JP3059572B2 - Pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine derivatives and therapeutic agents for hypertension containing the same as an active ingredient - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel pyrrolo [3,2-
e] Pyrazolo [1,5-a] pyrimidine derivatives or salts thereof, and therapeutic agents for hypertension containing the same as an active ingredient.

[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. It is an extremely effective method to lower blood pressure by vasodilation and to improve blood flow as a therapeutic agent for circulatory diseases, and to suppress platelet aggregation to prevent arterial thrombosis. 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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It has been found that a pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine derivative represented by the formula (where _Ra represents an alkyl group) has an excellent therapeutic effect on circulatory diseases. Filed a patent application (Japanese Unexamined Patent Publication No.
882).

[0006] However, this compound (A) exhibits excellent effects in vitro, but in vivo, the pyrrole ring moiety is easily oxidatively metabolized, resulting in inactivation and the effect is not sustained. Had disadvantages.

[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 a compound represented by the following general formula (1) has good medicinal properties, The present invention was found to be extremely effective in the prevention and treatment of cardiovascular diseases such as angina pectoris, and completed the present invention.

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

[0010]

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(Wherein, R represents a linear or branched alkyl group or a linear or branched aralkyl group, and these groups are a hydroxyl group, an alkoxy group, a nitro group, a primary, secondary or tertiary amino group, a carboxyl group , Cycloalkyl group, halogen atom, pyrrole, pyrrolidine, pyridine,
It may be substituted by piperidine, imidazole, imidazoline, morpholine or pyrrolidone. A) pyrrolo [3,2-e] pyrazolo [1,5-a]
An object of the present invention is to provide a pyrimidine derivative or a salt thereof, and a therapeutic agent for hypertension containing the same as an active ingredient.

In the compound of the present invention, in the formula (1), the straight-chain or branched alkyl group for R has 1 to 16 carbon atoms.
And specifically, a methyl group, an ethyl group, n
-Propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-
Examples include a hexyl group, an octyl group, and a decanyl group. Further, as the straight-chain or branched aralkyl group for R,
Benzyl group, α-methylbenzyl group, phenethyl group, α
-Or β-naphthylmethyl group, α- or β-naphthylethyl group and the like. These groups include a hydroxyl group, an alkoxy group, a nitro group, a primary, secondary or tertiary amino group, a carboxyl group, a cycloalkyl group, a halogen atom, and a heterocyclic group (pyrrole, pyrrolidine, pyridine, piperidine, imidazole, Imidazoline, piperidine, morpholine, pyrrolidone, etc.) and substituted heterocyclic groups.

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

[0014]

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(Wherein, R represents the same as above and X represents a halogen atom). That is, α-acetyl-γ-butyrolactone (ABL) (2) has 3-amino-4-
After dehydration condensation of cyanopyrazole (3), the lactone ring is cleaved to give 6- (2-hydroxyethyl) -5.
-Methyl-pyrazolo [1,5-a] pyrimidine-7 (4
H) -ones (4), which are then halogenated to form 7-halo-6- (2-haloethyl) -5-methylpyrazolo [1,5-a] pyrimidines (5), and further The compound of the present invention can be produced by reacting an amine.

To produce (4) from compounds (2) and (3), a suitable solvent such as dimethylformamide, toluene, xylene, ethanol, methyl ethyl ketone (M
(2) and (3) are reacted in a solvent such as EK), methyl isobutyl ketone (MIBK), tetrahydrofuran (THF), dioxane or acetic acid in the absence of a catalyst or in the presence of a catalyst such as a Lewis acid such as trifluoroborane. . In producing compound (4), the following compound (6) is used as an intermediate compound.

[0017]

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3-[[1- (tetrahydro-
2-oxo-3-furyl) ethylidene] amino] -4-
Although cyanopyrazole is produced, the compound (4) can also be obtained by isolating the compound once and then subjecting the lactone ring to cleavage and ring closure.

