JPH07242670A - Pyrrolo(3,2-e)pyrazolo(1,5-a)pyrimidine derivative and circulatory disease-treating agent using the same - Google Patents

Abstract

PURPOSE:To obtain a novel pyrimidine derivative which is useful as a therapeutic agent for cardio-vascular diseases because it has high vasodilation, hypotension, antilipemic action and platelet aggregation inhibition with durable effectiveness and high safety in reduced costs. CONSTITUTION:This compound is expressed by formula I [R is COOR<1>, NR<1>R<2> (R<1>, R<2> are H, a lower alkyl), cyano, halogen] or its salt, for example, ethyl 8-tert.-butyl-3-cyano-6,7-dihydro-8H-pyrrolo[3,2-e]pyrazolo-[1,5-a]pyr imidine-5- carboxylate. The compound is obtained, for example, by reaction of gamma- butyrolactone to react with a lower alkyl oxalate, reaction of the product, the compound of formula II (R' is a lower alkyl), with 3-amino-4-cyano-pyrazole, ring closure reaction, chlorination of the product of formula III followed by reaction of the chloride with tert.-butylamine.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel pyrrolo [3,2-e] pyrazolo [1,5-a] having excellent vasodilatory action, antihypertensive action, antihyperlipidemic action and platelet aggregation inhibitory action.
The present invention relates to a pyrimidine derivative or a salt thereof, and a therapeutic agent for cardiovascular disease containing the same as an active ingredient.

[0002]

2. Description of the Related Art It is a well-known fact that, with the aging of the population of Japan, the cause of death is increased cardiovascular diseases and accounts for a large proportion together with malignant tumors. As a cardiovascular disease therapeutic drug, lowering blood pressure by vasodilation and improving blood flow is an extremely effective method, and suppressing platelet aggregation is a powerful means for preventing the occurrence of arterial thrombosis. Is. In addition, compounds having a Ca ⁺⁺ blocker action often have an antiarrhythmic action, and these diseases are interrelated. Therefore, there is a demand for the development of a comprehensively effective drug against these cardiovascular diseases.

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

[0004]

[Chemical 2]

It has been found that the pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine derivative represented by ## STR1 ## has an excellent therapeutic effect on cardiovascular diseases, and a patent application has been filed (JP-A-2-275882). Gazette). However,
Although this compound (A) exhibits an excellent effect in vitro, it has a drawback that the pyrroline ring portion is easily subjected to oxidative metabolism in vivo to cause inactivation, and the effect is not sustained.

Next, the present inventors have made the following general formula (B):

[0007]

[Chemical 3]

It has been found that the compound represented by the formula (1) is less likely to be inactivated in vivo and has a good drug effect, and it is expected that it will be a drug that overcomes the drawbacks of the compound of the formula (A). (Japanese Patent Application Laid-Open No. 5-255377).

However, the compound of the above formula (B) has various stereoisomers because a substituent such as an alkyl group is introduced to avoid oxidative metabolism to the pyrroline ring portion. Therefore, when the compound of the formula (B) is commercialized as a drug, it is necessary to separate these stereoisomers, which causes a problem of high manufacturing cost.

[0010]

DISCLOSURE OF THE INVENTION As described above, while a compound having an excellent pharmacological activity on the circulatory system has been found, in vivo inactivation and production cost become problems,
The reality is that no compound that can be actually commercialized as an excellent therapeutic agent for cardiovascular diseases has been obtained.

[0011]

Means for Solving the Problems As a result of intensive studies in view of the above circumstances, the present inventors have found that the compound represented by the general formula (I) described below has excellent pharmacological activity on the circulatory system. The present invention has been completed by confirming that the drug efficacy is long-lasting and that the production cost can be kept low because stereoisomers are not produced in the production process.

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

[0013]

[Chemical 4]

In the formula, R is the following substituents: (i) COOR ¹ (ii) CONR ¹ R ² (iii) cyano group (iv) NR ¹ R ² (v) CH ₂ R ³ (vi) halogen atom ( Wherein R ¹ and R ² are each independently a hydrogen atom or a lower alkyl group, and R ³ is a benzyloxy group, a hydroxy group or a pyridinium group). e] A pyrazolo [1,5-a] pyrimidine derivative or a salt thereof, and a therapeutic agent for cardiovascular disease containing these compounds as active ingredients.

The compound provided by the present invention is capable of overcoming each of the problems of the compounds represented by the above formulas (A) and (B) in terms of sustained drug efficacy and production cost, and has excellent circulation. It is expected that it will be commercialized as a therapeutic agent for organ diseases. Hereinafter, the compound of the present invention will be described in more detail. In the present specification, the term "lower" means that the group or compound to which the term is attached has 1 to 7 carbon atoms,
It preferably means 1 to 4.

The "halogen atom" is chlorine, fluorine, bromine, iodine or the like, preferably chlorine or fluorine.

The "lower alkyl group" may be linear or branched and is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.
-Butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl and the like, but preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Butyl and tert-butyl.

(1) The substituent R in the compound (I) of the present invention
The compound (Ii) in which is (i) COOR ¹ can be produced, for example, according to each step of the following reaction formula A.

[0019]

[Chemical 5]

(In the formula, R'represents a lower alkyl group.)

That is, step (a) comprises γ-butyrolactone (II) and a di-lower alkyl ester of oxalic acid (II
I) is a step of synthesizing the compound represented by the formula (IV). The reaction is carried out in an inert solvent such as diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, cyclohexane,
n-hexane, dichloromethane, chloroform, N, N
-In a suitable solvent such as dimethylformamide, acetonitrile, dimethylsulfoxide, methanol, ethanol, isopropanol, tert-butanol, for example trimethylamine, triethylamine, N, N-diisopropyl-N-ethylamine, pyridine, picoline, lutidine, N, In the presence of a base consisting of an organic base such as N-dimethylpyridine, sodium methoxide, sodium ethoxide, or a combination of a di (lower) alkylamine such as diisopropylamine and an alkyllithium such as n-butyllithium, It can be carried out by stirring the compound of II) and the compound of formula (III) at a relatively low temperature of about -78 to about 0 ° C for several tens of minutes to several hours.

By the above reaction, the compound of formula (IV) is obtained, and the reaction solution can be used as it is in the next step, but if necessary, the reaction solution is usually subjected to purification means such as filtration and decantation. , Extraction, washing, solvent evaporation,
The compound of formula (IV) can also be isolated and purified by subjecting it to column or thin layer chromatography, recrystallization, distillation, sublimation and the like.

The next step (b) is a step of reacting the compound of formula (IV) obtained in the above step with 3-amino-4-cyanopyrazole to obtain a compound of formula (V). The reaction is carried out in a solvent appropriately selected from the above, in the presence of a Lewis acid such as trifluoroborane / methanol complex, at about 0 ° C.
It can be carried out by stirring at a temperature around the boiling point of the solvent for about 1 to about 24 hours.

The compound of formula (V) obtained by the above reaction can be used in the next step as it is as a reaction solution, but if necessary, it can be isolated and purified by the above-mentioned usual purification means. .

The next step (c) is a step of ring-closing the compound of the formula (V) obtained in the above step to obtain the compound of the formula (VI). The reaction is carried out with about 0 compound of the formula (V) in the presence of the above-exemplified organic base such as triethylamine in the absence of solvent or a solvent appropriately selected from the above.
It can be carried out by stirring at a temperature of about ℃ to the boiling point of the solvent for about 1 to about 24 hours.

The compound of formula (VI) obtained by the above reaction can be used in the next step as it is as a reaction solution, but if necessary, it can be isolated and purified by the above-mentioned ordinary purification means. .

