JPS6310788A - 3-aminopyrazolo(3,4-d)pyrimidine derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is (substituted) aryl or heteroaryl; R<2> is lower alkyl; R<3> and R<4> are H or lower alkyl; R<5> is H, lower alkyl or acyl; X is lower alkylene which may contain a heteroatom; the broken line represents 2 double bonds on a pyrazole ring; R<5> is bonded to either one of the 1- or 2-position] or a salt thereof. EXAMPLE:5-Ethyl-3-methylamino-7-( 4-methylbenzyl )pyrazolo[3,4-d]pyrimid ine-4,6(5H,7H)-dione. USE:A treating and preventive agent for mental symptoms including dementia symptoms caused by cerebral apoplexy, head external injury and brain atrophic disease, neurosis, etc. For example, useful for preventing and treating amnesia, hyermnesia, disorientation, affect incontinence and behavior anomaly. PREPARATION:For example, a compound of formula II is reacted with a compound of the formula R<3>-NCS to give a compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention provides novel 3-aminopyrazolo [3
, 4-d] pyrimidine derivative.

Conventional technology Patent applications have been filed for 3-aminopyrazolo[3,4-d]pyrimidine derivatives having diuretic, hypotensive, analgesic, and anti-inflammatory effects [JP-A-53-31694 and JP-A-61-5082. Publication] is a 3-aminopyrazolo J3. having an alkyl group substituted with an aralkyl group or a heterocycle at the 7-position. 'I d]pyrimidine derivatives are completely unknown.

Problems to be Solved by the Invention The present invention is based on its excellent effect of activating brain function and metabolism, and is useful for the treatment and prevention of dementia symptoms caused by cerebral apoplexy, head trauma, cerebral atrophy disease, etc. , and conventional compounds are all <R4 chemical) which provides compounds with 114 structures.

Means for solving the skin problem The present invention has the formula (+)
R3 and R4 each represent hydrogen or a lower alkyl group, R5 represents hydrogen, a lower alkyl group or an acyl group, and X represents a lower alkylene group which may contain a heteroatom. The broken line indicates that there are two double bonds in the pyrazole ring, and R5 is bonded to either the 1st or 2nd position, and provides a compound represented by the following and a salt thereof.

Regarding the above formula (1), the aryl group represented by R1 includes, for example, a phenyl group, a naphthyl group, and preferably a phenyl group. The phenyl group is 1-3f[! Examples of I include halogen (e.g., fluorine, chlorine, bromine), lower<C+-,)alkyl (e.g., methyl, ethyl), lower (C,-4)alkoxy (e.g., methoxy,
ethoxy), nitro, amino, N-lower (C1-4) alkylamino (e.g. methylamino), N, N-
di-lower (C,-,)alkylamino (e.g., dimethylamino), hydroxy, trifluoromethyl, carbamoyl, N-lower (CI-,)alkylcarbamoyl (e.g., N
-methylcarbamoyl), N,N-dilower (CI-, )
It may be substituted with a substituent such as alkylcarbamoyl (eg, N,N-dimethylcarbamoyl).

Among these substituents, halogen, lower alkyl, lower alkoxy, nitro, amino and the like are preferred, and halogen is more preferred. The substitution position is not particularly limited and may be any of the ortho, meta, and rose positions, but when the substituent is a halogen, the meta position is preferred.

Examples of the heteroaryl group represented by R1 include cinnolinyl, furyl, isobenzofuranyl, isodeazolyl, isoogisazolyl, naphdyridinyl, phthalazinyl, pyrazinyl, and pyridazinyl.

Pyridyl, pyrimidinyl, quinazolinyl, quinolyl.

Quinoxalinyl, chenyl. Oxygen atoms such as pyridinio, quinachirinio, quinolinio, and quinachirinio.

Examples include monocyclic or bicyclic heteroaromatic rings containing 1 to 3 gI of sulfur atoms and nitrogen atoms. The monocyclic heteroaromatic ring is preferably a 5- or 6-membered ring, and the bicyclic heteroaromatic ring is preferably a fused heteroaromatic ring consisting of a 5- or 6-membered heteroaromatic ring and a benzene ring. Among the heteroaryl groups, pyridyl and chenyl are preferred. The heteroaryl group may have the same substituent as the phenyl group described above.

