JP3295149B2 - Pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to an excellent vasodilator,
Antihypertensive action, antihyperlipidemic action, platelet aggregation inhibitory action, Ca
⁺⁺ A novel pyrrolo [3,2-e] which has an effect of treating cardiovascular diseases such as a blocker effect and is not easily metabolized, so that these effects are maintained.
Pyrazolo [1,5-a] pyrimidine derivatives or salts thereof,
And a therapeutic agent for circulatory diseases containing these compounds as active ingredients.

[0002]

2. Description of the Related Art It is a well-known fact that as the Japanese population ages, the cause of death is an increase in cardiovascular diseases, which accounts for a large proportion together with malignant tumors. As a therapeutic agent for circulatory diseases, lowering blood pressure by vasodilation and improving blood flow is an extremely effective method, and suppressing platelet aggregation is a useful means to prevent the occurrence of arterial thrombus. It is. Compounds having a Ca ⁺⁺ blocker action often have an antiarrhythmic action, and these diseases are mutually related. Therefore, the development of a comprehensively effective drug for these cardiovascular diseases has been desired.

Based on this point of view, the present inventors have previously described the following general formula (A)

[0004]

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A pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine derivative represented by the formula (wherein _Ra represents an alkyl group) has an excellent therapeutic effect on cardiovascular diseases. And applied for a patent (Japanese Unexamined Patent Publication No.
No. 75882).

[0006] However, this compound (A) exhibits excellent effects in vitro, but in vivo, the pyrrole ring moiety easily undergoes oxidative metabolism, inactivation occurs, and the effect is not sustained. Had.

[0007]

Accordingly, there has been a demand for a therapeutic agent for a circulatory disease which does not cause such inactivation and exhibits an excellent effect.

[0008]

Means for Solving the Problems In view of such circumstances, the present inventors have conducted intensive studies, and as a result, it has been found that the compound represented by the following general formula (I) is hardly inactivated in vivo and has a long lasting effect. The present invention has been found to be highly effective in preventing and treating cardiovascular diseases such as hypertension and angina, and completed the present invention.

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

[0010]

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(Wherein R ¹ is a hydrogen atom; a hydroxyl group, an alkoxy group, an alkenyloxy group, a nitro group, a primary, secondary or tertiary amino group, a carboxyl group, a cycloalkyl group, a phenyl group, a halogen atom and a heteroatom) A linear or branched alkyl group, alkenyl group or alkynyl group which may have a substituent selected from a cyclic group; or a hydroxyl group,
Alkoxy, alkenyloxy, nitro, primary,
A cycloalkyl group, a phenyl group or a heterocyclic group which may have a substituent selected from a secondary or tertiary amino group, a carboxyl group, a cycloalkyl group, a phenyl group and a halogen atom, and R ² , R ³ , R ⁴ and R ⁵ may be the same or different and are a hydrogen atom; a halogen atom; a hydroxyl group, an alkoxy group, an alkenyloxy group, a nitro group, a primary, secondary or tertiary amino group, a carboxyl group, a cycloalkyl group, A linear or branched alkyl group which may have a substituent selected from a phenyl group, a halogen atom and a heterocyclic group; or a cyano group, or R ² and R ³ or /
And R ⁴ and R ⁵ together represent an oxygen atom. However,
R ² , R ³ , R ⁴ and R ⁵ are all hydrogen atoms (except when they are hydrogen atoms), or a pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine derivative or a salt thereof. It is.

In the pyrimidine derivative (I) of the present invention, in the formula, the linear or branched alkyl group of R ^{1 to} R ^{5 has 1 to} 16 carbon atoms, for example, a methyl group, an ethyl group, an n- Examples include a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-hexyl group, an octyl group, and a decanyl group. Examples of the linear or branched alkenyl group and alkynyl group of R ¹ include those having 1 to 16 carbon atoms, for example, a vinyl group, an allyl group, an isopropenyl group, an n-butenyl group, an isobutenyl group, and a sec-butenyl group. Alkenyl groups such as ethynyl group, propargyl group, 1-propynyl group, n-butynyl group, sec-butynyl group, n-pentynyl group, and isopentynyl group. The cycloalkyl group for R ¹ has 4 to 8 carbon atoms.
, For example, a cyclopentyl group and a cyclohexyl group. Examples of the heterocyclic group for R ¹ include a piperidyl group, a piperazinyl group, a morpholinyl group, and a thienyl group. Further, these groups may have a substituent, such as a hydroxyl group, an alkoxy group, an alkenyloxy group, a nitro group, a primary, secondary or tertiary amino group, a carboxyl group, a cycloalkyl Group, phenyl group, substituted phenyl group, halogen atom, heterocyclic group (pyrrole, pyrrolidine, pyridine, piperidine, imidazole, imidazoline, piperidine,
Morpholine, pyrrolidone, etc.) and substituted heterocyclic groups. Examples of the halogen atom for R ^{2 to} R ⁵ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Of these, R¹Is linear or
An alkyl or alkenyl group having 1 to 6 carbon atoms in the branched chain
Or an alkynyl group or a cycloalkyl group is particularly preferred.
K, R ^Two~ R^FiveAs one or two of these,
May be substituted with an xy or alkenyloxy group
A linear or branched alkyl group having 1 to 6 carbon atoms, or
A halogen atom and the remaining substituents are hydrogen atoms
Or R^TwoAnd R^ThreeOr R^FourAnd R^FiveTogether
Particularly preferred is an oxygen atom.

When the compound (I) of the present invention has an asymmetric carbon atom at the 6-position or the 7-position, each optically active form is present. Accordingly, the compounds of the present invention include optically active and racemic forms of compound (I). In addition, the subscript a attached to the number of the following chemical structural formula in the present specification
Indicates that the compound is obtained as an optically active substance.

The compound (I) of the present invention and its optically active substance can be produced, for example, according to the following method. (I) Method for producing racemic 7-substituted compound (1) In compound (I), racemic (I-1) of a compound having a substituent introduced at the 7-position may be produced, for example, according to the following reaction formula (B). can do.

[0016]

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

That is, α-acetyl-γ-butyrolactone (ABL) γ-substituted compound (II) has 3-amino-4
-After the dehydration condensation of cyanopyrazole (III), the lactone ring is cleaved to give 6- (2-hydroxyethyl)
-5-methylpyrazolo [1,5-a] pyrimidine-7
(4H) -ones (IV-1), which were then halogenated to give 7-halo-6- (2-haloethyl) -5-methylpyrazolo [1,5-a] pyrimidines (V-1) None, and by further reacting an amine with the amine, the 7-substituted compound (I-1) of the present invention can be produced.

In order to produce (IV-1) from compounds (II) and (III), a suitable solvent such as dimethylformamide, toluene, xylene, methanol, ethanol, isopropanol, tetrahydrofuran (THF), dioxane, acetic acid, etc. Compound (II) and (II) in the presence of a catalyst such as a Lewis acid such as trifluoroborane in the solvent of
React I).

In order to produce (V-1) from compound (IV-1), compound (IV-1) is halogenated with thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, triphenylphosphine-carbon tetrachloride or the like. Agent without solvent or tetrachloroethane,
The reaction is carried out by heating in a solvent such as ethylene dichloride, chloroform, trichloroethylene, benzene or chlorobenzene. At this time, a catalyst such as N-methylmorpholine, triethylamine, pyridine, dimethylaniline, dimethylformamide and the like can also be used.

In order to produce (I-1) from compound (V-1), compound (V-1) is reacted with an amine in a solvent such as methanol, ethanol, dimethylformamide, and dimethylsulfoxide. At this time, a deoxidizing agent such as sodium carbonate, potassium carbonate, triethylamine, excess amines, and pyridine can be added.

(2) Production method of optically active substance (i) The optically active 7-substituted compound (I-1a) is, for example, an optically active α-acetyl-γ-butyrolactone (A.
B. L) It can be produced according to the following reaction formula (C) using the γ-substituted product (IIa) as a starting material.

[0023]

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Wherein R ¹ , R ² , R ³ and X are the same as described above.

That is, the optically active compound (IIa) and 3
-Amino-4-cyanopyrazole (III), and the resulting compound is acetylated to give an optically active 6-
(2-acetoxyethyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7 (4H) -ones (VI
a) and halogenating it to form an optically active 6- (2
-Acetoxyethyl) -7-halo-5-methylpyrazolo [1,5-a] pyrimidines (VIIa) and then reacted with amines to give optically active 6- (2-acetoxyethyl) -7-amino -5-methylpyrazolo [1,5-a] pyrimidines (VIIIa), followed by deacetylation to give optically active 7-amino-6- (2-hydroxyethyl) -5-methylpyrazolo [1,5- a]
Pyrimidines (IXa) and further cyclization,
The optically active 7-substituted compound (I-1a) of the present invention can be produced.

The optically active α- used as a starting material
The acetyl-γ-butyrolactone (ABL) γ-substituted (IIa) can be easily produced, for example, by reacting optically active propylene oxide with ethyl acetoacetate.

Compound (VIa) is converted from compound (IIa) and compound (III)
In order to prepare a), first, an optically active 6- (2-hydroxyethyl)-is prepared according to the method shown in the above reaction formula (B).
5-methylpyrazolo [1,5-a] pyrimidine-7 (4
H) -ones, to which an acetylating agent such as acetyl chloride or acetic anhydride is added without solvent or in dichloromethane, chloroform, tetrachloroethane, ethylene dichloride,
The reaction is carried out in a solvent such as trichloroethylene, benzene, chlorobenzene and the like. At this time, a catalyst such as triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine or the like can be used. Further, optically active 6- (2-hydroxyethyl) -5, which is the above intermediate,
-Methylpyrazolo [1,5-a] pyrimidine-7 (4
H) -ones are prepared by reacting compound (IIa) in a solvent such as dimethylformamide, toluene, xylene, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or the like without a catalyst or in the presence of a catalyst such as a Lewis acid such as trifluoroborane. And (III) are dehydrated and condensed, and then the obtained compound is treated with water, methanol, ethanol,
It can also be carried out by cleaving the lactone ring by treatment with sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine or the like in a solvent such as dimethylformamide or tetrahydrofuran.

In order to produce (VIIa) from compound (VIa), thionyl chloride, phosphorus oxychloride,
A halogenating agent such as phosphorus pentachloride or triphenylphosphine-carbon tetrachloride is heated and reacted without a solvent or in a solvent such as tetrachloroethane, ethylene dichloride, chloroform, trichloroethylene, benzene or chlorobenzene. At this time, a catalyst such as N-methylmorpholine, triethylamine, pyridine, dimethylaniline, dimethylformamide and the like can also be used.

In order to produce (VIIIa) from compound (VIIa), compound (VIIa) is reacted with an amine in a solvent such as methanol, ethanol, dimethylformamide, dimethylsulfoxide and methylethylketone. At this time, a deoxidizing agent such as sodium carbonate, potassium carbonate, triethylamine, tert-butylamine, excess amines, and pyridine can be added.

In order to produce (IXa) from compound (VIIIa), compound (VIIIa) is prepared by using sodium hydroxide, potassium hydroxide, potassium carbonate or the like in a solvent such as methanol, ethanol, dimethylformamide or tetrahydrofuran. To deacetylate.

In order to produce (I-1a) from compound (IXa), first, compound (IXa) is added to methanesulfonyl chloride, p-chloride in a solvent such as chloroform or dichloromethane.
And reacting with toluenesulfonyl or the like to obtain a reactive derivative of a hydroxy group. At this time, a deoxidizing agent such as sodium carbonate, potassium carbonate, triethylamine, pyridine and the like can be added. Next, the compound obtained by this reaction was dissolved in a solvent such as dimethylformamide, dimethylsulfoxide, and methylethylketone in N-methylmorpholine, triethylamine, pyridine, dimethylaniline,
The compound of the present invention (I-1a) can be obtained by ring closure using a catalyst such as dimethylformamide.

