JPH10120683A - Pyrrolopyrazolopyrimidine and medicine containing the same as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound which comprises a specific pyrrolopyrazolopyrimidine, has excellent bronchodilation and airways contraction inhibitory action and is useful as a medicine for respiratory diseases with weak action on circulatory organs and reduced in side-effects. SOLUTION: This compound is a new 1 pyerrolopyrazolopyrimidine represented by formula I [R<1> is an alkyl; R<2> is H, a halogen, a (substituted) alkyl, a (substituted) amino, carboxyl, an alkoxycarbonyl, carbamoyl, an alkylcarbamoyl; R<3> is nitro, amino, a heterocyclic group, a (halogen-substituted) alkylsulfonylamino, R<4> CONH (R<4> is an alkyl, carboxyl or the like), R<5> CO (R<5> is amino, OH, an alkyl, an alkoxy)] and is useful for prevention and treatment of respiratory diseases. The compound is prepared by reaction of a pyrazolopyrimidine of formula II (X is a halogen) with a compound represented by the formula: NH2 -R<1> .

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel pyrrolo [3,
The present invention relates to a 2-e] pyrazolo [1,5-a] pyrimidine compound, a production method and a production intermediate of the compound, and a medicament containing the compound as an active ingredient.

[0002]

2. Description of the Related Art Prevention of respiratory diseases such as asthma
Currently, the treatment is mainly performed by bronchodilation with a xanthine-based bronchodilator represented by theophylline, and the only other symptomatic use is a beta receptor stimulant such as ephedrine hydrochloride.

[0003] However, all of the above-mentioned drugs have serious side effects and have been problematic. However, since no excellent drug has been found to replace these drugs, these drugs have to be administered.

On the other hand, compounds having a pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine skeleton include 3-cyano-5-methylpyrrolo [3,2-e] pyrazolo [1,5-a]. It is known that pyrimidines have excellent vasodilatory and tracheal (bronchial) dilatory actions (Japanese Patent Publication No. 6-88999). However, it is difficult to separate the effect of the compound on the circulatory organ such as the blood pressure lowering effect from the effect on the trachea (bronchi), and it has been desired to develop a drug that selectively acts on the trachea (bronchi).

[0005]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a medicament which has few side effects and is excellent in the effect of preventing and treating respiratory diseases.

[0006]

Means for Solving the Problems In view of such circumstances, the present inventor has conducted intensive studies on synthesis, screening and the like for compounds effective for the prevention and treatment of respiratory diseases. )) Or a salt thereof has excellent bronchial (bronchial) dilatation and airway constriction inhibitory effects, and has a weak effect on the circulatory system, and is therefore useful as a preventive / therapeutic agent for respiratory diseases. The inventors have found that the present invention has been completed.

That is, the present invention provides the following general formula (1)

[0008]

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Wherein R ¹ represents a linear, branched or cyclic alkyl group; R ² represents a hydrogen atom, a halogen atom,
Optionally substituted amino group, an optionally substituted alkyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group or a alkylcarbamoyl group, R ³ is a nitro group, an amino group, a heterocyclic A cyclic group, an alkylsulfonylamino group optionally substituted by halogen, R ⁴ CONH- (where R ⁴ represents an alkyl group, a halogenoalkyl group, a carboxyl group or an alkoxycarbonyl group), or R ⁵ CO- ( Here, R ⁵ represents an amino group, a hydroxy group, an alkyl group, an alkoxy group, a halogenoalkyl group or a heterocyclic-amino group).] Or a salt of the pyrrolopyrazolopyrimidine compound represented by the formula: .

[0010] The present invention also provides a medicament comprising the compound (1) or a salt thereof as an active ingredient.

Further, the present invention provides a method for producing the above compound (1) or a salt thereof and a novel intermediate for the production.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula (1), the linear, branched or cyclic alkyl group represented by R ¹ preferably has 1 to 10 carbon atoms, and has 2 to 8 carbon atoms. More preferred are those having 3 to 7 carbon atoms. Among the alkyl groups, straight-chain or branched-chain alkyl groups include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, tert-pentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group and the like. Of which n-propyl group, isopropyl group, n-
Butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, tert-pentyl group (tert-amyl group), 1-ethylpropyl group, n-hexyl group, n-
A heptyl group is particularly preferred. Examples of the cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and the like, and among them, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group are particularly preferred.

The halogen atom represented by R ² includes a fluorine atom, a chlorine atom and a bromine atom, among which a fluorine atom and a chlorine atom are preferred. As the alkyl group, a linear or branched alkyl group having 1 to 10 carbon atoms is preferable, and a linear or branched alkyl group having 1 to 6 carbon atoms is more preferable. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
Isobutyl group, sec-butyl group, tert-butyl group, n-
Examples thereof include a pentyl group and an n-hexyl group, and among them, a methyl group, an ethyl group, and an isopropyl group are particularly preferable.
Examples of the alkyl group having a substituent include an alkoxyalkyl group, an aralkyloxyalkyl group, an aryloxyalkyl group, and an aminoalkyl group which may have a substituent (for example, an aminoalkyl group, a mono- or di-alkylaminoalkyl group, A 4- to 7-membered cyclic amino-substituted alkyl group which may further have an oxygen atom or a nitrogen atom as a hetero atom constituting the ring), a hydroxyalkyl group, and specifically, a methoxymethyl group, an ethoxymethyl group , Dinitrobenzyloxymethyl group, benzyloxymethyl group, phenoxymethyl group, aminomethyl group,
Examples include a methylaminomethyl group, a dimethylaminomethyl group, a morpholinomethyl group, a piperazinomethyl group, a 4-methylpiperazinomethyl group, and a hydroxymethyl group.
Examples of the amino group which may have a substituent include an amino group, a mono- or dialkylamino group, and a cyclic amino group (for example, a hetero atom constituting the ring may further have an oxygen atom or a nitrogen atom. A 4- to 7-membered cyclic amino group), an alkylsulfonylamino group optionally substituted by a halogen atom, an arylsulfonylamino group, an alkylcarbonylamino group, an arylcarbonylamino group,
Examples include a ureido group which may have a substituent, a thioureido group which may have a substituent, and a hydrazino group which may have a substituent. Here, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the substituent of the ureido group, thioureido group, and hydrazino group include the same linear, branched or cyclic alkyl groups as those for R ¹ . Specific examples of the amino group which may have a substituent include an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a cyclopropylamino group, a cyclobutylamino group, a pyrrolidino group, a piperidino group , Morpholino group,
Piperazino group, methanesulfonylamino group, trifluoromethanesulfonylamino group, benzenesulfonylamino group, acetylamino group, benzoylamino group, ureido group, methylureido group, thioureido group, methylthioureido group, hydrazino group, methylhydrazino group, etc. No. The alkoxycarbonyl group is preferably an alkoxycarbonyl group having 2 to 11 carbon atoms, and more preferably an alkoxycarbonyl group having 2 to 7 carbon atoms. Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, and an isopropyloxycarbonyl group. The alkylcarbamoyl group is preferably an alkylcarbamoyl group having 2 to 11 carbon atoms, and more preferably an alkylcarbamoyl group having 2 to 7 carbon atoms. Examples of the alkylcarbamoyl group include a methylcarbamoyl group, an ethylcarbamoyl group, an isopropylcarbamoyl group, a dimethylcarbamoyl group, and a diethylcarbamoyl group.

The heterocyclic group represented by R ³ is particularly preferably a nitrogen-containing heterocyclic group, for example, a tetrazolyl group.
Examples of the alkylsulfonylamino group optionally substituted by halogen include a group having 1 carbon atom optionally substituted by halogen.
10 to 10 alkylsulfonylamino groups,
1 to 6 carbon atoms which may be substituted by three halogen atoms
Alkylsulfonylamino group is more preferable. Examples of the alkylsulfonylamino group which may be substituted by the halogen atom include a methanesulfonylamino group, an ethanesulfonylamino group, a propanesulfonylamino group, a chloroethanesulfonylamino group, a trifluoromethanesulfonylamino group, and the like.

The alkyl group represented by R ⁴ is preferably a linear or branched alkyl group having 1 to 10 carbon atoms.
A linear or branched alkyl group having 1 to 6 carbon atoms is more preferable. Specific examples of the alkyl group include the same alkyl groups represented by R ^2. The halogenoalkyl group represented by R ^4, preferably halogenoalkyl group linear or branched chain having 1 to 10 carbon atoms, more preferably a halogenoalkyl group linear or branched chain containing from 1 to 6 carbon atoms. Specific examples of the halogenoalkyl group include:
A chloromethyl group, a chloroethyl group, a trifluoromethyl group and the like. The alkoxycarbonyl group represented by R ⁴ is preferably an alkoxycarbonyl group having 2 to 11 carbon atoms in total, and more preferably an alkoxycarbonyl group having 2 to 7 carbon atoms in total. Specific examples of the alkoxycarbonyl group include the same as the alkoxycarbonyl group represented by R ² .

The alkyl group represented by R ⁵ is preferably a linear or branched alkyl group having 1 to 10 carbon atoms.
A linear or branched alkyl group having 1 to 6 carbon atoms is more preferable. Specific examples of the alkyl group include the same as the alkyl group represented by R ² . The halogenoalkyl group represented by R ^5, preferably halogenoalkyl group linear or branched chain having 1 to 10 carbon atoms, more preferably a halogenoalkyl group linear or branched chain containing from 1 to 6 carbon atoms. Specific examples of the halogenoalkyl group include:
The same as the halogenoalkyl group represented by R ⁴ can be mentioned. As the heterocyclic-amino group represented by R ⁵ , a nitrogen-containing heterocyclic-amino group is preferable, and for example, a tetrazolylamino group is particularly preferable.

Among the groups represented by R ³ , a nitro group,
Amino group, acetamino group, trifluoroacetamino group, methanesulfonylamino group, trifluoromethanesulfonylamino group, ethyloxalylamino group, oxalylamino group, tetrazolyl group, tetrazolylcarbamoyl group, carbamoyl group, carboxyl group, ethoxycarbonyl group, A trifluoroacetyl group and the like are particularly preferred, and among them, a nitro group is more preferred.

Specific examples of the compound (1) include:
For example, 8-tert-butyl-6,7-dihydro-5-methyl-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 1), 8-tert-
Amyl-6,7-dihydro-5-methyl-3-nitro-
8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 2), 8-cyclopentyl-6,7-
Dihydro-5-methyl-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 3), 8-cyclohexyl-6,7-dihydro-5
-Methyl-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 4), 8-se
c-Butyl-6,7-dihydro-5-methyl-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-
a] pyrimidine (compound 5), 3-amino-8-cyclopentyl-6,7-dihydro-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 6), 3-acetylamino-8-cyclopentyl-6,7-dihydro-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 7), 8-cyclopentyl-6,7 -Dihydro-5
-Methyl-3-trifluoromethanesulfonylamino-
8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 8), 8-cyclopentyl-6,7-
Dihydro-5-methyl-3-trifluoroacetylamino-8H-pyrrolo [3,2-e] pyrazolo [1,5-
a] Pyrimidine (compound 9), 8-cyclopentyl-
6,7-dihydro-3-methanesulfonylamino-5
Methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] pyrimidine (compound 10), N- (8-cyclopentyl-6,7-dihydro-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-3
-Yl) oxamic acid (compound 11), ethyl N-
(8-cyclopentyl-6,7-dihydro-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a]
Pyrimidin-3-yl) aminoglyoxylate (compound 12), 8-tert-butyl-6,7-dihydro-5-
Methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] pyrimidine-3-N- (1H-tetrazole-5
-Yl) carboxamide (compound 13), 8-tert-amyl-6,7-dihydro-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-3
-N- (1H-tetrazol-5-yl) carboxamide (compound 14), 8-cyclopentyl-6,7-dihydro-5-methyl-3- (1H-tetrazol-5-yl) -8H-pyrrolo [3, 2-e] pyrazolo [1,5-
a] Pyrimidine (compound 15), 8-tert-butyl-
6,7-dihydro-5-methyl-3- (1H-tetrazol-5-yl) -8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 16), 8-tert
-Amyl-6,7-dihydro-5-methyl-3- (1H
-Tetrazol-5-yl) -8H-pyrrolo [3,2-
e] pyrazolo [1,5-a] pyrimidine (compound 1
7), 8-Cyclopentyl-6,7-dihydro-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-
a] pyrimidine-3-carboxamide (compound 18),
5-amino-8-cyclopentyl-6,7-dihydro-
3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 19), 5-amino-8-sec-butyl-6,7-dihydro-3-nitro-
8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 20), ethyl 8-cyclopentyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,
2-e] pyrazolo [1,5-a] pyrimidine-5-carboxylate (compound 21), ethyl 8-sec-butyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] Pyrazolo [1,5-a] pyrimidine-5
-Carboxylate (compound 22), 8-cyclopentyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5
-Carboxylic acid (compound 23), 8-sec-butyl-6,
7-dihydro-3-nitro-8H-pyrrolo [3,2-
e] Pyrazolo [1,5-a] pyrimidine-5-carboxylic acid (compound 24), 8-tert-butyl-6,7-dihydro-5-methyl-3-trifluoroacetyl-8H-pyrrolo [3,2 -E] pyrazolo [1,5-a] pyrimidine (compound 25), 8-tert-amyl-6,7-dihydro-5-methyl-3-trifluoroacetyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 26), 8-cyclopentyl-6,7-dihydro-5-methyl-3-trifluoroacetyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a ] Pyrimidine (compound 27), 8-cyclohexyl-6,7-dihydro-5-methyl-3-trifluoroacetyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 28) , 8-se c-Butyl-6,7-dihydro-5-methyl-3-trifluoroacetyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 29), 8-cyclopentyl-6 7-dihydro-3-ethoxycarbonyl-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 30), 8-tert-butyl-6,7-dihydro-3 -Ethoxycarbonyl-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 31), 8-tert-amyl-6,7-dihydro-3
-Ethoxycarbonyl-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 32), 3-carboxy-8-cyclopentyl-
6,7-dihydro-5-methyl-8H-pyrrolo [3,2
-E] pyrazolo [1,5-a] pyrimidine (compound 3
3), 8-tert-butyl-3-carboxy-6,7-dihydro-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 34), 8-te
rt-amyl-3-carboxy-6,7-dihydro-5-
Methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] pyrimidine (compound 35), 8-cyclopentyl-6,7-dihydro-5-methyl-8H-pyrrolo [3,
2-e] Pyrazolo [1,5-a] pyrimidine-3-N-
(1H-tetrazol-5-yl) carboxamide (compound 36), 8-tert-butyl-6,7-dihydro-3
-Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,
5-a] pyrimidine (compound 37), 8-cyclopentyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 38), 8- sec-butyl-6,7-dihydro-3
-Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,
5-a] pyrimidine (compound 39), 8-tert-butyl-5-chloro-6,7-dihydro-3-nitro-8H-
Pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 40), 5-chloro-8-cyclopentyl-
6,7-dihydro-3-nitro-8H-pyrrolo [3,2
-E] pyrazolo [1,5-a] pyrimidine (compound 4
1), 8-sec-butyl-5-chloro-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 42), 8-sec −
Butyl-6,7-dihydro-5-methoxymethyl-3-
Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] pyrimidine (compound 43), 8-sec-butyl-
6,7-dihydro-5-ethoxymethyl-3-nitro-
8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 44), 5-benzyloxymethyl-8
-Sec-butyl-6,7-dihydro-3-nitro-8H
-Pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 45), 8-sec-butyl-6,7-dihydro-3-nitro-5-phenoxymethyl-8H-pyrrolo [3, 2-e] pyrazolo [1,5-a] pyrimidine (compound 46), 5-aminomethyl-8-sec-butyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,
2-e] pyrazolo [1,5-a] pyrimidine (compound 4
7), 8-sec-butyl-6,7-dihydro-5-methylaminomethyl-3-nitro-8H-pyrrolo [3,2-
e] pyrazolo [1,5-a] pyrimidine (compound 4
8), 8-sec-butyl-6,7-dihydro-5-dimethylaminomethyl-3-nitro-8H-pyrrolo [3,2
-E] pyrazolo [1,5-a] pyrimidine (compound 4
9), 8-sec-butyl-6,7-dihydro-5-morpholinomethyl-3-nitro-8H-pyrrolo [3,2-
e] pyrazolo [1,5-a] pyrimidine (compound 5
0), 8-sec-butyl-6,7-dihydro-3-nitro-5-piperazinomethyl-8H-pyrrolo [3,2-
e] pyrazolo [1,5-a] pyrimidine (compound 5
1), 8-sec-butyl-6,7-dihydro-5- (4
-Methylpiperazinomethyl) -3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 52), 8-sec-butyl-6,7-dihydro-5- Hydroxymethyl-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 53), 8-sec-butyl-6,7-dihydro-5
-Methylamino-3-nitro-8H-pyrrolo [3,2-
e] pyrazolo [1,5-a] pyrimidine (compound 5
4), 8-sec-butyl-6,7-dihydro-5-ethylamino-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 55), 8-
sec-butyl-6,7-dihydro-5-dimethylamino-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 56), 8-sec-
Butyl-5-diethylamino-6,7-dihydro-3-
Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] pyrimidine (compound 57), 8-sec-butyl-
5-cyclopropylamino-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-
a] Pyrimidine (compound 58), 8-sec-butyl-5
-Cyclobutylamino-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a]
Pyrimidine (Compound 59), 8-sec-butyl-6,7
-Dihydro-3-nitro-5-pyrrolidino-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 60), 8-sec-butyl-6,7-dihydro-3-nitro -5-piperidino-8H-pyrrolo [3,2
-E] pyrazolo [1,5-a] pyrimidine (compound 6
1), 8-sec-butyl-6,7-dihydro-5-morpholino-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 62), 8-se
c-Butyl-6,7-dihydro-3-nitro-5-piperazino-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] pyrimidine (compound 63), 8-sec-butyl-
6,7-dihydro-5-methanesulfonylamino-3-
Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] pyrimidine (compound 64), 8-sec-butyl-
6,7-dihydro-3-nitro-5-trifluoromethanesulfonylamino-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 65), 5-benzenesulfonylamino-8-sec -Butyl-6,7-
Dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 66), 5-
Acetylamino-8-sec-butyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 67), 5-benzoylamino-8- sec-butyl-6,7-dihydro-3
-Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,
5-a] pyrimidine (compound 68), 8-sec-butyl-6,7-dihydro-3-nitro-5-ureido-8H
-Pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 69), 8-sec-butyl-6,7-dihydro-5-methylureido-3-nitro-8H-pyrrolo [3, 2-e] pyrazolo [1,5-a] pyrimidine (compound 70), 8-sec-butyl-6,7-dihydro-3
-Nitro-5-thioureido-8H-pyrrolo [3,2-
e] pyrazolo [1,5-a] pyrimidine (compound 7
1), 8-sec-butyl-6,7-dihydro-5-methylthioureido-3-nitro-8H-pyrrolo [3,2-
e] pyrazolo [1,5-a] pyrimidine (compound 7
2), 8-sec-butyl-6,7-dihydro-5-hydrazino-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 73), 8-se
c-Butyl-6,7-dihydro-5-methylhydrazino-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 74), 8-sec-
Butyl-5-carbamoyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-
a] Pyrimidine (compound 75), ethyl 8-cyclopropyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-e] pyrimidine-5
-Carboxylate (compound 76), ethyl 8-cyclobutyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-
5-carboxylate (compound 77), ethyl 6,7
-Dihydro-8-isopropyl-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5-carboxylate (compound 78), ethyl 6,
7-dihydro-8- (1-ethylpropyl) -3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-
a] Pyrimidine-5-carboxylate (Compound 7
9), 8-cyclopropyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-
a] Pyrimidine-5-carboxylic acid (compound 80), 8-
Cyclobutyl-6,7-dihydro-3-nitro-8H-
Pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5-carboxylic acid (Compound 81), 6,7-dihydro-8-isopropyl-3-nitro-8H-pyrrolo [3
2-e] pyrazolo [1,5-a] pyrimidine-5-carboxylic acid (compound 82), 6,7-dihydro-8- (1-
Ethylpropyl) -3-nitro-8H-pyrrolo [3,2
-E] pyrazolo [1,5-a] pyrimidine-5-carboxylic acid (compound 83), 5-amino-8-cyclopropyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,
2-e] pyrazolo [1,5-a] pyrimidine (compound 8
4), 5-amino-8-cyclobutyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 85), 5-amino-6 , 7-Dihydro-8-isopropyl-3-nitro-
8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 86), 5-amino-6,7-dihydro-8- (1-ethylpropyl) -3-nitro-8H-
Pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 87), 8-sec-butyl-6,7-dihydro-5- (2 ', 4'-dinitrobenzyloxymethyl) -3 -Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 88) and the like.

