JPH04139185A - Pyrazolopyridine derivatives - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R<1> is H, OH, lower alkyl, lower alkoxy, lower acyloxy, lower alkylsulfonyloxy or halogen; is 1 or 2; R<2> is H, nitro or acetylamino; X is O or S with the proviso that when X is O and R<2> is H, R<1> is not H). USE:An agent for circulatory organs, such as cardiac. PREPARATION:A compound shown by formula II is made to react with a phenylhydrazine derivative shown by formula III in a solvent such as methanol for 4-18 hours to give a compound shown by formula IV. Then, this compound is subjected to ring closure reaction through dehydration in a solvent in the presence of 0.1-1mol acid catalyst for 6-12 hours to give a compound shown by formula V. Then, this compound is allowed to react with excessive ammonia in a sealed tube for 6-12 hours to give a compound shown by formula I wherein group X is O.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel pyrazolopyridine derivatives. The compound of the present invention has cardiotonic action and is useful as a cardiovascular agent such as a cardiotonic agent.

BACKGROUND OF THE INVENTION The compounds of the present invention are novel compounds. Similar compounds having the same pyrazolopyridine skeleton as the compounds of the present invention are available from Izvestya Academy Nauk Nisnisnisar Selya Himicheskaya.
demii Nauk S S S R5eriya
Khimicheskaya), (10),
1785 (1966), Indian Journal
Of Chemistry (Indian Journal)
al of Chemistry) 12 (6),
570 (1974), Arzneimittel Fotschung
, 13 (8).

688 (1963), JP-A-52-78895, and JP-A-52-83394, all of which are described as synthetic methods or as having analgesic, anti-inflammatory, and antibacterial effects. However, there are no reports regarding the compound of the present invention and its cardiotonic effect.

Problems to be Solved by the Invention An object of the present invention is to provide a novel pyrazolopyridine derivative that has excellent coronary vasodilation and cardiotonic effects and is extremely useful as a cardiovascular agent such as a cardiotonic agent.

Means for Solving the Problems The present invention is based on the general formula [wherein represents a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkokene group, a lower acyloxy group, a lower alkylsulfonyloxy group, or a halogen atom, and g represents 1
or 2, R2 represents a hydrogen atom, a nitro group or an acetylamino group, and X represents an oxygen atom or a sulfur atom. however,
When X is an oxygen atom and R2 is a hydrogen atom, R1 is not a hydrogen atom. ] This relates to a pyrazolopyridine derivative represented by the following.

In the above general formula (1), the alkyl group defined by R1 is an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl group, etc., and the lower alkoxy group defined by R1 is a carbon alkyl group. The lower acyloxy group defined by R1 is an alkoxy group having 1 to 3 carbon atoms, such as methoxy, ethoxy, propoxy group, etc. The lower acyloxy group defined by R1 is an acyloxy group having 1 to 3 carbon atoms, such as acetoxy, propionyloxy group, etc. Examples of the lower alkylsulfonyloxy group include an alkylsulfonyloxy group having 1 to 3 carbon atoms, such as methanesulfonyloxy and ethanesulfonyloxy groups, and examples of the halokene atom include a fluorine atom, chlorine atom, and bromine atom.

The present invention includes a hydrate or any optical isomer of the pyrazolopyridine derivative represented by the general formula (1).

The compound of the present invention has cardiotonic action and is useful as a cardiotonic agent.

The pyrazolopyridine derivative (1) of the present invention can be produced by any of the methods shown in the following reaction scheme A-C. In addition, compounds (2) and (3) are known compounds.

; In the above methods A, B, and C, R1, R2Ω, and X are the same as above. R", Rb1 and Rd are alkyl groups having 1 to 3 carbon atoms, Ro is a lower acyloxy group having 1 to 3 carbon atoms, X
l represents a halogen atom.

However, R'' and R' represent different alkyl groups.

(Method A) The method for synthesizing the pyrazolopyridine derivative which is X-O will be described below.

Compound (2) and the phenylhydrazine derivative represented by general formula (3) are reacted in a solvent for about 4 to 18 hours to obtain a compound represented by general formula (4). The reaction solvent is not particularly limited as long as it does not participate in this reaction.

