JPH02275882A - Pyrrolo(3,2-e)pyrazolo(1,5-a)pyrimidine derivative and pharmaceutical containing the same - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R1 and R2 are H, (substituted) alkyl, (substituted) cycloalkyl, phenyl or (substituted) heterocyclic ring; R3 is H or cyano]. EXAMPLE:8-tert.-Butyl-3-cyano-6,7-dihydro-5-methyl-8H-pyrrolo[3,2-e]py razolo[1,5- a]pyrimidine. USE:Useful as a remedy for circulatory diseases or bronchodilator having excellent vasodilator, hypotensive, antihyperlipemic, blood platelet agglutination inhibitory, Ca<2+> blocker and bronchodilator action. PREPARATION:An alpha-acetyl-gamma-butyrolactone expressed by formula II and 5- aminopyrazoles expressed by formula III are subjected to dehydrating condensation to provide a compound expressed by formula IV, which is then subjected to cleavage of the lactone ring and cyclization to afford a compound expressed by formula V. The resultant compound expressed by formula V is then halogenated to provide a compound expressed by formula VI, which is further reacted with amines.

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention provides a novel drug which has excellent vasodilatory effect, antihypertensive effect, antihyperlipidemia effect, platelet aggregation inhibitory effect, Ca++ blocker effect and bronchodilatory effect. Pirolo [3,2-el
The present invention relates to a pyrazolo(I,5-a) pyrimidine derivative or a salt thereof, and a pharmaceutical containing the same as an active ingredient.

[Conventional technology and its problems]

It is a well-known fact that as the population ages, N-ring system diseases are increasing and account for a large proportion of the deaths together with malignant tumors.

As a treatment for cardiovascular diseases, lowering blood pressure and improving blood flow through vasodilation is an extremely effective method, and inhibiting platelet aggregation is a useful means of preventing the occurrence of arterial thrombosis. It is.

Furthermore, compounds having Ca++ blocker action often have antiarrhythmic action, and these diseases are mutually related.

Therefore, it has been desired to develop a drug that is comprehensively effective against these cardiovascular diseases.

On the other hand, bronchial asthma is thought to be caused in part by abnormal contraction of bronchial smooth muscle, swelling of the bronchial mucosa, and mucus secretion caused by various endogenous and exogenous factors; The mechanisms and mechanisms have not been fully elucidated. Therefore, treatment of bronchial asthma focuses on symptomatic drug therapy rather than causal therapy.

The main drugs currently used for therapeutic purposes are β-receptor stimulants, with the only other drugs being theophylline preparations. However, both of these drugs have many side effects and are currently subject to considerable restrictions on drug therapy in terms of dosage and administration period.

Therefore, it has been desired to develop a therapeutic agent for bronchial asthma with fewer side effects, such as a bronchodilator.

[Means for Solving the Problems] In view of the above circumstances, the present inventors have conducted intensive research over a long period of time and have found that the compound represented by soft formula (I) below has an excellent therapeutic effect on circulatory system diseases. They also discovered that it has a bronchodilating effect, and completed the present invention.

That is, the present invention provides the following general formula (I), (wherein R+
and R3 represents a hydrogen atom, a straight or branched alkyl group which may have a substituent, a cycloalkyl or phenyl group which may have a substituent, or a heterocyclic group which may have a substituent, R1 represents a hydrogen atom or a cyano group) pyrrolo(3,2-e)pyrazolo[1°5-
a] provides a pyrimidine derivative.

The present invention also provides a therapeutic agent for circulatory system diseases and a bronchodilator containing this as an active ingredient.

In the compound of the present invention, examples of the heterocyclic group for R and R2 in formula (I) include a piperidyl group, a piperazinyl group, a morpholinyl group, and a thienyl group. Examples of the straight or branched alkyl group include those having 1 to 16 carbon atoms, specifically methyl group, ethyl group, n-propyl group, n-butyl group, isobutyl group, 5ec-butyl group, n -Hexyl group, octyl group, decanyl group, etc.

Examples of the cycloalkyl group include those having 4 to 8 carbon atoms, and specific examples include a cyclopentyl group and a cyclohexyl group. Substituents for these groups include hydroxyl group, alkoxy group, nitro group, -class, secondary or tertiary amino group, carboxyl group, cycloalkyl group,
Examples thereof include a phenyl group, a substituted phenyl group, a halogen atom, a heterocyclic group (pyrrole, pyrrolidine, pyridine, piperidine, imidazole, imidacilline, piperidine, morpholine, pyrrolidone, etc.), a substituted heterocyclic group, and the like.

The compound (I) of the present invention is produced, for example, by the method shown in the following reaction formula.