To produce (5) from compound (4),
(4) A halogenating agent such as phosphorus oxychloride or phosphorus pentachloride is heated and reacted without solvent or in a solvent such as tetrachloroethane, ethylene dichloride, chloroform, trichloroethylene, benzene, or chlorobenzene. At this time, N
Catalysts such as -methylmorpholine, triethylamine, pyridine, dimethylaniline, dimethylformamide and the like can also be used.

In order to produce (1) from compound (5),
The reaction can be carried out by reacting (5) with an amine in a solvent such as alcohol, dimethylformamide, dimethylsulfoxide, and methyl ethyl ketone. At this time, a deoxidizing agent such as sodium carbonate, potassium carbonate, triethylamine, excess amine, and pyridine can be added.

The compound (1) of the present invention can be obtained in good yield by the above-mentioned method, and the compound (1) of the present invention thus obtained can be used in combination with a pharmaceutically acceptable salt of an inorganic or organic acid. And further reacted with an alkyl iodide or the like to form a quaternary salt.

When the compound (1) of the present invention is administered to humans as a medicament, it varies depending on the age and symptoms, but its effective amount, for example, 10 to 100 mg per day is usually orally administered in 1 to 3 divided doses. Is preferred.

The therapeutic agent of the present invention can be made into various dosage forms, for example, oral administration 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 of the present invention (1) is used as an excipient such as starch, mannitol and lactose; a binder such as sodium carboxymethylcellulose and hydroxypropylcellulose; a disintegrating agent such as crystalline cellulose and calcium carboxymethylcellulose; Lubricants: Tablets, capsules, powders, granules or lozenges can be prepared by appropriately combining and formulating a fluidity improver such as light anhydrous silicic acid.

[0024]

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

Example 1 A. B. L 19.5 g, 3-amino-4-cyanopyrazole (J. Amer. Chem. Soc. 78 , 78)
4 synthesized according to the (1956)) 60g, were mixed in absolute ethanol 200ml and BF _3-n-methanol reagent 5 ml, and stirred at room temperature for 1 day. The resulting light brown crystals were collected by filtration, washed with isopropanol, and further recrystallized from dimethylformamide-isopropanol to give light brown crystals of 3-[[1- (tetrahydro-2-oxo-3-furyl) having a melting point of 195 ° C. ) Ethylidene] amino] -4-cyanopyrazole [Compound (6)] 105 g (86.4% yield) was obtained. MS: m / e M ⁺ 218.

Example 2 15 g of the compound (6) obtained in Example 1, 35 ml of water and 9.7 ml of triethylamine are mixed and stirred in a warm bath at 50 ° C. to give a brown solution. After about 5 hours, stop heating and leave at room temperature overnight. Precipitation of brown crystals is observed. The crystals precipitated after acidification with acetic acid were collected by filtration and recrystallized from dimethylformamide to give 3-cyano-6, a slightly brown crystal having a decomposition point of 283 ° C.
13.5 g (90.0% yield) of-(2-hydroxyethyl) -5-methylpyrazolo [1,5-a] pyrimidin-7 (4H) -one [compound (4)] was obtained. MS: m / e M ⁺ 218.

Embodiment 3 A. B. Equimolar amounts of L and 3-amino-4-cyanopyrazole are heated to reflux in xylene on a 170 ° C. oil bath for 5 hours. The solvent was distilled off, and when the crystals slightly precipitated, concentration was stopped. After cooling, the precipitated crystals were collected by filtration to give compound (4).
In a 52% yield. This product completely matched the compound obtained in Example 2 with its instrumental analysis data.