The salt which can be used in the present invention is not particularly limited as long as it is physiologically acceptable. For example, mineral salts such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and citric acid , Oxalic acid, fumaric acid, maleic acid, formic acid, acetic acid,
Organic acid salts such as methanesulfonic acid, benzenesulfonic acid, and paratoluenesulfonic acid, and carbonates are preferably exemplified.

The compound (1) of the present invention also includes solvates such as hydrates.

The compound (1) of the present invention can be produced, for example, according to the following reaction formula.

[0022]

Embedded image

Wherein R ¹ , R ² and R ³ are the same as above, and X is a halogen atom.

That is, the substituent (R ² ,
Compound (3) into which R ³ ) has been introduced or a tautomer thereof,
Compound (1) can be produced by reacting a halogenating agent such as phosphoryl chloride or the like to form dihalogen (2) and reacting with amines (NH ₂ -R ¹ ) to close the ring. Further, the groups R ^{1 to} R ^{3 in} the general formula (1) can be converted into various substituents by a conventional method. Further, after converting the compound (3) into the compound (2), the substituent of R ² or R ³ may be converted into another substituent, and then the compound (1) may be obtained.

The tautomer of the compound (3) has the following structure.

[0026]

Embedded image

Wherein R ² and R ³ are the same as defined above. Compound (3) is prepared by the following method (1) or method (2)
Can be manufactured.

Method (1):

[0029]

Embedded image

Wherein R ² and R ³ are the same as described above. That is, the aminopyrazole derivative (4) and the carbonyl lactone derivative (5) are condensed using a Lewis acid or the like as a catalyst, and if necessary, Compound (3) can be obtained by ring closure by alkali treatment.

Method (2): Compound (3-1) wherein R ² of compound (3) is a hydroxyl group can be produced according to the following reaction formula.

[0032]

Embedded image

[Wherein R ³ is the same as described above;
BDMSi represents a tert-butyldimethylsilyl group,
Et represents an ethyl group.]

That is, after bromoethanol is t-butyldimethylsilylated with tert-butyldimethylsilyl chloride, diethyl malonate is condensed in the presence of an alkali such as sodium ethoxide and then reacted with aminopyrazole. Then, the compound (3) in which R ² is a hydroxyl group can be obtained.

By reacting compound (3) with a halogenating reagent, dihalide (2) can be obtained. The halogenating reagent used here is not particularly limited, and examples thereof include phosphorus oxychloride. The halogenating reagent is generally used in an amount of 1.0 to 10.0 mol, preferably 2.0 to 5.0 mol, based on compound (3). The solvent used for the reaction is not particularly limited as long as it is a non-aqueous solvent, and specifically,
N, N-dimethylformamide, chloroform, dichloromethane and the like. When the halogenating reagent is a liquid, the reaction can be performed without a solvent. A basic catalyst can be used to promote the progress of the reaction.
Alternatively, the reaction may be performed under a nitrogen stream. The reaction temperature depends on the physical properties of the solvent, the halogenating reagent and the catalyst, but heating to reflux is preferred. Post-treatment and purification of the reaction may be performed according to a general method. However, it is necessary to pay attention to the decomposition of R ² and R ³ in some cases. When phosphorus oxyhalide acts on compound (3) in which R ² is a hydroxyl group, compound (2) in which R ² is a halogen atom can be obtained. And R ² and / or R
³ can also be converted to various substituents.

The following general formula (6) containing the compounds of the above general formulas (2) and (3)

[0037]

Embedded image

Wherein Z represents a hydroxyl group or a halogen atom, Y represents a hydroxyl group or a halogen atom, and R ² and R ³
Is the same as described above], or a tautomer thereof, is a novel compound and an important compound as a production intermediate of the compound (1) of the present invention.

In the compound (6), Z represents a hydroxyl group or a halogen atom such as a chlorine atom, a bromine atom and an iodine atom, and among the halogen atoms, a chlorine atom is preferred. Y represents a hydroxyl group or the above-mentioned halogen atom, and among the halogen atoms, a chlorine atom is preferable. As an example of these compounds (6), for example, 7-chloro-6- (2-chloroethyl) -5-methyl-3-nitropyrazolo [1,5
-A] pyrimidine, ethyl 6- (2-hydroxyethyl) -5-methylpyrazolo [1,5-a] pyrimidine-
7 (4H) -one-3-carboxylate, ethyl 7
-Chloro-6- (2-chloroethyl) -5-methylpyrazolo [1,5-a] pyrimidine-3-carboxylate, ethyl 7-chloro-6- (2-chloroethyl)-
3-nitropyrazolo [1,5-a] pyrimidine-5-carboxylate, 7-bromo-6- (2-bromoethyl) -5-methyl-3-nitropyrazolo [1,5-a]
Pyrimidine, 7-chloro-6- (2-chloroethyl)-
5-ethyl-3-nitropyrazolo [1,5-a] pyrimidine, 7-chloro-6- (2-chloroethyl) -5-n
-Propyl-3-nitropyrazolo [1,5-a] pyrimidine, 7-chloro-6- (2-chloroethyl) -5-isopropyl-3-nitropyrazolo [1,5-a] pyrimidine, 7-chloro-6- ( 2-chloroethyl) -5-cyclopropyl-3-nitropyrazolo [1,5-a] pyrimidine, 5-n-butyl-7-chloro-6- (2-chloroethyl) -3-nitropyrazolo [1,5-a] Pyrimidine, 5-tert-butyl-7-chloro-6- (2-chloroethyl) -3-nitropyrazolo [1,5-a] pyrimidine, 7-chloro-6- (2-chloroethyl) -5-cyclopentyl-3- Nitropyrazolo [1,5-a] pyrimidine, ethyl 5-ethyl-6- (2-hydroxyethyl) pyrazolo [1,5-a] pyrimidine-7 (4H)-
On-3-carboxylate, ethyl 6- (2-hydroxyethyl) -5-n-propylpyrazolo [1,5-
a] Pyrimidin-7 (4H) -one-3-carboxylate, ethyl 6- (2-hydroxyethyl) -5-isopropylpyrazolo [1,5-a] pyrimidine-7 (4
H) -one-3-carboxylate, ethyl 6- (2
-Hydroxyethyl) -5-cyclopropylpyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylate, ethyl 5-n-butyl-6- (2-
Hydroxyethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylate, ethyl
5-t-butyl-6- (2-hydroxyethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-
Carboxylate, ethyl 6- (2-hydroxyethyl) -5-cyclopentylpyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylate, methyl 6- (2-hydroxyethyl) -5 -Methylpyrazolo [1,5-a] pyrimidin-7 (4H) -one-3
-Carboxylate, n-propyl 6- (2-hydroxyethyl) -5-methylpyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylate, t
-Butyl 6- (2-hydroxyethyl) -5-methylpyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylate, ethyl 7-bromo-6
(2-bromoethyl) -5-methylpyrazolo [1,5-
a] Pyrimidine-3-carboxylate, ethyl 7-
Chloro-6- (2-chloroethyl) -5-ethylpyrazolo [1,5-a] pyrimidine-3-carboxylate,
Ethyl 7-chloro-6- (2-chloroethyl) -5
n-propylpyrazolo [1,5-a] pyrimidine-3-
Carboxylate, ethyl 7-chloro-6- (2-chloroethyl) -5-isopropylpyrazolo [1,5-
a] Pyrimidine-3-carboxylate, ethyl 7-
Chloro-6- (2-chloroethyl) -5-cyclopropylpyrazolo [1,5-a] pyrimidine-3-carboxylate, ethyl 5-t-butyl-7-chloro-6-
(2-chloroethyl) pyrazolo [1,5-a] pyrimidine-3-carboxylate, methyl 7-chloro-6-
(2-chloroethyl) -5-methylpyrazolo [1,5-
a] Pyrimidine-3-carboxylate, n-propyl 7-chloro-6- (2-chloroethyl) -5-methylpyrazolo [1,5-a] pyrimidine-3-carboxylate, t-butyl 7-chloro-6 (2-chloroethyl) -5-methylpyrazolo [1,5-a] pyrimidine-
3-carboxylate, ethyl 7-bromo-6- (2
-Bromoethyl) -3-nitropyrazolo [1,5-a]
Pyrimidine-5-carboxylate, methyl 7-chloro-6- (2-chloroethyl) -3-nitropyrazolo [1,5-a] pyrimidine-5-carboxylate, n
-Butyl 7-chloro-6- (2-chloroethyl) -3
-Nitropyrazolo [1,5-a] pyrimidine-5-carboxylate, t-butyl 7-chloro-6- (2-chloroethyl) -3-nitropyrazolo [1,5-a] pyrimidine-5-carboxylate, 6- (2-chloroethyl) -5,7-dichloro-3-nitropyrazolo [1,5
-A] pyrimidine, 7-chloro-6- (2-chloroethyl) -5- (2 ', 4'-dinitrobenzyloxymethyl) -3-nitropyrazolo [1,5-a] pyrimidine and the like.

The compound (1) of the present invention is obtained by reacting a dihalogen (2) with an amine [NH ₂ -R ¹ ] to form a ring, and optionally converting R ² and / or R ³ to various substituents. It can be manufactured by conversion.

Here, the amine is used in an amount of usually 0.1 to 10.0 mol, preferably 1.0 to 10.0 mol, based on the dihalogen (2).
2.5 moles are used. Tertiary organic amines and inorganic bases are used as a condensing agent for the reaction, and specific examples include triethylamine, N, N-diisopropylethylamine,
Examples include anhydrous potassium carbonate and anhydrous sodium carbonate. These condensing agents are used in an amount of usually 0.5 to 30.0 mol, preferably 2.0 to 3 mol, per mol of the compound represented by the general formula (2).
5.0 moles are used. In addition, the raw material amine R ^1-
It is also possible to eliminate the need for a condensing agent by using NH ₂ large excess. The solvent used for the reaction is not particularly limited as long as it is a non-aqueous solvent capable of dissolving the two raw materials, and specific examples include N, N-dimethylformamide, chloroform, dichloromethane and the like. The amount of the solvent to be used may be 5 to 100 times the amount of these starting compounds. These solvents can be used alone or in combination of two or more. The solvent may be selected in accordance with the physical properties of the raw material compound and the condensing agent. The reaction temperature of the present production method may be any temperature from room temperature to a temperature near the boiling point, but room temperature is preferred. Although the reaction time of this production method varies depending on various conditions, it requires 30 minutes to 30 days. For the post-treatment and purification of the reaction, general methods such as water quenching, solvent extraction, column chromatography,
What is necessary is just to combine recrystallization etc. suitably. After the compound represented by the general formula (1) is obtained, the substituents R ² and R
Regarding ³ , various chemical transformations such as reduction and hydrolysis can be performed.

The compound (1) can be converted into a salt by a conventional method such as mixing with an acid in a polar or non-polar solvent. The compound (1) or a salt thereof thus obtained can be purified by a usual method such as column chromatography or recrystallization.

Compound (1) or a salt thereof has excellent bronchodilator and airway constriction inhibitory effects as shown in the test examples described below, and has a weak effect on the circulatory system. It is useful as a medicament for treating and preventing respiratory diseases such as lung diseases, bronchitis, and pneumonia.

The compound (1) or a salt thereof can be used as a medicament itself, but can also be made into various dosage forms (compositions) usually used as a medicament. Examples of such a dosage form include an inhalation agent, an injection, an oral administration, a rectal administration and the like.

The medicament of the present invention in these dosage forms may contain, besides compound (1) or a salt thereof, any ingredient usually used for pharmaceutical preparations. Such optional components include, for example, excipients, binders, coating agents, lubricants, sugar coatings, disintegrants, bulking agents, flavoring agents, emulsifying / solubilizing / dispersing agents, stabilizers, pH adjusting Agents, isotonic agents and the like. In addition, the medicament of the present invention can also contain known drugs usually used for treatment or prevention of respiratory diseases, for example, theophylline and the like. The medicament of the present invention can be produced according to a conventional method using these components.

The preferred dose of the medicament of the present invention depends on the condition,
Depending on the type, gender, age, physique, etc. of the disease, the compound (1) or a salt thereof is generally 1 per adult per day.
It is preferably administered in a dose of once to several times a day.

[0047]

The compound (1) of the present invention or a salt thereof has excellent bronchial (bronchial) dilatation and airway constriction inhibitory effects and has a weak effect on the circulatory system, so that asthma, chronic obstructive pulmonary disease, It is useful for prevention and treatment of respiratory diseases such as bronchitis and pneumonia.

[0048]

EXAMPLES Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

Reference Example 1 Production of 3-{[1- (tetrahydro-2-oxo-3-furyl) ethylidene] amino} pyrazole: 0.83 g (10.00 mmol) of 3-aminopyrazole, 2-acetyl-γ- 1.92 g of butyrolactone (15.00 mmo
l) was dissolved in 12 ml of dry ethanol, and 0.1 ml of a boron trifluoride methanol complex was added thereto while stirring at room temperature, followed by stirring for 4 hours under the same conditions. The precipitated solid was collected by filtration, washed with ethanol, and air-dried to obtain 1.34 g (yield 69.4%) of the desired product.