The following margin (in the formula, R2, R2 and R5 are the same as above), that is,
α-acetyl-γ-butyrolactone (8, B, L) (I
I) is subjected to dehydration condensation with 5-aminopyrazoles (I [I) to form compound (IV), which is then subjected to cleavage and ring closure of the lactone ring to form 6-(2-hydroxyethyl)-5-methyl-pyrazolo. (I,5-a]pyrimidine-7-(4-
hydro)-ones (V), which is then halogenated to form 7-hero6-(2-haloethyl)-5-meth+ruby-5zolo[1,5-a)pyrimidines (Vl) The compound (I) of the present invention is produced by further reacting this with an amine.

Compound (V) can also be produced directly by refluxing A, B, L (II) and 5-aminopyrazoles (III) in a suitable solvent, such as dimethylformamide, xylene, or acetic acid, under hot oil.

To prepare (IV) from compound (n) and (III),
(n) and (In) are reacted in a suitable solvent such as an alcohol in the presence of a catalyst such as a Lewis acid such as trifluoroborane.

The reaction from compound (TV) to (V) is carried out by mixing (rV) with water and a tertiary amine such as triethylamine, N-methylmorpholine, or pyridine in an aqueous solution of caustic alkaline, an aqueous alcohol solution, etc. .

To produce (VI) from compound (V), a halogenating agent such as phosphorus oxychloride or phosphorus pentachloride is added to (V) without a solvent or by adding tetrachloroethane, ethylene dichloride, chloroform, trichloroethylene, benzene, chlorobenzene, etc. The reaction is carried out by heating in a solvent. At this time, catalysts such as N-methylmorpholine, triethylamine, pyridine, dimethylaniline, and dimethylformamide can also be used.

To produce (I) from compound (Vl), (Vl) and amines are mixed in a solvent such as alcohol, dimethylformamide, dimethyl sulfoxide, or methyl ethyl ketone with a deoxidizing agent such as soda carbonate, potassium carbonate, triethylamine, or pyridine. react in the presence of

The compound (I) of the present invention thus obtained can be made into a pharmaceutically acceptable salt of an inorganic or organic acid, and can also be made into a quaternary salt by reacting with an alkyl iodite or the like.

When the compound (I) of the present invention is administered to humans as a pharmaceutical,
Although it varies depending on age, symptoms, etc., it is preferable to orally administer an effective amount, for example, usually 10 to 100+ og per day, divided into 1 to 3 times.

The therapeutic agent for circulatory system diseases or the bronchodilator of the present invention can be made into various dosage forms, such as tablets, capsules, powders, troches, liquids, and other oral preparations. The above formulation is
This can be done by a method known per se. That is, the compound (I) of the present invention is mixed with excipients such as starch, mannitol, and lactose; binders such as sodium carboxymethyl cellulose and hydroxypropyl cellulose; disintegrating agents such as crystalline cellulose and calcium carboxymethyl cellulose; and talc and magnesium stearate. Tablets, capsules, powders, granules, or troches can be produced by appropriately combining lubricants; fluidity improvers such as light anhydrous silicic acid, and the like.

〔Example〕

Next, the present invention will be explained with reference to Examples and Test Examples.

Example 1 (i) A, J, L 19.5 g, 3-amino-4-cyanopyrazole (J, ^mer, Chem, Sac
, 78.784 (synthesized according to I956)) 60g
, 200mj of absolute ethanol! and 5 ml of BFa n-methanol reagent! were mixed and stirred at room temperature for 1 day.

The formed pale brown crystals were collected by filtration, washed with Impropatol, and further recrystallized with dimethylformamide-impropanol to give pale brown crystals of 3-((I-(
Tetrahydro-2-oxo-3-furyl)ethylidene]amino]-4-cyanopyrazole [(■) Formula 9 Formula %) The following compound was obtained in the same manner.

(ii) 3-C[1-(tetrahydro-2-oxo-3-furyl)ethylidene]amino]-4-cyano-5-methylpyrazole [(■) in the formula, R2=C) 13
．． R5=CN) Yield 97.7%, melting point 222-224°C, white crystals, M
S: m/e M” 232° (ijf) 3-C(I-(tetrahydro-2-xo-3-furyl)ethylidene]Tmino]-5-methylpyrazole [(■) In the formula, Rt=CF13. R3 = original yield 66.94%, melting point 157-158°C (ethanol paste, white crystals, MSv/e M”20?.

(iv) 3-C[1-(tetrahydro-2-oxo-3-furyl)ethylidene]amino]-5-phenylpyra, zole [(■) in the formula, Ri=CJs, R1=old yield 76.9% , melting point 298-299°C, slightly brown crystals,
MS: m/e M” 269°(v) 3-C(I-(tetrahydro-2-year-old xo-3-furyl)ethylidenecoamino)-5-(3-thienyl)pyrazole [(■) In the formula, 82.0%, melting point 193-194°C, light brown crystals, MS: m/e M”
2 7 5゜(vi) 3-((I-(tetrahydro-2-oxo-3-furyl)ethylidene]amino]-5-methylpyrazole [(■) In the formula, R2=R3=old yield 99.1
%, melting point 132-137°C, white crystals.