Examples of the lower alkyl group represented by R' include methyl, ethyl, propyl, isopropyl, and butyl. Examples include alkyl groups having 1 to 4 carbon atoms, such as isobutyl, 5ec-butyl, and tert-butyl, among which propyl is preferred.

As the lower alkyl group represented by R3 or R4,
For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl. Examples include alkyl groups having 1 to 11 carbon atoms such as 5ec-butyl and tert-butyl.

Among compound (1), R3 is lower alkyl, and R4
is hydrogen, and compounds in which R3 is methyl or ethyl and R4 is hydrogen are more preferred.

The lower alkyl group represented by R5 is preferably an alkyl group having 1 or 2 carbon atoms (eg, methyl, ethyl).

Examples of the acyl group represented by R5 include lower alkanoyl groups having 1 to 5 carbon atoms such as acetyl, propionyl, and butyryl, and lower (CI-4) alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl.

Examples of the lower alkylene group represented by -7 branched alkylene groups, among which methylene. Ethylene is preferred, and methylene is more preferred.

The lower alkylene group containing a hetero atom represented by X is, for example, the formula % (%) [where m represents 2 or 3 and n represents an integer from θ to 3].

Y is oxygen atom, sulfur atom, imino, or N-low ff1
(c+-4) represents alkylimino] and the like.

Among the above compounds, l' (+ optionally substituted phenyl group (more preferably m-chlorophenyl),
R''h<cs-t alkyl group (more preferably propyl), R3 and R4 are each hydrogen or C1-2 alkyl group (more preferably R3 is methyl).

Compound (1) in which R4 is hydrogen), R5 is hydrogen or a C2-4 alkanoyl group (more preferably hydrogen), and X is methylene or ethylene (more preferably methylene)
is more preferable.

Salts of compound (I) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and, for example, acetate, tartrate, citrate, fullerate. Organic acid salts such as maleate: Any pharmacologically acceptable salts may be mentioned.

Further, R1 in compound (1) may be, for example, viridine f
, quinaxalinio, quinoxalinio, etc., in the case of a heteroaryl group having a tetravalent nitrogen atom, it may form a salt with an anion of the inorganic acid or organic acid, and these salts are also included in the present invention.

The compound represented by the above formula (1) can be produced, for example, by the following five methods.

x-R・Support-1?・(II)
(1'a) [where rt l ,
R! , rt 3 and X have the same meanings as above
R'X-R'(I
[I) (Ia) [wherein,
Rl, R! , R3 and X have the same meanings as above]
-Rl'X -R+ (n) (Ib) [wherein,
W and Z each represent a halogen, R3 and R4 each represent a lower alkyl]λ-R・
★-R・(I c) (
l d) [In the formula, R3 and R4 each represent hydrogen or a lower alkyl group, and R', R2, rt5 and X are as defined above a] (re) (IV) (V)
(I f) [In the formula, Bz represents benzyl, W represents halogen, and other symbols have the same meanings as above] The reaction of (a) above is performed using isothiocyanates per mol of compound (n). It is preferable to use about 1 to 5 moles of (IN'-NCS) and use dimethylformamide, pyridine, dimethylacetamide, dimethylsulfoxide, etc. as a solvent. The reaction conditions are preferably 50°C to 130°C for about 3 to 40 hours. Further, it is more preferable to initially react at about 50°C to 70°C for about 1 to 3 hours, and then raise the temperature to about 90°C to 130°C for a time window of about 3 to 40 hours.

The reaction product can be easily obtained as a crystal by adding an alcohol such as methanol or ethanol or a hydrous alcohol after the reaction is completed.

In reaction (b), it is preferable to carry out a heating reaction of compound (III) using a solvent such as dimethylformamide, tumedylacetamide, pyrinone, or dimethylformoquine. The reaction conditions are preferably about 50'C to 130C and a time window of about 3 to 40 hours. The reaction product can be obtained in the same manner as described above.

In reaction (C), it is preferable to add phosgeneiminium chloride to compound (II) in a solvent such as chloroform or methylene chloride, and to react the mixture under reflux and heating for 5 hours at 10°C. The reaction product is obtained by processing in the same manner as described above.