¹ H-NMR (DMSO-d ₆ , ppm) 2.45 (3H, s), 2.86 (2H, t, J = 7.
8Hz), 4.27 (2H, t, J = 7.8Hz),
6.07 (1H, d, J = 2.2 Hz), 6.67 (1
H, d, J = 2.2 Hz), 10.00 (1H, s),
12.46 (1H, brs)

Reference Example 2 Preparation of 6- (2-hydroxyethyl) -5-methylpyrazolo [1,5-a] pyrimidin-7 (4H) -one
1.17 g of 3-{[1- (tetrahydro-2-oxo-3-furyl) ethylidene] amino} pyrazole (6.
04 mmol) was suspended in 7.5 ml of water, and 0.73 g (7.23 mmol) of triethylamine was added thereto.
Stirred at C for 2 hours. Thereafter, the mixture was cooled with ice-water, and concentrated hydrochloric acid was added thereto with stirring to adjust the pH to around pH 2 (precipitation of solid). The insoluble solid was collected by filtration, washed with water several times, and air-dried to obtain 1.06 g (yield 90.6%) of the desired product.

¹ H-NMR (CDCl ₃ + CD ₃ OD, p
pm) 2.38 (3H, s), 2.81 (2H, t, J = 6.
5 Hz), 3.74 (2H, t, J = 6.5 Hz),
5.97 (1H, d, J = 2.0 Hz), 7.80 (1
H, d, J = 2.0 Hz)

Reference Example 3 Preparation of 7-chloro-6- (2-chloroethyl) -5-methylpyrazolo [1,5-a] pyrimidine: 6- (2-hydroxyethyl) -5-methylpyrazolo [1,5-a] ]
Pyrimidin-7 (4H) -one 5.30 g (27.46
8.5 ml of triethylamine (d = 0.726,
61.10 mmol), and 8.5 ml of phosphorus oxychloride (d = 1.645, while cooling under ice-cooling and nitrogen atmosphere).
91.19 mmol) was added dropwise over 2 minutes, followed by an oil bath temperature of 10
Stirred at 0 ° C. for 1 hour. After cooling with ice-water, the reaction solution was dissolved in 100 ml of chloroform and poured into 500 ml of ice-water. After shaking well, the chloroform layer was separated, the aqueous layer was further extracted with chloroform (100 ml × 2), and all the chloroform layers were combined, dried over sodium sulfate, and evaporated. The residue was subjected to silica gel column chromatography (chloroform), and 3.78 g of the desired product was obtained (yield: 59.
8%).

¹ H-NMR (CDCl ₃ , ppm) 2.71 (3H, s), 3.35 (2H, t, J = 7.
5Hz), 3.76 (2H, t, J = 7.5Hz),
6.67 (1H, d, J = 2.4 Hz), 8.15 (1
H, d, J = 2.4 Hz)

Example 1 7-chloro-6- (2-chloroethyl) -5-methyl-
Preparation of 3-nitropyrazolo [1,5-a] pyrimidine:
23 ml of 90% nitric acid was added dropwise to 46 ml of concentrated sulfuric acid under cooling with an ice-water-salt system under a nitrogen atmosphere over 3 minutes and 30 seconds while stirring under a nitrogen atmosphere, followed by stirring at about -5 ° C. for 7-chloro-6. −
(2-chloroethyl) -5-methylpyrazolo [1,5-
a] Pyrimidine (5.0 g, 21.74 mmol) was added little by little over 10 minutes and 30 seconds as a solid, and the mixture was stirred at -5 to 5 ° C for 5 hours. Thereafter, the reaction solution was poured into 800 ml of ice-water, stirred for about 45 minutes, and the precipitated solid was collected by filtration, washed with water several times, and air-dried to obtain 5.65 g (yield 94.5%) of the desired product. Was.

M. p. 172.1-174.2 ° C IR (KBr tablet, cm ^-1 ) 1620, 1502, 1481, 1403, 1383,
1315, 1213 ¹ H-NMR (CDCl ₃ , ppm) 2.91 (3H, s), 3.43 (2H, t, J = 7.
0 Hz), 3.83 (2H, t, J = 7.0 Hz),
8.80 (1H, s)

Example 2 Preparation of compound 1 (R ¹ : tert-butyl, R ² : methyl, R ³ : nitro): 8-tert-butyl-6,7-dihydro-5-methyl-3
-Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,
Preparation of 5-a] pyrimidine: 7-chloro-6- (2-chloroethyl) -5-methyl-3-nitropyrazolo [1,
1.75 g (6.36 mmol) of 5-a] pyrimidine were dissolved in 18 ml of dry dimethylformamide, and 0.93 g (12.72 mmol) of tert-butylamine and 1.61 g (15.94 mmol) of triethylamine were sequentially added thereto, and the mixture was added at room temperature. Stir for 6 hours. Thereafter, the reaction solution was poured into water and extracted with ethyl acetate (150 ml × 2). All the ethyl acetate layers were combined, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1) and recrystallized from ethanol to obtain 0.78 g of the desired product (44.6% yield).
Obtained.

¹ H-NMR (CDCl ₃ , ppm) 1.71 (9H, s), 2.47 (3H, s), 3.0
6 (2H, t, J = 9.2 Hz), 4.09 (2H,
t, J = 9.2 Hz), 8.61 (1H, s)

Example 3 Preparation of compound 2 (R ¹ : tert-amyl, R ² : methyl, R ³ : nitro): 7-chloro-6- (2-chloroethyl)
Compound 2 was obtained at a yield of 37.8% from -5-methyl-3-nitropyrazolo [1,5-a] pyrimidine and tert-amylamine in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ , ppm) 0.89 (3H, t, J = 7.6 Hz), 1.64 (6
H, s), 2.27 (2H, q, J = 7.6 Hz),
2.47 (3H, s), 3.07 (2H, t, J = 9.
0 Hz), 4.09 (2H, t, J = 9.0 Hz),
8.59 (1H, s)

Example 4 Compound 3 (R ¹ : cyclopentyl, R ² : methyl, R ³ :
Nitro): 7-chloro-6- (2-chloroethyl) -5
Compound 3 was obtained from -methyl-3-nitropyrazolo [1,5-a] pyrimidine and cyclopentylamine in a yield of 82.9% in the same manner as in Example 2.

IR (KBr tablet, cm ^-1 ) 1626, 1617, 1492, 1394, 1234,
1196 m. p. 228-234 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.60-1.85 (6H, m), 1.90-2.10.
(2H, m), 2.46 (3H, s), 3.16 (2
H, t, J = 8.9 Hz), 3.92 (2H, t, J =
8.9 Hz), 5.81 (1H, m), 8.56 (1
H, s)

Example 5 Compound 4 (R ¹ : cyclohexyl, R ² : methyl, R ³ :
Preparation of nitro): 7-chloro-6- (2-chloroethyl) -5-methyl-3-nitropyrazolo [1,5-a]
Compound 4 was obtained from pyrimidine and cyclohexylamine in a yield of 76.6% in the same manner as in Example 2.

IR (KBr tablet, cm ^-1 ) 1622, 1613, 1491, 1454, 1441,
1397, 1245, 1231, 1199 m. p. ^{256.8~258.1 ℃ 1 H-NMR (CDCl} 3, ppm) 1.00~1.30 (1H, m), 1.35~2.00
(9H, m), 2.46 (3H, s), 3.14 (2
H, t, J = 9.0 Hz), 3.91 (2H, t, J =
9.0 Hz), 5.15 to 5.35 (1H, m), 8.
57 (1H, s)

Example 6 Preparation of compound 5 (R ¹ : sec-butyl, R ² : methyl, R ³ : nitro): 7-chloro-6- (2-chloroethyl)
Compound 5 was obtained at a yield of 74.3% from -5-methyl-3-nitropyrazolo [1,5-a] pyrimidine and sec-butylamine in the same manner as in Example 2.

IR (KBr tablet, cm ^-1 ) 1626, 1614, 1488, 1443, 1397,
1229, 1200, 1180 m. p. 257.9-260.1 ° C. ¹ H-NMR (CDCl ₃ , ppm) 0.94 (3H, t, J = 7.4 Hz), 1.31 (3
H, d, J = 6.8 Hz), 1.55-1.75 (2
H, m), 2.48 (3H, s), 3.17 (2H,
t, J = 9.2 Hz), 3.73 to 3.95 (2H,
m), 5.50 to 5.68 (1H, m), 8.58 (1
H, s)

Example 7 Compound 6 (R ¹ : cyclopentyl, R ² : methyl, R ³ :
Production of amino): 0.287 g of compound 3 was weighed, 0.95 g of anhydrous tin (II) chloride and 2 ml of dry ethanol were added thereto, and the mixture was stirred at 70 to 80 ° C for 1 hour and 50 minutes under a nitrogen atmosphere. Cool with ice water and stir with water-cooled ethyl acetate 20ml
And 30 ml of saturated aqueous layer was poured into the mixture to remove insolubles, washed several times with ethyl acetate, combined with the filtrate, and separated the ethyl acetate layer. The aqueous layer was further extracted with ethyl acetate, and all the ethyl acetate layers were combined. After drying over sodium sulfate, the solvent was distilled off, and the residue was recrystallized from ethyl acetate to obtain 0.114 g of Compound 6 (44.4% yield).

IR (KBr tablet, cm ^-1 ) 3378, 1578, 1561, 1332 m. p. 134 to 134.5 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.55 to 1.80 (6H, m), 1.80 to 2.05
(2H, m), 2.35 (3H, s), 3.07 (2
H, t, J = 9.0 Hz), 3.77 (2H, t, J =
9.0 Hz), 5.88-6.05 (1H, m), 7.
70 (1H, s)

Example 8 Compound 7 (R ¹ : cyclopentyl, R ² : methyl, R ³ :
Preparation of acetylamino): 0.20 g of compound 3 was weighed, dissolved in 1.8 ml of acetic acid, and 0.13 g of reduced iron was added as it was at once, followed by heating and stirring at 100 ° C. for 1 hour and 30 minutes under a nitrogen atmosphere. did. Thereafter, acetic acid was distilled off, 10 ml of chloroform was added to the residue, and the mixture was poured into 30 ml of a saturated aqueous sodium hydrogen carbonate solution. The insoluble material was removed by filtration, and the chloroform layer of the filtrate was separated. The aqueous layer was further extracted with chloroform, and all the chloroform layers were combined, dried over sodium sulfate, and the solvent was distilled off.
0.20 g (yield 95.2%) of compound 7 was obtained.

IR (KBr tablet, cm ^-1 ) 3234,1633,1582,1558,1530,
1329, 1250, 1166 m. p. 233 to 234 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.60 to 1.80 (6H, m), 1.85 to 2.05
(2H, m), 2.19 (3H, s), 2.33 (3
H, s), 3.08 (2H, t, J = 9.2 Hz),
3.82 (2H, t, J = 9.2 Hz), 5.93-
6.10 (1H, m), 8.28 (1H, brs),
8.58 (1H, s)

Example 9 Compound 8 (R ¹ : cyclopentyl, R ² : methyl, R ³ :
Preparation of trifluoromethanesulfonylamino): 0.1 g of compound 6 was dissolved in 2 ml of dry methylene chloride, and 0.13 g of trifluoromethanesulfonic anhydride was dissolved in 2 ml of dry methylene chloride with stirring under a nitrogen atmosphere under ice water cooling. Then, stirring was continued for 25 minutes. The mixture was poured into chloroform-cold saturated sodium bicarbonate solution, the chloroform layer was separated, dried over sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 → 100: 1).
0.13 g (yield 86.7%) of compound 8 was obtained.

IR (KBr tablet, cm ^-1 ) 1636, 1300, 1203, 1163 m. p. 178 to 179 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.62 to 1.87 (6H, m), 1.90 to 2.10.
(2H, m), 2.37 (3H, s), 3.11 (2
H, t, J = 8.6 Hz), 3.96 (2H, t, J =
8.6 Hz), 5.95 to 6.10 (1H, m), 7.
98 (1H, s)

Example 10 Compound 9 (R ¹ : cyclopentyl, R ² : methyl, R ³ :
Preparation of trifluoroacetylamino): Compound 60
257 g was dissolved in 4.5 ml of dry pyridine, 0.42 ml of trifluoroacetic anhydride was added dropwise with stirring at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour and 10 minutes.
The reaction solution was concentrated under reduced pressure, the residue was dissolved in 20 ml of chloroform, and the solution was poured into 30 ml of water. After being made alkaline with saturated aqueous sodium hydrogen carbonate, the chloroform layer was separated. After drying over sodium sulfate, the solvent was distilled off. The residue was recrystallized from ethyl acetate to obtain 0.129 g of Compound 9 (yield: 36.5%).

IR (KBr tablet, cm ^-1 ) 1702, 1628, 1605, 1318, 1307,
1209, 1192, 1154 m. p. 175-176 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.60-1.85 (6H, m), 1.85-2.10.
(2H, m), 2.33 (3H, s), 3.10 (2
H, t, J = 9.2 Hz), 3.85 (2H, t, J =
9.2 Hz), 5.90-6.08 (1H, m), 8.
63 (1H, s)

Example 11 Compound 10 (R ¹ : cyclopentyl, R ² : methyl,
Preparation of R ³ : methanesulfonylamino): 0.14 g of compound 6 was dissolved in 2 ml of dry methylene chloride, 0.2 ml of triethylamine was added with stirring under an ice-cooled nitrogen atmosphere, and 2 ml of 75 mg of methanesulfonyl chloride were dried. Methylene chloride solution was added dropwise. 30 under ice-cooled nitrogen atmosphere
The mixture was stirred for 5 minutes, poured into 5 ml of chloroform and 30 ml of cold water, the chloroform layer was separated, dried over sodium sulfate, the solvent was distilled off, purified by silica gel column chromatography (elution solvent: chloroform), and recrystallized from ethanol. As a result, 0.105 g (yield 58.3%) of Compound 10 was obtained.

IR (KBr tablet, cm ^-1 ) 1618, 1595, 1542, 1323, 1149 m. p. 172 to 174 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.60 to 1.85 (6H, m), 1.85 to 2.05
(2H, m), 2.35 (3H, s), 3.04 (3
H, s), 3.08 (2H, t, J = 9.9 Hz),
3.82 (2H, t, J = 9.9 Hz), 5.90-
6.05 (1H, m), 8.04 (1H, s)

Example 12 Compound 12 (R ¹ : cyclopentyl, R ² : methyl,
Production of R ³ : ethyl oxalylamino): 0.257 g
Compound 6 was dissolved in 4 ml of dry methylene chloride and stirred under ice-cooled nitrogen atmosphere with triethylamine 0.37.
ml of ethyl oxalyl chloride.
ml of dry methylene chloride solution was added dropwise. The mixture was stirred under an ice-cooled nitrogen atmosphere for 60 minutes, poured into chloroform (10 ml) and cold water (50 ml), the chloroform layer was separated, dried over sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform). And recrystallized from ethanol to obtain 0.271 g of Compound 12 (yield: 7).
5.9%).

IR (KBr tablet, cm ^-1 ) 3400, 1764, 1702, 1625, 1609,
1504 m. p. 185-186 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.43 (3H, t, J = 7.0 Hz), 1.60-
1.85 (6H, m), 1.85 to 2.05 (2H,
m), 2.35 (3H, s), 3.10 (2H, t, J
= 9.0 Hz), 3.83 (2H, t, J = 9.0H)
z), 4.42 (2H, q, J = 7.0 Hz), 5.9
0 to 6.06 (1H, m), 8.69 (1H, s),
9.32 (1H, brs)

Example 13 Compound 11 (R ¹ : cyclopentyl, R ² : methyl,
Preparation of R ³ : oxalylamino): 0.3 of compound 12
4 g was suspended in 6.8 ml of methanol, and stirred in an ice-cooled nitrogen atmosphere.
3 ml was added, and stirring was continued for 1 hour under an ice-cooled nitrogen atmosphere. Further, 6 ml of water was added, and the mixture was stirred at room temperature for 8 hours and 30 minutes. After adding 20 ml of methanol and stirring, the insolubles were collected by filtration, dried, dissolved in 300 ml of hot ethanol, filtered, and the solvent was distilled off. Then, 15 ml of ethanol was added, and a 1N aqueous solution of hydrogen chloride was added to adjust the pH to around 3. And The precipitated solid was collected by filtration and dried to obtain 0.17 g of Compound 11 (yield: 54.8).
%)Obtained.

