C) is obtained.

Example 3 30 g of 3-nitrobenzaldehyde and 1-phenyl-2
- Crude 1-phenyl-2-piperidinoethyl α- synthesized from 67 g of piperidinoethyl acetoacetate
A 500 ml ethanol solution of 2-aminoimidazole prepared from 26.4 g of 2-aminoimidazole sulfate and sodium hydroxide is added to acetyl-3-nitrosinnamate, and the mixture is stirred at 50°C for 5 hours. From now on, if the precipitated crystals are filtered and further recrystallized from ethanol, 9.
7 g of one diastereomer (α body, melting point 205-20
6°C). Further, the filtrate is concentrated under reduced pressure and purified by silica gel column chromatography using a mixed solvent of chloroform-ethyl acetate-ethanol as an eluent. When the obtained crystals were recrystallized from a mixed solvent of chloroform-ethanol, 4.8 g of 1-phenyl-2-piperidinoethyl 7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo [1° 2-a] The other diastereomer of pyrimidine-6-carpoxylate (β form, melting point 216-217°C, decomposed) is obtained.

Example 4 10.5 g of 2-aminoimidazole sulfate in 11 ml
of water, and to this is added a sodium ethoxide solution prepared from 1.7 g of sodium metal and 200 ml of ethanol. The precipitated crystals are separated by filtration, and the filtrate is added with ethyl α-
Add 15.5 g of acetyl crotonate and incubate at 50°C for 30 minutes.
Heat and stir at 75° C. for 3 hours. After ethanol is distilled off under reduced pressure, the mixture is extracted with chloroform and washed with water. After drying,
The solvent was distilled off under reduced pressure to obtain white crystals, which were recrystallized from ethanol to yield 10.2 g of 6-nitoxycarbonyl-5,7-dimethyl-5,8-dihydroimidazo(1,2-a ) Pyrimidine (melting point 185-186
．． 5°C).

Example 5 Ethyl 3-nitro-α-acetyl sinname) 2.
6 g and 0.9 g of 5-aminotetrazole are heated under reflux for 16 hours in 50 ml of ethanol. Upon cooling, 2 g of 6-nitoxycarbonyl-5-methyl-7-(3-nitrophenyl)-4,7-cyhydrotetrazolo(1,5-
a) Pyrimidine (melting point 210-212°C) is obtained.

Example 6 7.8 g of ethyl α-acetyl crotonate and 4.2 g of 3=amino-1,2,4-)riazole were mixed with 5 ml of ethanol.
After stirring at 50° C. for 1 hour in 0-1, the mixture was heated under reflux for 1 hour. Ethanol was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethanol, yielding 7 g of 6-nitoxycarbonyl-5.7-dimethyl-4.7-sihydro1.2.4-
) Riazolo[1,5-a)pyrimidine (melting point 155-1
57°C).

Example 7 Low ethoxycarbonyl-5,7-dimethyl=4.7-
6.7 g of dihyde tl-1,2,4-triazolo(115-a)pyrimidine is dissolved in 40-cm of acetic acid and heated to 50°C. To this, add 8 solutions of acetic acid 20alt containing 4.8g of bromine.
The reaction solution was added dropwise for 0 minutes and further stirred at 50-60°C for 1 hour. The reaction solution was poured into water, extracted with chloroform, washed with water, dried, and purified by silica gel column chromatography to yield 0.5 g of 5-dibromomethyl-6. -Nitoxycarbonyl-7-methyl-4,7-sihydro1,2,4-triazolo(1,5-a)pyrimidine (melting point 170-171
°C, decomposition).

Example 8 Methyl 2-acetyl-3-(2-chenyl)acrylate 50g and 3-amino-1,2,4-triazole 2
0 g was heated to reflux in 300 sl of ethanol for 4 hours. When the precipitated white crystals were collected by filtration, 29.5 g of 6-medoxycarbonyl-5-methyl-7-(2-chenyl)-
4,7-sihydro1゜2.4-triazolo(1,5-
a) Pyrimidine (melting point 239-240°C) is obtained.

Methyl 2-7cetyl-3-(2-chenyl)acrylate was synthesized as follows.

2-thiophenecarbaldehyde 112g, methyl acetoacetate 116g, benzene 770ml 1° Vinegar M4
A solution of +*l and piperidine 31 is heated to reflux for 2.5 hours under azeotropic dehydration conditions. After removing benzene under reduced pressure,
When distilled under reduced pressure, 199 g of methyl 2-acetyl-3-
(2-chenyl)acrylate (boiling point 130-160℃
/ 0.2 s+aHg).

Example 9 6-Medoxycarbonyl-5-methyl-7-(2-chenyl)-4,7-sihydro1.2.4-triazoO(
1,5-a) 29.5 g of pyrimidine in 300 ml of acetic acid
Add 16 g of bromine to the solution heated to 60°C with stirring.
A solution of 50 ml of acetic acid was added dropwise over 20 minutes. After stirring at room temperature for 1 hour, the reaction solution was poured into water, extracted with chloroform, washed with water and an aqueous potassium carbonate solution, dried, and the solvent was distilled off under reduced pressure. The obtained pale yellow crystals were recrystallized from ethanol to yield 18 g of 5-bromomethyl-6-medoxycarbonyl-7-(2-chenyl)-4°7-sihydro-1.2.4-triazolo[l,5- a) Pyrimidine (melting point 155° C., decomposition) is obtained.

Example 10 29.2 g of benzalacetone and 3-amino-1.2.
4-triazole l? , 6g dimethylformamide 1
Reflux in 501 for 3 hours. When left to cool, crystals precipitate,
When this is collected by filtration and recrystallized from dimethylformamide,
17 g of 5-methyl-7-phenyl-4,7-sihydro-1,2,4-triazolo(1,5-a)pyrimidine (
(melting point 220-222°C).

Example 11 41.3 g of 2-aminoimidazole sulfate was added to 50 m of water.
6.8 g of sodium hydroxide and 50 g of methanol dissolved in
Add 0ml, stir, and dry with Glauber's salt. 77. Add methyl α-acetyl-3-nitrosine to this solution.
9 g was added, stirred at 50°C for 2.5 hours, and further heated under reflux for 1.5 hours. After cooling, the precipitated crystals were collected by filtration and
．． 4 g of 6-medoxycarbonyl-7-methyl-5-
(3-nitrophenyl)-5,8-dihydroimidazo(
1,2-a) Pyrimidine (melting point 263-264°C, decomposition) is obtained.