Example 4 30 g of the compound (4) obtained in Example 2 or 3 was added to POCl ₃
And reflux for 4 hours with stirring in an oil bath at 130-135 ° C. Then, most of the excess POCl ₃ is distilled off under reduced pressure, and the residual red candy is poured into 500 ml of water with ice flakes floating thereon. A small amount of a saturated Na ₂ CO ₃ solution is added under stirring to make the solution alkaline. The orange-red crystals precipitated here are collected by filtration and washed with water. After air-drying the crystals, methyl ethyl ketone 15
Dissolve in 0 ml, add 2 g of decolorizing carbon, stir in a water bath for about 30 minutes, and filter. A chromatographic tube is filled with 100 g of alumina (pH = 7) activated with methyl ethyl ketone in advance, into which the filtrate is poured and developed through a column.
Finally, 50 ml of methyl ethyl ketone is poured and poured out, and the entire developing solution is collected and concentrated. When crystals start to precipitate, isopropyl ether is added and the mixture is cooled with ice water. The yellow-orange crystals were collected by filtration, dissolved again by heating in methyl ethyl ketone, added again with isopropyl ether, and cooled with ice water to give a melting point of 143-1.
7-chloro-6- (2-chloroethyl) -3-cyano-5-methylpyrazolo [1,5-a] of orange crystals at 45 ° C.
22.0 g (yield 62.6%) of pyrimidine [compound (5), X = Cl] was obtained. MS: m / e M ⁺ 254.

Example 5 225 mg of the compound (5) obtained in Example 4, 107 mg of O-methylhydroxyamine hydrochloride and 340 mg of potassium carbonate
Was added to 5 ml of dimethylformamide, and the mixture was stirred at room temperature for 21 hours. 10 ml of ethyl acetate was added to the reaction solution, followed by filtration. The filtrate was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform-acetone 9).
5: 5) to give compound (1) [R =
CH ₃ ] 172.6 mg (75%). ¹ H-NMR (CDCl ₃ ): δ 2.54 (3H, s), 3.09 (2H, d, J = 7.9 Hz), 3.96 (2H, d, J = 7.9H)
z), 4.06 (3H, s), 8.29 (1H, s)

Example 6 255 mg of the compound (5) obtained in Example 4, 107 mg of O-benzylhydroxylamine hydrochloride and potassium carbonate 34
0 mg was added to 5 ml of dimethylformamide, and the mixture was stirred at room temperature for 21 hours. 10 ml of ethyl acetate was added to the reaction solution, which was filtered. The filtrate was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to give compound (1) as pale yellow crystals [R = CH ₂ P
h] 213.7 mg (70% yield). ¹ H-NMR (CDCl ₃ ): δ 2.51 (3H, s), 3.00 (2H, d, J = 8.09 Hz), 3.72 (2H, d, J = 8.09H)
z), 5.29 (2H, s), 7.3-7.5 (5H, m), 8.33 (1H, s)

Example 7 To 1.28 g of the compound (5) obtained in Example 4, 1.26 g of Ot-butylhydroxylamine hydrochloride and 2.0 g of triethylamine were added 10 ml of DMF, and the mixture was stirred at room temperature for 12 hours. After distilling off DMF with an evaporator, 50 ml of ethyl acetate was added, and the mixture was extracted and washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to give compound (1) [R =
[t-Bu] 1.22 g (90%). MS: m / e M ⁺ 271. ¹ H-NMR (CDCl ₃ ): δ 1.51 (9H, s), 2.52 (3H, s), 3.11 (2H, t), 3.97 (3H, bs) 8.
24 (1H, s)

Test Example 1 Spontaneously hypertensive rats (S
HR) was evaluated by the tail-cuff method. The following compounds of the present invention were used as test drugs. Compound 1: 3-cyano-6,7-dihydro-5-methyl-8-methoxy-8H-pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine Compound 2: 8-benzyloxy-3- Cyano-6,7
-Dihydro-5-methyl-8H-pyrrolo [3,2-e]
Pyrazolo [1,5-a] pyrimidine

As a control compound, compound (A) [Ra = C (CH ₃ ) _{3 in} formula (A);
No., refer to Japanese Patent Publication No. The test drug was orally administered by suspending 0.5 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. The blood pressure curve was obtained by plotting the time-dependent changes in the blood pressure lowering rate (%) at 5 hours and 8 hours after administration, and the duration of the blood pressure lowering action was evaluated from the area under the curve (hypertensive area). The results are shown in Table 1 in terms of the blood pressure reduction rate (%) and the blood pressure reduction area at the time of the maximum reaction as relative values to the control compound (A).