IR (KBr tablet, cm ^-1 ) 3235,2800-2350,1681,1625,
1547, 1496, 1346, 1296, 1173 m. p. 255-255.5 ° C

Example 14 Compound 13 (R ¹ : tert-butyl, R ² : methyl, R ³ :
Preparation of N- (1H-tetrazol-5-yl) carboxamide): 380 mg of compound 34 described in Examples below.
Weigh out, add 3 ml of dry DMF, add 280 mg of 1,
Add 1'-carbonyldiimidazole and add 30 ° C at 90 ° C.
After stirring for 5 minutes, 170 mg of 5-amino-1H-tetrazole was added while the crystals were dissolved. After further stirring at 90 ° C. for 3 hours, the reaction solution was cooled to 0 ° C., and water was added.
The mixture was acidified with concentrated hydrochloric acid. Thereafter, the reaction solution was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and the precipitated crystals were collected by filtration and dried. The crystals were washed with chloroform and dried to obtain 180 mg of compound 13. (Yield 38.2
%)

[0082] IR (KBr ^{tablet, cm -1) 1667,1580,1502,1303,1201 1 H-} NMR (DMSO-d 6, ppm) 1.50 (9H, s), 2.31 (3H, s) , 2.8
4 (2H, t, J = 8.9 Hz), 3.95 (2H,
t, J = 8.9 Hz), 8.42 (1H, s), 11.
59 (1H, s), 15.80 (1H, brs)

Example 15 Compound 14 (R ¹ : tert-amyl, R ² : methyl, R ³ :
Preparation of N- (1H-tetrazol-5-yl) carboxamide): 400 mg of compound 35 described in Examples below
Thus, 280 mg (yield 60.0%) of compound 14 was obtained in the same manner as in Example 14.

IR (KBr tablet, cm ^-1 ) 1666, 1578, 1501, 1297, 1200 ¹ H-NMR (DMSO-d ₆ , ppm) 0.90 (3H, t, J = 7.3 Hz), 1. 67 (6
H, s), 2.33 (2H, q, J = 7.3 Hz),
2.45 (3H, s), 3.09 (2H, t, J = 8.
9 Hz), 4.13 (2H, t, J = 8.9 Hz),
8.46 (1H, s), 11.89 (1H, s), 1
5.60 (1H, brs)

Example 16 Compound 15 (R ¹ : cyclopentyl, R ² : methyl
Preparation of R ³ : 1H-tetrazol-5-yl): 3-cyano-8-cyclopentyl-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine
21 ml of dry DMF was added to 62 g, 0.45 g of sodium azide and 0.51 g of ammonium acetate, and the mixture was stirred at 160 ° C. for 9 hours under a nitrogen atmosphere. During the process, 0.45 g of sodium azide and 0.51 g of ammonium acetate were appropriately added. While stirring under ice-water cooling, add 30 ml of water, add concentrated hydrochloric acid and adjust the pH.
Was adjusted to 1, and the pH was adjusted to 4 to 5 with saturated aqueous sodium hydrogen carbonate. Extracted with chloroform, dried and concentrated, silica gel column chromatography (elution solvent: chloroform: methanol = 1)
0: 0 → 30: 1) to give 0.54 g of compound 15.
(28.7% yield).

IR (KBr tablet, cm ^-1 ) 1625,1581,1322,1259,1201 m.p. p. 266.5 ° C. to 267.5 ° C. ¹ H-NMR (CDCl ₃ , ppm) 1.60 to 1.85 (6H, m), 1.85 to 2.10.
(2H, m), 2.40 (3H, s), 3.14 (3
H, t, J = 9.2 Hz), 3.90 (3H, t, J =
9.2 Hz), 5.54 (1H, brs), 5.80-
6.00 (1H, m), 8.57 (1H, s)

Example 17 Compound 16 (R ¹ : tert-butyl, R ² : methyl, R ³ :
Preparation of 1H-tetrazol-5-yl): 8-tert-butyl-3-cyano-5-methyl-8H-pyrrolo [3,2
-E] Pyrazolo [1,5-a] pyrimidine (1.38 g) was obtained in the same manner as in Example 16 to obtain 0.42 g of compound 16 (yield: 26.1%).

IR (KBr tablet, cm ^-1 ) 1627, 1560, 1245, 1196 m. p. 270 ° C. ¹ H-NMR (CDCl ₃ : DMSO-d ₆ = 4: 1, p
pm) 1.75 (9H, s), 2.46 (3H, s), 3.0
6 (2H, t, J = 8.9 Hz), 4.08 (2H,
t, J = 8.9 Hz), 5.90 (1H, brs),
8.51 (1H, s)

Example 18 Compound 17 (R ¹ : tert-amyl, R ² : methyl, R ³ :
Preparation of 1H-tetrazol-5-yl): 8-tert-amyl-3-cyano-5-methyl-8H-pyrrolo [3,2
-E] Pyrazolo [1,5-a] pyrimidine 1.40 g was obtained in the same manner as in Example 16 to obtain 0.46 g of compound 17 (yield 28.4%).

IR (KBr tablet, cm ^-1 ) 1633, 1569, 1256, 1186 m. p. 246 ° C. ¹ H-NMR (DMSO-d ₆ , ppm) 0.86 (3H, t, J = 7.3 Hz), 1.64 (6
H, s), 2.31 (2H, q, J = 7.3 Hz),
2.40 (3H, s), 3.04 (2H, t, J = 8.
7 Hz), 4.09 (2H, t, J = 8.7 Hz),
8.54 (1H, s)

Example 19 Compound 18 (R ¹ : cyclopentyl, R ² : methyl,
R ³ : carboxamide): 3-cyano-8-cyclopentyl-6,7-dihydro-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine in 0.53 g of ethanol 2 ml were added, and 0.58 g of sodium hydroxide dissolved in 2 ml of water was further added. The mixture was refluxed for 8 hours under a nitrogen atmosphere. After cooling, 30 ml of water was added, and the insoluble solid was collected by filtration and air-dried to obtain 0.33 g of Compound 18 (yield 57.9%).

IR (KBr tablet, cm ^-1 ) 3334, 3135, 1656, 1616, 1590,
1518, 1465, 1330, 1259, 1196 m. p. 280 ° C. or higher ¹ H-NMR (CDCl ₃ , ppm) 1.58 to 1.85 (6H, m), 1.85 to 2.05
(2H, m), 2.35 (3H, s), 3.11 (3
H, t, J = 8.9 Hz), 3.85 (3H, t, J =
8.9 Hz), 5.45 (1H, brs), 5.85
6.00 (1H, m), 8.36 (1H, brs),
8.45 (1H, s)

Example 20 Compound 19 (R ¹ : cyclopentyl, R ² : amino,
Preparation of R ³ : nitro): Compound 23 described in Examples below
Was suspended in 18 ml of dry acetone, and 0.65 ml of triethylamine was added with stirring under an ice-cooled nitrogen atmosphere. Subsequently, 0.47 g of ethyl chlorocarbonate was dissolved in 2 ml of dry acetone, added dropwise, and stirred for 1 hour. Under the same conditions, sodium azide (0.54 g) was dissolved in water (2 ml) and added dropwise. After stirring for 1 hour, the mixture was allowed to stand for 2 hours.
The reaction was poured into 200 ml of water, the insolubles were filtered off and washed with water. This was suspended in 25 ml of toluene, and
The mixture was heated and stirred for an hour. This was cooled with ice water, dissolved by adding 120 ml of chloroform, dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (elution solvent: chloroform: methanol = 100: 0 →
Purified by 100: 1) and concentrated. Residue in chloroform 1
The mixture was dissolved in 00 ml and extracted with 1N hydrochloric acid. The hydrochloric acid layer was made alkaline with baking soda and extracted with chloroform to give Compound 1.
0.74 g (yield 67.9%) of Compound 9 was obtained.

IR (KBr tablet, cm ^-1 ) 3487, 3310, 3210, 1624, 1583,
1400, 1258, 1214 m. p. 279 to 280 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.60 to 1.85 (6H, m), 1.85 to 2.05
(2H, m), 2.97 (2H, t, J = 8.9H)
z), 3.86 (3H, t, J = 8.9 Hz), 5.6
0 to 5.80 (1H, m), 5.72 (2H, br)
s), 8.42 (1H, s)

Example 21 Preparation of compound 20 (R ¹ : sec-butyl, R ² : amino, R ³ : nitro): Compound 24 was prepared in the same manner as in Example 20 by using Compound 24 described in the following Example as a raw material. 20 were produced. Yield 45.8%

IR (KBr tablet, cm ^-1 ) 1640, 1625, 1580, 1399, 1256 m. p. 201.5-203.1 ° C. ¹ H-NMR (CDCl ₃ , ppm) 0.92 (3H, t, J = 7.6 Hz), 1.25 (3
H, d, J = 6.5 Hz), 1.45 to 1.75 (2
H, m), 2.98 (2H, t, J = 8.9 Hz),
3.79 (2H, s, J = 8.9 Hz), 5.41 (1
H, s, J = 6.5 Hz), 6.14 (2H, br)
s), 8.40 (1H, s)

Reference Example 4 Production of ethyl (tetrahydro-2-oxo-3-furyl) glyoxylate: 25.80 g of sodium metal was added to and dissolved in 500 ml of dried Molecular sieves ethanol. Then, 148.21 g of diethyl oxalate was added, and the reaction system was cooled to -15 to -10 ° C. While maintaining this temperature, a solution of 88.79 g of γ-butyrolactone in 60 ml of ethanol was added dropwise, stirred for 2 hours, and then stirred at room temperature for 16 hours. The reaction solution was poured into 1 L of ice water, adjusted to pH 4 to 5 with concentrated hydrochloric acid, and extracted with chloroform.
The chloroform layer was dried with anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The crude product obtained was distilled under reduced pressure to obtain a fraction at 150 to 160 ° C. (5 to 6 mmHg) as a target. 156.21 g of a slightly yellow liquid. Yield 83.1
%.

¹ H-NMR (CDCl ₃ , ppm) 1.39 (3H, t, J = 7.4 Hz), 3.30 (2
H, t, J = 7.4 Hz), 4.37 (2H, q, J =
7.4 Hz), 4.50 (2H, t, J = 7.4H)
z), 10.92 (1H, br)

Example 22 Ethyl 7-chloro-6- (2-chloroethyl) -3-
Preparation of nitropyrazolo [1,5-a] pyrimidine-5-carboxylate: 8.12 g of 3-aminopyrazole
To a solution of (97.70 mmol) in 32 ml of acetic acid was added 8.12 g of synthetic zeolite A-4 powder while stirring at room temperature.
Further, ethyl (tetrahydro-2-oxo-3-furyl) glyoxylate 8.19 obtained in Reference Example 4 was further stirred under ice-cooling.
g (97.78 mmol) in 40 ml of acetic acid was added dropwise over 2 minutes, followed by stirring at room temperature for 4 hours. Thereafter, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. Residue is chloroform 150
dissolved in water and poured into 700 ml of water. After shaking well, the chloroform layer was separated, and the aqueous layer was further extracted with chloroform (1).
The combined chloroform layers were dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform) to give ethyl 6- (2-hydroxyethyl) pyrazolo [1,5-
a] 5.36 g of pyrimidine-7 (4H) -one-5-carboxylate were obtained. 7 ml of phosphorus oxychloride (d
= 1.645, 75.10 mmol), and the mixture was stirred under an atmosphere of nitrogen at an oil bath temperature of 100 ° C. for 40 minutes, cooled to near room temperature, and triethylamine (7 ml, d = 0.72)
6,50.32 mmol) and 30 at an oil bath temperature of 100 ° C.
Minutes. Then, the mixture was cooled with ice-water, and chloroform 10
Add 0 ml, pour into 600 ml of ice-water, shake well, separate the chloroform layer, extract the aqueous layer further with chloroform (100 ml x 2), combine all chloroform layers,
After drying over magnesium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography (chloroform) to obtain 3.60 g of ethyl 7-chloro-6- (2-chloroethyl) pyrazolo [1,5-a] pyrimidine-5-carboxylate. 1.60 ml of 90% nitric acid and 1 drop of concentrated sulfuric acid were sequentially added to 14.2 ml of acetic anhydride under ice-cooling and stirring, followed by cooling to -10 ° C. Ethyl 7-chloro-6
A solution of 3.60 g of (2-chloroethyl) pyrazolo [1,5-a] pyrimidine-5-carboxylate in 4.30 ml of acetic anhydride was added dropwise at -5 to 0 ° C. After stirring for 20 minutes under the same conditions, the mixture was poured into 300 ml of ice-water and extracted with 400 ml of ethyl acetate. The organic layer was washed twice with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution, dried over magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 5, chloroform) to obtain 2.49 g of the desired product (yield 7.6%).

¹ H-NMR (CDCl ₃ , ppm) 1.49 (3H, t, J = 7.3 Hz), 3.61 (2
H, t, J = 7.0 Hz), 3.85 (2H, t, J =
7.0 Hz), 4.56 (2H, q, J = 7.3H)
z), 8.93 (1H, s)

Example 23 Ethyl 8-cyclopentyl-6,7-dihydro-3-
Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] Preparation of pyrimidine-5-carboxylate (compound 21) (part 1): ethyl 7-chloro-6- (2-
1.16 g of chloroethyl) -3-nitropyrazolo [1,5-a] pyrimidine-5-carboxylate (3.48)
mmol) was dissolved in 12 ml of dry dimethylformamide and 2.4 ml of cyclopentylamine (d = 0.863, 24.
32 mmol) and stirred at room temperature for 4 hours. Thereafter, the reaction solution was poured into ice-water, the insoluble solid was collected by filtration, washed with water, and air-dried to obtain 1.15 g (yield 95.7%) of the desired product.

¹ H-NMR (CDCl ₃ , ppm) 1.47 (3H, t, J = 7.3 Hz), 1.65
1.90 (6H, m), 1.95 to 2.15 (2H,
m), 3.58 (2H, t, J = 8.9 Hz), 4.0
0 (2H, t, J = 8.9 Hz), 4.46 (2H,
q, J = 7.3 Hz), 5.85 to 6.05 (1H,
m), 8.67 (1H, s)

Example 24 Preparation of compound 21 (R ¹ : cyclopentyl, R ² : ethoxycarbonyl, R ³ : nitro) (part 2): ethyl 7
-Chloro-6- (2-chloroethyl) pyrazolo [1,5
-A] Pyrimidine-5-carboxylate (3.6 g) is dissolved in dry DMF (48 ml), and cyclopentylamine (7.3 ml) is added thereto while stirring at room temperature under a nitrogen atmosphere.
Stirred for 0 minutes. The reaction product was poured into 250 ml of ice water, insolubles were collected by filtration, and air-dried to give ethyl 8-cyclopentyl-6,7.
3.20 g (yield: 85.3%) of -dihydro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5-carboxylate was obtained. 1.16g of this
Was added little by little to a mixed acid prepared by mixing 7.8 ml of concentrated sulfuric acid and 3.9 ml of 90% nitric acid with stirring at -5 to 0 ° C. After stirring for 5 minutes under the same conditions, the reaction solution was added to 200 ml of ice water.
And extracted with chloroform. The chloroform layer was dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (ethyl acetate: n-ethyl acetate).
Hexane was purified by 1: 1) to obtain 0.76 g of compound 21.
(57.0% yield).

¹ H-NMR (CDCl ₃ , ppm) 1.47 (3H, t, J = 7.3 Hz), 1.65
1.90 (6H, m), 1.95 to 2.15 (2H,
m), 3.58 (2H, t, J = 8.9 Hz), 4.0
0 (2H, t, J = 8.9 Hz), 4.46 (2H,
q, J = 7.3 Hz), 5.85 to 6.05 (1H,
m), 8.67 (1H, s)

Example 25 Preparation of compound 22 (R ¹ : sec-butyl, R ² : ethoxycarbonyl, R ³ : nitro): ethyl 7-chloro-6
-(2-chloroethyl) -3-nitropyrazolo [1,5
-A] Compound 22 was obtained from pyrimidine-5-carboxylate and sec-butylamine in the same manner as in Example 23.
(Yield 90.1%)

¹ H-NMR (CDCl ₃ , ppm) 0.96 (3H, t, J = 7.3 Hz), 1.37 (3
H, d, J = 6.5 Hz), 1.47 (3H, t, J =
7.0 Hz), 1.64 to 1.80 (2H, m), 3.
58 (3H, t, J = 7.3 Hz), 3.82 to 4.0
4 (2H, m), 4.46 (2H, q, J = 7.0H
z), 5.73 (1H, s, J = 6.5 Hz), 8.6
7 (1H, s)

Example 26 Preparation of compound 23 (R ¹ : cyclopentyl, R ² : carboxyl, R ³ : nitro): 2.05 g of compound 21 was suspended in 30 ml of tetrahydrofuran and 10 ml of methanol, and 0.5N- 20 ml of sodium hydroxide solution
Was added dropwise, and the mixture was left standing for 15 minutes, and 20 ml of a 0.5N sodium hydroxide aqueous solution was further added dropwise. The mixture was allowed to stand for 15 minutes under cooling with ice water and subjected to ultrasonic treatment for 5 minutes, and concentrated sulfuric acid was added to adjust the pH to 3. Water 2
To the mixture was added 00 ml, the insolubles were collected by filtration, washed with water and dried to obtain 1.21 g of compound 23 (yield: 64.2%).