Example 12 6-Medoxycarbonyl-7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo(1,2-a
) Dissolve 20.0 g of pyrimidine in 200+ sl of acetic acid, add 3.0 g of 10% palladium-carbon, and stir at room temperature under a hydrogen stream for 5 hours. Filter the reaction solution, neutralize the filtrate with aqueous sodium bicarbonate, and add chloroform. Extract with The extract is dried, the solvent is distilled off under reduced pressure, and the precipitated pale yellow crystals are collected by filtration. This was recrystallized from methanol and 11.0 g of 5-(
3-aminophenyl)-6-medoxycarbonyl-7-
Methyl-5,8-dihydroimidazo(1,2-a)pyrimidine (melting point 224-225°C) is obtained. , Example 13 4.0 g of 2-aminoimidazole sulfate was added to 1 Oall of water.
Dissolved in 1.2 g of sodium hydroxide and 20 g of methanol
Add 01 and dry with Glauber's salt. 9.5 g of 2-methoxyethyl/α-acetyl-2-trifluoromethylcinnamate was added to this solution and stirred at 50°C for 3 hours. The mixture was further heated under reflux for 3.5 hours, the solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration. When this was reconsolidated from a mixed solvent of methanol and chloroform, 5.5 g of 6-(2-methoxyethoxycarbonyl)-7-methyl-5-(2-)lifluoromethylphenyl)-5,8-dihydroimidazo( 1
, 2-a) Obtain pyrimidine (melting point 181-182°C).

2-Methoxyethyl α-acetyl-2-trifluoromethylcinnamate was synthesized as follows.

12.2 g of 2-trifluoromethylbenzaldehyde,
2-methoxyethyl acetoacetate) 11.2g1
Add 1a+1 piperidine and 2ml of acetic acid to 150ml of benzene.
1 and heated under reflux for 3 and a half hours under azeotropic dehydration conditions,
The solvent was distilled off under reduced pressure to obtain a reddish brown oil. This was distilled under reduced pressure to obtain 15.5 g of 2-methoxyethyl α
-Acetyl-2-trifluoromethylcinnamate (boiling point 145-151'C10,5 m+wHg) is obtained.

Example 14 6.8 g of 2-aminoimidazole sulfate and methyl 2-
Acetyl-3-cyclohexyl acrylate 10.5
Crystals are obtained from g in the same manner as in Example 13. When this was recrystallized from methanol, 4.8 g of 5-cyclohexyl-6-medoxycarbonyl-7-methyl-5.
8-dihydroimidazo(1,2-a)pyrimidine (melting point 178°C) is obtained.

Example 15 10.7 g of 2-pyridinecarbaldehyde and methyl
13 g of acetoacetate was dissolved in 100 ml of benzene with 0 acetic acid.
．． 30 ~ in the presence of 5 ml and 0.25 ml of pimiridine
The reaction mixture was heated at 40° C. for 2 hours, washed with brine, dried, and the solvent was distilled off. To this, 150 g of isopropanol of 2-aminoimidazole prepared from 10.5 g of 2-aminoimidazole sulfate and 2.9 g of sodium hydroxide was added.
Add the a+1 solution and heat under reflux for 2 hours. The reaction solution was passed through a silica gel column, and the solvent of the obtained eluate was distilled off and crystallized from methanol, yielding 2.5 g of 6-medoxycarbonyl-7-methyl-5-(2-pyridyl)-5,8.
-dihydroimidazo(1,2-a)pyrimidine (melting point 2
24-226°C, decomposition).

Example 16 From 7.6 g of 3-nitrobenzaldehyde, 10.1 g of 2-N,N-diethylaminoethyl acetoacetate, and 4.5 g of 2-aminoimidazole sulfate, 1.6 g of 3-nitrobenzaldehyde was prepared in the same manner as in Example 15. 2-N,N-diethylaminoethyl 5-(3-nitrophenyl)-7-methyl-5,8-dihydroimidazo(1,2-a)pyrimidine-6-carboxylade (melting point 119-121'
C) is obtained.

Example 17 5-[3-(2-methyl-1,3-dioxolane-2
-yl)phenyl2-6-medoxycarbonyl-methyl-5,8-dihydroimidazo[1,2-a)pyrimidine 1.8g in acetone 50ml 1゜methanol 30-1
The mixture was dissolved in a mixed solvent of 201 and 201 of water, added with p-toluenesulfonic acid to bring the po to 1, and heated at 60° C. for 3 hours.

The solvent was distilled off, the mixture was neutralized with aqueous sodium bicarbonate solution, and the resulting white precipitate was collected by filtration. This was recrystallized from a mixed solvent of ethanol-acetone, and 1.1 g of 5-(3-7cetylphenyl)-6-medoxycarbonyl-7-methyl-5,8-dihydroimidazo(1,2-a)pyrimidine ( Melting point 227-229℃
).

5- (3-(2-methyl-1,3-dioxolane-2
-yl)phenyl-6-medoxycarbonyl-methyl-5,8-dihydroimidazo[1,2-al pyrimidine was synthesized as follows.

3-(2-methyl-1,3-dioxolan-2-yl)
Benzaldehyde 11g 1 Methyl acetoacetate 7
．． 3g of 5-(3-(2
-Methyl-1,3-dioxolan-2-yl)phenyl-6-medoxycarbonyl-methyl-5,8-dihydroimidazo(1,2-a)pyrimidine (melting point 19
9-201°C).

Example 18 To an isopropanol solution of 2-aminoimidazole prepared from 7.9 g of 2-aminoimidazole sulfate and 2.2 g of sodium hydroxide, 11.7 g of α-7 cetyl-3-nitrocrotonamide was added and heated for 5 hours. Reflux. From now on, the precipitated crystals were collected by filtration, and 12 g of 6-carpamoyl-7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine (melting point 23
8-240°C).