Generally, alcohols such as methanol, ethanol, and isopropanol are preferably used. The reaction ratio is approximately 1.5% of the compound of general formula (3) to that of compound (2). 0-1
．． It is preferable to use twice the mole. Further, the reaction proceeds at room temperature to the reflux temperature of the solvent, preferably at 10 to 30'C.

Next, the obtained compound of general formula (4) was added in a solvent at 0.1
A dehydration ring-closing reaction is carried out for about 6 to 12 hours in the presence of ~1 mole of acid catalyst to obtain a compound represented by general formula (5). The solvent is not particularly limited as long as it does not participate in this reaction. Generally, benzene, toluene, and xylene are preferably used.

As the acid catalyst, strong acids such as concentrated sulfuric acid, para-toluenesulfonic acid, and benzenesulfonic acid are used. The reaction advantageously proceeds near the boiling point of the solvent, for example at 80-150°C.

Next, the obtained compound of general formula (5) is reacted with excess ammonia in a solvent in a sealed tube for about 6 to 12 hours to form the general formula (
A compound represented by IA) is obtained.

The reaction solvent is not particularly limited as long as it does not participate in this reaction. Generally, ethanol, propatool, dioxane, dimethylformamide (DMF), etc. are preferably used. The reaction temperature generally proceeds advantageously at 90-150°C.

As ammonia, ammonia scum may be blown into a solvent to saturate it, or an ammonium salt such as ammonium carbonate may be dissolved therein.

(Alternative Method 1) When R1 is a lower alkoxy group, hydroxyl group, lower acyloxy group or lower alkylsulfonyloxy group, it can also be synthesized by the following method.

That is, the lower alkoxy derivative (IA-I) is dissolved in 1.
Dealkylation is carried out using about 0 to 3.0 times the molar amount of pyridine hydrochloride to lead to a phenol compound (LA-e). Preferably, no solvent is used. Reaction temperature is 180-250°C
One reaction time is preferably 1 to 5 hours. As the dealkylating agent, boron trichloride may be used in addition to pyridine hydrochloride.

Next, the phenol compound (IA-e) can be used as a raw material to lead to a lower alkoxy compound, a lower alkylsulfonyloxy compound, and a lower acyloxy compound, respectively, as shown below.

Phenol (IA-e) in a solvent at a reaction temperature of 0 to 10°C
, 1. under conditions of reaction time of 2 to 6 hours. When reacted with 0 to 1.5 times the mole of lower alkylsulfonyl chloride,
A lower alkylsulfonyloxy derivative (IA-II) is obtained. Pyridine is preferably used as the solvent.

Similarly, the phenol compound (IA-e) was prepared in a solvent at a reaction temperature of 0.
1.0 to 1 under the conditions of ~50°C and 2 to 8 hours of reaction time.
．． A lower acyloxy compound (IA-III) is obtained by reacting with a 5-fold molar amount of a lower acid anhydride. Pyridine is preferably used as the solvent.

Furthermore, the phenol compound (IA-e) was added in a solvent at a reaction temperature of 2.
1.0 to 1 under the conditions of 0 to 80°C and reaction time of 4 to 8 hours.
．． 5 times the molar amount of lower alkyl halide and 1.0 to 1.
5 times molar amount of base (potassium carbonate, sodium hydrogen carbonate,
sodium hydroxide, triethylamine, etc.) to obtain a lower alkoxy derivative (LA-IV). Dimethylformamide is preferably used as the solvent.

(Method B) Hereinafter, a method for synthesizing a pyrazolopyridine derivative in which X=S will be described.

The compound represented by the general formula (5) is reacted with phosphorus trisulfide in a solvent for about 4 to 8 hours to obtain the compound represented by the general formula (6). The reaction solvent is not particularly limited as long as it does not participate in this reaction.

Generally, solvents such as toluene, xylene, and dioxane are preferably used. The reaction ratio is preferably about 1.0 to 1.5 times the molar amount of phosphorus trisulfide to the compound represented by the general formula (5). The reaction temperature advantageously proceeds at the reflux temperature of the solvent.

As the sulfurizing agent, Lawesson's reagent may be used in addition to phosphorus trisulfide.

Next, the obtained compound of general formula (6) is reacted with ammonia according to the method used in Method A to obtain a compound of general formula (IB).