In reaction (d), compound (I c) is alkylated or acylated to obtain compound (d), and the alkylating agent is an alkyl halide, and the acylating agent is an acid anhydride or an acid halogen. compounds, halogenated alkyl carbonates, etc. are used. These reagents are compound (I c)
It is advantageous to use about 1 to 5 moles per 1 mole and to carry out the reaction in the presence of a deoxidizing agent. As a deoxidizing agent, potassium carbonate, sodium carbonate, triethylamine. Examples include pyridine, and using pyridine, dimethylformamide, acetonitrile, etc. as a solvent,
It is preferable to allow the reaction to take place at a temperature of 1 to 0 hours.

In reaction (e), the compound (Ie) obtained by reactions (a) and (b) is debennorized, the obtained compound (rV) is converted into compound (V) with a halogenating agent, and then various By reacting with a nucleophile, compound (If)
This is what you get. Examples of the debenzylation method include a reductive debenzylation method, a trimedelsilyl iodide method, and a method using hydrobromic acid. The reductive debenzylation method is preferably carried out in a hydrogen stream, in the presence of a suitable catalyst (for example, palladium on carbon, etc.), at about 10° C. to 80° C., under normal pressure or increased pressure, in a solvent such as alcohol. In addition, in the trimethylsilyl iodide method, trimedelsilyl iodide is added in a solvent such as acetonitrile at room temperature,
It is preferable to react at about 10°C to 80°C for 1 to 20 hours. Further, compound (Ie) and sodium iodide are suspended in acetonitrile, trimethylsilyl chloride is added dropwise at room temperature with sufficient stirring, and the mixture is heated for 1 to 20 minutes at about IO℃ to 80℃.
This is preferable because the reaction takes a long time. The obtained alcohol is halogenated using thionyl chloride, oquine phosphorus chloride, etc. as a halogenating reagent in the presence of a base catalyst (e.g., pyridine, triethylamine, etc.) in an ordinary organic solvent (e.g., chloroform, methylene chloride, etc.). Preferably, the temperature is 10°C or higher. The reaction between compound (V) and a nucleophile is carried out using a nucleophile (for example, an amine [R' N I4 (CHt ) n-R1 (in the formula, R', n are the same Q! as above, 'R' represents hydrogen or lower alkyl), alcohols [+1O-(C1l
l) -R'co or thiols [1-[S-(CHt)
11′]) is preferably reacted at lθ°C to reflux/reflux heating for 20 hours. At this time, a common base catalyst may be present. The reaction product can be obtained by adding hydrous alcohol or the like to the reaction solution and precipitating it as crystals. In the case of an amino-substituted product, it can be easily obtained as a crystal by first extracting it as a hydrochloride into an aqueous layer and neutralizing it with an alkali.

Among these compounds, (It) and (III) are new compounds and can be produced, for example, by the following method.

(Left below) X-R' (■) (■) X -R' X -R'
(II) (III) [In the formula, R1, R1, R3 and
mie)691.

142 (196(i) and Hemische Berichte (Che
Mische Berichte) 95, 1597
(1962).
1) is reacted with an alkylating agent in a conventional organic solvent (for example, tumedelformamide or acetonitrile) in the presence of an inorganic base such as potassium carbonate or sodium carbonate. The reaction conditions are 106C-100℃ and 2 to 20℃.
It is best to leave it for about an hour. As an alkylating agent, use chloride, chloride, etc. It is also possible to use it as an iodine form by pre-treating with sodium chloride etc. Compound (■ ) with hydrazine in a common organic solvent (e.g. ethanol or methanol).
It is reacted with hydrazine which may contain water. The reaction conditions are preferably 10° C. to reflux heating for about 1 to 3 hours. The reaction between compound (II) and isothiocyanates (R"NC5) is carried out at 10°C to 60°C for about 1 to 5 hours using a usual solvent (e.g. dimethylpolamide, pyridine, acetonitrile, etc.) Compounds (■), (II) and (ill) can be easily isolated and purified by conventional methods.

The salt of compound (I) may be obtained by the reaction itself to produce compound (1), but it can also be obtained by adding an acid to compound (1).