¹ H-NMR (DMSO-d ₆ , ppm) 1.50 to 2.00 (8H, m), 3.40 (2H,
t, J = 8.6 Hz), 3.99 (2H, t, J = 8.
6 Hz), 5.78 (1H, q, J = 8.0 Hz),
8.93 (1H, s)

Example 27 Compound 24 (R ¹ : sec-butyl, R ² : carboxyl,
Preparation of R ³ : nitro): Compound 22 as in Example 26
Was treated to give compound 24. (85.7% yield)

¹ H-NMR (DMSO-d ₆ , ppm) 0.86 (3H, t, J = 7.3 Hz), 1.29 (3
H, d, J = 6.5 Hz), 1.50 to 1.80 (2
H, m), 3.42 (3H, t, J = 8.9 Hz),
3.80-4.04 (2H, m), 5.45-5.65
(1H, m), 8.93 (1H, s), 13.56 (1
H, brs)

Example 28 Compound 25 (R ¹ : tert-butyl, R ² : methyl, R ³ :
Preparation of trifluoroacetyl): 7-chloro-6- (2
-Chloroethyl) -5-methylpyrazolo [1,5-a]
Pyrimidine (500 mg, 2.17 mmol) was dissolved in dry dimethylformamide (9 ml).
91 mg (2.61 mmol), 660 mg of triethylamine
(6.53 mmol) was sequentially added, and the mixture was stirred at room temperature for 172 hours. The reaction solution was poured into 50 ml of water, stirred for several minutes, and extracted with chloroform (10 ml × 4). All chloroform layers were combined, dried over sodium sulfate, and evaporated. The residue was dissolved in 20 ml of ethyl acetate and washed with saturated saline (50 ml).
× 6), and after drying with sodium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography (chloroform:
n-hexane = 8: 2) and 8-tert-butyl-
6,7-dihydro-5-methyl-8H-pyrrolo [3,2
-E] 0.24 g of pyrazolo [1,5-a] pyrimidine
(47.9% yield).

IR (KBr tablet, cm ^-1 ) 1593, 1558, 1498, 1313, 1250,
1209, 749 m. p. 143.5 to 145.5 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.73 (9H, s), 2.34 (3H, s), 2.9
6 (2H, t, J = 9.0 Hz), 3.95 (2H,
t, J = 9.0 Hz), 6.28 (1H, d, J = 2.
7Hz), 7.92 (1H, d, J = 2.7Hz)

0.24 g of this 8-tert-butyl-6,7-dihydro-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine was added to 2.5 ml of dry methylene chloride. Dissolve, trifluoroacetic anhydride 0.3 ml
Was added and stirred for 7 hours. The reaction solution was poured into 10 ml of chloroform and 50 ml of water, made alkaline with saturated aqueous sodium hydrogen carbonate, and the organic layer was separated. After drying over sodium sulfate, it was purified by silica gel column chromatography (chloroform).
Recrystallization from ethanol yielded 0.20 g of compound 25 (58.5% yield).

IR (KBr tablet, cm ^-1 ) 1672, 1596, 1583, 1503, 1222
1184, 1157, 1123, 883, 730 m. p. 201.9-203.2 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.72 (9H, s), 2.46 (3H, s), 3.0
5 (2H, t, J = 9.2 Hz), 4.07 (2H,
t, J = 9.2 Hz), 8.41 (1H, s)

Example 29 Compound 26 (R ¹ : tert-amyl, R ² : methyl, R ³ :
Preparation of trifluoroacetyl): 7 as in Example 28
8-tert-amyl-6,7-dihydro-5-produced from -chloro-6- (2-chloroethyl) -5-methylpyrazolo [1,5-a] pyrimidine and tert-amylamine
Methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] Pyrimidine to give compound 26. (Yield 43.
0%)

IR (KBr tablet, cm ^-1 ) 1671, 1584, 1501, 1222, 1185
1155, 1122, 882 m. p. 147.3-148.8 ° C. ¹ H-NMR (CDCl ₃ , ppm) 0.89 (3H, t, J = 7.8 Hz), 1.65 (6
H, s), 2.29 (2H, q, J = 7.8 Hz),
2.46 (3H, s), 3.06 (2H, t, J = 9.
2 Hz), 4.08 (2H, t, J = 9.2 Hz),
8.39 (1H, s)

Example 30 Compound 27 (R ¹ : cyclopentyl, R ² : methyl,
Preparation of R ³ : trifluoroacetyl): 8-cyclopentyl-6 prepared from 7-chloro-6- (2-chloroethyl) -5-methylpyrazolo [1,5-a] pyrimidine and cyclopentylamine in the same manner as in Example 28. Compound 27 was obtained from 7,7-dihydro-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine.
(Yield 85.0%)

IR (KBr tablet, cm ^-1 ) 1678, 1626, 1193, 1127, 885 m. p. 160.1 to 163.3 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.58 to 1.88 (6H, m), 1.88 to 2.10.
(2H, m), 2.46 (3H, s), 3.15 (2
H, t, J = 9.2 Hz), 3.90 (2H, t, J =
9.2 Hz), 5.73-5.95 (1H, m), 8.
39 (1H, s)

Example 31 Compound 28 (R ¹ : cyclohexyl, R ² : methyl,
Preparation of R ³ : trifluoroacetyl): 8-cyclohexyl-6 prepared from 7-chloro-6- (2-chloroethyl) -5-methylpyrazolo [1,5-a] pyrimidine and cyclohexylamine in the same manner as in Example 28. Compound 28 was obtained from 7,7-dihydro-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine.
(Yield 18.1%)

IR (KBr tablet, cm ^-1 ) 1677, 1624, 1601, 1515, 1508,
1241, 1191, 1175, 1129 m. p. 156.0 to 158.2 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.00 to 1.30 (1H, m), 1.30 to 2.00
(9H, m), 2.46 (3H, s), 3.14 (2
H, t, J = 8.9 Hz), 3.89 (2H, t, J =
8.9 Hz), 5.22 to 5.38 (1H, m), 8.
39 (1H, s)

Example 32 Compound 29 (R ¹ : sec-butyl, R ² : methyl, R ³ :
Preparation of trifluoroacetyl): 7 as in Example 28
8-sec-butyl-6,7-dihydro-5-produced from -chloro-6- (2-chloroethyl) -5-methylpyrazolo [1,5-a] pyrimidine and sec-butylamine
Methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] Pyrimidine to give compound 29. (Yield 58.
5%)

IR (KBr tablet, cm ^-1 ) 1675, 1630, 1600, 1515, 1245,
1225, 1180, 1155, 1125, 880, 7
75,725 m. p. 169.9-171.3 ° C. ¹ H-NMR (CDCl ₃ , ppm) 0.94 (3H, t, J = 7.6 Hz), 1.31 (3
H, d, J = 7.0 Hz), 1.55-1.80 (2
H, m), 2.46 (3H, s), 3.17 (2H,
t, J = 8.9 Hz), 3.70-3.95 (2H,
m), 5.50 to 5.68 (1H, m), 8.38 (1
H, s)

Example 33 Ethyl 6- (2-hydroxyethyl) -5-methylpyrazolo [1,5-a] pyrimidin-7 (4H) -one-
Production of 3-carboxylate: 1.55 g (10.00 g) of ethyl 3-aminopyrazole-4-carboxylate
mmol), 1.92 g of α-acetyl-γ-butyrolactone
(15.00 mmol) was added with 2 ml of dry ethanol, and 0.1 ml of a boron trifluoride methanol complex was added thereto with stirring at room temperature under a nitrogen atmosphere. Subsequently, the mixture was stirred for 15 minutes under the same conditions and allowed to stand for 2 hours and 35 minutes. Thereafter, ethanol was added, and the insoluble solid was collected by filtration, washed with ethanol, and air-dried. The obtained solid was suspended in 10.5 ml of water,
1.03 g (10.2 mmol) of triethylamine was added thereto, and the mixture was stirred at an oil bath temperature of 100 ° C. for 3 hours. Thereafter, the mixture was cooled with ice-water, and concentrated hydrochloric acid was added thereto while stirring to adjust the pH to about 4 (solid precipitation). After adding chloroform and water thereto and shaking well, the chloroform layer was separated, and the aqueous layer was further extracted with chloroform. All chloroform layers are combined,
After drying over sodium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography (chloroform, chloroform: methanol = 100: 1) to give the desired product in 2.
11 g (79.6% yield) was obtained.

IR (KBr tablet, cm ^-1 ) 3491, 3301, 1695, 1666, 1580,
1233, 1215, 1035, 778 ¹ H-NMR (CDCl ₃ , ppm) 1.39 (3H, t, J = 7.3 Hz), 2.50 (3
H, s), 2.88 (2H, t, J = 6.2 Hz),
3.88 (2H, t, J = 6.2 Hz), 4.35 (2
H, q, J = 7.3 Hz), 7.27 (1H, s),
9.53 (1H, brs)

Example 34 Ethyl 7-chloro-6- (2-chloroethyl) -5
Preparation of methylpyrazolo [1,5-a] pyrimidine-3-carboxylate: ethyl 6- (2-hydroxyethyl) -5-methylpyrazolo [1,5-a] pyrimidine-
0.34 g of 7 (4H) -one-3-carboxylate
(1.28 mmol) in 0.4 ml of phosphorus oxychloride (d = 1.
645, 4.29 mmol), 0.36 ml of triethylamine
(D = 0.726, 2.59 mmol) was added in succession, and the mixture was stirred under a nitrogen atmosphere at an oil bath temperature of 100 ° C. for 2 hours and 15 minutes.
Thereafter, the mixture was cooled with ice-water, dissolved in 10 ml of chloroform,
This was poured into 30 ml of water. After adjusting the pH to about 6 with saturated aqueous sodium hydrogen carbonate and shaking well, the organic layer was separated. The aqueous layer was further extracted with chloroform (10 ml × 2). The residue is purified by silica gel chromatography (chloroform).
To give 0.33 g (yield 84.6%) of the desired product.

¹ H-NMR (CDCl ₃ , ppm) 1.42 (3H, t, J = 7.3 Hz), 2.83 (3
H, s), 3.38 (2H, t, J = 7.2 Hz),
3.78 (2H, t, J = 7.2 Hz), 4.42 (2
H, q, J = 7.3 Hz), 8.57 (1H, s)

Example 35 Ethyl 8-cyclopentyl-6,7-dihydro-5
Methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5
Preparation of -a] pyrimidine-3-carboxylate (compound 30): ethyl 7-chloro-6- (2-chloroethyl) -5-methylpyrazolo [1,5-a] pyrimidine-
To a solution of 0.12 g (0.40 mmol) of 3-carboxylate in 1.6 ml of dry dimethylformamide, 0.04 g (0.47 mmol) of cyclopentylamine and 0.12 g (1.19 mmol) of triethylamine are sequentially added.
The mixture was stirred for 7 hours and 30 minutes. Thereafter, the reaction solution was poured into 50 ml of water and extracted with chloroform (10 ml × 3). All the chloroform layers were combined, dried over sodium sulfate, and evaporated. The residue was subjected to silica gel column chromatography (chloroform) to give 0.10 g of the desired product (yield 80.0 g).
%)Obtained.

M. p. 178-180 ° C IR (KBr tablet, cm ^-1 ) 1688, 1610, 1514, 1459, 1313
1295, 1180, 1110, 776 ¹ H-NMR (CDCl ₃ , ppm) 1.39 (3H, t, J = 7.3 Hz), 1.60-
1.85 (6H, m), 1.85 to 2.05 (2H,
m), 2.43 (3H, s), 3.11 (2H, t, J
= 9.0 Hz), 3.84 (2H, t, J = 9.0H)
z), 4.37 (2H, q, J = 7.3 Hz), 5.8
5-6.00 (1H, m), 8.34 (1H, s)

Example 36 Compound 31 (R ¹ : tert-butyl, R ² : methyl, R ³ :
Production of ethoxycarbonyl): 7-chloro-6- (2-
From 1 g of (chloroethyl) -3-ethoxycarbonyl-5-methylpyrazolo [1,5-a] pyrimidine and 3.2 ml of tert-butylamine, 0.57 g (yield 57%) of compound 31 was obtained in the same manner as in Example 35. Was.

IR (KBr tablet, cm ^-1 ) 1708, 1600, 1570, 1176 m. p. 164 to 165 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.34 (3H, t, J = 7.0 Hz), 1.69 (9
H, s), 2.47 (3H, s), 3.00 (2H,
t, J = 8.9 Hz), 4.00 (2H, t, J = 8.
9 Hz), 4.36 (2H, q, J = 7.0 Hz),
8.35 (1H, s)

Example 37 Compound 32 (R ¹ : tert-amyl, R ² : methyl, R ³ :
Production of ethoxycarbonyl): 7-chloro-6- (2-
1.45 g of chloroethyl) -3-ethoxycarbonyl-5-methylpyrazolo [1,5-a] pyrimidine and tert-
From 5 ml of amylamine, 0.89 g (yield 58.9%) of compound 32 was obtained in the same manner as in Example 35.

IR (KBr tablet, cm ^-1 ) 1705, 1600, 1507, 1174 m. p. 137-139 ° C ¹ H-NMR (CDCl ₃ , ppm) 0.86 (3H, t, J = 7.6 Hz), 1.38 (3
H, t, J = 7.0 Hz), 1.63 (6H, s),
2.30 (2H, q, J = 7.6 Hz), 2.42 (3
H, s), 3.00 (2H, t, J = 8.9 Hz),
4.01 (2H, t, J = 8.9 Hz), 4.36 (2
H, q, J = 7.0 Hz), 8.33 (1H, s)

Example 38 Compound 33 (R ¹ : cyclopentyl, R ² : methyl,
Preparation of R ³ : carboxyl): 0.90 g of compound 30
Was suspended in 13 ml of ethanol, and a solution prepared by dissolving 0.84 g of sodium hydroxide in 6.5 ml of water was added thereto, followed by heating and stirring at 100 ° C. for 30 minutes in a nitrogen atmosphere. Cool with ice water,
While stirring, 13 ml of water was added, and 1N-hydrochloric acid was added to adjust pH
Was adjusted to 2, and saturated aqueous sodium hydrogen carbonate was further added to adjust the pH to 3-4.
The insoluble solid was collected by filtration, washed with water and air-dried to obtain 0.75 g of Compound 33.
(91.5% yield).

IR (KBr tablet, cm ^-1 ) 1723,1610,1516,1301,1202
1191,778 m. p. 230-230.5 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.60-1.88 (6H, m), 1.88-2.10.
(2H, m), 2.34 (3H, s), 3.14 (2
H, t, J = 9.2 Hz), 3.91 (2H, t, J =
9.2 Hz), 5.78-5.95 (1H, m), 8.
36 (1H, s)

Example 39 Compound 34 (R ¹ : tert-butyl, R ² : methyl, R ³ :
Preparation of carboxyl): Compound 3 as in Example 38
0.70 g of 1 was treated to give 0.64 g (quantitative) of compound 34.

IR (KBr tablet, cm ^-1 ) 1718, 1584, 1508, 1203 m.p. p. 258-259 ° C ¹ H-NMR (DMSO-d ₆ , ppm) 1.67 (9H, s), 2.31 (3H, s), 2.9
9 (2H, t, J = 8.9 Hz), 4.08 (2H,
t, J = 8.9 Hz), 8.39 (1H, s)

Example 40 Compound 35 (R ¹ : tert-amyl, R ² : methyl, R ³ :
Preparation of carboxyl): Compound 3 as in Example 38
By treating 0.5 g of Compound 2, 0.41 g (yield: 89.7%) of Compound 35 was obtained.

IR (KBr tablet, cm ^-1 ) 1723,1578,1504,1186 m.p. p. 239-240 ° C ¹ H-NMR (DMSO-d ₆ , ppm) 0.89 (3H, t, J = 7.3 Hz), 1.73 (6
H, s), 2.30 (2H, q, J = 7.3 Hz),
2.36 (3H, s), 3.04 (2H, t, J = 8.
9 Hz), 4.08 (2H, t, J = 8.9 Hz),
8.38 (1H, s)

Example 41 Compound 36 (R ¹ : cyclopentyl, R ² : methyl,
Preparation of R ³ : N- (1H-tetrazol-5-yl) carboxamide): 0.286 g of compound 33 was dried in DM
The suspension was stirred in a nitrogen atmosphere at room temperature while adding 0.20 g of 1,1′-carbonyldiimidazole as a solid, and stirred at room temperature for 15 minutes and at 90 ° C. for 40 minutes.
To this reaction solution was added 5-amino-1H-tetrazole 0.12.
g was added and stirred for 1 hour and 30 minutes. Cool with ice water, water 1
Then, 1N-hydrochloric acid was added with stirring to adjust the pH to 1
Then, saturated aqueous sodium hydrogen carbonate was added to adjust the pH to 4. The insoluble solid was collected by filtration, washed with water and air-dried to obtain 0.315 g of Compound 36 (yield: 89.2%).