α-7 cetyl-3-nitrocrotonamide was synthesized by the following method.

10 g of acetoacetamide and 15 g of 3-nitrobenzaldehyde were dissolved in 0.0 g of piperidine in 100 ml of isopropanol.
:1+1 and stirred at 35° C. for 4 hours in the presence of 0.5 ml of acetic acid. When the precipitated yellow crystals were collected by filtration, 20g of α
-Acetyl-3-nitrocrotonamide (melting point 159~
161t) is obtained.

Example 19 3 g of 6-carpamoyl-7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1゜2-a]pyrimidine is dissolved in 30 ml of dimethylformamide, and 1.5 ml of thionyl chloride is added dropwise at room temperature. . After stirring for 1 hour, the reaction solution was poured into chloroform, washed with sodium bicarbonate solution, and then passed through a 40 g silica gel column using a mixed solvent of dichloromethane-ethanol as an eluent. If the eluted solution was allowed to stand, crystals would precipitate. When this is filtered, 1.1g
6-dia2-7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine (melting point 278-280°C, decomposed).

Example 20 4.5 g of 2-aminoimidazole sulfate and 1.3 g of sodium hydroxide were dissolved in 11 ml of water and 50 ml of ethanol was added.
Add and dry with Glauber's salt. Add ethyl 4,4 to this solution.
-dimethoxy-2-(3-nitrobenzylidene)-3-
Add 10 g of oxobutyrate, stir at 50° C. for 30 minutes, and further heat under reflux for 6 hours. Next, the precipitated yellow crystals were collected by filtration, purified by silica gel column chromatography using chloroform-methanol as an eluent, and recrystallized from methanol. 3-nitrophenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine (melting point 190-191°C, decomposition) is obtained.

Ethyl 4,4-dimethoxy-2-(3-nitrobenzylidene)-3-oxobutyrate was synthesized by the following method.

3-nitrobenzaldehyde 24g 1 ethyl 4.4-
30 g of dimethoxy-3-oxobutyrate, 0.51 l of piperidine and 1 s+1 acetic acid are dissolved in 200 ml of benzene and heated to reflux under azeotropic dehydration conditions for 4 hours. The solvent was distilled off under reduced pressure and 36 g of ethyl 4,4-
Dimethoxy-2-(3-nitrobenzylidene)-3-oxobutyrate (boiling point 195-210℃/0.2s
sHg).

Example 21 7-dimethoxymethyl-6-ethoxycarbonyl-5-
(3-nitrophenyl)-5,8-dihydroimidazo(
1,2-a) Dissolve 4.4 g of pyrimidine in a mixed solvent of 10 ml of acetone and 10 ml of water, add 10@-1 of 6N hydrochloric acid, stir at room temperature for 1 hour, and leave to stand overnight. When the solvent was distilled off under reduced pressure at 40°C or lower, 4g of 6-nitoxycarbonyl-7-formyl-5-(3-nitrophenyl)-5
, 8-dihydroimidazo(1,2-a)pyrimidine hydrochloride (melting point 228°C, decomposed).

Example 22 6-nitoxycarbonyl-7-formyl-5-(3-nitrophenyl)-5,8-dihydroimidazo(1,2-
a) Dissolve pyrimidine hydrochloride in 20 el of ethanol and 2 ml of dimethylformamide (1+1 mixed solvent), add 0.88 g of hydroxylamine hydrochloride and 1.2 g of sodium carbonate.
Add 2g and stir at 50°C for 1.5 hours. The solvent was distilled off under reduced pressure, water was added, and the precipitated yellow crystals were collected by filtration. When this was recrystallized from a mixed solvent of chloroform-methanol, 2.0 g of 6-nitoxycarbonyl-7-hydroxyiminomethyl-5-(3-nitrophenyl)-5°8-
Dihydroimidazo(1,2-a)pyrimidine (melting point 22
9-230°C, decomposition).

Example 23 6-nitoxycarbonyl-7-hydroxyiminomethyl-5-(3-nitrophenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine 1.25 g, sodium acetate 0.29 g and anhydrous 0.4-1 acetic acid to 1 acetic acid
The reaction solution was poured into water and the precipitated yellow crystals were collected by filtration and recrystallized from a mixed solvent of chloroform-ethanol to give 0.
5g of 7-cya-6-ethoxycarbonyl-5-(3
-nitrophenyl)-5,8-dihydroimidazo(1,
2-2) Obtain pyrimidine (melting point 260-26MC1 decomposition).

Example 24 12 g of 8-carboxy-3-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydroimidazo(1,5-a)pyrimidine was mixed with 2 at 215°C.
Heat for 0 minutes. Purification was performed by silica gel column chromatography using chloroform as an eluent, and the resulting yellow crystals were recrystallized from ethanol to yield 1.5 g of 3-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4. -dihydroimidazo(1,5-a)pyrimidine (melting point 196-197°C) is obtained.

8-Carboxy-3-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydroimidazo(1,5-a)pyrimidine was synthesized by the following method.

3.8-Jethoxycarbonyl-2-methyl-4-(3
-nitrophenyl)-1,4-dihydroimidazo(1,
5-a) Dissolve 1.0 g of pyrimidine in 20 ml of ethanol, add a solution of 17 g of potassium hydroxide O in 1.7 ml of water, gradually warm, and stir at 70°C for 10 hours. The ethanol is distilled off under reduced pressure, chloroform is added to the obtained oil, and the mixture is extracted with potassium carbonate solution. After washing this aqueous layer with chloroform, the pH was adjusted to 5 to 6 with acetic acid and the precipitated crystals were collected by filtration. When this is recrystallized from ethanol, 0
．． 32 g of 8-carboxy-3-ethoxycarbonyl-
2-Methyl-4-(3-nitrophenyl)-1°4-dihydroimidazo(1,5-a)pyrimidine (melting point 222
°C, decomposition).

3.8-Jethoxycarbonyl-2-methyl-4-(3
-nitrophenyl)-1,4-dihydroimidazo(1,
5-a) Pyrimidine was synthesized by the following method.