The next step (d) is a step of chlorinating the compound of formula (VI) obtained in the above step to obtain the compound of formula (VII). The reaction is carried out in the absence of a solvent or in a solvent appropriately selected from the above, in the presence of the organic base exemplified above, for example, triethylamine, with a compound of the formula (VI), for example, phosphorus pentachloride, thionyl chloride, phosphorus oxychloride and the like. It can be carried out by stirring the chlorinating agent at a relatively high temperature of about the boiling point of the solvent for about 30 minutes to about 5 hours. The above reaction is preferably carried out in a stream of an inert gas such as argon gas or nitrogen gas.

The compound of formula (VII) obtained by the above reaction can be used in the next step as it is as a reaction solution.
If necessary, it can be isolated and purified by the above-mentioned ordinary purification means.

In the next step (e), the compound of the formula (VII) obtained in the above step is reacted with tert-butylamine to give the compound of the formula (I-ia), that is, the compound of the formula (I) of the present invention. Is a step of obtaining a compound in which the substituent R of the compound is a carboxyl group esterified with a lower alkyl group. The reaction is carried out by stirring the compound of formula (VII) and tert-butylamine in a solvent appropriately selected from the above at a temperature of about 0 to about 100 ° C. for about 30 minutes to about 5 hours. be able to.

The compound of formula (VII) obtained by the above reaction can be used in the next step as it is as a reaction solution.
If necessary, it can be isolated and purified by the above-mentioned ordinary purification means.

The compound of formula (I-ia) obtained by the above reaction is optionally hydrolyzed in the following step (f) to give a substituent of the compound of formula (I) of the present invention. A compound (I-ib) in which R is a carboxyl group can be obtained.

The hydrolysis reaction of the compound of the formula (I-ia) in this step (f) is carried out under the general reaction conditions usually used for hydrolyzing the lower alkyl ester of carboxylic acid, such as alkaline or acidic. Can be implemented easily.

The compound of the above formula (I-ia) can be obtained by another method, that is, the compound of the formula (IV) obtained in the step (a).
It can also be produced by using the compound of as a raw material according to each step of the following reaction formula B.

[0034]

[Chemical 6]

(In the formula, R'is as defined above.)

That is, in the step (g), the compound of the formula (IV) is treated with 3-amino-in the same manner as in the step (b) of the reaction formula A.
In the step of reacting 4-cyanopyrazole, acetic acid is present in the reaction solvent and stirring is performed at a relatively high temperature to obtain the compound represented by the formula (VIII).

The compound (VIII) obtained in the above step is chlorinated in the next step (h) to be converted to the compound of the formula (IX). Such a chlorination reaction is
It can be carried out by the same method as described in the step (d) of the reaction formula A.

Step (i) is a step of introducing a tert-butylamino group into the compound (IX) obtained in the above step (h) to obtain a compound represented by the formula (X). The reaction can be carried out by the same method as described in the step (e) of the reaction formula A.

The step (j) is a step of ring-closing the compound (X) obtained in the above step (i) to obtain a compound (I-ia). The reaction is carried out at room temperature to about 80 ° C. in the presence of an inorganic metal such as an alkali metal such as lithium, sodium and potassium; an alkali metal hydride such as sodium hydride in a solvent appropriately selected from the above. It can be performed by stirring at a temperature of about 30 minutes to about 5 hours. (2) The substituent R in the compound (I) of the present invention is (ii) CON
The compound (I-ii) which is R ¹ R ² , the compound (I-iii) which is (iii) a cyano group, and the compound (I-iv) which is (iv) NR ¹ R ² are represented by the following reaction formulas, for example. It can be manufactured according to each step of C.

[0040]

[Chemical 7]

(In the formula, R ¹ and R ² are as defined above.)

That is, in the step (k), the carboxyl group of the compound represented by the formula (I-ib) obtained in the step (f) of the reaction formula A is activated and then reacted with an amine to give a compound of the formula of the present invention. This is a step of obtaining a compound represented by (I-ii). The reaction is carried out in a solvent appropriately selected from those exemplified above, preferably in the presence of an organic base such as triethylamine, a compound of the formula (I-ib) and a carboxylic acid activating reagent,
Chlorinating agents for carboxylic acids such as thionyl chloride, phosphoryl chloride, phosphorus pentachloride, oxalyl chloride;
Halogenated alkyl carbonate compounds such as ethyl chlorocarbonate, isobutyl chlorocarbonate and methyl chlorocarbonate; dicyclohexylcarbodiimide or 1-ethyl-3- (3 hydrochloride)
-Dimethylaminopropyl) carbodiimide and the like-
The reaction is carried out at a relatively low temperature of about 78 to about 0 ° C. for a few minutes to about 2 hours to obtain a reaction intermediate in which the carboxyl group of the compound of formula (I-ib) is activated, and then amines are added to this intermediate. In addition, it can be carried out by stirring at a temperature of about 0 to about 60 ° C. Examples of amines used in this reaction include ammonia, methylamine, diethylamine and the like.

The formula (Ii of the present invention obtained by the above reaction
A compound of the compound i) in which both of the substituents R ¹ and R ² are hydrogen atoms is further represented by the formula (I-iii) of the present invention by subjecting it to a dehydration reaction in the next step (l). It can be converted into a compound. The dehydration reaction is
By stirring the compound and a dehydrating agent such as phosphorus oxychloride at a relatively high temperature of about the boiling point of the solvent for about 30 minutes to about 2 hours in the absence of solvent or in a solvent appropriately selected from those defined above. It can be carried out.

On the other hand, as shown in step (m), the formula (I-
The compound of ib) can also be led to the compound of formula (I-iv) of the present invention. This step is performed in the presence of the organic base exemplified above, such as triethylamine, for example, t
stirring the compound of formula (I-ib) and diphenylphosphoric acid azide in ert-butanol for about 2 hours to about 1 day at a relatively high temperature around the boiling point of the solvent, and then hydrolyzing the resulting compound. Can be implemented by: By such a reaction, a compound in which the substituents R ¹ and R ² of the formula (I-iv) are hydrogen atoms can be obtained. If the resulting compound is further reacted with an alkyl halide, the mono or di-lower alkyl substitution can be easily carried out. The compound of formula (I-iv) can be obtained.

In addition, the formula (I-
A reaction intermediate in which the carboxyl group of the compound of ib) is activated is also used as a raw material, and this compound is also reacted with sodium azide to obtain the substituent R ^{1 of the} formula (I-iv).
And R ² is a hydrogen atom can be obtained (see Example 15 below).

(3) The substituent R in the compound (I) of the present invention
The compound (Iv) in which is (v) CH ₂ R ³ can be produced, for example, according to each step of the following reaction formula D.

[0047]

[Chemical 8]

(Wherein X ⁻ represents a salt-forming anion,
R'is as defined above. )

That is, step (n) is a step of reacting γ-butyrolactone (II) with a lower alkyl ester of benzyloxyacetic acid (XI) to synthesize a compound represented by the formula (XII). The reaction is a combination of an organic base exemplified above, for example, a di (lower) alkylamine such as diisopropylamine and an alkyllithium such as n-butyllithium, in a solvent appropriately selected from those exemplified above. In the presence of the compound of formula (II) and the compound of formula (XI) at a relatively low temperature of about -78 to about 0 ° C for several tens of minutes to several hours.

The compound of formula (XII) obtained by the above reaction can be used in the next step as it is as a reaction solution.
If necessary, it can be isolated and purified by the above-mentioned ordinary purification means.