IR (KBr tablet, cm ^-1 ) 1676, 1605, 1543, 1508, 1297,
1200, 1186, 764 m. p. 293 to 296 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.68 to 1.88 (6H, m), 1.90 to 2.08
(2H, m), 2.45 (3H, s), 3.17 (3
H, t, J = 9.2 Hz), 3.93 (3H, t, J =
9.2 Hz), 5.80-5.95 (1H, m), 8.
52 (1H, s)

Reference Example 5 Preparation of 1-bromo-2-t-butyldimethylsilyloxyethane: t-butyldimethylsilyl chloride 3.50 in 40 ml of molecular sieves dried acetonitrile
g and imidazole 4.00 g were added, and the mixture was stirred at room temperature for 10 minutes. Here, 2-bromoethanol 2.64
g was added, and the mixture was further stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium carbonate, and then the solvent was distilled off under reduced pressure. The crude product obtained here was subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate = 2: 1) to obtain 4.40 g (yield: 87.0%) of the desired product.

Colorless liquid ¹ H-NMR (CDCl ₃ , ppm) -0.10 (6H, s), 0.82 (9H, s), 3.
31 (2H, t, J = 6.3 Hz), 3.80 (2H,
t, J = 6.3 Hz)

Reference Example 6 Production of diethyl 2- (2-t-butyldimethylsilyloxyethyl) malonate: 22.90 g of sodium metal was dissolved in 1.70 L of molecular sieves dried ethanol, and 131.0 g of diethyl malonate was dissolved. 230 g of the compound of Reference Example 5 was added, and the mixture was stirred overnight under reflux with heating. After evaporating the solvent under reduced pressure, a little ether was added, the precipitated crystals were separated by filtration, the filtrate was concentrated and subjected to silica gel column chromatography (eluent: hexane only → hexane: ethyl acetate = 10: 1) to give the desired product. 234.4
2 g (89.9% yield) was obtained.

Colorless liquid ¹ H-NMR (CDCl ₃ , ppm) 0.02 (6H, s), 0.87 (9H, s), 1.2
5 (6H, t, J = 7.2 Hz), 2.10 (2H,
q, J = 6.5 Hz), 3.54 to 3.66 (3H,
m), 4.17 (4H, m)

Reference Example 7 Production of 5-hydroxy-6- (2-hydroxyethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one: Molecular sieves dried ethanol 1200
After dissolving 6.72 g of metallic sodium in 100 ml, Reference Example 6
64.0 g, 3-aminopyrazole 12.12
g was added, and the mixture was stirred for 3 days under reflux with heating. The solvent was distilled off under reduced pressure, and water was added to the residue to dissolve it. The aqueous layer was washed three times with ether. The aqueous layer was cooled to 0 ° C., adjusted to pH = 5.0 with 1N hydrochloric acid, and the precipitated crystals were collected by filtration. 200 ml of methanol and 3 drops of concentrated hydrochloric acid were added to the crystals, and the solvent was distilled off under reduced pressure together with water to precipitate crystals from a methanol / ether system to obtain 21.38 g (yield: 76.8%) of the desired product.

Light brown crystal ¹ H-NMR (DMSO-d ₆ , ppm) 2.66 (2H, t, J = 6.7 Hz), 3.52 (2
H, t, J = 6.7 Hz), 5.93 (1H, d, J =
1.9 Hz), 7.60 (1H, d, J = 1.9 Hz)

Reference Example 8 Production of 6- (2-chloroethyl) -5,7-dichloropyrazolo [1,5-a] pyrimidine: 5-hydroxy-6
100 ml of phosphorus oxychloride and 13.00 g of triethylamine were added to 12.45 g of-(2-hydroxyethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one,
The mixture was stirred under reflux for 2 hours. After the excess phosphorus oxychloride was distilled off under reduced pressure, the residue was poured into ice-water and extracted with chloroform. After washing the chloroform layer with water and drying over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform) to obtain 10.86 g (yield: 68.0%) of the desired product.

Light brown crystal ¹ H-NMR (CDCl ₃ , ppm) 3.49 (2H, t, J = 7.0 Hz), 3.82 (2
H, t, J = 7.0 Hz), 6.80 (1H, d, J =
2.4Hz), 8.21 (1H, d, J = 2.4Hz)

Example 42 Production of 6- (2-chloroethyl) -5,7-dichloro-3-nitropyrazolo [1,5-a] pyrimidine: 100 ml of concentrated sulfuric acid was cooled to 0 ° C. under ice cooling, and the temperature was lowered. But 50 ml of 90% nitric acid was gradually added so as not to rise. After stirring for a while, 13.80 g of the compound of Reference Example 8 was gradually added in the form of crystals so that the temperature did not rise, and the mixture was stirred at 0 ° C. for 4 hours. Since the raw material spot disappeared on TLC, stirring was stopped, and the reaction solution was poured into ice water. The precipitated crystals were collected by filtration and air-dried. Yield 15.61
g. 95.5% yield.

Yellow crystal ¹ H-NMR (CDCl ₃ , ppm) 3.55 (2H, t, J = 7.0 Hz), 3.89 (2
H, t, J = 7.0 Hz), 8.84 (1H, s)

Example 43 8-tert-butyl-5-chloro-6,7-dihydro-3-
Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] Preparation of pyrimidine (compound 40): 6.00 g of the compound of Example 42 was dissolved in 50 ml of dry dimethylformamide, 1.80 g of t-butylamine and 4.10 g of triethylamine were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform.
After washing with saturated saline and drying over sodium sulfate, the solvent was distilled off. From the residue, crystals were precipitated from a chloroform-ether system to obtain the desired product. Yield 5.54 g. Yield 92.
3%.

Yellow crystals m. p. 247 ° C. (decomposition) IR (KBr tablet, cm ⁻¹ ) 1610, 1580, 1480 ¹ H-NMR (CDCl ₃ , ppm) 1.78 (9H, s), 3.13 (2H, t, J = 8.
9 Hz), 4.15 (2H, t, J = 8.9 Hz),
8.61 (1H, s)

Example 44 5-Chloro-8-cyclopentyl-6,7-dihydro-
Preparation of 3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (Compound 41): Cyclopentylamine was added to 6.00 g of the compound of Example 42.
59 g and 4.10 g of triethylamine were allowed to act to synthesize according to the synthesis method of Example 43. 5.59 yield
g. Yield 89.2%.

Yellow crystals m. p. 209-210 ° C IR (KBr tablet, cm ⁻¹ ) 1610, 1480, 1230 ¹ H-NMR (CDCl ₃ , ppm) 1.76 (6H, m), 2.04 (2H, m), 3.2
6 (2H, t, J = 7.8 Hz), 3.86 (2H,
t, J = 7.8 Hz), 5.79 (1H, m), 8.5
7 (1H, s)

Example 45 8-sec-butyl-5-chloro-6,7-dihydro-3
-Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,
Preparation of 5-a] pyrimidine (compound 42): Example 42
1.80 g of sec-butylamine to 6.00 g of the compound
The synthesis was carried out according to the synthesis method of Example 43 by allowing 4.10 g of triethylamine to act. Yield 5.50 g. Yield 91.7%.

Yellow crystals m. p. 270 ° C. or higher IR (KBr ^{tablet, cm -1) 1630,1610,1490,1230,1220 1 H-} NMR (CDCl 3, ppm) 0.95 (3H, t, J = 7.0Hz), 1.34 ( 3
H, d, J = 7.0 Hz), 1.68 (2H, m),
3.24 (2H, t, J = 8.9 Hz), 3.89 (1
H, m), 5.58 (1H, m), 8.58 (1H,
s)

Reference Example 9 8-tert-butyl-5-chloro-6,7-dihydro-8
Production of H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine: 12.50 g of 6- (2-chloroethyl) -5,7-dichloropyrazolo [1,5-a] pyrimidine
Was dissolved in 70 ml of dimethylformamide, 9.55 g of tert-butylamine and 11.47 g of triethylamine were added, and the mixture was stirred at room temperature for 2 days. Excess amine and solvent were distilled off under reduced pressure, and the residue was dissolved in chloroform. The chloroform layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to precipitate crystals from a chloroform / ether system. The crystals were collected by filtration and recrystallized from ethanol to obtain 11.34 g (yield 90.6%) of the desired product.

White crystal ¹ H-NMR (CDCl ₃ , ppm) 1.79 (9H, s), 3.06 (2H, t, J = 7.
2 Hz), 4.00 (2H, t, J = 7.2 Hz),
6.31 (1H, d, J = 2.4 Hz), 7.95 (1
H, d, J = 2.4 Hz)

Reference Example 10 5-chloro-8-cyclopentyl-6,7-dihydro-
Production of 8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine: 6- (2-chloroethyl) -5,7-
Dichloropyrazolo [1,5-a] pyrimidine 11.0 g
Was reacted with 4.54 g of cyclopentylamine and 8.87 g of triethylamine, and the synthesis was carried out according to the synthesis method of Reference Example 9. Yield 10.42 g. 90.4% yield.

White crystal ¹ H-NMR (CDCl ₃ , ppm) 1.70 (6H, m), 2.10 (2H, m), 3.1
5 (2H, t, J = 6.2 Hz), 3.85 (2H,
t, J = 6.2 Hz), 6.04 (1H, m), 6.3
0 (1H, d, J = 2.4 Hz), 7.95 (1H,
d, J = 2.4 Hz)

Reference Example 11 8-sec-butyl-5-chloro-6,7-dihydro-8
Production of H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine: To 5.26 g of 6- (2-chloroethyl) -5,7-dichloropyrazolo [1,5-a] pyrimidine
4.00 g sec-butylamine, triethylamine 4.0.
82 g was allowed to act, and synthesis was performed according to the synthesis method of Reference Example 9. Yield 4.68 g. Yield 89.0%.

White crystal ¹ H-NMR (CDCl ₃ , ppm) 0.97 (3H, t, J = 7.3 Hz), 1.29 (3
H, d, J = 7.0 Hz), 1.69 (2H, m),
3.20 (2H, t, J = 6.2 Hz), 3.80 (2
H, m), 5.73 (1H, m), 6.30 (1
H, d, J = 1.9 Hz), 7.94 (1H, d, J =
1.9Hz)

Reference Example 12 Production of 8-tert-butyl-6,7-dihydro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine: 8-tert-butyl-5-chloro- 6,7-dihydro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a]
Pyrimidine (11.30 g) in tetrahydrofuran (300 m)
and 150 ml of methanol and dissolved in a mixed solvent, and the reaction system was cooled to 0 ° C. 3.75 g of palladium chloride and 7.83 g of sodium borohydride were gradually added thereto, and the mixture was stirred at 0 ° C. for 30 minutes. Further, palladium chloride (7.50)
g, 5.66 g of sodium borohydride gradually added,
The mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 2 hours. The reaction solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography (ethyl acetate → ethyl acetate: methanol =
10: 1) to give 3.94 g of the desired product (yield 40.4).
%)Obtained.

White crystal ¹ H-NMR (CDCl ₃ , ppm) 1.74 (9H, s), 3.04 (2H, t, J = 8.
9 Hz), 3.96 (2H, t, J = 8.9 Hz),
6.37 (1H, d, J = 2.2 Hz), 7.94 (1
H, s), 7.96 (1H, d, J = 2.2 Hz)

Reference Example 13 Production of 8-cyclopentyl-6,7-dihydro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine: 5-chloro-8-cyclopentyl-6,7- Dihydro-8H-pyrrolo [3,2-e] pyrazolo [1,5-
a] Using 10.42 g of pyrimidine, 3.44 g (yield 38.0%) of the desired product was obtained in the same manner as in Reference Example 12.

White crystals ¹ H-NMR (CDCl ₃ , ppm) 1.75 (6H, m), 1.98 (2H, m), 3.1
6 (2H, t, J = 8.9 Hz), 3.85 (2H,
t, J = 8.9 Hz), 6.05 (1H, m), 6.3
1 (1H, d, J = 2.4 Hz), 7.98 (1H,
s), 7.98 (1H, d, J = 2.4 Hz)

Reference Example 14 Production of 8-sec-butyl-6,7-dihydro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine: 8-sec-butyl-5-chloro- 6,7-dihydro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a]
Using 4.68 g of pyrimidine, 1.23 g (yield 30.4%) of the desired product was obtained in the same manner as in Reference Example 12.

White crystal ¹ H-NMR (CDCl ₃ , ppm) 0.94 (3H, t, J = 7.6 Hz), 1.27 (3
H, d, J = 6.5 Hz), 1.63 (2H, m),
3.17 (2H, t, J = 8.9 Hz), 3.75 (2
H, m), 5.73 (1H, m), 6.37 (1H,
d, J = 2.4 Hz), 7.96 (1H, s), 7.9
6 (1H, d, J = 2.4 Hz)

Example 46 8-tert-butyl-6,7-dihydro-3-nitro-8
Preparation of H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 37): gradually add 90 ml to 25 ml of acetic acid.
After adding 3.30 ml of% nitric acid, 3 drops of concentrated sulfuric acid were added, followed by stirring at room temperature for a while. Here, 8-tert-butyl-
6.90 g of 6,7-dihydro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine in 8.0 ml of acetic acid
The solution was added slowly. Since the raw material spot disappeared on TLC, stirring was stopped, and the reaction solution was poured into ice water,
Chloroform extraction was performed. The chloroform layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Crystals were precipitated from a chloroform / ether system. The crystals collected by filtration were recrystallized from ethanol and purified to obtain 2.32 g of the desired product (yield 49.0).
%)Obtained.

Yellow crystals m. p. 209 ° C IR (KBr tablet, cm ⁻¹ ) 1620, 1590, 1490, 1400 ¹ H-NMR (CDCl ₃ , ppm) 1.73 (9H, s), 3.16 (2H, t, J = 8.
9 Hz), 4.12 (2H, t, J = 8.9 Hz),
8.17 (1H, s), 8.61 (1H, s)

Example 47 8-Cyclopentyl-6,7-dihydro-3-nitro-
Production of 8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 38): 8-cyclopentyl-
Using 3.40 g of 6,7-dihydro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine, 2.57 g of the desired product was obtained in the same manner as in Example 46 (yield: 56. 0
%)Obtained.

Yellow crystals m. p. 181 ° C IR (KBr tablet, cm ⁻¹ ) 1620, 1610, 1480, 1245, 1220 ¹ H-NMR (CDCl ₃ , ppm) 1.75 (6H, m), 2.05 (2H, m), 3. 2
9 (2H, t, J = 8.4 Hz), 4.06 (2H,
t, J = 8.4 Hz), 5.83 (1H, m), 8.1
4 (1H, s), 8.60 (1H, s)

Example 48 8-sec-butyl-6,7-dihydro-3-nitro-8
Preparation of H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 39): 8-sec-butyl-6
Example 46 was prepared using 240 mg of 7-dihydro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine.
190 mg (65.5% yield) of the desired product was obtained in the same manner as in the above.

Yellow crystals m. p. 199 ° C. IR (KBr ^{tablet, cm -1) 1630,1610,1480,1250,1220 1 H-} NMR (CDCl 3, ppm) 0.95 (3H, t, J = 7.3Hz), 1.33 (3
H, d, J = 6.8 Hz), 1.73 (2H, m),
3.27 (2H, t, J = 9.2 Hz), 3.87 (2
H, m), 5.62 (1H, m), 8.18 (1H,
s), 8.62 (1H, s)

Example 49 8-sec-butyl-6,7-dihydro-5-hydroxymethyl-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 53) Preparation of 330 mg of compound 24 in dry tetrahydrofuran 1
The reaction mixture was suspended in 0 ml, cooled with ice-salt, and 0.17 ml of triethylamine was added with stirring under a nitrogen atmosphere. Further, a solution of 0.12 ml of ethyl chlorocarbonate in 2 ml of dry tetrahydrofuran was added dropwise over 1 minute, followed by stirring for 40 minutes. Next, add 100 mg of sodium borohydride to the reaction system.
Was added all at once, and the mixture was stirred at room temperature for 1 hour, and further 50 mg of sodium borohydride was added. At the same temperature, 1N hydrochloric acid was added little by little to adjust the pH to 1-2. A saturated aqueous solution of sodium hydrogen carbonate was added to the mixture to make it slightly alkaline, and 10 ml of water was added, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The aqueous layer was extracted again with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crude products obtained from both organic layers were combined and subjected to silica gel column chromatography (elution solvent: chloroform: methanol = 100:
0.5) to give 40 mg of the desired product. (Yield 12.7
%)

Yellow crystal IR (KBr tablet, cm ^-1 ) 3421, 1623, 1489, 1241 m.p. p. 222-226 ° C ¹ H-NMR (CDCl ₃ , ppm) 0.94 (3H, t, J = 7.3 Hz), 1.33 (3
H, d, J = 6.5 Hz), 1.65 (2H, m),
3.19 (2H, t, J = 8.9 Hz), 3.87 (2
H, m), 4.65 (2H, s), 5.60 (1H,
m), 8.56 (1H, s)

Example 50 Preparation of 8-sec-butyl-5-carbamoyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (Compound 75) Manufacturing:
0.19 g of compound 24 was added to 6 ml of dry tetrahydrofuran.
The reaction was cooled with ice-salt and 0.11 ml of triethylamine was added with stirring under a nitrogen atmosphere. Further, a solution of 0.08 ml of ethyl chlorocarbonate in 2 ml of dry tetrahydrofuran was added dropwise over 2 minutes, and the mixture was stirred under the same conditions for 40 minutes. Subsequently, 1.8 ml of concentrated aqueous ammonia was added at a stretch under the same conditions, followed by vigorous stirring at room temperature for 1 hour. The precipitated crystals were collected by filtration and air-dried. The obtained crystals were once dissolved in chloroform: methanol = 4: 1, insolubles were removed by filtration, and then concentrated under reduced pressure, and hexane was added to perform reprecipitation. Yield 150 mg (78.9% yield).