Effect The 3-aminopyrazolo[3,4-dj pyrimidine derivative (1) and its salts of the present invention have been shown to be effective against stroke 1 in mammals including humans, based on their brain function/metabolic activation effects.
It is useful for the treatment and prevention of psychiatric and neurological symptoms, including dementia symptoms, caused by head trauma or brain atrophic diseases (such as Alzheimer's disease), such as amnesia, memory impairment, disorientation, and emotional incontinence. , can be used to prevent and treat behavioral abnormalities that reduce spontaneity and motivation. Also, the compound (
I) has low toxicity [LD50 (oral): I OOOmg/
kg body weight or more (rats)], and when compound (1) is used as such a pharmaceutical, it can be prepared by itself or mixed with an appropriate pharmacologically acceptable carrier, excipient, or diluent, and one tablet of powder or granules is prepared. It can be safely administered orally or parenterally in the form of capsules, injections, skewers, ointments, and the like. The dosage varies depending on the target disease, symptoms, subject, administration method, etc., but the usual dose is 1 to 50
It is preferable to administer about 1-20 mg/kg (body weight), about 1 to 3 times a day, about 1 to 20 mg/kg (body weight), 1
It is more preferable to administer it about 1 to 3 times a day.

EXAMPLES The present invention will be explained in more detail by referring to Reference Examples, Examples and Formulation Examples below, but the present invention should not be limited to these.

Reference example-1 3-butyl-6-hydrazino-1-(jl-methquinbenzyl)uracil 3-butyl-6-chlorouracil (5.0 g, 24°6
+++M) was dissolved in dimethylformamide (5Q++J) and 4-methoxybenzyl chloride (4,651f
.

32+++M) and potassium carbonate (4.4g, 32mM)
and potassium iodide (0.17g, 1mM) were added,
Room 1. ', 5 for 5 hours. After the mixture was concentrated under reduced pressure, the residue was dissolved in chloroform (LOOY4) and water (LOOY4).
The organic layer was washed with water, dried, and concentrated to dryness. The obtained brown wrap was coated with silica gel (LOOG).
) using flash chromatography (eluent.

Purification with chloroform) gave 3-butyl-6-[true 1-(4-methoxybenzyl)uracil] as an oil. The obtained oil was dissolved in ethanol (50d), and hydrazine hydrate (201 liquid) was added at room temperature.
The mixture was left stirring for an hour. The crude crystals obtained by condensing the reaction solution under reduced pressure were washed with water and then recrystallized from 70% ethanol to obtain pale yellow crystals (4.23 g, 54%). Melting point 167-1
70℃ Elemental analysis value: C (%) as C+aH0N403■4(
%)N(%) Calculated value: 60,36. 6.97: 17.60
Experimental value: 60.4g, a, gg; 17.5
The following compound was obtained in the same manner as in Example 1.

(Left below) Reference example -X-R' R1 melting point ('C) Yield (%) 1-c++, -o-oue Bu 167
-170 542 -CIlIGM13 Et
170-172 693 -C1l￥D p r
193-196 50.1 -CL-Qo, Pr
135-137 765-cut-o-cc
Pr 205-208 786 -C1ltCN
Pr 95-98 647 -cu, -
Q r'r 110-113 32s-cut
<'>Pr 193-195 729 -CIIt
CII*@Pr 133-135 591o
-co, co, ocu, @ Pr 120-12
2 84u -co, -J■ 13u 17
5-177 6612 -cutQcc BLI
173-175 7313 -C:”,”a
nu 185-190 41114 -CIlt
GNot Bu147-149” 4 In the above table, M
e, Et, Pr and Bu are methyl, ethyl,
Indicates propyl and butyl.

Reference Example-15 1-(3-chlorobenzyl)-6-(4-methyldiosemicarbazide)-3-propyluracil! -(3-chlorobenzyl)-6-hydrazino-3-propyluracil (4.0 g, 13 mM) and methyl isodiocyanate (
1,16, 17n+M) in dimethylformamide [D
MF] (15 breweries) at 50°C for 5 hours. The crude crystals obtained by concentrating the reaction solution to dryness were recrystallized from DMF/methanol/water to give colorless crystals (4.15 g, 84%).
I got it.