(Ii) Optical Resolution Method An optically active 7-substituted compound (I-1a) is produced by an optical resolution method using carbobenzyloxy (Cbz) -L-alanine according to the following reaction formula (D). Can be.

[0033]

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(Wherein, R ¹ , R ² , R ³ and X are the same as described above, and Cbz-L-Ala-OH represents carbobenzyloxy-L-alanine)

That is, racemic compound (IV-1) and carbobenzyloxy (Cbz) in the above-mentioned reaction formula (B)
6- [2- (N-benzyloxycarbonyl-L-alanyloxy) ethyl]-
5-Methyl-pyrazolo [1,5-a] pyrimidine-7
Preparing two diastereoisomers of (4H) -ones,
Each of the isomers is separated and hydrolyzed to give two optically active 6- (2-hydroxyethyl) -5-methyl-
A pyrazolo [1,5-a] pyrimidin-7 (4H) -one (IV-1a) is obtained, and the compound is further reacted according to the method shown in the above reaction formula (B) to obtain an optically active compound of the present invention. (I-1a) can be produced.

The reaction between the racemic compound (IV-1) and carbobenzyloxy (Cbz) -L-alanine can be carried out, for example, in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, chloroform, dichloromethane, or the like.
The reaction can be carried out in the presence of a condensing agent such as N'-dicyclohexylcarbodiimide (DCC) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC). At this time, a catalyst such as triethylamine, diisopropylethylamine, and dimethylaminopyridine can also be used. The diastereomeric mixture obtained by the above reaction can be separated into two diastereoisomers by subjecting it to a commonly used separation and purification means, for example, column chromatography.

The hydrolysis reaction of the two separated diastereoisomers is carried out in a solvent such as, for example, alcohol or dimethylformamide by using sodium hydroxide, potassium hydroxide,
It can be performed using potassium carbonate or the like. The two optically active compounds (IV-
1a) can be derivatized to the desired optically active compound of the present invention (I-1a) by performing halogenation and reaction with an amine according to the method shown in the above reaction formula (B).

(Iii) Enzymatic method Using lipase, an optically active 7-substituted compound can be produced according to the following reaction formula (E).

[0039]

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(Wherein R ¹ , R ² , R ³ and X are the same as described above)

That is, racemic α-acetyl-
Using the γ-butyrolactone (ABL) γ-substituted (II) as a starting material, a racemic compound (VIII) is obtained according to the method shown in the above reaction formula (C). When this racemic compound is treated with lipase, only one enantiomer is selectively hydrolyzed to obtain only one enantiomer of compound (IXa), and this compound is represented by the aforementioned reaction formula (C). By cyclization according to the method, the optically active compound (I-1a) of the present invention can be produced. The other enantiomer (VIIIa) not hydrolyzed by the lipase treatment is hydrolyzed according to the method shown in the above reaction formula (C) to produce an optically active compound (IXa).
And then a cyclization reaction, another optically active compound of the present invention (I-1a) can be produced.

As the lipase used herein, commercially available lipases of various origins, for example, Aspergillus
“Lipase A-6” from Aspergillus niger, Mucor Japonicas (Mu)
lipase M-
10 ", Candida lugza
lipase AY-30 ”from Rosaps
Japonicas (Rhizopus japonicu)
s) -derived "Lipase F-AP15", Porcine Pancreate-derived "Pancreatin F", Rhizopus Niveus (Rhiz)
opus Niveus)
F ", Pseudomonas Fluorescence (Pseud
(lipase PS) or the like (above, manufactured by Amano Pharmaceutical Co., Ltd.). These lipases can be dissolved in water, added with celite, stirred, and used as a suspension adsorbed on celite.

The lipase treatment is carried out by, for example, suspending the racemic compound (VIII) in a solvent such as methanol, ethanol, isopropanol, n-butanol, ethyl ether, isopropyl ether, benzene, toluene, xylene, etc. It can be performed by stirring at about room temperature in a suspension. The hydrolysis reaction is completed within several hours to several days, and the reaction product (IXa) and the unreacted product can be separated by a usual separation and purification means such as column chromatography, fractional recrystallization and the like. it can.

(II) 6-Substituted Compound (1) Method for Preparing Racemic Form (i) Racemic forms (I-2) and (I-3) of compound (I) in which a substituent is introduced at the 6-position in compound (I) ) Can be produced, for example, according to the following reaction formula (F).

[0045]

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(Wherein, R ¹ , R ⁴ , R ⁵ and X are the same as described above, and R ⁶ and R ⁷ are a hydrogen atom or an ester residue)

That is, succinic acid or its ester derivative (X) and 3-amino-4-cyanopyrazole (III) are dehydrated and condensed to give 3-cyano-5-methyl-7 (4H) -oxopyrazolo [1,5 -A] pyrimidine compound (XI), which is then halogenated to give 3
-Cyano-5-methyl-7-halopyrazolo [1,5-
a) leads to pyrimidines (XII). Then the compound (XI
The compound (I) of the present invention is obtained by reacting an amine with I) to give a compound (XIII) and then performing a ring closure reaction.
Of these, 6,7-dihydro-7-oxo-8H-pyrrolo [3, wherein the substituents R ² and R ³ together form an oxygen atom
2-e] pyrazolo [1,5-a] pyrimidines (I-
2) can be obtained. Next, the compound (I-2) is reduced to a compound (XIV), and the compound (XIV) is closed again to give the 6-substituted compound (I) of the present invention.
-3) can be manufactured.

From compound (X) and compound (III), compound (XI)
Can be carried out by a reaction similar to the conversion from the compounds (II) and (III) shown in the reaction formula (B) to the compound (IV-1). That is, in acetic acid or in a mixed solvent of acetic acid and a suitable solvent, for example, dimethylformamide, toluene, xylene, isopropanol, tetrahydrofuran, dioxane, ethanol, etc., in the presence of a catalyst such as a Lewis acid such as no catalyst or trifluoroborane, The compound (X) is reacted with (III).

To produce (XII) from compound (XI),
Compound (XI) is mixed with a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, and triphenylphosphine-carbon tetrachloride without solvent or in a solvent such as tetrachloroethane, ethylene dichloride, chloroform, trichloroethylene, benzene, or chlorobenzene. And heat reaction. At this time, a catalyst such as N-methylmorpholine, triethylamine, pyridine, dimethylaniline, dimethylformamide and the like can also be used.

In order to produce (XIII) from compound (XII), compound (XII) and amines are converted to methanol, ethanol, dimethylformamide, dimethylsulfoxide,
The reaction is performed in a solvent such as isopropanol. At this time, a deoxidizing agent such as sodium carbonate, potassium carbonate, triethylamine, excess amines, and pyridine can be present. In this reaction, the reaction further proceeds depending on the reaction conditions, and a ring-closed compound (I-2) may also be produced. In order to produce (I-2) from the compound (XIII), after hydrolyzing the ester residue, N, in the presence or absence of a suitable solvent that does not directly affect the reaction,
A condensing agent such as N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) is added and reacted.

The compound (I-2) is converted into (XIV) by, for example, reduction with a reducing reagent such as sodium borohydride in an alcoholic solvent such as methanol, ethanol, or isopropanol, or a mixed solvent thereof with water. The reaction can be performed. Finally, to produce the compound (I-3) of the present invention from the compound (XIV), the compound (XI
V) is dissolved in a solvent that does not participate in the reaction, such as chloroform, dichloromethane, benzene, toluene, xylene,
Thionyl chloride is added, and the alcoholic hydroxyl group of compound (XIV) is halogen-substituted, followed by a ring-closing reaction with an amino group.

(Ii) The racemic (I-3) of the 6-substituted compound can also be produced according to the following reaction formula (G).

[0053]

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(Wherein, R ¹ , R ⁴ , R ⁵ , R ⁶ and X are the same as described above)

That is, the compound (XI) obtained by the method shown in the above reaction formula (F) is reduced to give 6- (2-hydroxyethyl) -5-methyl-pyrazolo [1,5-a] pyrimidine-7. (4H) -ones (IV-2), which were then halogenated to give 7-halo-6- (2-haloethyl) -5-methylpyrazolo [1,5-a] pyrimidines (V-2) None, and by further reacting with amines, the 6-substituted compound (I-3) of the present invention can be produced.

In order to produce the compound (IV-2) from the compound (XI), the compound (XI) is reacted with a metal hydride compound such as lithium aluminum hydride in a solvent such as tetrahydrofuran or dioxane. At this time, it is preferable to add silica gel to the reaction solution. In order to obtain the compound (I-3) of the present invention from the compound (IV-2) via the compound (V-2), the compound (IV-
It can be carried out according to the method derived from 1) to compound (I-1).

(2) Method for Producing Optically Active Compound The optically active 6-substituted compound can be produced, for example, using compound (XI) as a starting material according to the following reaction formula (H).

[0058]

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(Wherein R ¹ , R ⁴ , R ⁵ and X are the same as described above)

That is, an optically active (R)-(+)-methyl lactate is condensed with a carboxylic acid derivative obtained by hydrolyzing the compound (XI) obtained by the method shown in the above reaction formula (F). (1R) -1-methoxycarbonylethyl
2- [5-methyl-7 (4H) -oxopyrazolo [1,
5-a] pyrimidin-6-yl] propionates 2
A variety of diastereoisomers are produced, each of which is separated and reduced to give the enantiomer (IV-2a) of compound (IV-2) shown in Reaction Scheme (G),
The optically active 6-substituted compound (I-3a) of the present invention is obtained by reacting the two enantiomers as raw materials according to the method shown in the above reaction formula (G).
Can be manufactured.

The hydrolysis of compound (XI) can be carried out in a solvent such as methanol, ethanol, dimethylformamide, tetrahydrofuran or the like using sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or the like. The carboxylic acid derivative obtained here and (R)
The condensation reaction with-(+)-methyl lactate is carried out, for example, in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, chloroform, dichloromethane or the like in N, N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-hydrochloric acid). It can be carried out in the presence of a condensing agent such as (dimethylaminopropyl) carbodiimide (WSC). At this time, a catalyst such as triethylamine, diisopropylethylamine, and dimethylaminopyridine can also be used. The diastereomeric mixture obtained by the above reaction can be separated into two diastereoisomers by subjecting it to conventional separation and purification means, for example, column chromatography.

The reduction reaction of the two separated diastereoisomers can be carried out according to the reduction reaction from compound (XI) to compound (IV-2) shown in the above reaction formula (G). The two enantiomers (IV-2a) obtained by this reduction reaction are obtained according to the method of deriving compound (IV-1) into compound (I-1) shown in the aforementioned reaction formula (B). The desired optically active compound (I-
3a).

The compound of the present invention (I) can be obtained in good yield by appropriately combining the methods shown in the above reaction formulas (B) to (H). Can be converted into a pharmaceutically acceptable salt of an inorganic or organic acid, and further reacted with an alkyl iodide or the like to form a quaternary ammonium salt.

The compound (I) of the present invention, when administered to humans as a medicament, varies depending on the age and symptoms, but is administered in an effective amount, for example, usually 10 to 100 mg daily orally in 1 to 3 divided doses. Is preferred.

The therapeutic agent for circulatory system disease of the present invention can be prepared in various dosage forms, for example, orally administered preparations such as tablets, capsules, powders, troches and solutions. The above formulation can be carried out by a method known per se. That is, the compound (I) of the present invention is used as an excipient such as starch, mannitol, lactose;
Binders such as sodium carboxymethylcellulose and hydroxypropylcellulose; disintegrants such as crystalline cellulose and calcium carboxymethylcellulose; talc;
Tablets, capsules, powders, granules, or lozenges can be prepared by combining and formulating lubricants such as magnesium stearate; and fluidity improvers such as light anhydrous silicic acid as appropriate.