5-amino-4-ethoxycarbonylimidazole 2g
and ethyl α-acetyl-3-nitrosin name) 3
．． 4 g was dissolved in ethanol 50-1 and heated under reflux under nitrogen atmosphere for 7 hours. Ethanol is distilled off under reduced pressure, and the resulting oil is purified by silica gel column chromatography using a mixed solvent of chloroform-methanol as an eluent. Recrystallization from a mixed solvent of isopropyl alcohol-isopropyl ether yields 2.5 g of 3,8-jethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydroimidazo(1,5-a ] Pyrimidine (melting point 160-162°C) is obtained.

Example 25 17-g of 6-medoxycarbonyl-5-methyl-7-(2-trifluoromethylphenyl)pyrazolo[1°5-a]pyrimidine was dissolved in 1 ml of methanol and heated to 60°C while stirring. Gradually add 16 #g of sodium borohydride. 1. Pour the reaction mixture into water and extract with ethyl acetate.
dry. Removal of the solvent and recrystallization from methanol yielded 6-medoxycarbonyl-5-methyl-7-(2-trifluoromethylphenyl)-4,7-cyhydropyrazolo(1,5-a)pyrimidine (mp 209-210 ℃)
get.

For example, the following compounds are produced in the same manner as in the above examples.

(26) 6-nitoxycarbonyl-5-methyl-7
-(3-nitrophenyl)-4,7-cihydropyrazolo(1,5-a)pyrimidine, melting point 157-159°C (decomposed) (27) 6-nitoxycarbonyl-7-methyl-5
-(3-nitrophenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine, melting point 242-243°C (28)? -Chloromethyl-6-nitoxycarbonyl-5-(3-nitrophenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine, melting point 190-192°C
(Decomposition) (29) 6-tertiary butoxycarbonyl-7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine, melting point 219-22
2°C (decomposition) (30) 6- (2-cyanoethoxycarbonyl)
-7-methyl-5-(3-nitrophenyl)-5゜8-
Dihydroimidazo(1,2-a)pyrimidine, melting point 23
0-237°C (31) 6-nitoxycarbonyl-7-N-methylcarbamoyloxymethyl-5-(3-nitrophenyl)
-5,8-dihydroimidazoct, 2-a] Pyrimidine, melting point 207-208°C (min M) (32) 6-nitoxycarbonyl-7-hydroxymethyl-5-(3-
Nitrophenyl)-5,8-dihydroimidazo(1,2
-a) Pyrimidine, melting point 196-197°C (decomposition) (33) 6-nitoxycarbonyl-5-(3-nitrophenyl)-7-)lifluoromethyl-5,8-dihydroimidazo(1,2-a ) Pyrimidine, melting point 240~
242°C (decomposition) (34) 6-benzyloxycarbonyl-7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine, melting point 205°C (35) 6- (2-methoxyethoxycarbonyl)-7-methyl-5-(3-nitrophenyl)-5゜8
-dihydroimidazo(1,2-a)pyrimidine, melting point 1
85-186°C (36) 3-N,N-dimethylaminopropyl 7-methyl-5-(3-nitrophenyl)-5,8=dihydroimidazo(1,2-a)pyrimidine-6-carpoxylate (37 ) 6-nitoxycarbonyl-5-(3-nitrophenyl)-7-broby-5,8-dihydroimidazo(1,2-a)pyrimidine (38) 6-carpoxy7-formyl-5-(3-
Nitrophenyl)-5,8-dihydroimidazo(1,2
-a) Pyrimidine hydrochloride, melting point 350°C or higher (39)? -Methyl-5-(3-nitrophenyl)-
5,8-dihydroimidazo(1,2-a)pyrimidine, melting point 194-196°C (decomposed) (40) 6-nitoxycarbonyl-7-methyl-5
=(2-nitrophenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine, melting point 253-254°C (decomposed) (41) 6-medoxycarbonyl-7-methyl-5
-(2-nitrophenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine, melting point 256-258°C (decomposition) (42) 6-medoxycarbonyl-7-methyl-5
=(4-nitrophenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine, melting point 249°C (decomposition) (43) 6-nitoxycarbonyl-7-methyl-5
-(2-trifluoromethylphenyl)-5,8-dihydroimidazo(1,2-3)pyrimidine, melting point 276°C (44) 6-medoxycarbonyl-7-methyl-5-
(2-)Lifluoromethylphenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine, melting point 285-2
86℃ (decomposition) (45)? -acetoxymethyl-6-nitoxycarbonyl-5-(2-)lifluoromethylphenyl)-5,
8-dihydroimidazo(1,2-a)pyrimidine, melting point 174-176°C (46) 2-piperidinoethyl 7-methyl-5-
(2-Trifluoromethylphenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine-6=carboxilade, melting point 205-207°C (decomposition) (47) 6
-Nitoxycarbonyl-7-methyl-5-(3-trifluoromethylphenyl)-5,8-dihydroimidazo(
1,2-a) Pyrimidine, melting point 193-194°C (4B)? -Methyl-6-(2-nitroethoxycarbonyl)-5-(2-)lifluoromethylphenyl)
-5,8-dihydroimidazo(1,2-a)pyrimidine (49) 5- (2-benzylthiophenyl)-6-
Medoxycarbonyl-7-methyl-5,8-dihydroimidazo(1,2-a)pyrimidine, melting point 196-19
8℃ (50) 5-(2-chlorophenyl)-6-medoxycarbonyl-7-methyl-5,8-dihydroimidazo(
1,2-a) Pyrimidine, melting point 257-258°C (decomposition) (51) 6-nitoxycarbonyl-7-methyl-5-
Phenyl-5,8-dihydroimidazo(1,2-a)pyrimidine, melting point 183-184°C (52) 6-nitoxycarbonyl-7-methyl-5-(2-methylphenyl)-5,8-dihydroimidazo( 1,2-a) Pyrimidine, melting point 215°C (53) 5-(2-cyanophenyl)-6-medoxycarbonyl-7-methyl-5.8
-dihydroimidazo(1,2-a]pyrimidine, melting point 2
68℃ (decomposition) (54) 6-Medoxycarbonyl-7-methyl-5
-(2-methylthiophenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine, melting point 259-260
°C (decomposition) (55) 5-(4-aminophenyl)-6-medoxycarbonyl-7-methyl-5,8-dihydroimidazo(1,2-a)pyrimidine, pale yellow crystals (56) 6-
Medoxycarbonyl-5-(2-methoxyphenyl)-
7-Methyl-5,8-dihydroimidazo(1,2-a)
Pyrimidine, melting point 242-245°C (decomposed) (57) 6-nitoxycarbonyl-7-methyl-5-
Propyl-5,8-dihydroimidazo(1,2-a)pyrimidine, melting point 144-145°C (5B) 6-Medoxycarbonyl-7-methyl-5-(2-chenyl)-5
,8-dihydroimidazo(1,2-2)pyrimidine, melting point 230-232°C (decomposed) (59) 5-(2-furyl)-6-medoxycarbonyl-7-methyl-5,8-dihydroimidazo[1 ，
2-a) Pyrimidine (60) 6-nitoxycarbonyl-7-methyl-5°8-dihydroimidazo(1,2-a)pyrimidine, melting point 248-249°C (61) ? -Methyl-5-phenyl-5,8-dihydroimidazo(1,2-a)pyrimidine (62) 6-
Nitoxycarbonyl-5-methyl-7-(3-nitrophenyl)-4,7-dihydro=1.2.4-triazo
(1,5-a)pyrimidine, melting point 222-224°C (63) 5-acetoxymethyl-6-nitoxycarbonyl-7-(3-nitrophenyl)-4,7-sihydro1.2.4-)riazolo (1,5-al pyrimidine,
Melting point 169-171℃ (64) 6-Medoxycarbonyl-7- (3,4-
dimethoxyphenyl)-5-methyl-4,7-sihydro-1,2,4-triazolo(1,5-a,)pyrimidine, melting point 211-213°C (65)? -(2-chlorophenyl)-6-medoxycarbonyl-5-methyl-4,7-sihydro 1.2
．． 4-) Riazolo(1,5-a)pyrimidine, melting point 26
8-271t (Decomposition) (66) 6-Medoxycarbonyl-5-methyl-7-
(2-)Lifluoromethylphenyl)・-4,7-sihydro1.2.4-triazolo(1,5-a)pyrimidine, melting point 242°C (67) 5-bromomethyl-6-medoxycarbonyl-7- (2-)lifluoromethylphenyl)-4,7-
Sihydro 1.2.4-Triazolo [l.