Example 2 (i-1) Compound (rV) [R,=H,11,=c
N] 15g 1 water 35-, triethylamine 9.7rd
Mix and stir in a 50°C hot bath to form a brown solution.

Stop heating for about 5 hours and leave at room temperature overnight. Precipitation of brown crystals was observed. The precipitated crystals were acidified with acetic acid, collected by filtration, and recrystallized with dimethylformamide, resulting in a decomposition point of 283°C.
3-cyano-6-(2-hydroxyethyl)-5-methylpyrazo o [t, 5 a] pyrimidin-7(4H)-one [(■) in the formula, R2= H, Ra=
CN) 13.5g (yield 90.0%) was obtained.

MS: m/e M" 218° (i-2) Equimolar moles of A, B and 3-amino-4-cyanopyrazole are heated under reflux in xylene on a 170°C oil bath for 5 hours. The solvent is distilled off. When a few crystals were precipitated, the concentration was stopped, and the mixture was cooled and the precipitated crystals were collected by filtration to obtain compound (V) (R2=H,R,=CH) in a yield of 52%. The following compound was obtained in the same manner as (i-1).

(ii) 3-cyano-2,5-dimethyl-6-(2-hydroxyethyl)pyrazolo(I,5-a)pyrimidine-
7(4H)-onshiku ■) In the formula, Rs=C)l,, R
3=CH) Yield 77.5%, melting point 277-278°C, white crystals.

(iii) 2. 5-dimethyl-6-(2-hydroxyethyl)pyrazolo(I,5-a]pyrimidine-7(4
H)-one [(■) in the formula, R,=CH,, R,=old yield 56.8%, melting point 216°C, white needle crystals, MS: m
/e M” 207°(iv) 6-(2-hydroxyethyl)-5-methyl-
2-phenylpyrazolo(I,5-a]pyrimidine-7(
4H)-one [(■) in the formula, Rs”C3H5, R3 = old yield 88.3%, decomposition point 307°C, colorless crystals, MS: m
/e M” 26 9°(v)6-(2-hydroxyethyl)-5-methyl-
2-(3-thienyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one [(■) in the formula, yield 79.0%,
Decomposition point: 310°C, colorless plate crystals, MS: m/e M” 2
? 5゜(vi)2-(2-hydroxyethyl)-5-methylpyrazolo[1,5-a)pyrimidin-7(4H)-one[
(■) In the formula, R*=L=daily yield 85.0%, melting point 234
~238°C, white crystals.

Example 3 (i) Compound (V) (R, -41, Rs=CN)
30'g POCj! 1 and reflux for 4 hours with stirring in an oil bath at 130-135°C. Then remove excess PO under reduced pressure
CJ! Most of I is distilled off and the remaining red syrup is poured into 509 mg of water with crushed ice cubes. Saturated NazCO
3 solution to a small amount while stirring to make alkaline. The orange-red crystals precipitated on the fish are collected by filtration and washed with water.

After air-drying the crystals, dissolve them in 150 d of methyl ethyl ketone, add 2 g of decolorizing charcoal, stir in a water bath for about 30 minutes, and filter. Precaulked methyl ethyl ketone activated alumina (
100 g of pH=7) is packed into a chromatography tube, and the filtrate is poured into the tube and developed through the column. Finally, 50 d of methyl ethyl ketone is added and poured out, and all the developed solutions are collected and concentrated. When crystals start to precipitate, add isopropyl ether and cool with ice water. The yellow-orange crystals were collected by filtration, dissolved in methyl ethyl ketone by heating again, and isopropyl ether was added again and cooled with ice water to give a melting point of 143 to 1.
Orange crystals of 7-chloro-6-(2-chloroethyl)-3-cyano-5-methylpyrazolo(I,,5-a) at 45°C.
) Pyrimidine [(■) in the formula, R, = H, R, = CN]
22. Og (yield 62.6%) was obtained.

MS: m/e M” 254° (ii) Compound (V) (R2=CH3, R-=CH
) 11.6g (0.05 mol) POCj! , 2
3 mg (0.25 mol), 3 drops of dimethylaniline (
When a catalytic amount) is added and heated in an oil bath, it becomes agglomerated at about 90°C, but if heating is continued thereafter, it becomes a red solution at 130°C.

After refluxing for 4 hours, POCj! , the excess is distilled off.

Dry the residual red candy-like substance Cl1Cj? , 15 (ld!). Pour the extract into 300 ml of ice water and add saturated Na
Add 2COs solution little by little to make it alkaline. C
The HCj' layer is separated, washed with water, dried over Na*SO-, and filtered.