[0066]

Next, the present invention will be described with reference to examples and test examples.

Example 1 7-Substituted Compound (1) (1) To 700 ml of an anhydrous methanol solution in which 25 g of sodium was dissolved, 138 ml of ethyl acetoacetate and 75 ml of propylene oxide were added, and the mixture was stirred at room temperature for 2 days. Then the solvent is distilled off and the resulting solid is dissolved in water. The aqueous solution is acidified by adding a 50% aqueous sulfuric acid solution, and then extracted with benzene. After the extract is washed with water and dried over Na ₂ SO ₄ , the solvent is distilled off under reduced pressure. The residual slightly yellow liquid is subjected to distillation under reduced pressure, and is a colorless liquid having a boiling point of 110 to 115 ° C. (6 mmHg) α-acetyl-γ-valerolactone [where R ² = CH ₃ , R ³ = H] in the formula (II). 95.7 g (62% yield)
I got

¹ H-NMR (CDCl ₃ ) δ; 1.42 (1.5 H, d, J = 5.9 Hz),
1.44 (1.5H, d, J = 6.3Hz), 1.82-1.96 (0.5H, m), 2.35-2.44
(1H, m), 2.43 (1.5H, s), 2.47 (1.5H, s), 2.82-2.91 (0.5H,
m), 3.73-3.80 (1H, m), 4.57-4.72 (1H, m).

(2) Compound (II) obtained in the above (1)
[R ² = CH ₃ , R ³ = H] 25 g, 3-amino-4-cyanopyrazole (III) 11 g, BF ₃ -acetic acid reagent 1 m
l, 100 ml of toluene and 100 ml of acetic acid,
Dehydrate and reflux at 0-135 ° C for 12 hours. After the temperature of the reaction solution is returned to room temperature, chloroform is added and insolubles generated are filtered off through Celite. The obtained solution is washed with water and an aqueous solution of sodium carbonate, dried over Na ₂ SO ₄ , and the solvent is distilled off under reduced pressure to obtain 46 g of a pale orange-red oil. The oily product was subjected to silica gel column chromatography (elution solvent: n
-Hexane-methyl ethyl ketone), melting point 206
6- (2-acetoxypropyl)-which is white crystals at
11.4 g of 3-cyano-5-methylpyrazolo [1,5-a] pyrimidin-7 (4H) -one (23.7% yield)
I got

¹ H-NMR (DMSO-d ₆ ) δ; 1.22 (3H, d, J = 6.2 Hz),
1.93 (3H, s), 2.42 (3H, s), 2.69 (1H), 2.78 (1H), 4.99 (1H,
m), 8.33 (1H, s), 13.14 (1H, brs).

(3) 6- (2-acetoxypropyl) -3-cyano-5-methylpyrazolo [1,5-a] pyrimidin-7 (4H) -one obtained in the above (2) 1.3
g, 250 mg of sodium hydroxide and 60 ml of methanol, and the mixture was refluxed for 2 hours. After returning the reaction solution to room temperature, acetic acid is added to make it weakly acidic, and the solvent is distilled off under reduced pressure.
The obtained residue was subjected to alumina column chromatography (elution solvent; dichloromethane-methanol) to give 3-cyano-6, a slightly yellow crystal having a melting point of 248 to 250 ° C.
-(2-hydroxypropyl) -5-methylpyrazolo [1,5-a] pyrimidin-7 (4H) -one [(IV-
1) wherein R ² = CH ₃ , R ³ = H] 1.1 g (yield 9
9.9%).

¹ H-NMR (DMSO-d ₆ ) δ; 1.09 (3H, d, J = 6.3 Hz),
2.39 (3H, s), 2.41-2.60 (2H, m), 3.79-3.83 (1H, m), 4.55
(1H, brs), 8.34 (1H, s), 13.02 (1H, s).

(4) Compound (IV-) obtained in the above (3)
1) 1.1 g of [R ² ＣＨCH ₃ , R ³ ＨH], 10 ml of phosphorus oxychloride and 0.5 ml of triethylamine are mixed and heated under reflux at 135 ° C. for 3 hours. After returning the reaction solution to room temperature, it is poured into ice water, neutralized with a saturated aqueous solution of potassium carbonate, and extracted with chloroform. Wash the extract with Na ₂ S
After drying over O ₄ , this solution was subjected to silica gel column chromatography (elution solvent: chloroform-ethyl acetate) to give 7-chloro-6- (2-chloropropyl) -3-cyano-5-yellow green crystals. Methylpyrazolo [1,5-
a] pyrimidine [wherein R ² = CH ₃ , R ³ =
H, X = Cl] 1.1 g (85.7% yield).

¹ H-NMR (CDCl ₃ ) δ; 1.71 (3H, d, J = 6.5 Hz), 2.8
2 (3H, s), 3.28-3.37 (2H, m), 4.40 (1H, m), 8.39 (1H, s).

(5) The compound (V-
1) 1.35 g [R ² = CH ₃ , R ³ = H, X = Cl]
6 ml of tert-butylamine, 1.2 of triethylamine
Then, the mixture was mixed with 90 ml of anhydrous dimethylformamide and stirred at 90-95 ° C. for 10 hours in a sealed tube. The reaction solution is allowed to stand at room temperature for 5 days, and crystals precipitated at the bottom of the tube are collected by filtration, and the crystals are washed with isopropyl alcohol. Further, the filtrate and the washing solution are combined, and the solvent is distilled off under reduced pressure to obtain a yellow-green crystal similar to the previously obtained crystal. These crystals are dissolved in 40 ml of chloroform, and the solution is washed with diluted saline and dried over Na ₂ SO ₄ . The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluent: chloroform-ethyl acetate), melting point 2
8-tert-butyl-3-cyano-6,7-dihydro-5,7-dimethyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-] which is a pale yellow crystal of the present invention at 23 ° C.
a] pyrimidine [(I-1) wherein R ¹ = C (C
^{_{H 3) 3, R 2 =}} CH 3, R 3 = H ] 0.75 g (yield: 5
5.6%).

¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, d, J = 6.5 Hz), 1.7
2 (9H, s), 2.40 (3H, s), 2.51 (1H, dd, J = 14.9,1.4Hz), 3.27 (1
H, dd, J = 14.9,9.5Hz), 4.51 (1H, m), 8.14 (1H, s).

According to the method described in Example 1, the following 7-substituted compounds (2) to (10) were produced.

Example 2: 7-substituted compound (2) 3-cyano-6,7-dihydro-5,7-dimethyl-8
-(1-Methylethyl) -8H-pyrrolo [3,2-e]
Pyrazolo [1,5-a] pyrimidine [(I-1)
R ¹ = CH (CH ₃ ) ₂ , R ² = CH ₃ , R ³ = H] (melting point 1
95 ° C, 50% yield)

¹ H-NMR (CDCl ₃ ) δ; 1.33 (3H, d, J = 7.0 Hz), 1.4
3 (3H, d, J = 6.8Hz), 1.45 (3H, d, J = 7.0Hz), 2.39 (3H, s), 2.64
(1H, dd, J = 15.4,4.1Hz), 3.38 (1H, dd, J = 15.4,10.5Hz), 4.3
6 (1H, m), 5.53 (1H, m), 8.13 (1H, s).

Example 3 7-Substituted Compound (3) 3-Cyano-8-cyclopentyl-6,7-dihydro-
5,7-dimethyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine [(I-1) wherein R ¹ =
Cyclopentyl, R ² ＣＨCH ₃ , R ³ ＨH] (melting point 178)
° C white crystals, yield 78.8%)

¹ H-NMR (CDCl ₃ ) δ; 1.41 (3H, d, J = 6.2 Hz), 1.5
5-1.95 (8H, m), 2.39 (3H, s), 2.65 (1H, dd, J = 15.1,3.8Hz),
3.38 (1H, dd, J = 15.1,10.5Hz), 4.32 (1H, m), 5.43 (1H, m), 8.
13 (1H, s).

Example 4: 7-substituted compound (4) 8-allyl-3-cyano-6,7-dihydro-5,7-
Dimethyl-8H-pyrrolo [3,2-e] pyrazolo [1,
5-a] pyrimidine [(I-1) wherein R ¹ ＣＨCH ₂ C
H = CH ₂ , R ² = CH ₃ , R ³ = H] (white crystals with a melting point of 141 ° C., yield 70%)

¹ H-NMR (CDCl ₃ ) δ; 1.44 (3H, d), 2.43 (3H,
s), 2.74 (1H, dd), 3.38 (1H, dd), 4.22 (2H, m), 5.33 (3H,
m), 5.82 (1H, m), 8.13 (1H, s).

Example 5: 7-substituted compound (5) 3-cyano-6,7-dihydro-5,7-dimethyl-8
-Propargyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine [(I-1) wherein R ¹ = C
H ₂ C≡CH, R ² = CH ₃ , R ³ = H] (melting point: 204 ° C.
White crystals, yield 75%)

¹ H-NMR (CDCl ₃ ) δ; 1.49 (3H, d), 2.27 (1H,
t), 2.47 (3H, s), 2.77 (1H, q), 3.41 (1H, q), 4.28 (2H, d
d), 4.43 (1H, m), 5.82 (1H, dd), 8.18 (1H, s).

Example 6: 7-Substituted Compound (6) 3-cyano-6,7-dihydro-7-ethyl-5-methyl-8-tert-pentyl-8H-pyrrolo [3,2-
e] pyrazolo [1,5-a] pyrimidine [(I-1) wherein R ¹ ＣC (CH ₃ ) ₂ CH ₂ CH ₃ , R ² ＣＨCH ₂ C
H ₃ , R ³ = H] (yellow crystals having a melting point of 153 ° C., yield 6)
7.1%)

¹ H-NMR (CDCl ₃ ) δ; 0.88 (3H, t), 0.93 (3H,
t), 1.56 (3H, s), 1.70 (1H, m), 1.76 (1H, t), 2.43 (3H, s),
2.55 (2H, m), 2.66 (1H, d), 3.20 (1H, q), 4.25 (1H, t), 8.
12 (1H, s).

Example 7: 7-substituted compound (7) 7-[(2-propen-1-yl) oxymethyl] -3
-Cyano-6,7-dihydro-5-methyl-8-ter
t-pentyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine [(I-1) wherein R ¹ = C
_{(CH 3) 2 CH 2 CH} 3, R 2 = -CH 2 OCH 2 CH =
CH ₂ , R ³ = H]

¹ H-NMR (CDCl ₃ ) δ; 0.75 (3H, t), 1.53 (3H,
s), 1.66 (3H, s), 1.76 (2H, m), 2.34 (3H, s), 2.40 (1H, m),
2.76 (1H, d), 3.15 (1H, t), 3.20 (1H, q), 3.43 (1H, q), 3.
90 (2H, d), 4.46 (1H, q), 5.14 (2H, q), 5.78 (1H, m), 8.04
(1H, s).

Example 8: 7-substituted compound (8) 7-[(2-propen-1-yl) oxymethyl] -8
-Tert-butyl-3-cyano-6,7-dihydro-
5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine [(I-1) wherein R ¹ ＣC
(CH ₃ ) ₃ , R ² −—CH ₂ OCH ₂ CH ＝ CH ₂ , R ³
= H]

¹ H-NMR (CDCl ₃ ) δ; 1.71 (3H, s), 2.42 (3H,
s), 2.86 (1H, d), 3.15-3.33 (1H, m), 3.50 (1H, q), 3.96 (2
H, t), 4.57 (1H, q), 5.26 (2H, m), 8.17 (1H, s).