5-a] Pyrimidine, melting point 160-170°C (68)
5-chloromethyl-7-(4-hydroxyphenyl)
-6-Medoxycarbonyl-4.7-Sihydro1.2
．． 4-triazolo(1,5-a)pyrimidine, melting point 29
0°C (decomposition) (69) 6-nitoxycarbonyl-5-methyl-7-
(3-pyridyl)-4,7-sihydro1.2゜4-triazolo(1,5-a)pyrimidine, melting point 221-22
3℃ (70) 5-Tertiary butyl-7-(3-pyridyl)-
4,7-Sihydro1.2.4-Triazolo[1,5-
a) Pyrimidine, melting point 179-181°C (71) 1
-Phenyl-2-N,N-dibutylaminoethyl 7-
Methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine-6-carpoxylate, α-form melting point 146-147°C, β-form melting point 17
4-175℃ (72) 1-(2-chenyl)-2
-Piperidinoethyl 7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo(1,2-a)
Melting point of pyrimidine-6-carpoxylate, alpha form: 204
~206℃, melting point of β form 182-183℃ (73) 1
-phenyl-2-(N-methyl-N-benzylamino)
Ethyl 7-methyl-5-(3-nitrophenyl)-5
,8-dihydroimidazo[1゜2-a]pyrimidine-6
- Carpoxylate, melting point of α form 193-194°C, β
Melting point: 188-190°C (74) 1-(2-furyl)-2-piperidinoethyl 7-methyl-5-(3-nitrophenyl)-5,
8-dihydroimidazo(1,2-a)pyrimidine-6-
Carpoxylate, α-form melting point 199-200°C (decomposition), β-form melting point 186-187°C (decomposition) (75) 6-carpamoyl-7-methyl-5-(2
-trifluoromethylphenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine, melting point 254-25
5°C (76) 6-dia2-7-methyl-5-(2-trifluoromethylphenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine hydrochloride, melting point 275-27
8°C (77) 6-nitoxycarbonyl-5,7-dimethyl-4,7-sihydropyrazolo(1,5-a)pyrimidine, melting point 168-170°C (7B) 2-methoxy-1-phenylethyl 7-methyl -5-(3-nitrophenyl)-5,8-dihydroimidazo(1,2-a)pyrimidine-6-carpoxylate, α-form melting point 194-195°C, β-form melting point 184
°C (79) 6-medoxycarbonyl-5-methyl-7
-(3,4-dihydroxyphenyl)-4,7-cyhydrobyrazolo(1,5-a)pyrimidine, m.p. 253-2
55°C (80) 5-acetoxymethyl-6-nitoxycarboni)Lt-1-<2-trifluoromethylphenyl)-
4,7-cyhydropyrazolo(1,5-a)pyrimidine,
Melting point: 166-167°C (81) 6-nitoxycarbonyl-5-hydroxymethyl-7-(2-1-lifluoromethylphenyl)-4,
7-Sihydropyrazolo(1,5-a)pyrimidine, melting point 229-230°C (82) 6-Medoxycarbonyl-5-methyl-7-
(3-pyridyl)-4,7-cyhydropyrazolo(1,5
-2) Pyrimidine, melting point 222-223°C (83) 6-nitoxycarbonyl-5-propy15-
7-(2-chenyl)-4,'? -dihydropyrazo0(
1,5-a) Pyrimidine, melting point 169-170°C (84) 6-nitoxycarbonyl-5-methyl-7-
(2-chlorophenyl)-4,7-cyhydropyrazolo(
1,5-a) Pyrimidine, melting point 176-178°C (85) 6-ptoxycarbonyl-5-methyl-7-
(2-)Lifluoromethylphenyl)-4,7-cihydrobyrazolo(1,5-a)pyrimidine, melting point 134-1
36℃ (86) 6-Medoxycarbonyl-5-methyl-7-
(2-Hydroxyphenyl)-4,7-cyhydrobyrazolo(1,5-a)pyrimidine, melting point 218-220°C (87) 5-chloromethyl-6-nitoxycarbonyl-7-(2-)lifluoromethylphenyl )-4,7-
Cyhydropyrazolo(1,5-a)pyrimidine, melting point 14
7-149°C (88) 6-nitoxycarbonyl-5-fluoromethyl-7-(2-)lifluoromethylphenyl)-4,
7-Sihydropyrazolo(1,5-a)pyrimidine (89) 6-acetyl-5-methyl-7-(3-nitrophenyl)-4,7-cyhydropyrazolo[1°5-a
]Pyrimidine, melting point 190-192℃ (90) 6-
Benzyloxycarbonyl-5-methyl-'? -(2-
) Lifluoromethylphenyl)-4,7-cihydrobyrazolo(1,5-a)pyrimidine, melting point 164-166°C (91) 6-carboxy-5-methyl-? -(2-trifluoromethylphenyl)-4,7-cyhydropyrazolo(1,5-a)pyrimidine, melting point 172-173°C
(Decomposition) (92) 6-nitoxycarbonyl-5-methyl-7~
(3-Trifluoromethylphenyl)-4,7-cyhydropyrazolo(1,5-a)pyrimidine, melting point 189-1
90℃ (93) 6-nitoxycarbonyl-5-methyl-7-
(2-methylphenyl)-4,7-cyhydropyrazolo(
1,5-a) Pyrimidine, melting point 186-187°C Agent Patent attorney Takamiyagi Winning Procedure Dispute Manual (spontaneous) December 9, 1985 Commissioner of the Patent Office Michibu Uga 16 Display of the case 1985 Patent Application No. 52940 2, name of the invention Polyazaheterocyclic derivative 3, relationship with the case of the person making the amendment Patent applicant address 3-35 Hirano-cho, Higashi-ku, Osaka Name Yoshitomi Pharmaceutical Co., Ltd. (672) Representative Oku 1) Mitsuruo 4,
Agent address: 3-35 Hirano-cho, Higashi-ku, Osaka City The following statement is inserted between lines 9 and 10 on page 57 of the detailed description of the invention in column 6 of the detailed description of the invention in the specification.