(Alternative method 2) Next, similarly follow the method used in Alternative method 1 of Method A to obtain a lower alkylsulfonyloxy derivative (IB■), a lower acyloquine derivative (IB-III), and a lower alkoxy derivative (IB-IV), respectively. .

(Method C) Hereinafter, general formula (1) having a substituent other than hydrogen as R2
) The method for synthesizing the pyrazolopyridine derivative will be explained.

Compound (IC-1) is reacted with fuming nitric acid in acetic anhydride for 1 to 5 hours to obtain a nitro derivative (IC-II). The reaction ratio is 1.0 of fuming nitric acid to compound (IC-I).
It is preferable to use up to 1.2 times the mole. Reaction temperature is 0-5
The reaction proceeds advantageously at 0°C, preferably around room temperature.

Next, the obtained nitro derivative (IC-II) was dissolved in acetic acid for 1
．． The reaction is carried out for 4 to 8 hours using 0 to 2.0 times the mole of metallic zinc to reduce the nitro group and acetylate it to obtain an acetylamino derivative (IC-III). The reaction proceeds advantageously at a reaction temperature of room temperature to 130°C, preferably around the boiling point of the solvent.

The novel pyrazolopyridine derivative (1) of the present invention is produced by the above method A-C, which can be easily purified by conventional separation means such as recrystallization, column chromatography, etc.

EXAMPLES Next, the present invention will be specifically explained by referring to Reference Examples and Examples, but the present invention is not limited to these Reference Examples and Examples. .

Reference example 1 Paramethoxyphenylhydrazine hydrochloride (3) 4.2g
Sodium methoxide in 100 methanol solution.
After 1 g was added and stirred for several minutes, 4.0 g of compound (2) was added and stirred overnight at room temperature.

After the reaction, the plate product was collected in the furnace and recrystallized from ethanol.
2.5 g of compound 4C shown in the table was obtained. Melting point 145-14
69C Reference Example 2 Compounds (4a), (
4b), (4d) to (4f) were synthesized.

Reference Example 3 7.0 g of para-toluenesulfonic acid was added to 400 kg of a toluene solution containing 10.0 g of compound (4c) shown in Table 1.
The mixture was heated under reflux for 6 hours. After the reaction, the organic layer was washed with water and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off, the residue was recrystallized from ethanol, and the compound (5C) shown in Table 2 was obtained at 5.0
g (53.5%) was obtained. Melting point: 172-173°C Reference Example 4 Compounds (5a), (
5b), (5d) to (5f) were synthesized.

Reference Example 5 Compound (5c) 1 shown in Table 2. 1.5 g of phosphorus trisulfide was added to 5 g of a 100 ml solution of toluene, and the mixture was heated under reflux for 5 hours. After the reaction was completed, the insoluble matter was heated and the furnace liquid was concentrated. The residue was recrystallized from ethanol to obtain 1.3 g (81.8%) of the compound (6b) shown in Table 4. Melting point 19
5-196°C Reference Example 6 Compound (6a) shown in Table 4 was synthesized in the same manner as in Reference Example 5.

Example 1 Compound (5c) 1 shown in Table 2. ! 5g of ethanol5
A solution of DMF20- and DMF20- was saturated with ammonia and heated in a sealed tube at 100 to 110°C for 10 hours. After cooling the reaction, the solvent was distilled off, and the residue was recrystallized from methanol-acetone to obtain the compound (IA-c) shown in Table 3.
．． 2g (80.3%) obtained. Melting point 255-257°C Example 2 Compound (IA-a) shown in Table 3 in the same manner as Example 1
, (IA-b), (IA-d) to (IAJ) were synthesized.

Example 3 Compound (IA-c) 0. 2.0 g of pyridine hydrochloride was added to 5 g and heated at 200 to 220° C. for 2 hours. After cooling the reaction, ice water was added, insoluble matter was removed in an oven, and the compound (IA-e) shown in Table 3 was obtained by recrystallizing from ethanol.
4g (84.0%) obtained. Melting point: 300° C. or higher Example 4 1.0 g of isopropyl bromide and 0.3 g of potassium carbonate were added to a DMF solution 10 of 0.5 g of the compound (IA-e) shown in Table 3, and the mixture was heated and stirred at 80° C. for 4 days. After the reaction, the solvent was distilled off, and the residue was extracted with ethyl acetate and dried over anhydrous sodium sulfate.