The compound of the formula (XII) obtained in the above step is reacted in the following steps (o) to (r) according to the method performed in the steps (g) to (j) of the reaction formula B. Thereby, the compound represented by the formula (I-va) of the present invention in which the substituent R ³ is a benzyloxy group can be converted.

Then, in the step (s), the formula (I-
By debenzylating the compound of va), a compound of the formula (I-vb) of the present invention in which the substituent R ³ is a hydroxy group can be obtained. The reaction is carried out in a solvent that can be appropriately selected from those exemplified above in the presence of a mercapto compound such as ethylthiol and the compound of the formula (I-va) and a Lewis acid such as trifluoroborane ether complex in about 0 to about 0. About 2 hours at a temperature of about 60 ℃
It can be performed by stirring for about one week.

Furthermore, the formula (Iv
The compound of b) has the formula (Iv) of the present invention in which the substituent R ³ is a pyridinium group by first activating the hydroxy group in step (t) and then reacting with pyridine.
The compound represented by c) can be synthesized. Activation of the hydroxy group is carried out in a solvent appropriately selected from those exemplified above in the presence of an organic base such as triethylamine,
To the compound of the formula (I-vb), an activating reagent for a hydroxy group such as an organic sulfonyl halide such as methanesulfonyl chloride or 4-toluenesulfonyl chloride,
The reaction can be carried out at a relatively low temperature of about -20 ° C to room temperature for about 2 hours to about 2 days. The compound obtained by such a reaction can be used in the next step as it is in the reaction solution, but can be isolated and purified by the above-mentioned ordinary purification means, if necessary.

Then, pyridine is added to the compound in a solvent appropriately selected from the above-mentioned examples, and the mixture is stirred at a temperature of about 0 to about 60 ° C. for about 1 day to about 1 week. A compound of formula (I-vc) can be obtained.

The formula (Iv obtained by the above reaction)
The pyridinium compound of c) can be isolated as a salt with a salt-forming anion. Here, as the salt-forming anion, a halogen atom is removed from the activating reagent used to activate the hydroxy group. Suitable are anions of remote groups such as organic sulfonyl groups.

(4) The substituent R in the compound (I) of the present invention
The compound (I-vi) in which is a (vi) halogen atom can be produced, for example, according to each step of the following reaction formula E.

[0057]

[Chemical 9]

(In the formula, R ⁰ represents a hydroxy-protecting group, and Hal represents a halogen atom.)

That is, in step (u), the hydroxy group of ethyl bromohydrin (XVI) is protected to give a compound of formula (XVI
This is the step of obtaining the compound represented by I). Here, examples of the protective group for the hydroxy group include aliphatic or aromatic acyl groups such as acetyl and benzoyl; aralkyl groups such as benzyl and triphenylmethyl; benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyl. A substituted or unsubstituted benzyloxycarbonyl group such as oxycarbonyl; a substituted silyl group such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, phenylisopropyldimethylsilyl; and a tetrahydropyranyl group can be exemplified, but preferably , A triphenylmethyl group, a tert-butyldimethylsilyl group or a tetrahydropyranyl group is used.

The reaction is carried out with a compound of the formula (XVI), preferably in the presence of an organic base such as imidazole, in a solvent appropriately selected from those exemplified above, for example, triphenylmethyl chloride, tert-butyldimethylsilyl chloride. Can be carried out by adding a compound in which the groups exemplified as the above protecting groups are halogenated and stirring, or by adding dihydropyran in the presence of an organic acid such as tosylic acid and stirring. The reaction is completed by stirring at a temperature of about 0 to about 60 ° C. for several minutes to about 2 hours.

The reaction is preferably carried out in a stream of an inert gas such as nitrogen gas or helium gas.

Step (v) is a step of reacting the compound of formula (XVII) obtained in the above step with diethyl malonate to obtain the compound of formula (XVIII).
The reaction is carried out by adding the compound of formula (XVII) and diethyl malonate to the boiling point of the solvent in the presence of the organic base or inorganic base exemplified above, for example, a base such as sodium in a solvent appropriately selected from the above. 2 ~ under relatively high temperature
It can be performed by stirring for about 24 hours.

The compound of formula (XVIII) obtained by the above reaction can be used as it is in the reaction step in the next step, but if necessary, it can also be isolated and purified by the usual purification means described above. .

The next step (w) is a step of reacting the compound of formula (XVIII) obtained in the above step with 3-amino-4-cyanopyrazole to obtain the compound of formula (XIX). In the reaction, both compounds are stirred in a solvent appropriately selected from the above in the presence of a base such as sodium methoxide or sodium ethoxide at a relatively high temperature of about the boiling point of the solvent for about 2 hours to about 1 day. Can be done by

The reaction is preferably carried out in a stream of an inert gas such as nitrogen gas or helium gas.

The compound of formula (XIX) obtained by the above reaction can be used in the next step as it is as a reaction solution.
If necessary, it can be isolated and purified by the above-mentioned ordinary purification means.

The next step (x) is a step of halogenating the compound of the formula (XIX) obtained in the above step to obtain the compound of the formula (XX). The reaction is carried out without solvent or in a solvent appropriately selected from the above, preferably in the presence of the organic base exemplified above, for example, triethylamine,
It can be carried out by stirring the compound of the formula (XIX) and a halogenating agent such as phosphorus pentachloride, thionyl chloride or phosphorus oxychloride at a relatively high temperature of about the boiling point of the solvent for about 30 minutes to 5 hours. .

The compound of formula (XX) obtained by the above reaction can be used in the next step as it is as the reaction solution, but if necessary, it can be isolated and purified by the above-mentioned usual purification means. .

The next step (y) is a step of reacting the compound of formula (XX) obtained in the above step with tert-butylamine to obtain the compound of formula (I-vi) of the present invention. The reaction is carried out in a solvent appropriately selected from the above, preferably in the presence of the organic base exemplified above, for example, triethylamine, with the compound of the formula (XX) and tert.
-Butylamine can be carried out by stirring at a relatively high temperature around the boiling point of the solvent for about 30 minutes to 5 hours.

The reaction is preferably carried out in a stream of an inert gas such as nitrogen gas or helium gas.

When the substituent Hal of the compound of formula (XX) used as a raw material in the step (y) is a chlorine atom, the obtained compound is a halogen atom of the compound of formula (I-vi) is a chlorine atom. For the compound, a solvent that can be appropriately selected from the examples given above, or 3,
When cesium fluoride is reacted in the presence of tetraphenylphosphonium chloride in 4-dichlorotoluene, the compound of formula (I)
The compound of the present invention in which the substituent R is a fluorine atom can be obtained. Similarly, by reacting the compound with phosphorus tribromide in a suitable solvent, preferably dimethylformamide, a compound of the present invention in which the substituent R of the formula (I) is a bromine atom can be obtained. . Further, by reacting the bromine-substituted compound with, for example, potassium iodide / copper (I) iodide or potassium iodide / nickel catalyst,
It is also possible to obtain compounds of the invention in which the substituent R of formula (I) is an iodine atom.

The obtained compound can be isolated and purified by the above-mentioned usual purification means.

The compound of the present invention can be synthesized according to the above method, but the substituent R of the compound of the formula (I) is (i
v) NR ¹ R ² , or (v) when the substituent R ³ of CH ₂ R ³ is a pyridinium group, the compound is optionally treated with an organic acid or an inorganic acid It can also be an addition salt. Examples of the organic acid used here include lower fatty acids such as formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid and trichloroacetic acid; substituted or unsubstituted benzoic acid such as benzoic acid and p-nitrobenzoic acid; methanesulfone. Acids, (halo) lower alkyl sulfonic acids such as trifluoromethane sulfonic acid; benzene sulfonic acid, p-nitrobenzene sulfonic acid, p-bromobenzene sulfonic acid, toluene sulfonic acid, 2,4,6-triisopropylbenzene sulfonic acid, etc. A substituted or unsubstituted aryl sulfonic acid; organic phosphoric acid such as diphenyl phosphoric acid can be mentioned, and examples of the inorganic acid include hydrochloric acid,
Sulfuric acid, hydrobromic acid, hydroiodic acid, borofluoric acid,
Examples include perchloric acid and nitrous acid.