Concentrate the filtrate to obtain orange-yellow crystals. Recrystallized from methyl ethyl ketone-isopropyl ether mixture, melting point 113 ~
Yellow-orange crystals of 7-chloro-6-(2-chloroethyl)-3-cyano-2°5-dimethylpyrazolo(I) at 115°C.
,5-a) Pyrimidine [(■) In the formula, R=CH3,R
co=CN'] 9.5 g (yield 70.6%) was obtained.

MS: m/e M” 268° The following compound was obtained in the same manner.

(in)? -Kuroro 8. -(2-chloroethyl)2.
5-dimethylpyrazolo(I,5-a)pyrimidine [(■
) In the formula, R2=CH3,'R-=1 Yield 56.1%, melting point 111°C, yellow-orange crystals, m/a M" 243° (iv)?-Fucloro6-2-chloroethyl)- 5-
Methyl-2-phenylpyrazolo[1,5-a]pyrimidine [(■) in the formula, R*=CaHs, R,=H] Yield 55.6%, melting point 139-140°C, yellow-green crystals,
MS: m/e M” 306°(v) 7-chloro-6-(2-chloroethyl)5-methyl-2-(3-thienyl)-pyrazolo[1,5-a)pyrimidine [(■) in the formula , yield 75.3%, melting point 156°C
, yellow crystals, MS: m/e M” 311°(vi)?-fuchloro6-2-chloroethyl)-5-
Methylpyrazolo(I,5-a)pyrimidine [(■) where Rs=Rs=old yield 70.1%, melting point 91-92°C, pale yellow crystals.

Example 4 (i) Compound (Vl) (R2=)1. R-=CN
] 7. Og (0,0275 mol), anhydrous NatC a
5. Og, methyl ethyl ketone 8Q mj! 5 tarts
- A mixture of seven butylamines is heated under reflux for 4 hours with stirring in a water bath at 85-90°C. After cold filtration and further filtration using methyl ethyl ketone 100, the remaining red substance is extracted again under heating, and the filtrate is combined with the previous filtrate. Separately, 20 g of silica gel (pH = 7,200 mesh) was pre-caulked and filled into a column chromatography tube using methyl ethyl ketone, and the combined filtrate was poured into the tube and developed. The entire developing solution is concentrated in a 60° C. water bath under reduced pressure. When crystals begin to precipitate, add isopropyl ether to a cloudy level and cool with ice water.

- After cooling, yellow-orange crystals of B with a melting point of 217-220 °C
-tert-butyl-3-cyano-6,7-cyhydro-5-methyl-8H-pyrrolo(3,2-e]pyrazolo[1
,5-a) Pyrimidine [(I) in the formula, RI=C(C)1
3)3. R2=ll, Rs=CN; Compound 114.
8 g (yield 6B, 57%) was obtained.

MS: m/e M” 255° (it-1) Compound (Vl) [R,=CH3,R,
=CN]2.7g (0.01 mol), triethylamine 2mj! 3.2 d of tert-butylamine and 15 ml of absolute ethanol were placed in a sealed tube and heated in a water bath at 85° C. for 8 hours.

Next, the tube was opened, 100 mt' of methyl ethyl ketone was added, heated, and then filtered. The filtrate was treated with silica gel (p)I=
7. 200 mesh) lOg are purified by passing them through a chromatography tube prefilled with methyl ethyl ketone. The developing solution was concentrated to obtain 3-tert-butyl-3-cyano-6,7-cyhydro-2,5-dimethyl-8H-piDO [3,2-e] as yellow-orange plate crystals with a melting point of 229-230°C.
Pyrazo0 (I゜5-a]pyrimidine [(I) in the formula, R
,=C(CH3),.

2.4 g (yield: 80.0%) of R,=C113,R,=CN; Compound 2 was obtained.

MS: m/e M” 269° (ii-2) Compound (VI) (R snow = CH3, Rj
=CN]7, Og (0,026 mol9, triethylamine Bml.

0.1 g of fine powder of tart-butylamine l5rnlSNB3r.

Anhydrous Na1COs (or 2COs) 2.881 Anhydrous tanol 30ml! , methyl ethyl ketone 100d
The mixture was allowed to react for 8 hours under stirring in an oil bath at 95°C. The reaction solution is filtered while hot. The filtrate was purified by chromatography as described above to obtain compound (I) CR,C(CL)s,
R2=C)1. , R,=CH) in a yield of 78.5%.