Example 9: 7-substituted compound (9) 3-cyano-6,7-dihydro-5-methyl-7-methoxymethyl-8-tert-pentyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine [(I-1) wherein R ¹ ＣC (CH ₃ ) ₂ CH ₂ CH ₃ , R
² ＣＨCH ₂ OCH ₃ , R ³ ＨH] (pale yellow crystals, yield 89
%)

¹ H-NMR (CDCl ₃ ) δ; 0.82 (3H, t), 1.57 (3H,
s), 1.74 (3H, s), 1.82 (1H, quintet), 2.43 (3H, s), 2.48
(1H, quintet), 2.84 (1H, dd), 3.18 (1H, dd), 3.24 (1H, d
d), 3.35 (3H, s), 3.44 (1H, dd), 4.48 (1H, m), 8.14 (1H, s).

Example 10: 7-Substituted Compound (10) 3-cyano-6,7-dihydro-8-tert-butyl-7-methoxymethyl-5-methyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine [(I-1) wherein R ¹ ＣC (CH ₃ ) ₃ , R ² ＣＨCH ₂
OCH ₃ , R ³ = H] (pale yellow crystal, yield 85%)

¹ H-NMR (CDCl ₃ ) δ; 1.70 (9H, s), 2.42 (3H,
s), 2.82 (1H, dd), 3.18 (1H, dd), 3.25 (1H, dd), 3.35 (1H,
s), 3.44 (1H, dd), 4.53 (1H, m), 8.15 (1H, s).

Example 11 3.3 ml of ethyl acetoacetate and 2 ml of (S) -propylene oxide were added to 15 ml of anhydrous methanol in which 597 mg of the optically active 7-substituted compound (1) sodium was dissolved, and the mixture was stirred at room temperature for 40 hours. I do. After completion of the reaction, an appropriate amount of ice water is added to the residue obtained by evaporating the solvent under reduced pressure. After adjusting the pH of the solution to 4 to 5 using concentrated hydrochloric acid, the solution is extracted with methylene chloride. The extract is washed with water and saturated saline, dried over MgSO ₄ , and the solvent is distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (elution solvent: n-hexane-ethyl acetate) to give a colorless oil (S) -α-acetyl-γ-valerolactone [where R ² = H, R ³
= CH ₃ ] 2.033 g (55% yield). The boiling point and NMR spectrum of the obtained compound were as described in Example 1 above.
It completely agreed with that of the compound obtained in (1).

(2) Compound (II) obtained in the above (1)
a) [R ² ＨH, R ³ ＣＨCH ₃ ] 1.933 g, 3-amino-4-cyanopyrazole (III) 0.9 g and BF ₃
0.08 ml of the ether complex is dissolved in a mixed solvent of 16 ml of acetic acid and 16 ml of toluene, and this solution is heated under reflux overnight. After returning the reaction solution to room temperature, the residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (elution solvent: chloroform-methanol) to give 6-[(2R)-as a pale yellow-white solid. 2-acetoxypropyl] -3-cyano-5-methylpyrazolo [1,5-a]
Pyrimidin-7 (4H) -one [(VIa) wherein R ² =
CH ₃ , R ³ = H] 1.787 g (78% yield). The melting point and NMR spectrum of the obtained compound completely matched those of the compound obtained in Example 1 (2).

(3) According to the method described in the above (1), (R) -α-acetyl-γ-valerolactone [formula (IIa)] was obtained using 1 ml of (R) -propylene oxide as a colorless oil. Medium, R ² = CH ₃ , R ³ = H] 1.46 g
(79% yield). Melting point of the obtained compound, NMR
The spectrum was completely consistent with that of the compound obtained in Example 1 (1).

(4) Compound (II) obtained in the above (3)
a) To a suspension of 1.46 g of [R ² ＣＨCH ₃ , R ³ ＨH] and 0.822 g of 3-amino-4-cyanopyrazole (III) in 1.5 ml of ethanol, BF ₃ -methanol complex 7 was added.
Add 6 μl and stir at room temperature for 18 hours. The solvent of the reaction solution was distilled off under reduced pressure, 6 ml of ethyl acetate was added to the residue obtained, and the precipitated crystals were collected by filtration and dried to give 3- [1-((5R) -tetrahydro-) as a pale yellow-white solid. 2-oxo-
1.5 g (yield 85%) of 5-methyl-3-furylden) ethylamino] -4-cyanopyrazole was obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.43 (3H, d, J = 6.2 Hz), 2.
21 (3H, s), 2.50 (1H, dd, J = 14.6,6.1Hz), 3.06 (1H, dd, J = 14.
6,8.2Hz), 4.64-4.76 (1H, m), 7.92 (1H, s), 10.26 (1H, s),
11.07 (1H, brs).

(5) Compound 1.5 obtained in the above (4)
g was suspended in 3.2 ml of water, and 5.0 ml of triethylamine was added to the suspension, followed by stirring at room temperature for 16 hours. The reaction solution was adjusted to pH 4 by adding 6N-hydrochloric acid, and the precipitated colorless crystals were collected by filtration to give a colorless solid, 3-cyano-6-[(2R) -2.
-Hydroxypropyl] -5-methylpyrazolo [1,5
-A] pyrimidin-7 (4H) -one (935 mg, yield 62%) was obtained. The NMR spectrum of the obtained compound completely matched that of the compound obtained in Example 1 (3).

(6) Compound 0.8 obtained in the above (5)
g in 8 ml of dichloromethane was added to 0.42 ml of acetic anhydride.
0.53 ml of triethylamine and 42 mg of dimethylaminopyridine are sequentially added, and the mixture is stirred at room temperature for 2 hours. The reaction solution was washed with 2N hydrochloric acid and water, dried over MgSO ₄ ,
The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluent: n-hexane-ethyl acetate) to give 6-[(2R) -2 as pale yellowish white crystals.
-Acetoxypropyl] -3-cyano-5-methylpyrazolo [1,5-a] pyrimidin-7 (4H) -one [(VIa) wherein R ² = CH ₃ , R ³ = H] 0.9 g (yield 95%). The NMR spectrum of the obtained compound completely matched the one obtained in Example 1 (2).

(7) The compound (VI) obtained in the above (2)
a) 0.9 g of [R ² ＣＨCH ₃ , R ³ ＨH], 1.5 ml of phosphorus oxychloride and 0.46 ml of triethylamine are mixed and refluxed at 130 ° C. for 2 hours. After returning the reaction solution to room temperature, it is poured into ice water, neutralized with an aqueous solution of potassium carbonate, and extracted with chloroform. Wash the extract with water
After drying over O ₄ , the solvent is distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent;
n-hexane-ethyl acetate) to give 6-[(2R) -2-acetoxypropyl] -7-chloro-3-cyano-5-methylpyrazolo [1,5-a] which is a pale yellow-white solid.
Pyrimidine [(VIIa) wherein R ² ＣＨCH ₃ , R ³ ＨH,
X = Cl] 865 mg (90% yield).

¹ H-NMR (CDCl ₃ ) δ; 1.42 (3H, d, J = 6.3 Hz), 1.
96 (3H, s), 2.81 (3H, s), 3.08 (1H, dd, J = 5.0,14.5Hz), 3.2
1 (1H, dd, J = 9.2,14.5Hz), 5.18-5.30 (1H, m), 8.37 (1H, s).

(8) The compound (VII) obtained in the above (7)
a) _{^{[R 2 = CH 3, R 3}} = H, X = Cl ] 865 mg,
1.55 ml of t-butylamine and 0.1 ml of triethylamine.
41 ml are dissolved in 10 ml of dimethylformamide and the solution is stirred at 90 ° C. for 2 hours. After returning the reaction solution to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane-
Ethyl acetate) to give 6-[(2
R) -2-Acetoxypropyl] -7-tert-butylamino-3-cyano-5-methylpyrazolo [1,5-
a] pyrimidine [(VIIIa) wherein R ¹ = C (C
^{_{H 3) 3, R 2 =}} CH 3, R 3 = H ] 876 mg (yield: 90
%).

¹ H-NMR (CDCl ₃ ) δ; 1.32 (3H, d, J = 6.3 Hz), 1.
56 (9H, s), 2.05 (3H, s), 2.62 (3H, s), 2.91 (1H, dd, J = 6.9,
15.2Hz), 2.99 (1H, dd, J = 6.9,15.2Hz), 4.95 (1H, dq, J = 6.
3,6.9Hz), 5.72 (1H, s), 8.19 (1H, s).

(9) Compound (VIII) obtained in the above (8)
a) [R ¹ = C (CH ₃ ) ₃ , R ² = CH ₃ , R ³ = H]
To a solution of 767 mg of methanol in 11.5 ml was added potassium hydroxide 308 mg of an aqueous solution of 1.5 ml, and the mixture was stirred at room temperature for 7 hours. The reaction solution is neutralized with 2N hydrochloric acid, the solvent is distilled off under reduced pressure, and the obtained residue is extracted with ethyl acetate. The extract was washed with saturated saline, dried over MgSO ₄ , and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (elution solvent: n-hexane-ethyl acetate).
6-[(2R) -2-hydroxypropyl] -7-tert-butylamino-3- which is a pale yellow-white solid
Cyano-5-methylpyrazolo [1,5-a] pyrimidine [(IXa) wherein R ¹ ＣC (CH ₃ ) ₃ , R ² ＣＨCH ₃ ,
R ³ = H] 532 mg (90% yield).

¹ H-NMR (CDCl ₃ ) δ; 1.37 (3H, d, J = 6.3 Hz), 1.
52 (9H, s), 2.53 (3H, s), 2.74 (1H, dd, J = 8.7,15.2Hz), 2.8
6 (1H, dd, J = 2.3,15.2Hz), 4.14-4.19 (1H, m), 6.58 (1H, s),
8.15 (1H, s).

(10) The compound (VI) obtained in the above (8)
IIa) [R ¹ ＣC (CH ₃ ) ₃ , R ² ＣＨCH ₃ , R ³ ＨH]
876 mg of methanol-tetrahydrofuran (3: 1)
1.1 g of potassium carbonate is added to 10 ml of the mixed solution, and the mixture is stirred at room temperature for 30 minutes. After the salt precipitated in the reaction solution is removed by filtration, the solvent is distilled off under reduced pressure. The obtained residue was dissolved in ethyl acetate, and this solution was washed with 2N hydrochloric acid and water, and then washed with MgO.
Dry over SO ₄ . The residue obtained by distilling off the solvent under reduced pressure is subjected to silica gel column chromatography (elution solvent: n
-Hexane-ethyl acetate) to give 6-[(2R) -2-hydroxypropyl] -7-te as a pale yellow-white solid.
rt-butylamino-3-cyano-5-methylpyrazolo [1,5-a] pyrimidine [(IXa) wherein R ¹ ＣC
(CH ₃ ) ₃ , R ² ＣＨCH ₃ , R ³ ＨH] 688 mg (90% yield). The NMR spectrum of the obtained compound completely matched that of the compound obtained in the above (9).

(11) The compound (IX) obtained in the above (9)
a) [R ¹ = C (CH ₃ ) ₃ , R ² = CH ₃ , R ³ = H]
A suspension of 366 mg in 4 ml of dichloromethane was cooled to -30 DEG C., 0.13 ml of methanesulfonyl chloride and 0.23 ml of triethylamine were added, and the mixture was stirred at the same temperature for 1.5 hours. A saturated aqueous ammonium chloride solution is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed with a saturated saline solution and dried over MgSO ₄ . The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluent: n-hexane-ethyl acetate) to give 6-[(2R) -2-methanesulfonyloxypropyl as a pale yellow-white solid. ] -7-tert-Butylamino-3-cyano-5-methylpyrazolo [1,5-a] pyrimidine460
mg (98.8% yield).