As described above, since the compound of the present invention does not have an asymmetric carbon atom in its structural formula, stereoisomers do not occur in the production process and mass production is possible at low cost. The excellent pharmacological effect of the compound of the present invention will be described later.

The therapeutic agent for cardiovascular disease of the present invention can be made into various dosage forms, for example, oral administration agents such as tablets, capsules, powders, troches and liquids. The above-mentioned 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, etc .; a binder such as carboxymethyl cellulose sodium, hydroxypropyl cellulose, etc .; crystalline cellulose, carboxymethyl cellulose calcium. Tablets, capsules, powders, granules, or troches by appropriately combining and formulating disintegrating agents such as; talc, lubricants such as magnesium stearate, and fluidity improving agents such as light anhydrous silicic acid. It can be manufactured. When such an orally administered agent is administered to humans, it is preferable to orally administer an effective amount thereof, for example, 10 to 100 mg per day in 1 to 3 divided doses, although it varies depending on age and symptoms.

Further, the therapeutic agent for cardiovascular disease of the present invention may be an injection. This formulation may be, for example, previously dispersed or solubilized in an aqueous carrier such as physiological saline with a surfactant or a dispersant, or alternatively, it may be dispersed or solubilized each time when necessary. It may be a crystal formulation for injection or a lyophilized formulation. In addition to the above-mentioned components, a pH adjuster and a stabilizer may be added to the above aqueous carrier as optional components. The administration route of such an injection is not particularly limited, and can be selected from intravenous administration, intraarterial administration, subcutaneous administration, intraperitoneal administration and the like depending on the condition and the characteristics of the patient. These administrations may be performed all at once or gradually by infusion or the like.

The results of the pharmacological test and toxicity test of the compound of the present invention will be described below.

[Pharmacological test] The antihypertensive effect of the compound (I) of the present invention in unanesthetized spontaneously hypertensive rats (SHR) was evaluated.
It was evaluated by the tail-cuff method. As the test drug, the compounds (21) and (22) produced in the Examples below are used.
And (30) were used. Further, the compound as a control compound (A) [Ra = C ( CH 3) 3; JP 2-27
No. 5882]. 5 mg / kg of each of the test drug and the control compound was suspended in 0.5% CMC physiological saline and orally administered to 4 rats per group. The antihypertensive effect is the change in blood pressure after drug administration to 100% of normal blood pressure.
The pressure reduction rate (%) was expressed as, and the pressure reduction rate (%) at the time of maximum reaction was determined and evaluated. In addition, the time course of the blood pressure reduction rate (%) at 3 hours, 5 hours and 8 hours after administration was plotted to obtain a blood pressure reduction rate curve, and the duration of the blood pressure reduction effect was evaluated from the area under this curve (hypotensive area). . The results are shown in Table 1.

[0079]

[Table 1]

As is clear from the above results, a hypotensive action was observed for all of the test drugs that were the compounds of the present invention, and the hypotensive rate and persistence were similar to those of the control compound (A).

Further, as a result of examining the vasodilatory effect of the compound of the present invention by the Magnus method, the inhibitory effect on the vasoconstriction by norepinephrine, the coronary vasodilatory effect, etc., it was found that it has a sustained effect.

[Toxicity test] An acute toxicity test of the compound of the present invention was conducted by the following method. ICR male mice were purchased at the age of 4 weeks, and subjected to an experiment after preliminary breeding for about 10 days. The test drug was suspended in 1% cell methylcellulose solution so as to be 0.1 ml per 10 g of mouse body weight, and was orally administered by force using a metal gastric tube. The mice were fasted for 16 hours from the day before the experiment. The observation period after administration was set to 14 days, and the LD ₅₀ value was determined from the survival rate 14 days later by the Richfield-Wilcoxon method. As a result, the LD ₅₀ values of the compounds (21), (22) and (30) were all 2 g / kg or more.

[0083]

EXAMPLES The present invention will be described in more detail below with reference to Examples and formulation examples of the compounds of the present invention, but it goes without saying that the present invention is not limited to these examples.

The abbreviations used in the following description are:
Each has the following meaning. Et: Ethyl Ph: Phenyl t-Bu: tert-Butyl Boc: t-Butoxycarbonyl Ms: Methanesulfonyl

Example 1

[0086]

[Chemical 10]

A solution of 7.6 ml of diisopropylamine in 50 ml of tetrahydrofuran was cooled to -78.degree. C., and 33.5 of a solution of n-butyllithium in n-hexane was added to this solution.
ml is added dropwise and stirred at the same temperature for 10 minutes. A solution of 3.87 g of γ-butyrolactone (1) in 30 ml of tetrahydrofuran was added dropwise to this solution at -78 ° C over 35 minutes, and then the mixture was stirred at the same temperature for 20 minutes. To this solution was added diethyl oxalate 6.9 g of tetrahydrofuran 1
Add 5 ml solution and stir at -78 ° C to -40 ° C for 2 hours. After the reaction is completed, adjust the pH of the reaction solution to 1-2 with 2N hydrochloric acid.
Adjust to, and extract with ethyl acetate. The obtained organic layer is washed successively with water and saturated saline and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate) to give the compound (2) as a colorless oil (8.13 g, yield: 80%). )Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.39 (t, J =
7.3 Hz, 3 H), 3.29 (t, J = 7.6 Hz,
2H), 4.37 (q, J = 7.3 Hz, 2H), 4.
50 (t, J = 7.6 Hz, 2H), 10.90 (s,
1H)

Example 2

[0089]

[Chemical 11]

3-amino-4-cyanopyrazole 570
In a solution of 5 mg of ethanol in 1 ml of the compound (2) obtained in Example 1 above and 0.2 ml of BF ₃ · methanol.
Is added and the mixture is stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluting solvent: chloroform-methanol) to give compound (3) as crystals in an amount of 890 mg (yield: 6
0.9%) was obtained. ¹ H-NMR (DMSO-d ⁶ ) δ: 1.15 (t, J
= 7.3 Hz, 3H), 2.84 (t, J = 7.3H
z, 2H), 4.12 (q, J = 7.3 Hz, 2H),
4.30 (t, J = 7.3 Hz, 2H), 8.46
(S, 1H), 9.23 (s, 1H), 13.33
(S, 1H)

Example 3

[0092]

[Chemical 12]

Compound (3) 89 obtained in Example 2 above
1 ml of dry triethylamine is added to 0 mg, and the mixture is stirred at room temperature for 24 hours. After completion of the reaction, triethylamine was distilled off under reduced pressure to obtain 890 mg of compound (4) (yield: quantitative). ¹ H-NMR (DMSO-d ⁶ ) δ: 1.08 (t, J
= 7.3 Hz, 3H), 3.03 (t, J = 7.6H
z, 2H), 4.18 (t, J = 7.6Hz, 2H),
4.42 (t, J = 7.3 Hz, 2H), 8.44
(S, 1H), 9.46 (s, 1H), 13.26
(S, 1H)

Example 4

[0095]

[Chemical 13]