Yellow-green crystal IR (KBr tablet, cm ^-1 ) 3432, 1697, 1490, 1236 m. p. 300 ° C. or higher ¹ H-NMR (DMSO-d ₆ , ppm) 0.93 (3H, t, J = 7.3 Hz), 1.34 (3
H, d, J = 6.5 Hz), 1.73 (2H, m),
3.53 (2H, t, J = 8.6 Hz), 4.00 (2
H, m), 5.60 (1H, m), 7.83 (1H, b
r), 7.93 (1H, br), 8.99 (1H, s)

Example 51 Ethyl 8-cyclopropyl-6,7-dihydro-3-
Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] pyrimidine-5-carboxylate (compound 7
Preparation of 6): Ethyl 7-chloro-6- (2-chloroethyl) -3-nitro-pyrazolo [1,5-a] pyrimidine-5-carboxylate and cyclopropylamine in the same manner as in Example 23 to give the desired product I got (Yield 97.6
%)

¹ H-NMR (CDCl ₃ , ppm) 1.00 to 1.09 (4H, m), 1.42 (3H,
t, J = 7.0 Hz), 3.50 (2H, t, J = 8.
9Hz), 3.70 (1H, m), 3.95 (2H,
t, J = 8.9 Hz), 4.42 (2H, q, J = 7.
0 Hz), 8.72 (1H, s)

Example 52 Ethyl 8-cyclobutyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-
a] Pyrimidine-5-carboxylate (Compound 77)
Preparation of: ethyl 7-chloro-6- (2-chloroethyl) -3-nitro-pyrazolo [1,5-a] pyrimidine-5-carboxylate and cyclobutylamine to give the desired product in the same manner as in Example 23. . (Yield 99.8%)

¹ H-NMR (CDCl ₃ , ppm) 1.46 (3H, t, J = 6.8 Hz), 1.84 (2
H, m), 2.38 (4H, m), 3.59 (2H,
t, J = 8.6 Hz), 4.13 (2H, t, J = 8.
6 Hz), 4.45 (2H, q, J = 6.8 Hz),
6.05 (1H, m), 8.67 (1H, s)

Example 53 Ethyl 6,7-dihydro-8-isopropyl-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-
a] Pyrimidine-5-carboxylate (Compound 78)
Preparation of: ethyl 7-chloro-6- (2-chloroethyl) -3-nitro-pyrazolo [1,5-a] pyrimidine-5-carboxylate and isopropylamine to give the desired product in the same manner as in Example 23. . (Yield 97.1%)

¹ H-NMR (CDCl ₃ , ppm) 1.40 (6H, d, J = 7.0 Hz), 1.47 (3
H, t, J = 7.0 Hz), 3.56 (2H, t, J =
8.9 Hz), 3.99 (2H, t, J = 8.9H)
z), 4.45 (2H, q, J = 7.0 Hz), 5.8
9 (1H, m), 8.65 (1H, s)

Example 54 Ethyl 6,7-dihydro-8- (1-ethylpropyl) -3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5-carboxylate Preparation of (Compound 79): Ethyl 7-chloro-6- (2
-Chloroethyl) -3-nitro-pyrazolo [1,5-
a] The target compound was obtained from pyrimidine-5-carboxylate and 3-aminopentane in the same manner as in Example 23. (Yield 96.4%)

¹ H-NMR (CDCl ₃ , ppm) 0.93 (6H, t, J = 7.3 Hz), 1.47 (3
H, t, J = 7.3 Hz), 1.65 to 1.82 (4
H, m), 3.61 (2H, t, J = 8.6 Hz),
3.87 (2H, t, J = 8.6 Hz), 4.46 (2
H, q, J = 7.3 Hz), 5.61 (1H, m),
8.67 (1H, s)

Example 55 8-Cyclopropyl-6,7-dihydro-3-nitro-
Preparation of 8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5-carboxylic acid (Compound 80): Ethyl 8-cyclopropyl-6,7-
Treatment of dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5-carboxylate afforded the desired product. (Yield: quantitative)

¹ H-NMR (DMSO-d ₆ , ppm) 0.86 to 1.07 (4H, m), 3.33 (2H,
t, J = 8.9 Hz), 3.68 (1H, m), 3.8
8 (2H, t, J = 8.9 Hz), 8.91 (1H,
s)

Example 56 8-Cyclobutyl-6,7-dihydro-3-nitro-8
Production of H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5-carboxylic acid (Compound 81): Ethyl 8-cyclobutyl-6,7-dihydro-3-as in Example 26 Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5-carboxylate was treated to give the desired product. (Yield: 94.1%)

¹ H-NMR (DMSO-d ₆ , ppm) 1.78 to 1.86 (2H, m), 2.30 to 2.46
(4H, m), 3.59 (2H, t, J = 8.4H
z), 4.15 (2H, t, J = 8.4 Hz), 4.2
3 (1H, br), 6.04 (1H, m), 8.68
(1H, s)

Example 57 6,7-Dihydro-8-isopropyl-3-nitro-8
Preparation of H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5-carboxylic acid (compound 82): ethyl 6,7-dihydro-8-isopropyl-3-as in Example 26 Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5-carboxylate was treated to give the desired product. (Yield: 97.0%)

¹ H-NMR (DMSO-d ₆ , ppm) 1.39 (6H, d, J = 7.0 Hz), 3.55 (2
H, t, J = 8.6 Hz), 4.01 (2H, t, J =
8.6 Hz), 5.86 (1 H, m), 8.69 (1
H, s)

Example 58 6,7-Dihydro-8- (1-ethylpropyl) -3-
Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] Preparation of pyrimidine-5-carboxylic acid (compound 83): ethyl 6,7-dihydro-8 as in Example 26
-(1-Ethylpropyl) -3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5
-The carboxylate was treated to give the desired product. (Yield: 97.3%)

¹ H-NMR (DMSO-d ₆ , ppm) 0.93 (6 H, t, J = 7.3 Hz), 1.59-
1.86 (4H, m), 3.67 (2H, t, J = 8.
9 Hz), 3.93 (2H, t, J = 8.9 Hz),
5.63 (1H, m), 8.68 (1H, s)

Example 59 5-amino-8-cyclopropyl-6,7-dihydro-
Preparation of 3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 84): 8-
Cyclopropyl-6,7-dihydro-3-nitro-8H
Using -pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5-carboxylic acid as a raw material, the target product was produced in the same operation as in Example 20 (yield: 74.4%). The obtained target product was reprecipitated from chloroform-methanol-ether.

Yellow crystal IR (KBr tablet, cm ^-1 ) 1636, 1400, 1260 m. p. 280 ° C. or higher ¹ H-NMR (DMSO-d ₆ , ppm) 0.84 (4H, m), 2.80 (2H, t, J = 8.
9Hz), 3.18 (1H, m), 3.72 (2H,
t, J = 8.9 Hz), 7.04 (2H, br), 8.
51 (1H, s)

Example 60 5-amino-8-cyclobutyl-6,7-dihydro-3
-Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,
Preparation of 5-a] pyrimidine (compound 85): 8-cyclobutyl-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5
-Using carboxylic acid as a raw material, the desired product was produced in the same manner as in Example 20 (yield: 54.1%). The obtained target product was reprecipitated from chloroform-methanol-ether.

Yellow crystal IR (KBr tablet, cm ^-1 ) 1640, 1400, 1240 m.p. p. 275 ° C. or higher ¹ H-NMR (DMSO-d ₆ , ppm) 1.70 (2H, m), 2.16 (2H, m), 2.3
3 (2H, m), 2.96 (2H, t, J = 9.2H
z), 3.93 (2H, t, J = 9.2 Hz), 5.7
5 (1H, m), 6.62 (2H, br), 8.37
(1H, s)

Example 61 5-amino-6,7-dihydro-8-isopropyl-3
-Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,
Preparation of 5-a] pyrimidine (compound 86): 6,7-dihydro-8-isopropyl-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine-5
-Using carboxylic acid as a raw material, the desired product was produced in the same manner as in Example 20 (yield: 48.9%). The obtained target product was reprecipitated from chloroform-methanol-ether.

Yellow crystal IR (KBr tablet, cm ^-1 ) 1635, 1400, 1260 m. p. 275 ° C. or higher ¹ H-NMR (DMSO-d ₆ , ppm) 1.27 (6 H, d, J = 6.2 Hz), 2.97 (2
H, t, J = 9.5 Hz), 3.81 (2H, t, J =
9.5 Hz), 5.54 (1H, m), 6.03 (2
H, br), 8.37 (1H, s)

Example 62 5-Amino-6,7-dihydro-8- (1-ethylpropyl) -3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 87) Production:
6,7-dihydro-8- (1-ethylpropyl) -3-
Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] Using pyrimidine-5-carboxylic acid as a raw material, the desired product was produced in the same manner as in Example 20.
5%). The obtained target product was chloroform-methanol-
Reprecipitation was performed from ether.

Yellow crystal IR (KBr tablet, cm ^-1 ) 1650, 1400, 1253 m.p. p. 106-109 ° C ¹ H-NMR (CDCl ₃ , ppm) 0.90 (6H, t, J = 7.3 Hz), 1.54-
1.67 (4H, m), 3.00 (2H, t, J = 8.
9 Hz), 3.75 (2H, t, J = 8.9 Hz),
5.35 (1H, m), 5.78 (2H, br), 8.
41 (1H, s)

Example 63 Preparation of 8-sec-butyl-5-diethylamino-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (Compound 57) Manufacturing:
8-sec-butyl-5-chloro-6,7-dihydro-
To 400 mg of 3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 42), 1.00 g of diethylamine and 1.00 of triethylamine were added.
g and dimethylformamide (6.0 ml) were added, and the mixture was stirred under reflux for 3 hours. Since the raw material spot almost disappeared on TLC, stirring was stopped, a part of the solvent was distilled off under reduced pressure, the reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and air-dried.
Further, the obtained crystals were recrystallized from ethanol. Yield 410 mg (91.1% yield).

Yellow crystal IR (KBr tablet, cm ^-1 ) 1630, 1540, 1400, 1252 m.p. p. 174-175 ° C ¹ H-NMR (CDCl ₃ , ppm) 0.92 (3H, t, J = 7.3 Hz), 1.20-
1.30 (8H, m), 1.52-1.68 (2H,
m), 3.26 (2H, t, J = 9.2 Hz), 3.6
2-3.73 (6H, m), 5.43-5.56 (1
H, m), 8.41 (1H, s)

Example 64 8-sec-butyl-5-cyclobutylamino-6,7
-Dihydro-3-nitro-8H-pyrrolo [3,2-e]
Preparation of pyrazolo [1,5-a] pyrimidine (Compound 59): 8-sec-butyl-5-chloro-6,7-dihydro-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1, 200 mg of 5-a] pyrimidine (compound 42) was dissolved in 6.0 ml of dimethylformamide, and 800 mg of cyclobutylamine and 800 mg of triethylamine were added thereto, followed by stirring at 130 ° C. for 4 hours. Since the raw material spot disappeared on TLC, stirring was stopped, the reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and air-dried. Yield 120mg
(51.3% yield). Purification is further performed by silica gel column chromatography (elution solvent: hexane: ethyl acetate =
1: 1), and further, crystals were precipitated from a chloroform / ether system.

Yellow crystal IR (KBr tablet, cm ^-1 ) 3395, 1635, 1600, 1380, 1250 m. p. 249-251 ° C ¹ H-NMR (CDCl ₃ , ppm) 0.91 (3H, t, J = 7.3 Hz), 1.22 (3
H, d, J = 6.5 Hz), 1.59 (2H, m),
1.77 (2H, m), 1.92 (2H, m), 2.4
8 (2H, m), 2.96 (2H, t, J = 8.9H)
z), 3.73 (2H, m), 4.73 (2H, m),
5.39 (1H, m), 8.39 (1H, s)

Example 65 8-Sec-butyl-6,7-dihydro-3-nitro-
Production of 5-pyrrolidino-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (Compound 60): 8-
sec-butyl-5-chloro-6,7-dihydro-3-
Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] Pyrimidine (compound 42) To 400 mg, pyrrolidine (1.00 g), triethylamine (1.00 g), and dimethylformamide (6.0 ml) were added, and the mixture was stirred with heating under reflux for 2 hours. Since the raw material spot almost disappeared on TLC, stirring was stopped, and the solvent and excess amine were briefly distilled off under reduced pressure.
Chloroform / ether was added to the residue, and the precipitated crystals were collected by filtration and dried. Further, the obtained crystals were recrystallized from ethanol. Yield 390 mg (yield 87.4
%).

Yellow crystal IR (KBr tablet, cm ^-1 ) 1633, 1540, 1394, 1256 m. p. 237 ° C. ¹ H-NMR (CDCl ₃ , ppm) 0.94 (3H, t, J = 7.0 Hz), 1.24 (3
H, d, J = 6.7 Hz), 1.52 to 1.68 (2
H, m), 1.96 (4H, m), 3.36 (2H,
t, J = 8.9 Hz), 3.56 to 3.69 (2H,
m), 3.78 (4H, m), 5.45 (1H, m),
8.37 (1H, s)

Example 66 8-Sec-butyl-6,7-dihydro-3-nitro-
Production of 5-piperidino-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 61): 8-
sec-butyl-5-chloro-6,7-dihydro-3-
Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] Pyrimidine (compound 42) 200 mg was added with piperidine 10 ml, and the mixture was stirred under heating and reflux for 1 hour. Excess piperidine is distilled off under reduced pressure, the residue is dissolved in chloroform,
The organic layer was washed with 1N hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Crystals were precipitated from a chloroform / ether system, and the crystals were collected by filtration and dried. The obtained crystals were further recrystallized from ethanol. Yield 140 mg (60.9% yield).

Yellow crystal IR (KBr tablet, cm ^-1 ) 1638, 1398, 1230 m. p. 182 ° C. ¹ H-NMR (CDCl ₃ , ppm) 0.92 (3H, t, J = 7.2 Hz), 1.21 (3
H, d, J = 6.5 Hz), 1.61 to 1.80 (8
H, m), 3.24 (2H, t, J = 9.5 Hz),
3.75 (6H, m), 5.51 (1H, m), 8.3
9 (1H, s)

Example 67 Preparation of 8-sec-butyl-6,7-dihydro-5-morpholino-3-nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (Compound 62) Production: 8-
sec-butyl-5-chloro-6,7-dihydro-3-
Nitro-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] Pyrimidine (compound 42) To 400 mg, morpholine (4.0 ml) was added, and the mixture was stirred with heating under reflux overnight. Since little change was observed on TLC, 4 ml of dimethylformamide and 1 ml of triethylamine were added, and the mixture was further stirred under heating and reflux overnight. Since the raw material spot almost disappeared on TLC, stirring was stopped, the solvent and excess amine were distilled off under reduced pressure, the residue was dissolved in chloroform, and the organic layer was washed with 1N hydrochloric acid and saturated saline, and then washed with anhydrous sodium sulfate. Dry,
The solvent was distilled off under reduced pressure. Chloroform and ether were added to the residue, the precipitated crystals were collected by filtration, and the crystals were recrystallized from ethanol. 260 mg (56.5 yield)
%).

Yellow crystal IR (KBr tablet, cm ^-1 ) 1642, 1400, 1250 m. p. 262 ° C. ¹ H-NMR (CDCl ₃ , ppm) 0.92 (3H, t, J = 7.6 Hz), 1.23 (3
H, d, J = 7.0 Hz), 1.55-1.64 (2
H, m), 3.26 (2H, t, J = 9.2 Hz),
3.67-3.80 (10H, m), 5.43 (1H,
m), 8.41 (1H, s)

Reference Example 15 Production of ethyl benzyloxyacetate: 4.42 g of sodium hydride was washed twice with dry ether, and toluene
Add 10.8 ml of benzyl alcohol under a nitrogen atmosphere.
A 20 ml solution of 1 ml of toluene was added dropwise over 25 minutes under ice cooling, and the mixture was stirred at room temperature for 3 hours and 30 minutes. Next, the reaction system was cooled on ice, and a solution of 16.76 g of ethyl bromoacetate in 20 ml of toluene was added dropwise over 30 minutes. After further stirring at 0 ° C. for 25 minutes, the mixture was poured into a mixture of 400 ml of cold water and 2 ml of 5N hydrochloric acid, and extracted with benzene. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product is subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate = 15: 1 →
12: 1 → 10: 1) to give the target compound as a colorless oil in 1
4.75 g were obtained. Yield 76.0%.