(in) Compound (Vl) (L=CL, R,=CH
) 4.0 g (0,015 mol) was mixed with 20-20% 99.5% ethanol and 20-20% aqueous ammonia and heated in a sealed tube at 50°C, then at 70°C for 2 hours each, and then at 95°C for 6 hours.
Warmed for hours. Open the refrigerator and filter. The reddish-brown crystals are washed with ice water, dissolved by heating with dimethylformamide, and cooled with ice water. A small amount of isopropyl alcohol was added to promote crystal precipitation, resulting in a reddish brown 3-cyano-6,7-cyhydro-2,5-dimethyl-8H-pyrrolo[3,2-e]pyrazolo[1,5] with a decomposition point of 275-280°C. -a] pyrimidine [(
I) In the formula, R,=H,R2=CH,,R,=CN] is 7
Obtained with a yield of 2%.

MS: m/e M4″213° Example 5 (i) Compound (Vl) [L=H, R3=CH) 8
8.9g -tart-butylamine 33.0g, anhydrous potassium carbonate 89g and anhydrous dimethylformamide 70g
The mixture of 0 and 0 was stirred at room temperature, day and night. 500 rnl of p-roform was added to the 0 reaction solution, insoluble materials were removed by filtration, and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was recrystallized from benzene to give 3-tart-butyl-3-cyano-6,7- Sihydro-5-methyl-8
H-bi00[3,2-e)pyrazolo(I,5-a)pyrimidine [(I) in the formula, R,=C(CH3)! , R,=
H,R,=CN] 73.6g (yield 82.8%) was obtained. The following compound was obtained in the same manner with a melting point of 220-224°C.

(ii) 8-Butyl-3-cyano-6,7-cyhydro-5-methyl-8H-pi00(3,2-e]pyrazolo[1
,5-a) Pyrimidine [(in the formula, R,=(CL)3C
L, R, = H, R3 = CN; Compound 3] Yield 79.7
%, melting point 143-145°C, pale yellow-orange crystals.

(in) 8-iso-butyl-3-cyano-6,7-
Sihydro-5-methyl-8H-pyrrolo(3,2-e)pyrazolo(I,5-alpyrimidine [(I) in the formula, R1=
CHICH(C)13), R2=H, R3=CN
; Compound 4] Yield 78.1%, melting point 182-184°C, white crystals.

(iv) 8-sec-butyl-3-cyano-6,7
-Sihydro-5-methyl-8H-pyrrolo[3,2-e]
Pyrazolo[1,5-a]pyrimidine [(I) in the formula, R,
=C)l(CHriC)1. cI(3, R2=H, Rs=
CN; Compound 5] Yield 74.1%, melting point 241-243°C, pale yellow-green crystals.

(v) 3-cyano-6,7-cyhydro-5-methyl-
8-Pentyl-8H-pyrrolo(3,2-e)pyrazolo(
I,5-a) Pyrimidine [(I) in the formula, R,=(C)1
m) 4[:Hl, L=H, Rs=CN; Compound 6] Yield 80.5%, melting point 139-142°C, yellow crystals.

(vi) 3-cyano-6,7-cyhydro-8-hexyl-5-methyl-8H-pioo[3,2-e]pyrazolo (
I,5-a) Pyrimidine [(■) In the formula, R+=(CHs
)sC)Is, R*=I(,Rs=CN; Compound 7]
Yield 80.6%, melting point 125-126°C, pale yellow-orange columnar crystals.

(vii) 3-cyano-8-cyclopentyl-6,7-
Cyhydro-5-methyl-8H-pyrrolo[3,2-e]
Pyrazolo[1,5-a]pyrimidine [(I) in the formula, R,
=CH(C)12), , R, =H, Ra=CN; Compound 8] Yield 90.9%, melting point 240-242°C, pale yellow crystals.

hffl) 3-cyano-8-cyclohexylmethyl-6
,7-sihydro-5-methyl-8H-pyrrolo[3,2-
e] Pyrazolo[1,5-a) pyrimidine [(I) in the formula, R+ = CHsCH(CHz) s, R*=
It.

R,=CN; Compound 9] Yield 89.8%, melting point 217-219°C, pale yellow crystals.

Example 6 (i) Compound (Vl,) [R2=C8H5,R,=
H) 0.40g1 anhydrous potassium carbonate 0.40g, t
A mixture of 0.14 g of ert-butylamine and 3.5 g of dimethylformamide was heated in a water bath at 50 to 60°C with stirring for 5 hours. Cold soaked chloroform 50ml! was added, filtered to remove insoluble matter, and then dried under reduced pressure. Water was added to this, extracted with chloroform, the chloroform layer was concentrated under reduced pressure, and then purified by thin layer chromatography. Obtained tL
The crystals were recrystallized from isopropyl alcohol to give 8-tert-butyl-6,7-hydro 5.
-Methyl-2-7enyl-8H-pyrrolo[3,2-e]
Pyrazolo [1,5-a) pyrimidine (formula (I), R+=C(CHs)s, R2=C8H5°Rs") 0.13 g (yield 27.0%) was obtained.