Compound (4) 51 obtained in Example 3 above
15 ml of phosphorus oxychloride is added to 0 mg, and the mixture is stirred at 100 ° C. for 2 hours in a nitrogen gas stream. Next, 0.5 ml of triethylamine is added to the reaction solution, and the mixture is stirred at the same temperature for 30 minutes. The reaction solution is poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluting solvent: chloroform) to give 530 mg of compound (5) (yield: 91.7). %)Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.50 (t, J =
7.6 Hz, 3 H), 3.58 (t, J = 7.6 Hz,
2H), 3.86 (t, J = 7.6Hz, 2H), 4.
52 (q, J = 7.6 Hz, 2H), 8.60 (s, 1
H)

Example 5

[0098]

[Chemical 14]

Compound (5) 53 obtained in Example 4 above
2 ml of t-butylamine is added to a 10 ml solution of 9 mg of dimethylformamide, and the mixture is stirred at room temperature for 1 hour. The reaction solution is poured into ice water and the precipitated crystals are filtered and dried.
The crystals were subjected to silica gel column chromatography (eluting solvent: chloroform-methanol) to give ethyl 8-tert-butyl-3-cyano-6,7- of the present invention.
Dihydro-8H-pyrrolo [3,2-e] pyrazolo-
520 mg (yield: 99.0%) of [1,5-a] pyrimidine-5-carboxylate (6) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (t, J =
7.6Hz, 3H), 1.74 (s, 9H), 3.45
(T, J = 8.9 Hz, 2H), 4.12 (t, J =
8.9 Hz, 2 H), 4.44 (q, J = 7.6 Hz,
2H), 8.25 (s, 1H)

Example 6

[0101]

[Chemical 15]

Compound (2) 1.16 obtained in Example 1
g and 0.5 g of 3-amino-4-cyanopyrazole were dissolved in 20 ml of a mixed solution of toluene-acetic acid (1: 1),
To this solution, add 57 μl of BF ₃ · Et ₂ O and add 130 ° C.
Stir for 2.5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluting solvent: chloroform-methanol) to give compound (7) as a brown solid (446 mg, yield 3
0%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.37 (t, J
= 6.9 Hz, 3H), 1.96 (s, 3H), 2.9
8 (t, J = 6.6 Hz, 2H), 4.14 (t, J =
6.6 Hz, 2 H), 4.43 (q, J = 6.9 Hz,
2H), 8.44 (s, 1H)

Example 7

[0104]

[Chemical 16]

Compound (7) 436m obtained in Example 6
0.2 ml of triethylamine was added to 1.5 ml of a solution of g of phosphorus oxychloride under ice cooling, and the mixture was stirred at 120 ° C. for 1.5 hours. Ice water and potassium carbonate are added to the reaction solution, the solution is extracted with chloroform, and the obtained organic layer is washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate) to give the compound (8) as a brown solid, 233 mg (yield: 51
%)Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.48 (t, J =
7.3 Hz, 3H), 2.02 (s, 3H), 3.45
(T, J = 6.6 Hz, 2H), 4.37 (t, J =
6.6 Hz, 2 H), 4.53 (q, J = 7.3 Hz,
2H), 8.54 (s, 1H)

Example 8

[0107]

[Chemical 17]

Compound (8) 579 m obtained in Example 7
g in 5.7 ml of dimethylformamide, 0.26 ml of t-butylamine and 0.26 of triethylamine.
Add ml and stir at 90 ° C. for 2 hours. After the reaction,
The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate) to give compound (9) as a light brown solid.
8 mg (yield: 82%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (t, J =
7.3 Hz, 3H), 1.63 (s, 9H), 2.11.
(S, 3H), 3.05 (t, J = 7.3 Hz, 2
H), 4.26 (t, J = 7.3 Hz, 2H), 4.4
8 (q, J = 7.3 Hz, 2H), 6.21 (s, 1
H), 8.30 (s, 1H)

Example 9

[0110]

[Chemical 18]

Compound (9) 457m obtained in Example 8
Sodium hydride (52 mg) was added to dimethylformamide (10 ml) solution, and the mixture was stirred at 50 ° C. for 2 hours.
A saturated aqueous solution of ammonium chloride is added to the reaction solution, and the mixture is extracted with ethyl acetate. The obtained organic layer is washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate) to give ethyl 8-tert-butyl-3-cyano-6,7 of the present invention.
-Dihydro-8H-pyrrolo [3,2-e] pyrazolo-
294 mg (yield: 77%) of [1,5-a] pyrimidine-5-carboxylate (6) as a pale yellow powder.
Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (t, J =
7.3 Hz, 3H), 1.74 (s, 9H), 3.45
(T, J = 8.9 Hz, 2H), 4.12 (t, J =
8.9 Hz, 2H), 4.44 (q, J = 7.3 Hz,
2H), 8.26 (s, 1H)

Example 10

[0113]

[Chemical 19]

Compound (6) 638 m obtained in Example 9
g was dissolved in 34 ml of a mixed solution of tetrahydrofuran-ethanol (1: 1), 1N aqueous sodium hydroxide solution was added to this solution at 0 ° C, and the mixture was stirred at the same temperature for 2 hours.
The reaction solution is neutralized with 2N hydrochloric acid, the solvent is evaporated under reduced pressure, 2N hydrochloric acid is further added, and the mixture is extracted with ethyl acetate. The obtained organic layer is washed successively with ice water and saturated saline and then dried over magnesium sulfate. The solvent of the obtained solution was distilled off under reduced pressure to give 8-tert-butyl-3-cyano- of the present invention.
6,7-Dihydro-8H-pyrrolo [3,2-e] pyrazolo- [1,5-a] pyrimidine-5-carboxylic acid (1
0) was obtained as a pale yellow powder to obtain 560 mg (yield: 96%). ¹ H-NMR (CDCl ₃ ) δ: 1.77 (s, 9
H), 3.53 (t, J = 9.2 Hz, 2H), 4.2
1 (t, J = 9.2 Hz, 2H), 8.27 (s, 1
H)

Example 11

[0116]

[Chemical 20]

Compound (10) 66 obtained in Example 10
To a solution of mg in 1 ml of tetrahydrofuran is added 39 μl of triethylamine. To this solution, further add 0.25 ml of tetrahydrofuran containing 27 μl of ethyl chlorocarbonate to -3.
The mixture is added dropwise at 0 ° C. and stirred at the same temperature for 40 minutes. Then,
To this reaction solution is added 28% aqueous ammonia (0.23 ml), and the mixture is stirred at room temperature for 1 hour. The solvent of the reaction solution is evaporated under reduced pressure, 10% citric acid is further added, and the mixture is extracted with ethyl acetate. The obtained organic layer is washed with saturated saline and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent:
8-t of the present invention by subjecting it to chloroform-methanol).
ert-Butyl-3-cyano-6,7-dihydro-8H
-Pyrrolo [3,2-e] pyrazolo- [1,5-a] pyrimidine-5-carboxamide (11) was obtained as a pale yellow powder in an amount of 47 mg (yield: 71%). ¹ H-NMR (CDCl ₃ and CD ₃ OD) δ: 1.7
5 (s, 9H), 3.53 (t, J = 8.9Hz, 2
H), 4.14 (t, J = 8.9 Hz, 2H), 8.2
7 (s, 1H)

Example 12

[0119]

[Chemical 21]