Melting point 221-223°C Elemental analysis value: CIeIEtoCQNsOtS as C(
%) H(%'I 'N(%) Calculated value: 50.
32. 5.28; Hl, 34 experimental value: 50.
61; 5.30; 18.19 Reference example-16 5-butyl-7-(2-hydroxyethyl)-3-medylaminopyrazolo[3,4-d]pyrimidine-4,6(
5H,7II)-dione 7-(2-penzyloxyethyl)-5-butyl-3-
Methylaminopyrazolo[3,4-d]pyrimidine-4,
6(5H,7H)-dione (1.0g, 2.7mM) and sodium iodide (3L 20mM) were suspended in acetonitrile (20tnl) and stirred thoroughly at room temperature.
Trimethylsilyl chloride (2.6g, 20mM) was added dropwise. The mixture was stirred at room temperature for 2 hours. The brown reaction solution was poured into ice water, and the resulting crystals were mixed with DMF/methanol/
Recrystallization from water gave pale yellow crystals (0.3 g, 40%).

Melting point 248-253℃ Elemental analysis value: C+tl11aC (%) as N50a■
] (%) N (%) Calculated value: 51.23. 6.81. 24.90 Experimental value: 51.09; 6,93. 24.71 Reference Example-17 5-Butyl-7-(2-chloroethyl)-3-methylaminopyrazolo[3,4-d]pyrimidine-! 1.

6(51-L71D-dione 5-butyl-7-(2-hydroxyethyl)-3-methylaminopyrazolo[3,4-d-copyrimidine-4,6(
5H,710-dione (2.5g, 8.9mM) was suspended in chloroform (301n1) and pyridine (4-15
0mM) and thionyl chloride (3.7m, 50mM) were added at room temperature. The resulting reaction solution was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained silica was poured into ice water to obtain a colorless powder. Recrystallization from DMF/methanol/water gave colorless crystals (2.5 g, 94%).

Melting point 270-272℃ Elemental analysis value: C,, I-1, mCQN60* as C(
%) 1-1(%)N(%) Calculated value: 48.0g, 6.05. 23.36
Experimental value: 48.21. 5.82. 23.39 Example-1 5-ethyl-3-methylamino-7-(4-methylbenzyl)pyrazolo[3,4-d]pyrimidine-4,6(5
1,1,7 summer-■)-dione 3-ethyl-6-hydrazino-1-(4-methylbenzyl)uracil (5g, 1
8 mM) and methylisothiocyanate (3.7 ml!
, 55mM) in DMF (Company 50) at 90°C for 14 hours and then at 110°C for 14 hours. Water (IOd)
was added, and the precipitated crystals were recrystallized from DMF/ethanol/water to give colorless needle crystals (4.49 g, 79 g).
%) was obtained.

Melting point 〉300℃ Elemental analysis value: C11lH1°N, 0. as C(%)H
(%) N (%) Calculated value: 61.33. 6.11. 22.35 Experimental Value 2 Old, 29. 5.93; 22.1? Example-2 5-ethyl-2-methyl-3-methylamino-7-(4
-methylbenzyl)-2H-pyrazolo[3°4-d]pyrimidine-4,6(51■,7H)-dione 5-ethyl-3-methylamino-7-(4-methylbenzyl)-2
8-pyrazolo[3,4-d]pyrimidine-4,6(5H
,7l-1)-dione (0.5g, 1°6mM), methyl iodide (0.46g, 3.2mM) and potassium carbonate (0.45g, 3.2mM) in DMF (8d).
The mixture was stirred at 0°C for 30 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (15 g, chloroform). The obtained crystals were recrystallized from 70% ethanol to give colorless needle crystals (0.28 g, 54%
) was obtained.

Melting point 175-176℃ Elemental analysis value: CI? ! -1t t N s Ot
As C (%) H (%) N (%) Calculated value: 62.37. 6.47: 21.39
Experimental value: 62.29. 6.39. 21.51 Example-3 2-acetyl-5-ethyl-3-methylamino-7-(
4-methylbenzyl)-21-1-pyrazolo[3,4-
d] Pyrimidine-4,6(5N,7H)-dione 5-
Ethyl-3-methylamino-7-(4-methylbenzyl)pyrazolo[3,4-cDpyrimidine-4,6-(5H
,710-dione (0.5 g, 1.6+++M) and acetic anhydride (0.33 g, 3.2 mM) were reacted in pyridine (5%) at 60° C. for 18 hours. The reaction solution was concentrated to dryness,
The residue was purified by silica gel chromatography (15 g, chloroform), and the resulting crystals were recrystallized from acetone/isopropyl ether to give colorless needles (0.43 g).
, 76%).