¹ H-NMR (CDCl ₃ ) δ; 1.49 (3H, d, J = 6.3 Hz), 1.
53 (9H, s), 2.65 (3H, s), 2.84 (3H, s), 3.07-3.22 (2H, m),
4.89-4.99 (1H, m), 5.40 (1H, brs), 8.20 (1H, s).

(12) Compound 4 obtained in the above (11)
To a solution of 00 mg in 4 ml of dimethylformamide is added 0.16 ml of triethylamine, and the mixture is stirred at 90 ° C. for 2.5 hours. The residue obtained by evaporating the solvent of the reaction solution under reduced pressure was subjected to silica gel column chromatography (elution solvent: n-hexane-ethyl acetate) to obtain (7S) -8-tert-butyl of the present invention as a colorless solid. -3-Cyano-6,7
-Dihydro-5,7-dimethyl-8H-pyrrolo [3,2
-E] pyrazolo [1,5-a] pyrimidine [(I-1
a) wherein R ¹ ＣC (CH ₃ ) ₃ , R ² ＨH, R ³ ＣＨCH
₃ ] 294 mg (99.7% yield). The NMR spectrum of the obtained compound completely matched that of the compound obtained in Example 1 (5). Further, the obtained compound showed an optical rotation of (+), and its optical purity was 80% ee.
This is the result (by the liquid chromatography method).

Embodiment 12:Optically active 7-substituted compound
(Optical resolution method) (1) Compound (IV-1) obtained in Example 1 (3)
[R^Two= CH_Three, R^Three= H] 3 g, carbobenzyloxy
4.32 g of cy (Cbz) -L-alanine, 1-ethyl hydrochloride
Ru-3- (3-dimethylaminopropyl) carbodiimi
(WSC) 3.72 g and dimethylaminopyrid
78 mg of dimethylformamide and dichloromethan
Dissolve in 30 ml of a mixed solvent and stir at room temperature overnight.
You. The solvent obtained by distilling off the solvent of the reaction solution under reduced pressure was treated with acetic acid.
Extract with ethyl, and sequentially with water, saturated aqueous sodium bicarbonate, and saturated saline
After washing, MgSO_FourDry with. The solvent is distilled off under reduced pressure
Residue obtained by silica gel column chromatography
-(Elution solvent: n-hexane-ethyl acetate)
The lower two diastereoisomers were isolated.

(A) 6-[(2R) -2- (N-benzyloxycarbonyl-L-alanyloxy) propyl]
-3-cyano-5-methylpyrazolo [1,5-a] pyrimidin-7 (4H) -one; colorless crystals

¹ H-NMR (CDCl ₃ ) δ; 1.34 (3H, d, J = 6.6 Hz), 1.
34 (3H, d, J = 6.6Hz), 2.52 (3H, s), 2.71-2.80 (1H, m), 2.97
-3.00 (1H, m), 4.20-4.26 (1H, m), 5.00 and 5.06 (2H, ABq, J
= 12.2Hz), 5.24 (1H, brs), 5.50 (1H, d, J = 7.3Hz), 7.28 (5
H, s), 7.94 (1H, s).

(B) 6-[(2S) -2- (N-benzyloxycarbonyl-L-alanyloxy) propyl]
-3-cyano-5-methylpyrazolo [1,5-a] pyrimidin-7 (4H) -one; colorless crystals

¹ H-NMR (CDCl ₃ ) δ; 1.31 (3H, d, J = 6.9 Hz), 1.
34 (3H, d, J = 6.6Hz), 2.54 (3H, s), 2.8-3.0 (2H, m), 4.2-4.
4 (1H, m), 5.07 (2H, s), 5.12-5.18 (1H, m), 5.49 (1H, d, J =
(7.3Hz), 7.31 (5H, s), 7.92 (1H, s).

(2) Compound (a) obtained in the above (1)
To a solution of 26.2 g of ethanol in 200 ml of ethanol was added 150 ml of a 1N aqueous sodium hydroxide solution under ice cooling, and the mixture was stirred at 0 ° C. for 4 hours. The reaction mixture was acidified by adding 90 ml of 1N hydrochloric acid, and the solvent was distilled off under reduced pressure. To the residue obtained, 50 ml of methanol was added, and the precipitated salt was filtered off. The residue obtained by evaporating the solvent of the filtrate under reduced pressure was subjected to silica gel column chromatography (eluent: n-hexane-ethyl acetate) to give 6-[(2R) -2-hydroxypropyl]-as colorless crystals. 3-cyano-5-methylpyrazolo [1,5
-A] pyrimidin-7 (4H) -one [(IV-1a) wherein R ² = CH ₃ , R ³ = H] 12.8 g (yield 92
%). The NMR spectrum of the obtained compound completely matched that of the compound obtained in Example 1 (3).

(3) The compound (IV-) obtained in the above (2)
1a) 8.5 ml of carbon tetrachloride was added to a solution of 1.495 g of [R ² = CH ₃ , R ³ = H] and 3.38 g of triphenylphosphine in 45 ml of tetrahydrofuran, and the mixture was heated under reflux at 80 ° C. for 2 hours. The residue obtained by evaporating the solvent of the reaction solution under reduced pressure was subjected to silica gel column chromatography (elution solvent: n-hexane-ethyl acetate) to obtain 6-[(2R) -2-chloroform as pale yellowish white crystals. Propyl) -3-cyano-5-methylpyrazolo [1,5-a] pyrimidine-
1.47 g (yield 91%) of 7 (4H) -one was obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.64 (3H, d, J = 6.3 Hz), 2.
54 (3H, s), 2.81 (1H, dd, J = 9.6,14.2Hz), 3.13 (1H, dd, J = 3.
6,14.2Hz), 4.4-4.6 (1H, m), 8.03 (1H, s).

(4) Compound 1.4 obtained in the above (3)
7 g was dissolved in 4.5 ml of phosphorus oxychloride, and 0.83 ml of triethylamine was added to the solution under ice cooling.
Heat to reflux for hours. After returning the reaction solution to room temperature, it is poured into ice water, neutralized with an aqueous solution of potassium carbonate, and extracted with chloroform. After the extract is washed with water and dried over MgSO ₄ , the solvent is distilled off under reduced pressure. The resulting residue is subjected to silica gel column chromatography (elution solvent: n-hexane-
Ethyl acetate) to give 6-[(2
R) -2-chloropropyl] -7-chloro-3-cyano-5-methylpyrazolo [1,5-a] pyrimidine [(V
-1a) wherein R ² = CH ₃ , R ³ = H, X = Cl]
0.983 g (67% yield) was obtained. The NMR spectrum of the obtained compound completely matched that of the compound obtained in Example 1 (4).

(5) The compound (V-
1a) [R ² = CH ₃ , R ³ = H, X = Cl] 0.98
According to the method described in the above Example 1 (5), 3 g of (7S) -8-tert of the present invention, which is a colorless crystal, is used.
-Butyl-3-cyano-6,7-dihydro-5,7-dimethyl-8H-pyrrolo [3,2-e] pyrazolo [1,5
-A] pyrimidine [(I-1a) wherein R ¹ ＣC (CH
₃ ) ₃ , R ² = H, R ³ = CH ₃ ] 683 mg (yield 69)
%). The NMR spectrum of the obtained compound completely matched that of the compound obtained in Example 1 (5). In addition, the obtained compound shows optical rotation of (+),
The optical purity was 96% ee or more (by liquid chromatography).

(6) Compound (b) obtained in the above (1)
Using 2.1 g, according to the method described in the above (2) to (5), (7R) -8-te of the present invention, which is a colorless solid, is used.
rt-butyl-3-cyano-6,7-dihydro-5,7
-Dimethyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine [(I-1a) wherein R ¹ =
C (CH ₃ ) ₃ , R ² = CH ₃ , R ³ = H] 756 mg (total yield from compound (b) 46.5%) was obtained. The NMR spectrum of the obtained compound completely matched that of the compound obtained in Example 1 (5). The obtained compound showed an optical rotation of (-), and the optical purity was 99%.
It was ee or more (by liquid chromatography).

Embodiment 13:Optically active 7-substituted compound
(Enzymatic method) (1) Compound (VI) [R] obtained in Example 1 (2)
^Two= CH_Three, R^Three= H] using 15.54 g
According to the method described in Example 11 (7) and (8),
6- (2-acetoxypropyl) -7- which is a white solid
tert-butylamino-3-cyano-5-methylpyra
Zolo [1,5-a] pyrimidine [(VIII)¹=
C (CH_Three)_Three, R^Two= CH_Three, R^Three= H] 14.13 g
(Total yield 75.7% from compound (VI))
Obtained as a product. The NMR spectrum of the obtained compound is
This is completely the same as that obtained in Example 11 (8).
Was.

(2) Candida lugoza (Candid)
a Rugosa) (500 mg, Lipase AY-30) (manufactured by Amano Pharmaceutical Co., Ltd.) is dissolved in 1 ml of water. Celite (No. 535, Johns-Manv) was added to this solution.
1.3 g) were added thereto, and the mixture was stirred until the suspension became homogeneous to obtain a lipase solution. Next, 100 mg of the compound obtained in the above (1), the lipase solution obtained above, 7 ml of isopropyl ether, 3 ml of toluene and 0.1 ml of n-butanol are mixed and shaken at 37 to 40 ° C. for 4 days. Celite was collected by filtration from the reaction solution,
Wash with 0 ml. The washings were combined with the filtrate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: n-hexane-ethyl acetate) to give 6-[(2R) -2-acetoxypropyl as pale yellowish white crystals. ) -7
-Tert-butylamino-3-cyano-5-methylpyrazolo [1,5-a] pyrimidine [(VIIIa)
^{_{1 = C (CH 3) 3}} , R 2 = CH 3, R 3 = H ] 46.1m
g (46.1% yield) and 6-[(2
S) -2-Hydroxypropyl) -7-tert-butylamino-3-cyano-5-methylpyrazolo [1,5-
a] pyrimidine [(IXa) wherein R ¹ ＣC (CH ₃ ) ₃ ,
^{R 2 = H, R 3 =} CH 3 ] 47.0 mg (yield: 53.9
%). The NMR spectrum of the obtained compound completely matched the one obtained in Example 11 (8) and (9), respectively.

(3) Compound (VIII) obtained in the above (2)
a) [R ¹ = C (CH ₃ ) ₃ , R ² = CH ₃ , R ³ = H]
Example 11 (9), (11) and (12)
According to the method described in (1), (7) of the present invention which is a colorless solid
S) -8-tert-Butyl-3-cyano-6,7-dihydro-5,7-dimethyl-8H-pyrrolo [3,2-
e] pyrazolo [1,5-a] pyrimidine [(I-1a)
Where R ¹ ＣC (CH ₃ ) ₃ , R ² ＨH, R ³ ＣＨCH ₃ ]
Was obtained (total yield 64.7% from compound (VIIIa)).
The NMR spectrum of the obtained compound was as described in Example 1 above.
This was completely consistent with that of the compound obtained in (5). In addition, the obtained compound showed optical rotation of (+), and its optical purity was 95% ee or more (by liquid chromatography).

(4) Compound (IX) obtained in the above (2)
a) [R ¹ = C (CH ₃ ) ₃ , R ² = H, R ³ = CH ₃ ]
And (7R) -8 of the present invention, which is a colorless solid, according to the method described in the above Examples 11 (11) and (12).
-Tert-butyl-3-cyano-6,7-dihydro-
5,7-dimethyl -8H- pyrrolo in [3,2-e] pyrazolo [1,5-a] pyrimidine [(I-1a) formula, R ¹
ＣC (CH ₃ ) ₃ , R ² ＣＨCH ₃ , R ³ ＨH] (total yield 74.6% from compound (IXa)). The NMR spectrum of the obtained compound completely matched that of the compound obtained in Example 1 (5). In addition, the obtained compound showed optical rotation of (-), and the optical purity was 95% ee.
This is the result (by the liquid chromatography method).