Pale yellow crystals, melting point 244-248°C.

The following compound was obtained in the same manner.

(ti) 8-tart-butyl-6,7-cyhydro-5-methyl-2-(3-thienyl)-8H-pyrrolo[
3,2-e) Pyrazolo(I,5-a) Pyrimidine yield 2
4.0%, melting point 204-207°C, pale yellow crystals.

Example 7 Compound (VI) (R=R3=old 16.l1g,
Anhydrous potassium carbonate 38 gs tart-butylamine 5.85 g and dimethylformamide 140 ml. The mixture was heated on a water bath at 50-60°C for 2 days with stirring. The mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 150% chloroform, and after washing with water, the chloroform solution was concentrated under reduced pressure to obtain 15.72 g of an oily substance. This was purified by silica gel column chromatography, and benzene-
Recrystallized from isopropyl ether-hexane to give 3-
tert-butyl-6,7-cyhydro-5-methyl-8
H-pyrrolo(3,2-e)pyrazolo(I,5-a)pyrimidine [(■) in the formula, R1=C(CH3)3. R-;
R3=H; Compound 11) was obtained.

Yield 70.1%, melting point 147-149°C, pale yellow plate crystals.

Example 8 (i) Compound (Vl) [R2=H,R,=CN)
5. OOg.

6 ml of triethylamine, 40 ml of dimethylformamide
1! 2.20 g of 4-aminomorpholine was added to the mixture, and the mixture was stirred at room temperature all day and night. The generated crystals were filtered, washed with ethanol, and then recrystallized with chloroform-2-propanol to give 3-cyano-6,7-cyhydro-5-
Methyl-8-(4-morpholyl)-8H-pyrrolo(3
,2-e] pyrazolo[1,5-al pyrimidine[(■
) where R,=llJl, R,=)I, R,=
CN; Compound 10) was obtained.

Yield: 86.5%, melting point: 300°C or higher, white plate-like crystals.

The following compound was obtained in the same manner.

(if) 3-cyano-6,7-cyhydro8- (3゜4-dimethoxyphenylethyl)-5-methyl-8H-
Pyro(3,2-e)pyrazo 1:+[:1.5-yield 8
0.2%, melting point 172°C, white plate-like crystals.

Example 9 Compound (Vl) [R1-H, Rs=CN] 2.5
5g, triethylamine 5-, ethanol 30mj!
Primary amine (HJ-R+) IJmmoj
! is then heated to reflux for 3 hours with stirring in a water bath at 90-1.00°C. After cooling the reaction solution, the following (a=f)
The target compound (I) shown in Table 1 was obtained by treatment according to [R
+=described in Table 1, R1=H, Rs=CNI was obtained.

(a) The precipitated crystals are collected by filtration and recrystallized from isopropyl alcohol-water and the solvents listed in the table.

ii) Recrystallize the crude crystals obtained by concentrating the reaction solution under reduced pressure.

(C) The reaction solution was concentrated under reduced pressure, the rewarmed crude crystals were dissolved in 30 ml of chloroform, and alumina (pH 9-11)7.
Pour into a column chromatography tube packed with 0 g and develop and purify. The developed eluate is concentrated under reduced pressure, crystallized by adding ethyl acetate under cooling, and further recrystallized.

(6) After concentrating the reaction solution under reduced pressure, the residue was dissolved in chloroform 30-
Extract with The chloroform solution is washed with water, dried with Glauber's salt, packed with 10 g of alumina (pH 9-11), and developed and purified through a ζ column chromatography tube. The developed eluate is concentrated under reduced pressure and recrystallized.

(e) After concentrating the reaction solution under reduced pressure, it is extracted with 80 ml of ethyl acetate. Add the extract to 10g of alumina (pH 9-11.)
Purify through a column chromatography tube filled with The developed eluate is concentrated under reduced pressure, crystallized by adding isopropyl ether, and further recrystallized.

(Concentrate the reaction solution under reduced pressure and extract with 70 ml of ethyl acetate. The extract is washed with saturated brine, dried over Glauber's salt, condensed under reduced pressure, crystallized by adding isopropyl ether, and further recrystallized.

Below is a margin test example 1 Trapidil, which is used clinically as a coronary vasodilator, has a vasodilatory effect
503 (I980)) as a control drug, it was measured by the Magnus method.

An adult mongrel dog (8 to 10 kg) was anesthetized with bendoparbital sodium (25 mg/kg, i, v, ), bled to death from the carotid artery, and the basilar artery and coronary vein were immediately removed. The extracted blood vessels were made into ring specimens with a width of approximately 4 to 5 mm and heated with a mixed gas (0.95%, CD25) at 37°C.
%) in aerated rebs-Hensaleit solution (
mM: NaC1,118: KCC4,75; Ca
C12+2.54; 832 mouths 4. 1.19;
Mg5O<, 1.19HNaHCOs.