Melting point 185-187℃ Elemental analysis value: Cl* Ht IN s OaC (%)
H (%) N (%) Calculated value: 6G, 83. 5.96. 19.71 Experimental value: 61,06. 5.98; 19.52 Example-4 7-benzyl-3-methylamino-5-propylpyrazolo'[3,4-d]pyrimidine-4,6 (5H.

7tl)-dione -benzy-6-hydrazino 3-propyluracil (2.0g, 7.3mM) and methylisothiocyanate (1.5d, 22mM) in DMF' (20 volumes) for 12
The mixture was stirred at 0°C for 20 hours. Ethanol (20 ml) was added and the resulting crystals were recrystallized from DMF/ethanol to give colorless needles (1.6 g, 70%).

Melting point 307-310℃ Elemental analysis value: C1el-11eNsOtC (%)
I-((%) N(%) Calculated value: 61.33.
6.11. 22.35 experimental value: 61.40:
6.02;, 22.25 Example-5 7-(2-chlorobenzyl)-3-methylamino-5-
Propylpyrazolo[3,4-d]pyrimidine-4,6(
51-1,7H)-dione 1-(2-chlorobenzyl)-6~hydrazino-3-propyluracil (1,33g, 4.3mM) and methylisothiocyanate (0,9m, 12.9mM) in DMF
(20d), the reaction was carried out by heating at 120°C for 20 hours. Methanol (10d) was added and left to cool, and the resulting crystals were recrystallized from DMP/methanol to give colorless crystals (0,
64g, 42%) was obtained.

Melting point 〉300℃ Elemental analysis value 2 Cl1■-11, Cl2N, Of C (%) H (%) N (%) Calculated value 2 55.25. 5.22. 20.14 Experimental values: 55.53; 5.42; 20. Q3 Example-6 7-, (3-chlorobenzyl)-3-methylamino-5
-propylpyrazolo[3,4-d]pyrimidine-4,6
(5tI, 71()-dione ■-(3-chlorobenzyl)-6-hydrazino-3-propyluracil (3,0 g, 9.6 mM) and methylisothiocyanate (2,2&,Il, 32 mM) in DMr.
;' (30d), the reaction was carried out by heating at 120° C. for 27 hours. 50% methanol (10d) was added to the reaction solution, and the resulting crystals were recrystallized from D~IF/methanol to give colorless crystals (1.22 g, 36%).

Melting point: 263-265°C Elemental analysis: C,, H, aCσN, 0. as C (%)
I (%) N (%) Calculated value: 5
5.25. 5.22. 20.14 Experimental value: 55
．． 34. 5.31. 20.12 Example-7 7-(3-chlorobenzyl)-3-methylamino-5-
Propylpyrazolo[3,4-d]pyrimidine-4,6(
5H,7H)-dione 1-(3-chlorobenzyl)-6-(4-methylthiosemicarbazido)-3-propyluracil (3°81g,
10mM) DMF (401n1) solution at 100℃ for 2 hours.
Stirred for 0 hours. 50% methanol (20d) to the reaction solution
was added and left to cool, and the resulting crystals were recrystallized from DMP/methanol to give colorless crystals (2°49g, 72%
) was obtained.

Melting point 263-265℃ Elemental analysis value: C, 8H, 8CI2NSO, C (%
) H (%) N (%) Calculated value: 55.25. 5.22. 20.14 Experimental value・55.29. 5.1111: 20.13
Example-8 7-(4-chlorobenzyl)-3-methylamino-5-
Propylpyrazolo[3,4-d-copyrimidine-4,6(
50,7H)-dione! -(4-chlorobenzyl)-6-(4-methylthiosemicarbazide)-3-propyluracil (4°8g, 1
2.6mM) in DMF (50d) at 100°C.
0 hours [P] 50% methanol (20d) to the reaction solution
was added and allowed to cool, and the resulting crystals were recrystallized from DMF/methanol to give a colorless crystal (2.8 g, 50%
) was obtained.