¹ H-NMR (CDCl ₃ , ppm) 1.30 (3H, t, J = 7.0 Hz), 4.09 (2
H, s), 4.22 (2H, q, J = 7.0 Hz),
4.64 (2H, s), 7.30 to 7.42 (5H,
m)

Reference Example 16 Production of 2-benzyloxyacetyl-γ-butyrolactone: A solution of 10.6 ml of diisopropylamine in 75 ml of tetrahydrofuran was cooled to -70 ° C., and 46 ml of a 1.6 N n-butyllithium-hexane solution was added dropwise. . After completion of the dropwise addition, the mixture was stirred for 15 minutes, and a solution of 54.8 g of γ-butyrolactone in 50 ml of tetrahydrofuran was added dropwise over 55 minutes.
Stir for 50 minutes. Ethyl benzyloxyacetate 1
4.75 g of a 50 ml solution of tetrahydrofuran are added,
The mixture was stirred at 60 to -50 ° C for 2 hours and 30 minutes. Then 20
5N hydrochloric acid was added so as not to exceed ℃, and the pH was adjusted to 1 to 2. Ethyl acetate was added to the reaction system, which was washed with saturated saline. The organic layer is dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1).
→ 2: 1 → 1: 1) to give the target compound as a colorless oil 13.
01 g was obtained. Yield 87.2%.

¹ H-NMR (CDCl ₃ , ppm) 2.30 (1H, m), 2.75 (1H, m), 3.8
8 (1H, m), 4.27 to 4.47 (4H, m),
4.68 (2H, s), 7.29-7.38 (5H,
m)

Reference Example 17 Production of 3-{[2- (benzyloxy) -1- (tetrahydro-2-oxo-3-furyl) ethylidene] amino} pyrazole: 1.83 g of 2-benzyloxyacetyl-γ-butyrolactone , 3-aminopyrazole 0.50
g was dissolved in 2.0 ml of ethanol, 60 μl of boron trifluoride methanol complex was added, and the mixture was stirred at room temperature for 16 hours and 30 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1 → 1: 2) to obtain 1.18 g of the objective yellow oil. Yield 65.5%.

¹ H-NMR (CDCl ₃ , ppm) 2.93 (2H, t, J = 7.8 Hz), 4.33 (2
H, t, J = 7.8 Hz), 4.42 (2H, s),
4.52 (2H, s), 6.06 (1H, d, J = 2.
4 Hz), 7.29 to 7.37 (5H, m), 7.44
(1H, d, J = 2.4 Hz), 9.96 (1H, b
r)

Reference Example 18 5- (benzyloxymethyl) -6- (2-hydroxyethyl) pyrazolo [1,5-a] pyrimidine-7 (4
Preparation of H) -one: 3-{[2- (benzyloxy)-
To 1.18 g of 1- (tetrahydro-2-oxo-3-furyl) ethylidene] aminodipyrazole, 600 μl of triethylamine and 2.0 ml of water were added, and the mixture was stirred under reflux with heating for 40 minutes. After the temperature of the reaction system was returned to room temperature, 1N hydrochloric acid was added to adjust the pH to 4. After extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 1.18 g (quantitative) of the desired product.

¹ H-NMR (CDCl ₃ , ppm) 2.71 (2H, t, J = 5.7 Hz), 3.79 (2
H, t, J = 5.7 Hz), 4.64 (2H, s),
4.67 (2H, s), 6.01 (1H, d, J = 2.
2Hz), 7.30 to 7.38 (5H, m), 7.74
(1H, d, J = 2.2Hz)

Reference Example 19 5- (benzyloxymethyl) -7-chloro-6- (2
Preparation of -chloroethyl) pyrazolo [1,5-a] pyrimidine: 5- (benzyloxymethyl) -6- (2-hydroxyethyl) pyrazolo [1,5-a] pyrimidine-7
(4H) -one was added to 0.52 g of phosphorus oxychloride 4.0 ml,
0.55 ml of triethylamine was added, and the oil bath temperature was 100-1.
The mixture was stirred at 10 ° C for 1 hour and 20 minutes. Excess phosphorous oxychloride was distilled off under reduced pressure, the reaction residue was poured into ice water, and chloroform extraction was performed. After the chloroform layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The crude product obtained here was subjected to silica gel column chromatography (elution solvent: chloroform only) to obtain 0.37 g of the desired product. Yield 63.4%.

¹ H-NMR (CDCl ₃ , ppm) 3.39 (2H, t, J = 7.3 Hz), 3.75 (2
H, t, J = 7.3 Hz), 4.65 (2H, s),
4.77 (2H, s), 6.79 (1H, d, J = 2.
2 Hz), 7.30 to 7.37 (5H, m), 8.19
(1H, d, J = 2.2Hz)

Example 68 7-Chloro-6- (2-chloroethyl) -5- (2 ′,
Production of 4'-dinitrobenzyloxymethyl) -3-nitropyrazolo [1,5-a] pyrimidine: concentrated sulfuric acid 4.0
The mixture was cooled to 0 ° C., and 2.0 ml of 90% concentrated nitric acid was gradually added so that the temperature did not rise. Under the same conditions, 5-benzyloxymethyl-7-chloro-6- (2-chloroethyl) was added.
0.37 g of pyrazolo [1,5-a] pyrimidine was gradually added, followed by stirring for 1 hour. Since the raw material spot disappeared on TLC, stirring was stopped, and the reaction solution was poured into ice water. The resulting crystals were collected by filtration, washed several times with water, and dried to obtain the desired product. Yield 0.35g. Yield 67.5%.

¹ H-NMR (DMSO-d ₆ , ppm) 3.45 (2H, t, J = 7.6 Hz), 3.87 (2
H, t, J = 7.6 Hz), 5.14 (2H, s),
5.19 (2H, s), 8.20 (1H, d, J = 8.
9Hz), 8.60 (1H, dd, J = 8.9Hz,
2.4Hz), 8.79 (1H, d, J = 2.4H)
z), 9.19 (1H, s)

Example 69 8-sec-butyl-6,7-dihydro-5- (2 ′,
4'-dinitrobenzyloxymethyl) -3-nitro-
Preparation of 8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine (compound 88): 7-chloro-6- (2
-Chloroethyl) -5- (2 ', 4'-dinitrobenzyloxymethyl) -3-nitropyrazolo [1,5-a]
Pyrimidine (0.35 g) was added to dimethylformamide (5.0 ml).
, 0.18 g of sec-butylamine was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The solvent was distilled off under reduced pressure, 50 ml of chloroform was added to the residue, and the mixture was washed with 1 N hydrochloric acid and saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were reprecipitated from a chloroform-ether system and air-dried. The crude product was further subjected to preparative thin-layer chromatography (developing solvent: chloroform: methanol = 19: 1) to give the desired product in an amount of 0.14.
g was obtained. Yield 40.0%.

Yellow crystal IR (KBr tablet, cm ^-1 ) 1624,1225 m.p. p. 167-168 ° C ¹ H-NMR (CDCl ₃ , ppm) 0.96 (3H, t, J = 7.3 Hz), 1.34 (3
H, d, J = 6.5 Hz), 1.69 (2H, m),
3.29 (2H, t, J = 8.9 Hz), 3.86 (2
H, m), 4.81 (2H, s), 5.13 (2H,
s), 5.65 (1H, m), 8.23 (1H, d, J
= 8.4 Hz), 8.53 (1H, dd, J = 8.4H)
z, 2.2 Hz), 8.62 (1H, s), 8.92
(1H, d, J = 2.2Hz)

Example 70 Tracheal Dilation (In Vitro) The compound (1) of the present invention was used for the treatment of respiratory diseases such as asthma.
Magnus method for tracheal dilatation beneficial for treatment and / or prevention
Investigated by. That is, Hartley white male guinea pig
Bruise (250-300g)
The tube was removed. A strip-shaped specimen was prepared from this trachea and mixed.
Gas (95% O_Two, 5% CO_Two) And keep at 37 ° C.
Magnus tube filled with warm Krebs-Henseleit solution
Hanged up. Apply a static tension of 1.0 g to increase isometric tension.
Recorded. Test compound is 3 × 10 ^-7M's carbachol and
And 10^-6Cumulatively injected to specimens contracted with M histamine
The relaxation effect was examined. After cumulative administration, 10^-FourM's pa
Administered paverine to confirm maximal relaxation of tracheal specimen
Was. Test that the maximum relaxation is 100% and the relaxation is 50%
Calculate the negative logarithm of the concentration of the compound and calculate the pIC₅₀Value. Conclusion
The results are shown in Table 1. From this, it is represented by the general formula (1) of the present invention.
Compounds and / or their physiologically acceptable salts are
It turns out that it is excellent in tracheal dilation. Also, R^ThreeAnd the substituent
It can also be seen that a nitro group is preferred.

[0228]

[Table 1]

Example 71 Tracheal Dilation (In Vitro) As in Example 70, using an isolated trachea by the Magnus method (LTD ₄ , concentration 10 ^-6 M), (CTA ₂ , concentration 10 ^-7 M)
M), the pIC ₅₀ value of the compound of the present invention with respect to contraction by (OA, concentration 1 mg / ml) was determined. Table 2 shows the results.
It can be seen that the compounds of the present invention and / or their physiologically acceptable salts are also effective against these contractions.

[0230]

[Table 2]

Example 72 Inhibitory Effect of Airway Contraction Response (In Vivo) White Hartley male guinea pigs of 6 animals per group (250
３５０350 g) was anesthetized with a pentobarbitur and the trachea, carotid artery and jugular vein were cannulated. The experiment was performed under artificial ventilation after connecting the airway cannula to a ventilator incorporated in the circuit of the Bronco Spasm Transducer (Kotzett-Lessler method), stopping spontaneous breathing by excision of the diaphragm, and then performing artificial ventilation. Airway constriction response was measured using ventilation overflow as an index. Also, at the same time, via a cannula inserted into the carotid artery,
Blood pressure was also monitored using a blood pressure measurement amplifier. 0.
A test compound (1 mg / ml / kg) dissolved in 1N hydrochloric acid was intravenously administered, and 0.5, 5, and 10 minutes after acetylcholine (2 mg / ml / kg).
0 μg / kg) or histamine (15 μg / kg) was administered intravenously, and the induced airway contraction reaction was observed. As a comparative example, theophylline (6 mg / ml / kg), which is widely used for the treatment of asthma, was used. The numerical value was calculated as the suppression rate. The results are shown in Table 3 together with the change in blood pressure (unit: mmHg). It can be seen that all the compounds of the present invention have a small effect on blood pressure despite being excellent in suppressing tracheal contraction.

[0232]

[Table 3]

Example 73 Inhibition of airway constriction reaction (in vivo) A cannula was inserted into the esophagus, and
Test compound suspended in 1% CMC (100 mg / 2 ml / k
The effect of the compound of the present invention on airway constriction by oral administration was determined in the same manner as in Example 72, except that g) was administered and intravenous injection of acetylcholine and histamine was performed for 15, 30, 60 and 120 minutes. The results are shown in Table 4.
It can be seen that all the compounds of the present invention have a small effect on blood pressure despite being excellent in suppressing tracheal contraction. The decrease in blood pressure was 120 minutes, and the dose of theophylline for comparison was 100 mg / kg. Furthermore, no deaths were observed at a dose of 100 mg / kg, and thus the safety of the compound of the present invention is considered to be high.

[0234]

[Table 4]

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Satoshi Ichinomiya 560 Paula-cho, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Inside the Totsuka Research Laboratory (72) Inventor Yukio Kawazu 560 Pola Kashio-cho, Toshika-ku, Yokohama-shi, Kanagawa Inside Totsuka Laboratory Co., Ltd. (72) Inventor Kenichi Kishii 560 Pola, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Inside the Totsuka Laboratory Co., Ltd. (72) Nobuo Funayama 560 Kashio-cho, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Japan (72) Inventor Mariko Harada, Inventor Mariko Harada 560 Pola, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Pref.Totsuka Research Laboratories (72) Kyoko Taneda, 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Pref. Inside the research institute (72) Inventor Naoki Hiyama Kashiwa, Totsuka-ku, Yokohama, Kanagawa 560 POLA Kasei Kogyo Co., Ltd.Totsuka Research Laboratories (72) Inventor Tomohiro Yahiro 560 POLA Kasei Kogyo Co., Ltd.Totsuka Research Laboratories Yokohama City, Kanagawa Prefecture (72) Inventor Mayumi Sugio Mayumi Kashiocho, Totsuka-ku Yokohama City, Kanagawa Prefecture 560 Pola Kasei Kogyo Co., Ltd.

Claims (7)

[Claims] 1. The following general formula (1): [In the formula, R ¹ represents a linear, branched or cyclic alkyl group, and R ² represents a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, or a substituent. amino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group or a alkylcarbamoyl group, R ³
Is a nitro group, an amino group, a heterocyclic group, an alkylsulfonylamino group optionally substituted with halogen, R ⁴ CON
H- (where R ⁴ is an alkyl group, a halogenoalkyl group,
Represents a carboxyl group or an alkoxycarbonyl group),
Or R ⁵ CO— (where R ⁵ represents an amino group, a hydroxy group, an alkyl group, an alkoxy group, a halogenoalkyl group or a heterocyclic-amino group) or a salt thereof. . 2. R ¹ is a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms; R ² is a hydrogen atom, a halogen atom, an amino group which may have a substituent, a substituent R ³ is a C _1-10 alkyl group, a carboxyl group or a C _2-11 alkoxycarbonyl group; R ³ is a nitro group, an amino group, a tetrazolyl group, or a C _1-10 alkylsulfonylamino group,
R ⁴ CONH— (where R ⁴ is a C _1-10 alkyl group, C 4
_{A 1-10} halogenoalkyl group, a carboxyl group or a C _2-11 alkoxycarbonyl group), or R ⁵ CO— (where R ⁵ is an amino group, a hydroxy group, a C _1-10 alkyl group,
C _1-10 alkoxy groups, C _1-10 halogenoalkyl group compound or a salt thereof according to claim 1, wherein a or an tetrazolyl groups). 3. A medicament comprising the compound according to claim 1 or 2 or a salt thereof as an active ingredient. 4. The medicament according to claim 3, which is a drug for a respiratory disease. 5. The following general formula (2): [In the formula, X represents a halogen atom, and R ² represents a hydrogen atom, a halogen atom, an alkyl group optionally having a substituent, an amino group optionally having a substituent, a carboxyl group, an alkoxycarbonyl group. , A carbamoyl group or an alkylcarbamoyl group, wherein R ³ is a nitro group, an amino group, a heterocyclic group, an alkylsulfonylamino group optionally substituted by halogen, R ⁴ CONH— (where R ⁴ is A halogenoalkyl group, a carboxyl group or an alkoxycarbonyl group), or R ⁵ CO— (where R ^{5 represents}
Represents an amino group, a hydroxy group, an alkyl group, an alkoxy group, a halogenoalkyl group or a heterocyclic-amino group)
Is represented by the formula NH ₂ —R ¹ (where,
R ¹ represents a straight-chain, branched-chain or cyclic alkyl group], and the following general formula (1): [Wherein, R ¹ , R ² and R ³ are the same as defined above]
A method for producing a pyrrolopyrazolopyrimidine compound represented by the formula: or a salt thereof. 6. The following general formula (3): [Wherein, R ² represents a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, an amino group which may have a substituent, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group or an alkylcarbamoyl group. And R ³
Is a nitro group, an amino group, a heterocyclic group, an alkylsulfonylamino group optionally substituted with halogen, R ⁴ CON
H- (where R ⁴ is an alkyl group, a halogenoalkyl group,
Represents a carboxyl group or an alkoxycarbonyl group),
Or a compound represented by R ⁵ CO— (where R ⁵ represents an amino group, a hydroxy group, an alkyl group, an alkoxy group, a halogenoalkyl group or a heterocyclic-amino group) or a tautomer thereof. By reacting with a halogenating agent, the following general formula (2) Wherein R ² and R ³ are the same as described above, and X represents a halogen atom.
Reacting an amine represented by H ₂ -R ¹ (where R ¹ represents a linear, branched or cyclic alkyl group), characterized by the following general formula (1): [Wherein, R ¹ , R ² and R ³ are the same as defined above]
A method for producing a pyrrolopyrazolopyrimidine compound represented by the formula: or a salt thereof. 7. The following general formula (6):Wherein Z represents a hydroxyl group or a halogen atom, and Y represents
A group or a halogen atom;^TwoIs hydrogen atom, halogen
Atom, an alkyl group which may have a substituent,
Amino group, carboxyl group, alkoxy
Sicarbonyl group, carbamoyl group or alkylcarbamo
Represents an yl group;^ThreeIs nitro, amino, heterocyclic
Group, alkylsulfonyl optionally substituted by halogen
Amino group, R ^FourCONH- (where R^FourIs an alkyl group,
Halogenoalkyl group, carboxyl group or alkoxyca
A carbonyl group) or R^FiveCO- (where R^FiveIs
Mino group, hydroxy group, alkyl group, alkoxy group, c
Represents a logenoalkyl group or a heterocyclic-amino group).
Pyrazolopyrimidine compounds represented by the formula
Sex substance or salt thereof.