Example 14: 6-substituted compound (1) diethyl 2-acetyl-3-methylsuccinate [wherein R ⁴ = CH ₃ , R ⁵ = H, R ⁶ = R ⁷ = C
H ₂ CH _3] 69g was dissolved in acetic acid 150 ml, 7 by the addition of 3-amino-4-cyano pyrazole (III) 64.8 g
Heat to reflux for hours. After returning the reaction solution to room temperature, water 80
Add to 0 ml and extract with chloroform. Extract Mg
After drying over SO ₄ and evaporating the solvent under reduced pressure, the residue obtained was subjected to silica gel column chromatography (elution solvent: ethanol-chloroform) to crystallize from a mixed solution of n-hexane-ethyl acetate. Melting point 114-11
Ethyl 2- [3-cyano-
5-methyl-7 (4H) -oxopyrazolo [1,5-
a] Pyrimidin-6-yl] propionate [wherein R ⁴ = CH ₃ , R ⁵ = H, R ⁶ = CH ₂ CH ₃ ] 38.8
1 g (47.2% yield) was obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.24 (3H, t, J = 7.0 Hz), 1.
52 (3H, d, J = 7.6Hz), 2.51 (3H, s), 3.90 (1H, q, J = 7.6Hz),
4.18 (2H, m), 8.00 (1H, s), 12.22-12.26 (1H, m).

(2) Compound (XI) obtained in the above (1)
_{^{[R 4 = CH 3, R 5}} = H, R 6 = CH 2 CH 3 ] 38.81
g of phosphorus oxychloride 130 ml and triethylamine 13
Add ml and heat to reflux for 6 hours with stirring. The reaction solution was returned to room temperature, and phosphorus oxychloride was distilled off.
Pour into 200 ml. The aqueous solution is made alkaline with powdered sodium hydrogen carbonate and extracted with chloroform. The extract was dried over MgSO ₄ and the solvent was distilled off under reduced pressure. The residue obtained was subjected to silica gel column chromatography (elution solvent: methanol-chloroform and n-hexane-ethyl acetate) to give a pale yellow oil. Ethyl 2-
(7-chloro-3-cyano-5-methylpyrazolo [1,
5-a] pyrimidin-6-yl) propionate [(XI
I) wherein R ⁴ ＣＨCH ₃ , R ^{5 、} H, R ⁶ ＣＨCH ₂ CH ₃ , X
= Cl] 30.65 g (74.0% yield) was obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.24 (3H, t, J = 7.3 Hz), 1.
61 (3H, d, J = 7.3Hz), 2.70 (3H, s), 4.23 (2H, q, J = 7.3Hz),
4.27 (1H, q, J = 7.3Hz), 8.40 (1H, s).

(3) The compound (XI) obtained in the above (2)
I) [R ⁴ = CH ₃ , R ⁵ = H, R ⁶ = CH ₂ CH ₃ , X = C
l] 6.94 g, 4.34 g of tert-butylamine and 30 ml of isopropanol are mixed and heated under reflux for 8 hours. After returning the reaction solution to room temperature, the solvent is concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogen carbonate is added thereto. The obtained solution is extracted with chloroform, washed with saturated saline, dried over MgSO ₄ , and the solvent is distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: n-hexane-ethyl acetate) to give a melting point of 12
Ethyl 2- (7-te), a white crystal at 6 to 130 ° C.
rt-butylamino-3-cyano-5-methylpyrazolo [1,5-a] pyrimidin-6-yl) propionate [wherein R ¹ ＲC (CH ₃ ) ₃ , R ⁴ ＣＨCH ₃ , R ^Five
= H, R ⁶ ＣＨCH ₂ CH ₃ ] 3.77 g (48.3 yield)
%) And 8 as a pale yellow-white crystal having a melting point of 175 to 182 ° C.
-Tert-butyl-3-cyano-6,7-dihydro-
5,6-dimethyl-7-oxo-8H-pyrrolo [3,2
-E] pyrazolo [1,5-a] pyrimidine [(I-2)
Wherein R ¹ ＣC (CH ₃ ) ₃ , R ⁴ ＣＨCH ₃ , R ⁵ ＲH]
10 g (yield 31.3%) was obtained.

Compound (XIII) [R ¹ ＣC (CH ₃ ) ₃ , R ⁴
= CH ₃ , R ⁵ = H, R ⁶ = CH ₂ CH ₃ ] ¹ H-NMR (CDCl ₃ ) δ; 1.24 (3H, t, J = 7.3 Hz), 1.54 (3H, d, J = 7.
3Hz), 1.55 (9H, s), 2.60 (3H, s), 4.16-4.32 (3H, m), 5.98
(1H, brs), 8.17 (1H, s). Compound (I-2) [R ¹ ＣC (CH ₃ ) ₃ , R ⁴ ＣＨCH ₃ ,
R ⁵ = H] ¹ H-NMR (CDCl ₃ ) δ; 1.57 (3H, d, J = 7.3 Hz), 1.88 (9H, s), 2.6
1 (3H, s), 3.51 (1H, q, J = 7.3Hz), 8.32 (1H, s).

(4) The compound (XII) obtained in the above (3)
I) [R ¹ = C (CH ₃ ) ₃ , R ⁴ = CH ₃ , R ⁵ = H, R ⁶ =
[CH ₂ CH ₃ ] 3.77 g, KOH 1.29 g, methanol 30 ml and water 24.5 ml are mixed and stirred at room temperature for 2 hours. After acidifying the reaction solution with 1N hydrochloric acid, methanol is distilled off under reduced pressure. The pH of the resulting aqueous solution is adjusted to 6 to 7 by adding a saturated aqueous solution of sodium hydrogen carbonate, saturated with sodium chloride, and extracted with chloroform. Extract the MgSO
After drying in ₄ , the solvent is distilled off under reduced pressure and the residue obtained is dissolved in 40 ml of dioxane. 2.83 g of N, N'-dicyclohexylcarbodiimide was added to this solution while stirring under ice-cooling, and the mixture was returned to room temperature and stirred for 14 hours.
After completion of the reaction, the solvent of the filtrate obtained by distilling out the insoluble precipitate is distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (elution solvent: methanol-chloroform) to give 8-tert-butyl-3-cyano-6,7-dihydro-5,6-dimethyl-7-oxo-
8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine [(I-2) wherein R ¹ ＣC (CH ₃ ) ₃ , R ⁴ =
CH ₃ , R ⁵ = H] 1.45 g (44.7% yield). The melting point and NMR spectrum of the obtained compound completely matched those of the compound (I-2) obtained in the above (3).

(5) The compound (I-) obtained in the above (3)
2) [R¹= C (CH_Three)_Three, R^Four= CH _Three, R^Five= H] 3.
55 g are dissolved in 125 ml of methanol. The resulting solution
And 1.4 g of sodium borohydride while stirring under ice cooling.
Add 3g and at the same temperature for 15 minutes, return to room temperature for 1 hour
Stir. The reaction solution was cooled on ice again, and hydrogenated
Add sodium iodide 1.43g and at the same temperature for 15 minutes
During the reaction, the temperature is further returned to room temperature and stirred for 1 hour. After the reaction is complete,
The concentrated solution obtained by evaporating the solvent under reduced pressure
After adding an aqueous solution of lithium, the mixture is extracted with chloroform. Lottery
Discharge MgSO 4_FourAnd then the solvent is distilled off under reduced pressure.
The obtained residue is subjected to silica gel column chromatography.
(Elution solvent; n-hexane-ethyl acetate).
Recrystallized from ethanol to give a white powder with a melting point of 172-175 ° C.
7-tert-butylamino-3-cyano which is a color crystal
-6- (2-hydroxy-1-methylethyl) -5-me
Tylpyrazolo [1,5-a] pyrimidine [(XIV)
Medium, R¹= C (CH_Three)_Three, R^Four= CH_Three, R^Five= H] 1.5
8 g (43.9% yield) was obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.48 (3H, d, J = 7.3 Hz), 1.
57 (9H, s), 2.53 (3H, s), 3.31 (1H, broad), 3.47 (1H, m),
3.98 (1H, m), 4.05 (1H, m), 7.38 (1H, broad), 8.12 (1H, s).

(6) The compound (XI) obtained in the above (5)
V) [R ¹ = C (CH ₃ ) ₃ , R ⁴ = CH ₃ , R ⁵ = H]
58 g are dissolved in 50 ml of dichloromethane. 1.31 g of thionyl chloride was added to the resulting solution, and the mixture was stirred at room temperature for 1 hour 30 hours.
Stir for a minute. To this solution is added 20 ml of a 20% aqueous sodium hydroxide solution, and the mixture is stirred at room temperature for 2 hours. After completion of the reaction, the extract obtained by separating the organic layer is dried over MgSO ₄ and the solvent is distilled off under reduced pressure. The resulting residue is recrystallized from isopropyl alcohol to give 8-tert-butyl-3-cyano-6,7-dihydro-5,6-dimethyl-8H-pyrrolo of the present invention as white crystals having a melting point of 225 to 228 ° C. [3,2-e] pyrazolo [1,5-a] pyrimidine [(I-3) wherein R ¹ ＣC (CH ₃ ) ₃ , R ⁴ ＣＨCH ₃ ,
To give R ⁵ = H] 1.2g of (81.0% yield).

¹ H-NMR (CDCl ₃ ) δ; 1.26 (3H, d, J = 7.0 Hz), 1.
70 (9H, s), 2.44 (3H, s), 3.30 (1H, m), 3.64 (1H, dd, J = 10.0,
3.2Hz), 4.08 (1H, t, J = 10.0Hz), 8.14 (1H, s).

Example 15: 7-oxo compound (1) diethyl 2-acetylsuccinate [wherein R ⁴ = R ⁵ = H, R ⁶ = R ⁷ = CH ₂ CH ₃ ] 43.28
g was dissolved in 100 ml of acetic acid, 26 g of 3-amino-4-cyanopyrazole (III) was added, and the mixture was refluxed for 8 hours.
After returning the reaction solution to room temperature, it is poured into 500 ml of ice water and extracted with chloroform. The extract is dried over MgSO ₄ ,
The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (elution solvent: ethanol-chloroform) to obtain ethyl [3-cyano-5-5-yellow-brown crystals having a melting point of 216 to 219 ° C. Methyl-7 (4H)
-Oxopyrazolo [1,5-a] pyrimidin-6-yl] acetate (wherein R ⁴ = R ⁵ = H, R ⁶ = C
H ₂ CH ₃ ] (24.21 g, yield 46.5%).

¹ H-NMR (CDCl ₃ ) δ; 1.28 (3H, t, J = 7.0 Hz), 2.
48 (3H, s), 3.68 (2H, s), 4.19 (2H, q, J = 7.0Hz), 8.01 (1H,
s), 12.04 (1H, s).

(2) Ethyl obtained in the above (1) [3
-Cyano-5-methyl-7 (4H) -oxopyrazolo [1,5-a] pyrimidin-6-yl] acetate (X
I) 85 ml of phosphorus oxychloride was added to 24.1 g of [R ⁴ = R ⁵ = H, R ⁶ = CH ₂ CH ₃ ], and the mixture was refluxed for 4 hours while stirring. The reaction solution is returned to room temperature and poured into 1200 ml of ice water. The aqueous solution is made alkaline with powdered sodium carbonate and extracted with chloroform. The extract was washed with saturated saline, dried over MgSO ₄ , and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: ethanol-chloroform) to give a residue having a melting point of 106-106. Ethyl [108]
-Chloro-3-cyano-5-methylpyrazolo [1,5-
a] pyrimidin-6-yl] acetate (wherein R ⁴ ＲR ^{5 、} H, R ⁶ ＣＨCH ₂ CH ₃ , X ＝ Cl) 2
0.73 g (80.3% yield) was obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, t, J = 7.0 Hz), 2.
72 (3H, s), 3.95 (2H, s), 4.24 (2H, q, J = 7.0Hz), 8.40 (1H,
s).