Melting point: 305-307°C Elemental analysis: 〇161-1. ．． C( as CQNSO2
%) H (%) N (%) Calculated value: 55.25; 5.22. 20.14
Experimental value: 55.21. 5.25. 20.23 Example-9 7-(4-fluorobenzyl)-3-methylamino-5
-propylpyrazolo[3,4-d]pyrimidine-4,6
(5H,7H)-dione 1-(4-fluorobenzyl)-6-hydrazino-3-
Propyl uracil (1,5L, 5.1mM) and methylisothiocyanate (1,2L, 17mM) were dissolved in DMF (20L, 17mM).
In +d), the reaction was carried out by heating at 120°C for 24 hours. 50% methanol (1, Od) was added to the reaction solution, and the resulting crystals were recrystallized from DMP/methanol/water to obtain pale yellow crystals (0.62 g, 36%). .

Melting point 262-265℃ Elemental analysis value: C (%) as C1el-11sFNsO2
) l-1 (%) N (%) Calculated value: 58.0
0; 5,48; 21,14 Experimental value: 57.
73. 5.37. 21.39 Example-10 7-(4-bromobenzyl)-3-methylamino-5-
Propylpyrazolo[3,4-d]pyrimidine-4,6(
51171-1)-dione 1-(4-bromobenzyl)-6-hydrazino-3-propyluracil (4,15 g, 11.8 mM) and methylisothiocyanate (2,77 J, 40 mM) were dissolved in DMF (50 ml). ) for 24 hours at 120°C. 50% methanol (15d) was added to the reaction solution, and the resulting crystals were recrystallized from DMF/methanol to obtain colorless needle crystals (2.19 g, 47%).

Melting point 308-310℃ Elemental analysis value: C+el[+eB rNso 2 as C
(%)■((%) N(%) Calculated value: 4g, 99. 4.63: 17.85
Experimental value: 48.59. 4.52. 17.98 Example-11 3-Medylamino-7-(4-pyridylmethyl)-5-
Propylpyrazolo[3,4-d]pyrimidine-4,6(
51-1,7H)-dione 6-hydrazino-1-(4-pyridylmethyl)-3-propyluracil (1,5g, 5.7mM) and methylisothiocyanate CI, 55J, 23mM) in DMP (
15++j2) at 90°C for 14 hours and then at 110°C
The mixture was heated and reacted for 14 hours. 50% methanol (10d
) and left to cool, the resulting crystals were recrystallized from DMF/ethanol/water to obtain -it colored needles (1.02 g
, 57%).

Melting point 〉300°C Elemental analysis value: C + sl' (+.C (%) as N80.
■4(%)N(%) Calculated value: 57.31; 5.77, 26.73
Experimental value: 57.16: 5.57. 26.50 Example-12 3-Medylamino-7-(3-pyridylmethyl)-5-
Propylpyrazolo[3,4-d]pyrimidine-4,6(
51(,7H)-dione 6-hydrazino-1-(3-pyridylmethyl)=3-propyluracil (0.7 g, 2.66 mM) and methylisothiocyanate (0.7!, I O, 3 mM). D'
MF' (10 AM) at 90°C for 14 hours, then 11
The reaction was heated at 0° C. for 14 hours. 50% methanol (l
DMF/
Recrystallized from ethanol/water to give colorless needles (0.5g
, 60%).

Melting point 〉300℃ Elemental analysis value: C (%) as C+sH+5NaOt
■t(%)N(%) Calculated value: 57.31. 5.77, 26.73 Experimental value: 57.20. 5.60. 26.92 Example-13 3-Methylamino-5-propyl-7-(2-dienylmethyl)pyrazolo[3,4-d]pyrimidine-4,6(
D
Ml;' (30°C) for 5 hours at 60°C, and then heated at 110°C for 5 hours.
Stirred at ℃ for 12 hours. Methanol (1' OttJl
) was added and left to cool, resulting in crystals D M P /
Recrystallized from methanol to give colorless crystals (0.9 g, 44
%) was obtained.

Melting point 〉300℃ Elemental analysis value: C (%) as C14HBNsOtS (
(%) N (%) Calculated value:' 52.65. 5.36. 21.93
Experimental value: 52.6B, 5.02. 21
．． 96 Example-14 3-Methylamino-7-phenethyl-5-propylpyrazolo[3,4-d]pyrimidine-,1,6 (5H.

7l-1)-dione 6-hydrazino-1-phenethyl-3-probyluracil (1.5 g, 5.2 mM) and methylisothiocyanate (1,1 dimethyl, 16 mM) in DMP (15-) solution The mixture was stirred at 60°C for 2 hours and then at 120°C for 15 hours. 50% methanol (1, Od) was added, and the precipitated crystals were recrystallized from DMF/methanol to give colorless crystals (0.7 g, 41%).