r(94) 5-methyl-6-propoxycarbonyl-? -(2-)lifluoromethylphenyl) -4,7
-cyhydropyrazolo(1,5-a)pyrimidine, melting point 1
68-169°C (95) 6-isopropoxycarbonyl-5-methyl-7-(2-trifluoromethylphenyl)-4,7
-cyhydropyrazolo(1,5-a)pyrimidine, melting point 1
60-162°C (96) 6-isobutoxycarbonyl-5-methyl-7-(2-trifluoromethylphenyl)-4,7-
Cyhydrovirazolo(1,5-a)pyrimidine, melting point 14
4-145°C (97) 6-tertiary butoxycarbonyl-5-methyl-7-(2-)lifluoromethylphenyl)-4,7
-cyhydrobirazolo(1,5-a)pyrimidine, melting point 1
68 to 170℃'' Procedural Order (self-motivated) April 2, 1985 Michibe Uga, Director General of the Patent Office 1. Indication of the case 1985 Patent Application No. 52940 2. Name of the invention Polyaza Heterocyclic derivative 3, relationship with the case of the person making the amendment Patent applicant address: 3-35 Hirano-cho, Higashi-ku, Osaka Name: Yoshitomi Pharmaceutical Co., Ltd. (672) Representative: Oku 1) Mitsuo 4;
Agent address: 3-35 Hirano-cho, Higashi-ku, Osaka City Column 6 of the detailed description of the invention in the specification, the description of the contents of the amendment, is amended as follows.

(1) After “Mijin” on page 56, line 10, “,
Melting point 118-119°C" is added.

(2) Insert the following statement between lines 9 and 10 on page 57.

r(9B) 6-nitoxycarbonyl-5-propyl-? -(2-)lifluoromethylphenyl') -4,
7-Sihydropyrazolo(1,5-a)pyrimidine, melting point 151-152°C a) Pyrimidine, melting point 182-184°C (100) 7-(2-fluorophenyl)-5-
Methyl-6-bropoxycarbonyl-4,7-cyhydropyrazolo(1,5-a)pyrimidine, melting point 162-16
4℃ (101) 6-tertiary butoxycarbonyl-7-(
2-Fluorophenyl)-5-methyl-4,7-cyhydrovyrazolo(1,5-a)pyrimidine, mp 179-1
81℃ (102)? -(2-fluorophenyl)-6-
Isobutoxycarbonyl-5-methyl-4,7-cihydropyrazolo(1,5-a)pyrimidine, melting point 150°C (103) 6-ptoxycarbonyl-7-(2-fluorophenyl)-5-methyl-4,7 -Cyhydropyrazolo(1,5-a)pyrimidine 1/8 hydrate, melting point 16
4-165°C (104) 5-ethyl-7-(2-fluorophenyl)-6-isopropoxycarbonyl-4,7-cyhydropyrazolo(1,5-a)pyrimidine, melting point 98-99
°C (105)? -(2-fluorophenyl)-5-
Isopropyl-6-isobroboxycarbonyl 4.7
-cyhydropyrazolo(1,5-a)pyrimidine, melting point 1
83~185℃ (106)? -(2-fluorophenyl)-5-
Hydroxymethyl-6-itsuproboxycarbonyl-4
．． 7-Sihydropyrazolo(1,5-a)pyrimidine, melting point 168-170°C (107) 5-Butyl-7-(2-fluorophenyl)-6-itsuproboxycarbonyl-4,7-cyhydropyrazolo(1,5- a) Pyrimidine, melting point 155-1
57°C (10B) 5-fluoromethyl-7-(2-fluorophenyl)-6-itupropoxycarbonyl 4.7
-cyhydropyrazolo(1,5-a)pyrimidine, melting point 1
26-127℃ (109)? -(2-chlorophenyl)-6-itsuproboxycarbonyl-5-methyl-4,7-cyhydropyrazolo(1,5-a)pyrimidine, melting point 176-1
78℃ (110)? -(2-Bromophenyl)-6-isopropoxycarbonyl-5-methyl-4,7-cyhydrovyrazolo(1,5-a)pyrimidine, mp 158-16
0°C (111) 6-isopropoxycarbonyl-5-methyl-7-(2-methylphenyl)-4,7-cyhydropyrazolo(1,5-a)pyrimidine, melting point 177-17
8°C (112) 6-yptoxycarbonyl-5-methyl-7-(2-methylphenyl)-4,7-cyhydropyrazolo(1,5-a)pyrimidine, melting point 185186°C (113) 5-7'Til -6-Ituproboxycarbonyl-7-(2-)lifluoromethylphenyl)-4
,7-cyclohydropyrazolo(1,5-a)pyrimidine, melting point 133-135°C (114) 6-isopropoxycarbonyl-5-methyl-7-phenyl-4,7-cyclopyrazolo(11
5-a) Pyrimidine, melting point 193-194°C (115)
2-N, N-dimethylaminoethyl 5-methyl-7-(2-)lifluoromethylphenyl)-4,7-
Cyhydropyrazolo(1,5-a)pyrimidine-6-carpoxylate, melting point 161-163°C (116)? -(2-cyanophenyl)-.6-isopropoxycarbonyl-5-methyl-4,7-cyhydropyrazolo(1,5-a)pyrimidine, melting point 185-1
87 degrees Celsius" Above, the main procedural author's letter (spontaneous) April 2g, 19851, case description 1985 Patent Application No. 529402, title of invention polyaza heterocyclic derivative 3, person making amendment case and Relationship Patent Applicant Address 3-35 Hirano-cho, Higashi-ku, Osaka Name Yoshitomi Pharmaceutical Co., Ltd. (672) Representative Oku 1) Mitsuo 4;
Agent address: 3-35 Hirano-cho, Higashi-ku, Osaka The following statement is inserted between line 9 and line 1O of page 57 of the specification of the contents of the amendment in column 6 of the detailed explanation of the invention in the specification.