After drying, the solvent was distilled off and the residue was recrystallized from ethanol to obtain 0.3g (51.7%) of the compound (IA-d) shown in Table 3.
)Obtained. Melting point: 233-234°C Example 5 4ml of acetic anhydride was added to a pyridine solution 6- containing 0.5g of compound (IA-e) shown in Table 3, and heated at 70-80°C for 1 hour. The precipitate was poured into reaction-cooled condensate water, removed from the furnace, and then recrystallized from ethanol to obtain the compound shown in Table 3 (IA-
0.45 g (77.8%) of f) was obtained. Melting point 281-2
82 DEG C. Example 6 To 3 ml of DMF solution of compound (IA-e) O, Ig shown in Table 3, 0.06 g of methanesulfonyl chloride and 1 mfi of triethylamine O were added and stirred at room temperature for 10 hours. The precipitate was poured into reaction condensate water, and the precipitate was collected in a furnace and then recrystallized from methanol to obtain the compound (IA-g) shown in Table 3.
12 g (92.3%) were obtained. Melting point 272-273°C Example 7 Compound (6a) shown in Table 4 in the same manner as Example 1, (
6b), the compounds (IB-a) and (IB-a) shown in Table 5
-b) was synthesized.

Example 8 Compound (IB-b) shown in Table 5 in the same manner as Example 3
From this, a compound (IB-c) shown in Table 5 was synthesized.

Example 9 Compound (IB-c) was prepared in the same manner as in Example 5.
IB-d) was synthesized.

Example 10 1-phenyl-3,6-dimethylpyrazolo[4°3-c
] 0.1 μl of fuming nitric acid was added to a solution of 0.5 g of pyridin-4-one in acetic anhydride under water cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction, the precipitate was collected in a furnace and recrystallized from methanol to give 0.4 g of the compound (], Ca) shown in Table 6 (67,5
%)Obtained. Melting point 285-286°C.

Example 11 Acetic acid solution 2 of 0.2 g of the compound (IC-a) shown in Table 6
0.2 g of zinc powder was added to 0- and heated under reflux for 6 hours. After reaction cooling and insoluble materials were separated, the furnace liquid was concentrated, and the resulting residue was recrystallized from isopropyl alcohol to obtain 0.13 g (62.8%) of the compound (IC-b) shown in Table 6. Melting point 300℃ or higher.

The results of pharmacological tests showing the effectiveness of the compound (1) of the present invention are shown below in comparison with a control compound.

<Carotonic effect> (Test method) Guinea pigs (Iartley strain, male) were bled to death, the heart was removed, and the papillary muscle was cut out from the right ventricle.

The specimen was prepared using a modified Tyrode solution (composition in mM: NaCρ 119.8; KCN 5.
4; CaCΩ 2 1.8MgC, Q 2 1.05
; NaH2po40.42; NaHCO322,6; Na2DETA O,05; Curcose 5.0). The specimen was driven by an electrical stimulation device (Nihon Denki Sanei, 3F46) with a frequency of IHz, duration of 5 m5 ec, and a square wave of 1.2 times the threshold voltage, and the contraction tension was determined by an isometric transducer (Ugobasile, 7004).
It was measured by The test drug was dimethyl sulfoxide (DM
The test drug was dissolved in SO) and added to a final concentration of 2%, and the effect of the test drug at a 1X10-4 molar concentration was expressed as an increase rate (6%) in the contractile tension of papillary muscles. The results are shown in Table 7.

Effects of the Invention As is clear from Table 7, the compound (1) of the present invention has a stronger cardiotonic effect than the control compound.

No. table (Note) 1) Concentration 3 x 10-5M Concentration lx105M 1-phenyl-3,6-cyme Chilpyrazolo [4,3-C) pyridin-4-one (that's all)

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is a hydrogen atom, a hydroxyl group, a lower alkyl group,
a lower alkoxy group, a lower acyloxy group, a lower alkylsulfonyloxy group or a halogen atom, l is 1 or 2;
, R^2 represents a hydrogen atom, a nitro group or an acetylamino group, and X represents an oxygen atom or a sulfur atom. However, when X is an oxygen atom and R^2 is a hydrogen atom, R^1 is not a hydrogen atom. ] A pyrazolopyridine derivative represented by.