Compound (11) 10 obtained in Example 11
5 ml of phosphorus oxysalt was added to 0 mg, and the mixture was heated under reflux for 1
Stir for hours. After completion of the reaction, the reaction solution is poured into water and extracted with chloroform. The obtained organic layer is dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n
-Hexane-ethyl acetate) to obtain 8-te of the present invention.
rt-butyl-3,5-dicyano-6,7-dihydro-
8H-pyrrolo [3,2-e] pyrazolo- [1,5-a]
70 mg (yield: 74.5%) of pyrimidine (12) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.76 (s, 9
H), 3.31 (t, J = 8.9 Hz, 2H), 4.2
3 (t, J = 8.9, 2H), 8.28 (s, 1H)

Example 13

[0122]

[Chemical formula 22]

Compound (10) 46 obtained in Example 10
To a solution of 7 mg of t-butanol in 9.3 ml was added 0.25 ml of triethylamine and 0.54 of diphenylphosphoric acid azide.
g and stirred at 90 ° C. for 21 hours. The organic layer obtained by extracting the reaction solution with chloroform is washed successively with a 5% aqueous citric acid solution and saturated aqueous sodium hydrogen carbonate, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate) to obtain 429 mg (yield: 74%) of compound (13) as a pale yellow solid. It was ¹ H-NMR (CDCl ₃ ) δ: 1.42 (s, 9
H), 1.62 (s, 9H), 3.08 (t, J = 9.
2Hz, 2H), 3.95 (t, J = 9.2Hz, 2
H), 8.05 (s, 1H)

Example 14

[0125]

[Chemical formula 23]

Compound (13) 40 obtained in Example 13
To a solution of 9 mg of dichloromethane in 1.8 ml of trifluoroacetic acid was added at 0 ° C., and the mixture was stirred at the same temperature for 21 hours. The solvent of the reaction solution was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluting solvent: chloroform-methanol) to give 5-amino-8-tert-butyl-3-cyano-6 of the present invention. , 7-Dihydro-8H-pyrrolo [3,2-e] pyrazolo- [1,5-
a] Pyrimidine trifluoroacetate salt (14) was obtained as a colorless powder (182 mg, yield: 43%). ¹ H-NMR (CDCl ₃ ) δ: 1.64 (s, 9
H), 2.82 (t, J = 9.2 Hz, 2H), 3.9
7 (t, J = 9.2 Hz, 2H), 5.88 (brs,
2H), 7.94 (s, 1H)

Example 15

[0128]

[Chemical formula 24]

Compound (10) obtained in Example 10 above
To a solution of 1.54 g of acetone in 6 ml of triethylamine 6
Then, a solution of 0.7 ml of ethyl chlorocarbonate in 1.5 ml of acetone is added to the solution under ice cooling, and the mixture is stirred at 0 ° C. for 30 minutes. Sodium azide 720 in the reaction solution
A 2 ml aqueous solution of mg is added dropwise and the mixture is stirred for another 30 minutes. The reaction solution is poured into ice water, and the precipitated crystals are collected by filtration.
After the obtained crystals are dried, the solution obtained by dissolving in 30 ml of toluene is heated under reflux for 1 hour. The crystals obtained by distilling off the solvent under reduced pressure were recrystallized from ethanol to give 5-amino-8-tert-butyl-3-cyano- of the present invention.
1.36 g of 6,7-dihydro-8H-pyrrolo [3,2-e] pyrazolo- [1,5-a] pyrimidine (14)
(Yield: 98.6%) was obtained. The NMR data of the obtained compound completely agreed with those obtained in Example 14 above.

Example 16

[0131]

[Chemical 25]

A solution of 4.1 ml of diisopropylamine in 32 ml of tetrahydrofuran was cooled to -78 ° C., and a solution of n-butyllithium in n-hexane (1.6
1M) (18.2 ml) was added dropwise and the mixture was stirred at the same temperature for 10 minutes. A solution of 2.09 g of γ-butyrolactone (1) in 21 ml of tetrahydrofuran was added dropwise to this solution at -78 ° C over 40 minutes, and then the mixture was stirred at the same temperature for 20 minutes. A solution of 5.26 g of methyl benzyloxyacetate in 10.5 ml of tetrahydrofuran is added to this solution, and the mixture is stirred at -60 ° C to -50 ° C for 2 hours. After the completion of the reaction, the temperature is returned to 0 ° C., the pH of the reaction solution is adjusted to 1-2 with 6N hydrochloric acid, and the mixture is extracted with ethyl acetate. The obtained organic layer is washed with saturated saline and then dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate) to give compound (15) as a colorless oil.
57 g (yield: 97.9%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.19 to 2.38
(M, 1H), 2.68 to 2.82 (m, 1H), 3.
91 (dd, J = 7.58, 9.56 Hz, 1H),
4.30 to 4.44 (m, 2H), 4.30 and 4.4
9 (ABq, J = 17.32 Hz, 2H), 4.60 and 4.65 (ABq, J = 11.55 Hz, 2H),
7.28-7.37 (m, 5H)

Example 17

[0134]

[Chemical formula 26]

Compound (15) obtained in Example 16
57 g and 3-amino-4-cyanopyrazole 2.83
g is dissolved in 13.1 ml of acetic acid, and heated and stirred at 95 ° C. for 20 hours. To this solution, 57 μl of BF ₃ · ether was added and stirred at 130 ° C. for 2.5 hours. After the reaction,
The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate, and chloroform-acetone) to give compound (16) as a brown paste-like solid. 64 g
(Yield 41.8%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.93 (s, 3
H), 2.83 (t, J = 6.6 Hz, 2H), 4.2
2 (t, J = 6.6 Hz, 2H), 4.67 (s, 2
H), 4.74 (s, 2H), 7.34 to 7.37.
(M, 5H), 8.00 (s, 1H), 9.86 (b
s, 1H)

Example 18

[0137]

[Chemical 27]

Compound (16) obtained in Example 16 1.
0 g and 1.27 ml of phosphorus oxychloride were dissolved in 4.76 ml of N, N-diisopropylethylamine, and the mixture was heated at 130 ° C.
And heat and stir for 1 hour. After completion of the reaction, the reaction solution is poured into ice water, potassium carbonate is added, and the mixture is extracted with chloroform. The obtained organic layer is applied to a short column (silica gel 10 g, elution solvent: chloroform), concentrated, ethyl acetate is added, and the mixture is washed with 1N hydrochloric acid. The solution was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give compound (1
546.7 mg as a brown solid of 7) (yield: 52%)
Obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.01 (s, 3
H), 3.37 (t, J = 6.6 Hz, 2H), 4.3
2 (t, J = 6.6 Hz, 2H), 4.67 (s, 2
H), 4.84 (s, 2H), 7.29 to 7.36.
(M, 5H), 8.43 (s, 1H)

Example 19

[0140]

[Chemical 28]

Compound (17) obtained in Example 18 1.
12 g, t-butylamine (1.6 ml) and triethylamine (0.42 ml) are dissolved in dimethylformamide (31 ml), and the mixture is heated with stirring at 90 ° C. for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate) to give compound (18) as a light brown solid.
2.1 mg (yield: 61.0%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.59 (s, 9
H), 2.09 (s, 3H), 3.07 (t, J = 7.
26Hz, 2H), 4.18 (t, J = 7.26Hz,
2H), 4.61 (s, 2H), 4.69 (s, 2
H), 5.90 (bs, 1H), 7.32 to 7.37.
(M, 5H), 8.24 (s, 1H)

Example 20

[0143]

[Chemical 29]