r(117)? -(2,5-difluorophenyl)
-6-isopropoxycarbonyl-5-methyl-4,7
-dihydropyrazolo(1,5-a)pyrimidine, melting point 1
85-187℃ (118)? -(2,3-difluorophenyl)-
6-isopropoxycarbonyl-5-methyl-4,7-
Dihydropyrazolo(1,5-a)pyrimidine, melting point 17
5-177℃ (119)? -(2-chloro-3-fluorophenyl λ-6-ipropoxycarbonyl-5-methyl-4
,7-dihydropyrazolo(1,5-a)pyrimidine, melting point 205°C (12G)? -(2,6-dichlorophenyl)-6
-Nitoxycarbonyl-5-methyl-4,7-dihydropyrazolo(1,5-a)pyrimidine, melting point 218-21
9℃ (121)? -(2,3-dichlorophenyl)-6
-Nitoxycarbonyl-5-methyl-4,7-dihydropyrazolo(1,5-a)pyrimidine, melting point 213-21
4℃ (122) 7-(2,3-dichlorophenyl)-6
-Imbropoxycarbonyl-5-methyl-4,7-dihydropyrazolo(1,5-a)pyrimidine, melting point 196
~198℃ (123)? -(2,3-difluorophenyl)-
6-Nitoxycarbonyl-5-methyl-4,7-dihydropyrazolo(1,5-a)pyrimidine, melting point 185-1
86℃ (124)? -(2,5-difluorophenyl)-
6-Nitoxycarbonyl-5-methyl-4,7-dihydropyrazolo(1,5-a)pyrimidine, melting point 199-2
00℃ (125)? -(2-chloro-6-fluorophenyl)-6-nitoxycarbonyl-5-methyl-4,7-
Dihydropyrazolo(1,5-a)pyrimidine, melting point 17
3~175℃ (126)? -(2-chloro-6-fluorophenyl)-6-impropoxycarbonyl-5-)4-4,7-dihydropyrazolo(1,5-a)pyrimidine,
Melting point 132-134℃ (127) 6-nitoxycarbonyl-7- (2,
4-difluorophenyl)-5-methyl-4,7-dihydropyrazolo(1,5-a)pyrimidine, melting point 157~
159℃ (128)? -(2,4-difluorophenyl)-
6-isopropoxycarbonyl-5-methyl-4,7-
Dihydropyrazolo(1,5-a)pyrimidine, melting point 14
4-145°C (129) 6-nitoxycarbonyl-7-(2-fluoro-3-chlorophenyl)-5-methyl-4,7-
Dihydropyrazolo(1,5-a)pyrimidine, melting point 20
5~206℃ (130)? -(2-fluoro-3-chlorophenyl)-6-isopropoxycarbonyl-5-methyl-
4,7-dihydropyrazolo(1,5-a)pyrimidine,
Melting point 180-181℃ (131)? -(2,6-difluorophenyl)-
6-nitoxycarbonyl-5-methyl-4,7-dihydropyrazolo(1,5-a)pyrimidine, melting point 144-1
46℃ (132)? -(2,6-difluorophenyl)-
6-Ituproboxycarbonyl-5-methyl-4,7-
Dihydropyrazolo(1,5-a)pyrimidine, melting point 14
3~144℃ (133)? -(2,4-dichlorophenyl)-6
-Ituproboxycarbonyl-5-methyl-4,7-dihydropyrazolo(1,5-a)pyrimidine, melting point 198
~200°C” Above Procedures Juho Seisho (Volunteer) June 72, 1985 1. Indication of the case 1985 Patent Application No. 52940 2. Name of the invention polyazaheterocyclic derivative 3. Person making the amendment 5. Insert the following statement between lines 9 and 10 on page 57 of the specification subject to amendment in column 6 of the detailed description of the invention in the specification subject to amendment.