[0034]

[Table 1]

As is evident from the above results, the compounds 1 and 2 of the present invention have a hypotensive effect,
The blood pressure reduction rate and sustainability were almost the same as those of the control compound (A).

Test Example 2 (Toxicity) The acute toxicity test of the compound of the present invention was performed by the following method. I
CR male mice were purchased at the age of 4 weeks, and preliminarily reared for about 10 days before being subjected to the experiment. The test drug was a mouse weighing 10 g.
The suspension was suspended in a 1% cell methylcellulose solution so as to be 0.1 ml per cell, 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 and 2 was 2 g / kg.
That was all.

Further, as a result of examining the vasodilator effect of the compound of the present invention by the Magnus method, the inhibitory effect on vasoconstriction by norepinephrine, the coronary vasodilator effect, and the like, it was found that the compound had a sustained effect.

The following are formulation examples. Example 8 (tablets) Composition: Compound 1 25 g Lactose 130 g Crystalline cellulose 20 g Corn starch 20 g 3% aqueous solution of hydroxypropylcellulose 100 ml Magnesium stearate 2 g

Production method: Lactose, crystalline cellulose and corn starch were sieved to compound 1 through a 60-mesh sieve, mixed uniformly, and then placed in a kneading machine, whereupon a 3% aqueous solution of hydroxypropylcellulose was poured and kneaded. Then, the mixture was sieved and granulated with a 16-mesh sieve, and dried by blowing at 50 ° C. After drying, the mixture was sieved through a 16-mesh sieve, mixed with magnesium stearate, and made into tablets having a diameter of 8 mm and a weight of 200 mg by a tableting machine.

Example 9 (Capsule) Composition: Compound 1 25 g Lactose 125 g Corn starch 48.5 g Magnesium stearate 1.5 g

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

Example 10 (Tablets) Composition: Compound 2 25 g Lactose 130 g Crystalline cellulose 20 g Corn starch 20 g 3% aqueous solution of hydroxypropylcellulose 100 ml Magnesium stearate 2 g

Production method: Lactose, crystalline cellulose, and corn starch were sieved to compound 2 with a 60-mesh sieve, uniformly mixed, and then placed in a kneading machine, whereupon a 3% aqueous solution of hydroxypropylcellulose was added and kneaded. Then, the mixture was sieved and granulated with a 16-mesh sieve, and dried by blowing at 50 ° C. After drying, the mixture was sieved through a 16-mesh sieve, mixed with magnesium stearate, and made into tablets having a diameter of 8 mm and a weight of 200 mg by a tableting machine.

[0044]

INDUSTRIAL APPLICABILITY The compound (1) of the present invention exhibits an excellent antihypertensive effect and is highly safe, and thus is useful as a therapeutic agent for hypertension.

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Toshimitsu Suzuki 560 Paula-cho, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Inside the New Chemical Research Laboratory (72) Inventor Toshihiro Morimoto 560 Paula-cho, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa (72) Inventor Norihiko Tsujitani 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Inside the New Chemical Research Laboratory (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 487 / 14 A61K 31/519 A61P 9/00-9/14 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] (1) The following general formula (1): (In the formula, R represents a linear or branched alkyl group or a linear or branched aralkyl group, and these groups are a hydroxyl group,
It may be substituted by an alkoxy group, nitro group, primary, secondary or tertiary amino group, carboxyl group, cycloalkyl group, halogen atom, pyrrole, pyrrolidine, pyridine, piperidine, imidazole, imidazoline, morpholine or pyrrolidone. A) a pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine derivative or a salt thereof; 2. An antihypertensive agent comprising the pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine derivative or a salt thereof according to claim 1 as an active ingredient.