12.5; glucose, 10.0) 10m
j! A tension of 2 g was applied into an organ bath filled with water, and the tension was recorded isometrically.

The test drug was applied to specimens contracted at U-466191x 10-'M (final concentration) at lXl0-' to lX10-M (
The diastolic effect was examined by cumulative administration of the maximum concentration (maximum concentration).

8-tart-butyl-3-cyano-6,7-cyhydro-5-methyl-8H-pyrrolo[3
, 2-e) Pyrazolo[1,5-a]pyrimidine (compound 1), 8-tert-butyl-3-cyano-6,7
-Sihydro2,5-dimethyl-8H-pyro [3,
2-e) The 50% contraction inhibitory concentrations of pyrazo(][1,5-a]pyrimidine (compound 2) and trapidil are shown in Table 2. Both compounds 1 and 2 are 37 times more potent than trapidil in vascular It showed dilation effect.

Compound 1.2 and Trapidil 5 on Coronary Artery Specimens
The 0% contraction inhibition concentration is shown in Table 3. Compared to Trapidil,
Compound 1 showed a 39 times stronger vasodilatory effect, and compound 2 showed a 35 times stronger vasodilatory effect.

Table 2 Table 3 Test Example 2 The vasodilatory effect was measured using Method 1, and the coronary blood flow increasing effect was measured using Method 2, using Trapidil, which is currently used clinically as a coronary vasodilator, as a control drug.

Method 1> In the Magnus method of Test Example 1, U-466191XI
Instead of O-'M (final concentration), PGF, C5xlo-
The same procedure was performed except that M (final concentration) or potassium chloride (60 mM) was used, and the results are shown in Table 4.

Method 2: An adult mongrel dog (I0-15 kg) was anesthetized with bendoparbital sodium (25 mg/kg, I, V,), a tracheal cannula was inserted, and artificial respiration was performed using a ventilator. The chest was opened at the fourth left intercostal space, the cardiac abdomen was incised, and the heart was exposed. 1 am from the bifurcation of the coronary artery (left rotation technique)
Approximately lea was removed from the surrounding tissue, and an ultrasonic blood flow meter probe was attached to measure coronary blood flow. Furthermore, left ventricular pressure, heart rate, right femoral artery pressure, and lower limb blood flow were monitored, and all test drugs were administered intravenously.

The coronal flow increasing effect of each test drug reduces the blood flow rate by 1
00%, and the maximum increase in blood flow after administration of the test drug was calculated as the rate of increase, and the effects were compared and shown in Table 5.

The following margin Compound 3: 8-Butyl-3-cyano-6,7-cyhydro-5-methyl-8H-pyrroloC3,2-a) pyrazolo(I,5-a]pyrimidine Compound 4: 8-iso-butyl-3 -cyano-6゜7-
Cyhydro-5-methyl-8H-pyrrolo(3,2-e)pyrazolo[1,5-a], pyrimidine compound 5:8-sec-butyl-3-cyano-6゜7-
Cyhydro-5-methyl-8H-pyrrolo[3,2-e]
Pyrazolo[1,5-a]pyrimidine compound 6:3-cyano-6,7-cyhydro-5-methyl-8-pentyl-8H-pyrrolo[3,2-e]pyrazoloN,5-a]pyrimidine compound 7:3 -cyano-6,7-cyhydro8-hexyl-5-methyl-8H-pyrrolo[3,2-e] pyrazolo[1,5-a]pyrimidine compound 'JilJ8: 3-cyano-8-cyclopentyl-
6゜7-cyhydro-5-methyl-8H-pyrrolo(3,2-e)pyrazolo[1,5-a]pyrimidine compound 9: 3-cyano-8-cyclohexylmethyl-6
,7-cyhydro-5-methyl-8H-pyrrolo[3,2-e]pyrazolo[1,5-a]pyrimidine compound 10:3-cyano-6,7-sihydro-5-methyl-8-(4-morphoryl) -8H-pyrrolo[:3.2-e] pyrazolo[:1.5-a]pyrimidine compound 11: 8-tert-butyl-6,7-sihydro-5-methyl-8H-pyrrolo[3,2-e] Pyrazolo (I, 5-a) pyrimidine Below margin table Test example 3 Acetylcholine (ACh) in isolated guinea pig trachea
and bronchodilator effect on histamine (His)-induced contraction Male Nihard Rei guinea pigs (400-500 g) were killed by exsanguination from the carotid artery, and the trachea was immediately removed. Takagi et al.'s method (Chem, Pharm 0 ull, 6゜7
16-720 (I958)) was heated to 37 ± 0.5°C with a mixed gas (L95%, 00
25%) aerated rebs-) 1enseleit
Solution (mM: NaCj!, 118; Cβ, 4
．． 75; CaC15,2,54; KHtP04. 1
．． 19; MgS rho, 1.19: NaHC
Os, 12.5:glucose, 1'0.0
) A load of 0.5 g was suspended in an organ bath filled with water, and the isometric tension was recorded.