r(134) 6-nitoxycarbonyl-5-methyl-7-(2-trifluoromethylphenyl)-4,7-
Cyhydrotetrazolo(1,5-a)pyrimidine, melting point 2
20-221°C (135) Two-(2-fluorophenyl)-6-itubropoxycarbonyl-5-methyl-4,7-cyhydrotetrazolo(1,5-a)pyrimidine, melting point 208-
209°C (136) 6-isopropoxycarbonyl-5-methyl-7-phenyl-4,7-cyhydrotetrazolo (1
,5-a) Pyrimidine, melting point 210-211°C (137) 6-isopropoxycarbonyl-5-methyl-7-(2-)lifluoromethylphenyl)-4,
7-Sihydrotetrazolo(1,5-a)pyrimidine, melting point 227-229°C (13B) 6-ptoxycarbonyl-5-methyl-
7-(2-)Lifluoromethylphenyl)-4,7-sihydro1.2.4-)riazolo(1,5-a]pyrimidine, melting point 193-195°C (139) 6-nitoxycarbonyl-5- Methyl-7-(2-trifluoromethylphenyl)-4,7-sihydro1.2.4-triazolo(1,5-a)pyrimidine, melting point 250-252
°C (140)? -(2-fluorophenyl)-6-
Itubroboxycarbonyl-5-methyl-4,7-sihydro-1,2,4-triazolo(1,5-a)pyrimidine, melting point 188-189°C (141)? -(2-fluorophenyl) -5
-(2-Hydroxyethyl)-6-ituproboxycarbonyl-4,7-cyhydropyrazolo(1,5-a)pyrimidine (142)? -(2-fluorophenyl) -5
-(3-Hydroxypropyl)-6-impropoxycarbonyl-4,7-cihydropyrazolo(1,5-a]pyrimidine (143) 6-Dia-2-7-(2-fluorophenyl)-5-methyl-4,7- Cyhydropyrazolo [1,5
-a) Pyrimidine, melting point 215-217°C (144)
? -(2,3-dimethylphenyl)-6-isopropoxycarbonyl-5-methyl-4,7-cihydropyrazolo(1,5-a)pyrimidine (145) 5-acetoxymethyl-7-(2-fluorophenyl) -6-Ituproboxycarbonyl-4,7-sihydrovirazolo (
1,5-a) Pyrimidine (146) 7- (2,5-dichlorophenyl)-
6-itubropoxycarbonyl-5-methyl-4,7-
Cyhydropyrazolo(1,5-a)pyrimidine, melting point 19
1-192°C (147) 5-chloromethyl-7-(2-fluorophenyl)-6-imbroboxycarbonyl-4.7-
Cyhydropyrazolo(1,5-a)pyrimidine, (14B
)? -(2-fluoro-5-chlorophenyl)-
6-isopropoxycarbonyl-5-methyl-4,7-
Cyhydrovirazolo(1,5-a)pyrimidine, melting point 17
9-181℃ (149) 6-tertiary butoxycarbonyl-7-(
2,3-dichlorophenyl)-5-methyl-4,7-cyhydropyrazolo(1,5-a)pyrimidine, melting point 212
~213℃ (150) 5- (3-chloropropyl)-7-
(2-Fluorophenyl)-6-itubropoxycarbonyl-4,7-cihydropyrazolo(1,5-8)pyrimidine, melting point 155-157°C (151) 6-tert-butoxycarbonyl-7-(2
-chlorophenyl)-5-methyl-4,7-cihydropyrazolo(1,5-a)pyrimidine (152) 7-
(2-bromophenyl)-6-tert-butoxycarbonyl-5-methyl-4,7-cyhydropyrazolo(1,5-
a) Pyrimidine (153) 5-acetoxymethyl-
7-(2-fluorophenyl)-6-itubroboxycarbonyl-4,7-cihydropyrazolo(1,5-a)pyrimidine (154) 6-tert-butoxycarbonyl-7-(
2-cyanophenyl)-5-methyl-4,7-cyhydropyrazolo(1,5-a)pyrimidine (155) 6-
Ituproboxycarbonyl-5-methyl-7-(2-methylthiophenyl)-4,7-cyhydrovirazolo(1,
5-a) Pyrimidine (156)? -(2-chlorophenyl)-5-methyl-4,7-cyhydropyrazolo(
1,5-a) Pyrimidine'' (Spontaneous) ■, Indication of the case, 1985 Patent Application No. 52940, 2, Name of the invention, polyazaheterocyclic derivative 3, Person making the amendment, Relationship with the case Patent applicant address: 3-35 Hiranocho, Higashi-ku, Osaka Name: Yoshitomi Pharmaceutical Co., Ltd. (672) Representative: Oku 1) Mitsuo 4;
Address of agent: 3-35-6 Hirano-cho, Higashi-ku, Osaka, Japan Contents of amendment: 6 lines from the bottom of page 5 of the written amendment dated June 12, 1985, after “...pyrimidine”, “,” Melting point 186
〜188℃'' and [, melting point 205 to 206℃'' after ``...pyrimidine'' in three lines from the bottom.

that's all

Claims (1)

[Claims] A polyazaheterocyclic derivative represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ or a pharmaceutically acceptable salt thereof. In the above formula, each symbol is as follows. R is hydrogen, lower alkyl, cyclic alkyl, furyl, thienyl, pyridyl, or as a substituent 1 to 1 of halogen, lower alkyl, trifluoromethyl, alkoxy, aralkyloxy, alkylthio, aralkylthio, acyl, hydroxyl group, amino, nitro, and cyano Indicates phenyl which may have two atoms, R^1 is hydrogen, cyano, carbamoyl, carboxyl,
Alkoxy, cyano, formula - as a substituent on the alkoxy part
N(R^1_a) (R^1_b) (here R^1_a,
R^1_b each represents alkyl or aralkyl, or represents a group forming a 5- to 7-membered heterocycle together with the adjacent nitrogen atom. ), nitro, phenyl,
Represents alkoxycarbonyl or alkanoyl which may have 1 to 2 heteroaryls, R^2 is lower alkyl, hydroxyalkyl, acetoxyalkyl, haloalkyl, dihaloalkyl, trifluoromethyl, alkoxyalkyl, dialkoxymethyl, Lower alkylcarbamoyloxyalkyl, lower alkylthiocarbamoyloxyalkyl, formyl, hydroxyiminomethyl or cyano, X, Y, Z are ring members of ring A, and each is N or C
Indicates H.