(3) The ethyl [7] obtained in the above (2)
-Chloro-3-cyano-5-methylpyrazolo [1,5-
a] Pyrimidin-6-yl] acetate (XII) [R ^{4
= R 5 = H, R 6} = CH 2 CH 3, X = Cl ] 20.6
g, 13.53 g of tert-butylamine and 80 ml of isopropanol, and the mixture is refluxed for 5 hours. After returning the reaction solution to room temperature, the solvent is concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogen carbonate is added thereto. After the obtained solution is extracted with chloroform and dried over MgSO ₄ , the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: ethanol-chloroform) to give ethyl [7-tert-butylamino-3-cyano-] as white crystals having a melting point of 150 to 153 ° C.
5-methylpyrazolo [1,5-a] -pyrimidine-6
Yl] acetate [(XIII) wherein R ¹ = C (C
^{_{H 3) 3, R 4 =}} R 5 = H, R 6 = CH 2 CH 3 ] 22.12
g (95.2% yield).

¹ H-NMR (CDCl ₃ ) δ; 1.32 (3H, t, J = 7.0 Hz), 1.
52 (9H, s), 2.66 (3H, s), 3.76 (2H, s), 4.21 (2H, q, J = 7.0H
z), 5.85 (1H, brs), 8.20 (1H, s).

(4) The ethyl [7] obtained in the above (3)
-Tert- butyl-amino-3-cyano-5-methylpyrazolo [1,5-a] pyrimidin-6-yl] acetate (XIII) _{^{[R 1 = C (CH 3)}} 3, R 4 = R 5 = H, R
⁶ ＣＨCH ₂ CH ₃ ] 10.0 g, potassium hydroxide 3.53
g, 100 ml of tetrahydrofuran and 70 ml of water, and stirred at room temperature for 14 hours. After acidifying the reaction solution with 1N hydrochloric acid, tetrahydrofuran is distilled off under reduced pressure. A saturated aqueous solution of sodium hydrogen carbonate was added to the aqueous solution obtained.
The pH is adjusted to 6-7, saturated with sodium chloride, and extracted with chloroform. After the extract is dried over MgSO ₄ , the solvent is distilled off under reduced pressure, and the residue obtained is dissolved in 140 ml of dioxane. To this solution, 6.98 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added while stirring under ice-cooling, and the mixture was returned to room temperature and stirred for 3 hours. The reaction solution is poured into 400 ml of water and extracted with chloroform. After drying the extract over MgSO ₄ , the solvent is distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane-ethyl acetate).
And 8-tert-butyl-3-cyano-6,7-dihydro-5-methyl-7-oxo-8 as white crystals
H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine [(I-2) wherein R ¹ ＣC (CH ₃ ) ₃ , R ⁴ ＲR
⁵ = H] 3.98 g (43.7% yield).

¹ H-NMR (CDCl ₃ ) δ; 1.90 (9H, s), 2.56 (3H,
s), 3.62 (2H, s), 8.32 (1H, s).

Example 16: Optically active 6-substituted compound (1) Compound (XI) obtained in Example 14 (1)
_{^{[R 4 = CH 3, R 5}} = H, R 6 = CH 2 CH 3 ] 1.1
g of methanol (6 ml), tetrahydrofuran (6 ml) and 10% aqueous potassium hydroxide solution (9 ml) were added, and the mixture was heated and stirred at 70 ° C. for 2 hours. The pH of the reaction solution is adjusted to acidic by adding 4N hydrochloric acid, and the precipitated crystals are collected by filtration. The obtained crystals are washed with water and tetrahydrofuran, and then dried under reduced pressure to give 2- [3-cyano-5-methyl-7 (4H) as white crystals.
-Oxopyrazolo [1,5-a] pyrimidin-6-yl] propionic acid [wherein R ⁴ = CH ₃ , R ⁵ =
To give R ⁶ = H] 0.78g of (79.2% yield).

¹ H-NMR (DMSO-d ₆ ) δ; 1.29 (3H, d, J = 7.2 Hz),
2.39 (3H, s), 3.76 (1H, q, J = 7.2Hz), 8.36 (1H, s), 12.12 (1
H, brs), 13.18 (1H, brs).

(2) Compound (XI) obtained in the above (1)
[R ⁴ = CH ₃ , R ⁵ = R ⁶ = H] 591 mg, hydrochloric acid 1-
460 mg of ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), triethylamine 20
2 mg and 25 mg of dimethylaminopyridine are dissolved in 15 ml of dichloromethane, and the mixture is stirred for 1 hour at room temperature in a stream of nitrogen gas. Further, 208 mg of (R)-(+)-methyl lactate is added to the reaction solution, and the mixture is stirred in a nitrogen gas stream at room temperature for 15 hours. Dichloromethane was added to the reaction solution for extraction, washed with water and dried over MgSO ₄ . The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (elution solvent: chloroform-methanol) to isolate the following two diastereoisomers.

(A) (1R) -1-methoxycarbonylethyl 2- [3-cyano-5-methyl-7 (4H)-
Oxopyrazolo [1,5-a] pyrimidin-6-yl]
Propionate; colorless oil ¹ H-NMR (CDCl ₃ ) δ; 1.46 (3H, d, J = 7.2 Hz), 1.50 (3H, d, J = 7.
2Hz), 2.50 (3H, s), 3.69 (3H, s), 4.14 (1H, q, J = 7.2Hz), 5.
13 (1H, q, J = 7.2Hz), 7.98 (1H, s).

(B) (1R) -1-methoxycarbonylethyl 2- [3-cyano-5-methyl-7 (4H)-
Oxopyrazolo [1,5-a] pyrimidin-6-yl]
Propionate; colorless oil ¹ H-NMR (CDCl ₃ ) δ; 1.35 (3H, d, J = 7.2 Hz), 1.46 (3H, d, J = 7.
2Hz), 2.51 (3H, s), 3.72 (3H, s), 3.97 (1H, q, J = 7.2Hz), 5.
05 (1H, q, J = 7.2Hz), 8.00 (1H, s).

(3) Lithium aluminum hydride 114
silica gel in a solution of 3 mg of anhydrous tetrahydrofuran in 3 ml of anhydrous tetrahydrofuran.
Add 75 g and stir at room temperature for 1 hour in a stream of nitrogen gas
You. The compound obtained in the above (2) was added to this solution under ice cooling.
(B) Add 166 mg, 1 hour at 60 ° C in a nitrogen gas stream
Stir while heating. After cooling the reaction mixture with ice, a small amount of saturated
After adding an aqueous solution of monium, the silica gel in the reaction solution was filtered off.
Leave. The filtrate was washed with MgSO _FourAnd then remove the solvent under reduced pressure.
The residue obtained is distilled off and the resulting residue is purified by silica gel column chromatography.
Fee (eluent: chloroform-methanol)
And a colorless oil, 3-cyano-6- [2-hydroxy
C-1-methylethyl] -5-methylpyrazolo [1,5
-A] pyrimidine-7 (4H) -one [(IV-2a)
Medium, R^FourAnd R^Five= CH_ThreeAnd H] 98 mg (Yield 84.
4%) as an optically active substance.

¹ H-NMR (DMSO-d ₆ ) δ; 0.99 (3H, d, J = 6.2 Hz),
2.38 (3H, s), 3.51-3.56 (2H, m), 3.72-3.79 (1H, m), 4.48
(1H, brs), 8.31 (1H, s), 12.97 (1H, brs).

(4) The compound (IV-) obtained in the above (3)
2a) 98 mg of [R ⁴ and R ⁵ = CH ₃ and H], 322 mg of phosphorus oxychloride and 43 mg of triethylamine are mixed and heated with stirring at 120 ° C. for 3 hours in a nitrogen gas stream.
After returning the reaction solution to room temperature, it is poured into ice water, and potassium carbonate is added to the solution to make the pH alkaline. After extraction with chloroform and drying over MgSO ₄ , the residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluent: n-hexane-chloroform-ethyl acetate) to give white crystals. -Chloro-6-
[2-Chloro-1-methylethyl] -3-cyano-5
Methylpyrazolo [1,5-a] pyrimidine [(V-2
a) wherein R ⁴ and R ⁵ ＣＨCH ₃ and H, X = Cl] 8
1 mg (71.2% yield) was obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.56 (3H, d, J = 7.5 Hz), 2.
81 (3H, s), 3.74-3.92 (2H, m), 4.08-4.18 (1H, m), 8.38 (1
H, s).

(5) The compound (V-
2a) [wherein R ⁴ and R ⁵ = CH ₃ and H, X = Cl] 81
mg of anhydrous dimethylformamide (0.8 ml)
174 mg of t-butylamine and triethylamine
7 mg was added, and the mixture was heated and stirred at 90 ° C. for 2 hours in a nitrogen gas stream. After returning the reaction solution to room temperature, the solvent is distilled off under reduced pressure, and the obtained residue is dissolved in dichloromethane. The solution was washed with water, dried over MgSO ₄ , and the residue obtained by evaporating the solvent under reduced pressure was recrystallized from ethanol to give 8-tert-butyl-3-cyano-white crystals of the present invention as white crystals.
6,7-dihydro-5,6-dimethyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine [(I-3a) wherein R ¹ ＣC (CH ₃ ) ₃ , R ⁴ and R
⁵ = CH ₃ and H] (52 mg, yield 64.1%) as an optically active substance. The obtained compound showed the optical rotation of (-), and its optical purity was 81.7% ee or more (by liquid chromatography).

¹ H-NMR (CDCl ₃ ) δ; 1.25 (3H, d, J = 6.9 Hz), 1.
69 (9H, s), 2.43 (3H, s), 3.26-3.33 (1H, m), 3.63 (1H, dd, J
= 9.9,2.9Hz), 4.07 (1H, dd, J = 9.9,9.7Hz), 8.13 (1H, s).

(6) Compound (a) obtained in the above (2)
Using 166 mg, according to the method described in the above (3) to (5), 8-tert-butyl-3-cyano-6,7-dihydro-5,6-dimethyl-8H of the present invention as white crystals. -Pyrrolo [3,2-e] pyrazolo [1,5-a]
Pyrimidine [(I-3a) wherein R ¹ ＣC (CH ₃ ) ₃ ,
R ⁴ and R ⁵ = CH ₃ and H] 27.6 mg (total yield from compound (a) 21.6%) were obtained as an optically active substance. The NMR spectrum of the obtained compound is as described in (5) above.
Completely corresponded to the compound obtained in the above. The obtained compound showed optical rotation of (+), and the optical purity was 80.0% ee or more (by liquid chromatography).

Test Example 1 Spontaneously Hypertensive Rats of the Anesthetized Compound (I) (S
HR) was evaluated by the tail-cuff method. The following compounds of the present invention were used as test drugs. Compound 1: (±) 8-tert-butyl-3-cyano-
6,7-dihydro-5,7-dimethyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine, compound 2: (±) 3-cyano-6,7-dihydro-5
7-dimethyl-8- (1-methylethyl) -8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine, compound 3: (±) 8-tert-butyl-3-cyano-
6,7-dihydro-5,6-dimethyl-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine, compound 4: 8-tert-butyl-3-cyano-6,7
-Dihydro-5-methyl-7-oxo-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine, compound 5: (+) (7S) -8-tert-butyl-3
-Cyano-6,7-dihydro-5,7-dimethyl-8H
-Pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine, compound 6: (−) (7R) -8-tert-butyl-3
-Cyano-6,7-dihydro-5,7-dimethyl-8H
-Pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine

The compound (A) [R
a = C (CH ₃ ) ₃ ; see JP-A-2-275882]. Each of the test drug and the control compound was orally administered by suspending 5 mg / kg and 10 mg / kg in a 0.5% CMC physiological saline solution. The antihypertensive effect was expressed as a change in blood pressure after administration of the test drug expressed as a blood pressure reduction rate (%) with the normal blood pressure taken as 100%, and evaluated by determining the blood pressure reduction rate (%) at the time of the maximum response. In addition, the blood pressure reduction rate (%) at 5 hours and 8 hours after administration
The blood pressure curve was obtained by plotting the time-dependent changes of the blood pressure, and the duration of the blood pressure lowering action was evaluated from the area under the curve (hypertensive area).
The result is the maximum reaction pressure reduction rate (%) and the pressure reduction area,
The results are shown in Table 1 as relative values to the control compound (A).