Compound (18) 82 obtained in Example 19
5 mg is dissolved in a mixed solvent of 15 ml of methanol and 5 ml of tetrahydrofuran, 847 mg of potassium carbonate is added, and the mixture is stirred at room temperature for 3 hours. After completion of the reaction, the solvent is distilled off under reduced pressure and the obtained residue is dissolved in ethyl acetate and washed with water and saturated saline. After drying over sodium sulfate, the solvent was evaporated under reduced pressure to obtain 0.74 g (yield: quantitative) of compound (19) as a pale white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.54 (s, 9
H), 2.96 (t, J = 5.28 Hz, 2H), 3.
96 (t, J = 5.28 Hz, 2H), 4.58 (s,
2H), 4.67 (s, 2H), 6.74 (bs, 1)
H), 7.31 to 7.35 (m, 5H), 8.21
(S, 1H)

Example 21

[0146]

[Chemical 30]

Compound (19) 3 obtained in Example 20
To a solution of 7.5 mg of chloroform in 1.0 ml, 0.01 ml of methanesulfonyl chloride with stirring at 0 ° C.
After that, 0.019 ml of triethylamine is gradually added dropwise. After completion of dropping, the mixture is stirred at the same temperature for 1 hour. After the reaction was completed, the solvent was concentrated and subjected to silica gel chromatography (developing solvent: n-hexane-ethyl acetate) to give the compound (20) as a pale yellowish white solid, 38.5 mg.
(Yield: 84.6%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.56 (s, 9
H), 2.85 (s, 3H), 3.23 (t, J = 6.
77Hz, 2H), 4.36 (t, J = 6.77Hz,
2H), 4.61 (s, 2H), 4.71 (s, 2
H), 5.60 (bs, 1H), 7.33 to 7.37.
(M, 5H), 8.24 (s, 1H)

Example 22

[0149]

[Chemical 31]

Compound (20) 89 obtained in Example 21
A solution of 8.3 mg and 0.28 ml of triethylamine in 25 ml of dimethylformamide is stirred at 90 ° C. for 3 hours. The residue obtained by evaporating the solvent from the reaction solution under reduced pressure was subjected to silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate) to give 5-benzyloxymethyl-8-tert-butyl- of the present invention. 3-cyano-
564.7 mg (yield: 79.8%) of 6,7-dihydro-8H-pyrrolo [3,2-e] pyrazolo- [1,5-a] pyrimidine (21) was obtained as a pale yellowish white solid. IR (cm ^-1 , KBr): 2225, 1620, 158
0 ¹ H-NMR (CDCl ₃ ) δ: 1.70 (s, 9
H), 3.14 (t, J = 9.24 Hz, 2H), 4.
02 (t, J = 9.24 Hz, 2H), 4.60 (s,
2H), 4.61 (s, 2H), 7.31 to 7.38.
(M, 5H), 8.17 (s, 1H)

Example 23

[0152]

[Chemical 32]

Compound (21) 99 obtained in Example 22
2.0 mg, BF ₃ .Et ₂ O (27 ml) and ethylthiol (5.6 ml) are dissolved in dichloromethane (16 ml), and the mixture is stirred at room temperature for 89 hours. After completion of the reaction, water and dichloromethane are added to this solution and the layers are separated to obtain an organic layer. on the other hand,
The separated aqueous layer is adjusted to be alkaline and further extracted with dichloromethane. The obtained organic layers are combined, washed with saturated saline and then dried over sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate, and chloroform-acetone) to give 8-tert of the present invention.
-Butyl-3-cyano-6,7-dihydro-5-hydroxymethyl-8H-pyrrolo [3,2-e] pyrazolo-
460.6 mg (yield: 61.8%) of [1,5-a] pyrimidine (22) was obtained as a pale yellowish white solid. IR (cm ^-1 ): 3410, 2205, 1605, 15
80 ¹ H-NMR (CDCl ₃ ) δ: 1.72 (s, 9
H), 2.99 (t, J = 9.24 Hz, 2H), 4.
10 (t, J = 9.24 Hz, 2H), 4.59 (s,
2H), 8.18 (s, 1H)

Example 24

[0155]

[Chemical 33]

Compound (22) 70 obtained in Example 23
To a solution of 6.3 mg of dichloromethane in 35 ml, under ice cooling,
After adding 026 ml of methanesulfonyl chloride while stirring, 0.47 ml of triethylamine was gradually added dropwise, and after the addition was completed, the mixture was stirred at 0 ° C. for another 25 hours. The reaction solution was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound (23) as a pale yellow-white solid crude product (yield: quantitative). ¹ H-NMR (CDCl ₃ ) δ: 1.72 (s, 9
H), 3.19 (t, J = 8.75 Hz, 2H), 3.
22 (s, 3H), 4.11 (t, J = 8.75Hz,
2H), 5.21 (s, 2H), 8.20 (s, 1H)

Example 25

[0158]

[Chemical 34]

Compound (23) 15 obtained in Example 24
0 mg and pyridine 0.35 ml in dichloromethane,
Stir at room temperature for 91.5 hours. After completion of the reaction, the precipitated insoluble material was collected by filtration, washed with dichloromethane and n-hexane, and dried to give 8-tert-butyl-3- of the present invention.
Cyano-6,7-dihydro-5-pyridiniummethyl-
8H-pyrrolo [3,2-e] pyrazolo- [1,5-a]
123.0 mg (yield: 66.9%) of pyrimidine mesylate (24) was obtained as a pale yellowish white solid. IR (cm ^-1 , KBr): 3060, 2210, 161
0, 1580 ¹ H-NMR (CD ₃ OD) δ: 1.75 (s, 9
H), 2.69 (s, 3H), 3.25 (t, J = 9.
24Hz, 2H), 4.28 (t, J = 9.24Hz,
2H), 5.89 (s, 2H), 8.16 to 8.22.
(M, 2H), 8.32 (s, 1H), 8.67-8.
73 (m, 1H), 9.03 to 9.06 (m, 2H)

Example 26

[0161]

[Chemical 35]

T-Butyldimethylsilyl chloride 1
5.05 g and 17.02 g of imidazole are dissolved in 200 ml of anhydrous acetonitrile and stirred at room temperature for 10 minutes in a nitrogen gas stream. 13.2 g of ethyl bromohydrin (25) is added to this solution, and the mixture is stirred at room temperature for 18 hours in a nitrogen gas stream. The solvent is distilled off from the reaction solution under reduced pressure, the resulting residue is dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid and water, and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluting solvent: n-hexane) to give Compound (26) as a colorless liquid.
75 g (yield: 74.2%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.08 (s, 6
H), 0.90 (s, 9H), 3.39 (t, J = 6.
6 Hz, 2 H), 3.89 (t, J = 6.6 Hz, 2
H)

Example 27

[0164]

[Chemical 36]

1.59 g of sodium was dissolved in 150 ml of absolute ethanol in a nitrogen gas stream at room temperature, and 9.6 g of diethyl malonate and 16.5 g of the compound (26) obtained in Example 26 were added to this solution. Then, the mixture is heated under reflux in a nitrogen gas stream for 16 hours. After completion of the reaction, the solvent is distilled off under reduced pressure, the obtained residue is dissolved in ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate),
15.1 g of compound (27) as a colorless liquid (yield: 7
9.1%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.03 (s, 6
H), 0.88 (s, 9H), 1.26 (t, J = 7.
0Hz, 6H), 2.07 to 2.14 (m, 2H),
3.58 (t, J = 7.2 Hz, 1H), 3.65
(T, J = 5.9 Hz, 2H), 4.13 to 4.24
(M, 4H)

Example 28

[0167]

[Chemical 37]