The test drugs were ACh and old S at 5 x 10-'M each.
(final concentration) of I × 10−' to I
Cumulative administration of X 10-'M (final concentration) was performed, and its dilative effect was investigated.

Efficacy of each derivative when the 50% contraction-inhibiting concentration of pyrrolo[3,2-e]pyrazolo(I,5-a) pyrimidine derivative and theophylline and theophylline's 50% contraction-inhibiting concentration on ACh and former S contraction The ratios are shown in Table 6.

Test Example 4 (Toxicity) An acute toxicity test of the compound (I) of the present invention was conducted in the following manner.

ICR male mice were purchased at the age of 4 weeks and subjected to experiments after preliminary breeding for about 10 days. The test drug was applied to mouse body weight 10
The suspension was suspended in a 1% cell methylcellulose solution at a concentration of 0.1-g/g and administered orally by force using a metal stomach tube.

The mice were fasted for 16 hours from the day before the experiment. The observation period after administration was 14 days, and the survival rate after 14 days was determined by the Litchfield-Wilcochran method. I found the value.

As a result, Compounds 1 and 2 were 2 g/kg or more, and Compounds 3 to 11 were Ig/kg or more.

Example 10 Compound 125g Lactose 130g Crystalline cellulose 20g Corn starch 20g 3% hydroxypropyl 100 - Cellulose aqueous solution Magnesium stearate 2° Compound 1, lactose, crystalline cellulose and corn starch were sieved through a 60 mesh sieve and mixed uniformly. The mixture was placed in a kneading machine, and a 3% aqueous hydroxypropyl cellulose solution was added thereto and kneaded. Next, it was sieved and granulated using a 16-mesh sieve.
It was dried by blowing air at 0°C. After drying, the particles are sized through a 16-mesh sieve, and magnesium stearate is mixed.
It was made into tablets with a diameter of g mm and a weight of 200 mg using a tablet press.

Example 11 Compound 525g Lactose 125g Cornstarch 48.5g Magnesium stearate 1.5g The above ingredients were finely powdered and thoroughly stirred to form a uniform mixture, and 0.2g each was filled into gelatin capsules for oral administration. capsules were obtained.

Example 12 Compound 825g Lactose 130g Crystalline cellulose 20g Corn starch 20g 3% hydroxypropyl 100mj! Cellulose Mecer Liquid Magnesium Stearate 2g Compound 8, lactose, crystalline cellulose, and corn starch were sieved through a 60-mesh sieve, mixed uniformly, put into a kneader, and 3% hydroxypropyl cellulose aqueous solution was added and kneaded. . Next, it was sieved and granulated using a 16-mesh sieve.
It was dried by blowing air at 50°C. After drying, the mixture was sieved through a 16-mesh sieve, mixed with magnesium stearate, and made into tablets with a diameter of 3 mm and a weight of 200 mg using a tablet machine.

〔Effect of the invention〕

The compound (I) of the present invention has excellent vasodilatory effects, coronary flow increasing effects, bronchodilatory effects, antihyperlipidemic effects, platelet aggregation inhibiting effects, antihypertensive effects, Ca++ antagonistic effects, etc., and is safe. It is also useful as a therapeutic agent for cardiovascular system diseases and as a bronchodilator.

Therefore, the therapeutic agent for circulatory system diseases of the present invention containing this compound is suitable for ischemic heart diseases, such as angina pectoris and myocardial infarction, diseases associated with circulatory failure involving the brain, hypertension, arteriosclerosis, and thrombosis. It is useful as a preventive and therapeutic agent for diseases such as diseases. Furthermore, the bronchodilator of the present invention can be effectively applied to the treatment of bronchial asthma and the like.

that's all Applicant: POLA CHEMICAL INDUSTRIES, INC.

Claims (1)

[Claims] 1. The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 and R_2 are hydrogen atoms, straight chains that may have substituents, or Branched alkyl group, cycloalkyl or phenyl group which may have a substituent, or heterocyclic group which may have a substituent; 2-e] Pyrazolo[1,5-
a] Pyrimidine derivative or salt thereof. 2. pyrrolo[3,2-e]pyrazolo[1] according to claim 1
, 5-a] A therapeutic agent for circulatory system diseases containing a pyrimidine derivative or a salt thereof as an active ingredient. 3. Pyrrolo[3,2-e]pyrazolo[1] according to claim 1
, 5-a] A bronchodilator containing a pyrimidine derivative or a salt thereof as an active ingredient.