[0161]

[Table 1]

As is clear from the above results, antihypertensive effects were observed for all of the compounds of the present invention 1 to 6.
In particular, Compounds 1, 3 and 5 exhibited almost the same antihypertensive rate and sustainability as the control compound (A).

Test Example 2 The antihypertensive action of the compound of the present invention in anaesthetized normotensive rats was evaluated by invasive measurement. Compounds 1 to 3 were used as test drugs and Compound (A) was used as a control compound.
The test drugs were 0.1 mg / kg and 0.5 mg / kg at 0.05
It was dissolved in a normal saline solution or PEG400-ethanol solution and administered through a cannula inserted into a femoral vein.
The antihypertensive effect was evaluated by connecting a cannula inserted into the femoral artery to a pressure transducer, measuring blood pressure, and comparing the antihypertensive rate (%) at the time of the maximum response obtained by the method described in Test Example 1 above. The results are shown in Table 2 as relative values to the control compound (A) at each dose.

[0164]

[Table 2]

As apparent from the above results, Compound 1
And 3 showed a blood pressure reduction rate (%) almost the same as that of the control compound (A) at the high concentration (0.5 mg / kg).

Test Example 3 The vasodilator effect of the compound of the present invention was measured by the Magnus method. That is, Wistar male rats (9 to 13 weeks of age) were killed by exsanguination, and the thoracic aorta was immediately removed. The extracted blood vessel was used as a ring specimen with a width of about 2 to 3 mm at 37 ° C.
Kre, which is aerated with mixed gas (O ₂ 95%, CO ₂ 5%)
A tension of 2 g was applied to an organ bath filled with 10 ml of the bs-Henseleit solution, and the tension was recorded isometrically. Compounds 1 to 6 were used as test drugs and compound (A) was used as a control compound. The test drug was potassium chloride 30
1 × 10 ⁻⁷ to 1 × 10
Cumulative administration of ^-5 M was performed and its dilating effect was examined. The results are shown in Table 3 at 50% inhibitory concentration.

[0167]

[Table 3]

Test Example 4 Inhibition of Norepinephrine Contraction by Compounds of the Invention
Was measured. That is, according to the method described in Test Example 3.
To prepare a specimen, and test drug 1 × 10 ^-7~ 1 × 10^-FiveTo M
Thus, norepinephrine 1 × 10^-9~
1 × 10^-7M range and 1 × 10^-9~ 1 × 10^-6M's
Cumulative administration was performed over a range. From the obtained concentration-response curve
The effect of suppressing vasoconstriction was examined. Compound as test drug
Compounds (A) were used as 1 to 6 and a control compound. Conclusion
The results are shown in Table 4 as the 50% inhibitory concentration of the maximum response.

[0169]

[Table 4]

Test Example 5 The effects of the compound of the present invention on blood pressure lowering and coronary blood flow in anesthetized dogs were measured. That is, beagle dogs (8-11k
g) with sodium pentobarbital (30 mg / kg)
After anesthesia was performed, a tracheal cannula was inserted and artificial respiration was performed with an artificial respirator. The chest was opened between the left fourth and fifth ribs, and the pericardium was incised to expose the heart. Approximately 1 cm from the bifurcation of the coronary vessel (left circumflex)
After detaching from the surrounding tissue, an ultrasonic blood flow meter probe was attached, and coronary blood flow was measured. In addition, heart rate and right femoral artery pressure were monitored. Compounds 1 to 3 and compound (A) were used as test drugs. Antihypertensive action and coronary blood flow increasing action
The maximum change rate (Δ%) after intravenous administration of the test drug at 100 μg / kg was calculated and evaluated, assuming that the values of the blood pressure and coronary blood flow at the time of no treatment were 100%. Table 5 shows the results.

[0171]

[Table 5]

Test Example 6 The antianginal effect of the compound of the present invention was measured by the following method. That is, the test drug was administered to Donryu rats,
Administer orally under anesthesia. After 45 minutes, 60 mg / kg of pentobarbital was intraperitoneally administered, and 15 minutes later, 0.75 U / kg of vasopressin was intravenously administered to measure the second lead electrocardiogram. Were compared. Compounds 1, 5, and 6 were used as test drugs. The results are shown in Table 6 as the 40% inhibitory concentration (IC ₄₀ ) of the drop value.

[0173]

[Table 6]

Test Example 7 The stability of the compound of the present invention against oxidation was evaluated. That is, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was used as an oxidizing agent, and the decomposition rate constant (K) of the test drug in a chloroform solution at 25 ° C. was determined and compared. . The concentration of DDQ in the solution is 0.0032
mol / l, and the concentration of the test drug was 0.0016 mol / l.
And Compound 1 was used as a test drug and compound (A) was used as a control compound. The results are shown in Table 7.

[0175]

[Table 7]

Test Example 8 (Toxicity) The acute toxicity test of the compound of the present invention was carried out by the following method. I
CR male mice were purchased at the age of 4 weeks, and preliminarily reared for about 10 days, and then subjected to experiments. The test drug was mouse weight 10
The suspension was suspended in a 1% methylcellulose solution to a volume of 0.1 ml per g, and administered orally by gavage using a metal gastric tube.
The mice were fasted for 16 hours from the day before the experiment. The observation period after the administration was 14 days, and the LD ₅₀ value was determined from the survival rate 14 days later by the Richfield Wilcoxon method. As a result, each of compounds 1 to 3 and 5 was 2 g.
/ Kg or more.

[0177]

Example 17 (Tablets) Composition: Compound 1 25 g Lactose 130 g Crystalline cellulose 20 g Corn starch 20 g 3% hydroxypropylcellulose aqueous solution 100 ml Magnesium stearate 2 g

Production method: Compound 1 was sieved with lactose, crystalline cellulose and corn starch through a 60 mesh sieve.
After being uniformly mixed, the mixture was put into a kneading machine, and a 3% aqueous solution of hydroxypropylcellulose was poured to knead. Then 1
The mixture was sieved and granulated with a 6-mesh sieve, and dried by blowing at 50 ° C. After drying, sieving through 16 mesh sieve,
Mix magnesium stearate and use a tableting machine with a diameter of 8m
m, tablets weighing 200 mg.

[0179]

Example 18 (Capsule) Composition: Compound 1 25 g Lactose 125 g Corn starch 48.5 g Magnesium stearate 1.5 g

Production method: The above-mentioned components were finely powdered, sufficiently stirred to form a uniform mixture, and then 0.2 g of each was filled into gelatin capsules to obtain capsules for oral administration.

[0181]

Example 19 (tablets) Composition: Compound 5 25 g Lactose 130 g Crystalline cellulose 20 g Corn starch 20 g 3% hydroxypropylcellulose aqueous solution 100 ml Magnesium stearate 2 g

Production method: Compound 5 was sieved with lactose, crystalline cellulose and corn starch through a 60-mesh sieve.
After being uniformly mixed, the mixture was put into a kneading machine, and a 3% aqueous solution of hydroxypropylcellulose was poured to knead. Then 1
The mixture was sieved and granulated with a 6-mesh sieve, and dried by blowing at 50 ° C. After drying, sieving through 16 mesh sieve,
Mix magnesium stearate and use a tableting machine with a diameter of 8m
m, tablets weighing 200 mg.

[0183]

The compound (I) of the present invention has excellent vasodilatory action, coronary blood flow increasing action, antihyperlipidemic action, platelet aggregation inhibitory action, antihypertensive action, Ca ⁺⁺ antagonistic action, etc. It is also highly safe and useful as a therapeutic agent for cardiovascular diseases.
In addition, since the compound (I) of the present invention has a long lasting effect,
The therapeutic agent for a circulatory system disease of the present invention containing the same is useful for preventing ischemic heart diseases such as angina pectoris, myocardial infarction and other diseases associated with circulatory failure including the brain, hypertension, arteriosclerosis, thrombosis and the like And it is useful as a therapeutic agent.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 9/08 A61P 9/08 9/12 9/12 (72) Inventor Yoshiaki Motoki 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture La Kasei Kogyo Co., Ltd. (72) Inventor Kenichi Kishii 560 Kashio-cho, Totsuka-ku, Yokohama, Kanagawa Prefecture Pola Kasei Kogyo Co., Ltd. In the Pharmaceutical Research Laboratories of POLA KASEI KOGYO CO., LTD. (72) Inventor Ichiro Matsuo 1-25-5 Higashi Tamagawa Gakuen, Machida City, Tokyo (72) Inventor High Kuwa ▼ Takako 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Inside the Pharmaceutical Research Laboratory (72) Inventor Yunosuke Nagase 3-2-7 Nishi Oizumi, Nerima-ku, Tokyo (72) Inventor Toshio Kumagai Saitama (72) Inventor Hiroshi Matsunaga 3-3-3-307 Niiza, Niiza City, Saitama Prefecture (72) Inventor Hisashi Shimizu 1-17-33-202 (Niiza City, Niiza City, Saitama Prefecture) 72) Inventor Souichi Kaneda 2-26-7-202 Minamiurawa, Urawa-shi, Saitama (56) References JP-A-2-275882 (JP, A) JP-A-5-262774 (JP, A) JP-A 4-307543 (JP, A) JP-A-2-76880 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 487/00-487/22 A61K 31/505 A61P 3 / 00-3/14 A61P 7/02 A61P 9/00-9/14 MEDLINE (STN) WPI (DIALOG) REGISTRY (STN) CA (STN) CAOLD (STN)

Claims (2)

(57) [Claims] 1. The following general formula (I): (Wherein R ¹ is a hydrogen atom; from a hydroxyl group, an alkoxy group, an alkenyloxy group, a nitro group, a primary, secondary or tertiary amino group, a carboxyl group, a cycloalkyl group, a phenyl group, a halogen atom and a heterocyclic group) A straight-chain or branched-chain alkyl group, alkenyl group or alkynyl group optionally having a substituent; or a hydroxyl group, an alkoxy group, an alkenyloxy group, a nitro group, a primary, secondary or tertiary amino group, a carboxyl group , Cycloalkyl group,
A phenyl group and a cycloalkyl group which may have a substituent selected from a halogen atom, a phenyl group or a heterocyclic group, wherein R ² , R ³ , R ⁴ and R ⁵ may be the same or different, Hydrogen atom; halogen atom; a substituent selected from a hydroxyl group, an alkoxy group, an alkenyloxy group, a nitro group, a primary, secondary or tertiary amino group, a carboxyl group, a cycloalkyl group, a phenyl group, a halogen atom and a heterocyclic group Or a cyano group, or R ² and R ³ or / and R ⁴ and R ⁵ together represent an oxygen atom. Where R ² ,
Pyrrolo [3,2-e] pyrazolo [1, except that all of R ³ , R ⁴ and R ⁵ are hydrogen atoms).
5-a] Pyrimidine derivatives or salts thereof. 2. The pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine derivative or a salt thereof according to claim 1, which is optically active.