0.92 g of sodium was dissolved in 100 ml of absolute ethanol at room temperature in a nitrogen gas stream, and 6.36 g of the compound (27) obtained in Example 27 was dissolved in this solution.
And 2.16 g of 3-amino-4-cyanopyrazole are added, and the mixture is heated under reflux for 21 hours in a nitrogen gas stream. After completion of the reaction, the precipitate is collected by filtration, washed with ethanol and dried under reduced pressure. The obtained solid is dissolved in water, the pH is adjusted to 4 with 1N hydrochloric acid under ice cooling, and then salting out is performed with sodium chloride. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain 3.33 g (yield: 49.9%) of compound (28) as a pale red solid. ¹ H-NMR (DMSO-d ₆ ) δ: −0.04 (s,
6H), 0.84 (s, 9H), 2.59 to 2.71
(M, 2H), 3.53 (t, J = 6.4Hz, 2
H), 3.96 to 5.00 (m, 2H), 8.24
(S, 1H)

Example 29

[0170]

[Chemical 38]

Compound (28) obtained in Example 28.3.
To 34 g, 10.7 g of phosphorus oxychloride was added, and 1.01 g of triethylamine was added under ice cooling. 12 of this mixture
After heating and stirring at 0 ° C. for 2 hours, the temperature is returned to room temperature, and the mixture is poured into ice water. The pH of this aqueous solution is adjusted to be alkaline with potassium carbonate, extracted with chloroform, and the obtained organic layer is dried with potassium carbonate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate-chloroform) to give Compound (29) as white crystals (1.56 g, yield: 56). .6%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.51 (t, J =
6.9 Hz, 2 H), 3.86 (t, J = 6.9 Hz,
2H), 8.45 (s, 1H)

Example 30

[0173]

[Chemical Formula 39]

The compound (29) obtained in Example 29.
74 g was dissolved in anhydrous dimethylformamide, 0.197 g of t-butylamine and 0.545 g of triethylamine were added to this solution, and the mixture was stirred at 90 ° C. in a nitrogen gas stream for 2 hours.
Heat and stir for hours. After completion of the reaction, the reaction mixture is cooled to room temperature and the precipitated solid is collected by filtration, washed with ethanol and then dried under reduced pressure to give 8-tert-butyl-5-chloro-invention.
3-Cyano-6,7-dihydro-8H-pyrrolo [3,2
0.63 g (yield: 85.1%) of -e] pyrazolo- [1,5-a] pyrimidine (30) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.71 (s, 9
H), 3.10 (t, J = 9.2 Hz, 2H), 4.0
9 (t, J = 9.2 Hz, 2H), 8.16 (s, 1
H)

Example 31

[0176]

[Chemical 40]

Compound (30) 20 obtained in Example 30
0 mg was dissolved in 3 ml of 3,4-dichlorotoluene, and 219 mg of cesium fluoride and (C ₆ H
₅ ) ₄ P ⁺ Cl ⁻ 2.7 mg is added, and the mixture is heated with stirring at 200 ° C. for 24 hours in a nitrogen gas stream. After the reaction,
The solvent was distilled off from the solution obtained by filtering off the insoluble matter under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (elution solvent: n-hexane-ethyl acetate),
8-tert-Butyl-3-cyano-6,7- of the present invention
Dihydro-5-fluoro-8H-pyrrolo [3,2-e]
56.5 mg of pyrazolo- [1,5-a] pyrimidine (31) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.71 (s, 9
H), 3.06 (t, J = 9.4 Hz, 2H), 4.1
1 (t, J = 9.4 Hz, 2H), 8.15 (s, 1
H)

Formulation Example 1 (tablets) Composition: Compound (21) 25 g Lactose 130 g Crystalline cellulose 20 g Corn starch 20 g 3% Hydroxypropyl cellulose aqueous solution 100 ml Magnesium stearate 2 g Preparation method: Compound 21, lactose, crystalline cellulose The corn starch and corn starch were sifted through a 60-mesh sieve and mixed uniformly, and then added to a kneader to give 3% hydroxypropyl cellulose.
An aqueous solution was added and kneaded. Then, the mixture was sieve-granulated with a 16-mesh sieve and blow-dried at 50 ° C. 16 after drying
The particles were sized through a mesh sieve, mixed with magnesium stearate, and made into tablets having a diameter of 8 mm and a weight of 200 mg with a tableting machine.

Formulation Example 2 (capsule) Composition: Compound (22) 25 g Lactose 125 g Corn starch 48.5 g Magnesium stearate 1.5 g Manufacturing method: The above ingredients are finely pulverized and sufficiently stirred to form a uniform mixture. After that, 0.2 g of each was filled in a gelatin capsule to obtain a capsule for oral administration.

Formulation Example 3 (tablets) Composition: Compound (10) 25 g Lactose 130 g Crystalline cellulose 20 g Corn starch 20 g 3% Hydrococypropyl cellulose aqueous solution 100 ml Magnesium stearate 2 g Preparation method: Lactose and crystal on compound (10) Cellulose and corn starch were sifted through a 60-mesh sieve, mixed evenly, and then put in a kneader to add a 3% hydroxypropyl cellulose aqueous solution and knead. Then, the mixture was sieve-granulated with a 16-mesh sieve and blow-dried at 50 ° C. After drying
The particles are sized through a 16-mesh sieve, mixed with magnesium stearate, and then sized with a tablet machine to a diameter of 8 mm and a weight of 200.
made into tablets of mg.

[0181]

INDUSTRIAL APPLICABILITY The compound (I) of the present invention does not produce stereoisomers in the production process, so that there is no loss due to the separation operation of the isomers, and the production cost is lower than that of the similar compounds showing the similar efficacy. Therefore, it is advantageous when developing as a drug used in actual clinical situations. Further, the cardiovascular disease therapeutic agent of the present invention containing the compound has excellent vasodilatory action, coronary blood flow increasing action, antihyperlipidemic action, platelet aggregation inhibiting action, hypotensive action, etc. It is highly sustainable and safe. Therefore, it is useful as a preventive and therapeutic agent for ischemic heart diseases such as angina and myocardial infarction, diseases associated with circulatory insufficiency including brain, hypertension, arteriosclerosis, thrombosis and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/505 ADN (72) Inventor ▲ High ▼ ▲ Muwa ▼ Takiko Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa 560 Pola Kasei Kogyo Co., Ltd. Totsuka Research Laboratory (72) Inventor Kenichi Kishi Kashio-cho, Totsuka-ku, Yokohama, Kanagawa 560 Pola Kasei Kogyo Co., Ltd. Totsuka Research Laboratory (72) Inventor Hiroshi Matsunaga 3-6 Niiza, Niiza City, Saitama Prefecture 3-307 (72) Inventor, Satoshi Shimizu 4-35-8, Minamisho-cho, Tokushima City, Tokushima Prefecture No. 202 Sejour Sato (72) Inventor, Soichi Kanada 4-3-63, Kashiwa-cho, Shiki City, Saitama Prefecture No. 101 Sunny Court Kashiwa ( 72) Inventor Toshio Kumagai 3-15-37 Kosenba-cho, Kawagoe City, Saitama Prefecture (72) Yunosuke Nagase 3-2-7 Nishioizumi, Nerima-ku, Tokyo

Claims (2)

[Claims] 1. The following general formula (I): In the formula, R is the following substituent: (i) COOR ¹ (ii) CONR ¹ R ² (iii) cyano group (iv) NR ¹ R ² (v) CH ₂ R ³ (vi) halogen atom (where R ¹ and R ² are each independently a hydrogen atom or a lower alkyl group, and R ³ is any one of a benzyloxy group, a hydroxy group or a pyridinium group), or a pyrrolo [3,2-e] pyrazolo A [1,5-a] pyrimidine derivative or a salt thereof. 2. A therapeutic agent for cardiovascular disease comprising the pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine derivative according to claim 1 or a salt thereof as an active ingredient.