Melting point 256-258°C Elemental bone Ffr value: Cl? ! −1t + Ns
Ot as C (%) H (%) N (%) Calculated value: 62.37. 6.47. 21.39 experimental value + 62.40. 6.03. 21.64 Example-15 3-methylamino-7-(3-phenylpropyl)-5
-Propylpyrazolo[3',4-d]pyrimidine-4゜6(51-1,7l-f)-dione 6-hydrazino-1
-(3-phenylpropyl)-3-propyluracil (
1.7g, 6.3mM) and methylisothiocyanate (
0,8 #ll! , 12mM) to DMr;'(20πJ)
The mixture was stirred at 60°C for 2 hours and then at 100°C for 12 hours. Methanol (lod, ) was added and after cooling, the precipitated crystals were recrystallized from DMF/methanol to give colorless needles (0.9 g, 47%).

Melting point: 267-269℃ Elemental analysis value: C+5l-1taNsO* as C (%)
H (%) N (%) Calculated value: 63.32. 8.79. 20.51 Experimental value: 63.1g, 6.59; 20.3g
Example-16 3-methylamino-7-(2-benzyloxyethyl)
-5-propylpyrazolo[3,4-d]pyrimidine-4
,6(5H,711)-dione 6-hydrazino-1-(
2-benzyloxyethyl)-3-propyluracil (
2.0g, 6.3mM) and methylisothiocyanate (
1,2 diluted, 18mM) in DMF (20Ml) at 60°C.
The mixture was further stirred at 100° C. for 20 hours. 50%
Methanol (10d) was added and the mixture was allowed to cool, and the precipitated crystals were recrystallized from DMF/methanol to obtain colorless prism-like crystals (1.39 g, 62%).

Melting point 224-226°C Elemental analysis value: C+ @Ht 3 N s C (%) H (%) N (%) Calculated value: 60.49. 6.49; 19.59
Experimental value: 60.74. 6.41; 19.53 Example-17 Two-benzyl-2-butyryl-3-medylamino-5-
Propyl-2H-pyrazolo[3,4-d]pyrimidine-
4,6(5H,78)-dione 7-benzyl-3-methylamino-5-propylpyrazolo[3,4-d]pyrimidine-4,G(5H.

7■()-Dione (0.7g, 2.2mM) and butyric anhydride (0°71g, 4.5mM) were mixed with pyridine (10y+12
) for 24 hours at 60°C. The reaction solution was concentrated to dryness, and the residue was purified by silica gel column chromatography (20 g, chloroform). The obtained crude crystals were recrystallized from acetone/isopropyl ether to give colorless needle crystals (0,61
g, 71%) was obtained.

Melting point 138-139°C Elemental analysis value: Cx o Ht s N s C (%) H (%) N (%) as O3 Calculated value: 62.65. 6.57. 18.26 Experimental value: 62.82. 6.64. 18.41 Example-18 2-acetyl-7-(3-chlorobenzyl)-3-methylamino-5-propyl-2l-1-pyrazolo[3,4
-dcopyrimidine-4,6(5H,7H)-dione 7-(3-chlorobenzyl)-3-methylamino-5-
Propylpyrazolo[3,4-d]pyrimidine-4,6(
5H,7H)-dione (1.0g, 2.9mM) and acetic anhydride (1,Ome, 9.8mM) were dissolved in pyridine (15yf
fl) at 80° C. for 5 hours. The reaction solution was concentrated to dryness, water (LOY4) was added to the residue, and the precipitated crude crystals were recrystallized from chloroform/ethyl ether to obtain colorless needles (0.95 g, 85%).

Melting point 169-171'C Elemental analysis value: CIatlzoCI2NsC): + C (%) I ((%) N (%) Calculated value: 55.46. 5.17: 17.96
Experimental value: 55.13. 5.19. 18.51 Example-19 7-(3-chlorobenzyl)-2-isobutyryl-3-
Methylamino-5-propyl-2H-pyrazolo[3,4
-dlpyrimidine-4,6(51-1,7)1)-dione 7-(3-chlorobenzyl)-3-methylamino-5-
Propylpyrazolo[3,4-d]pyrimidine-4,6(
514,7H)-dione (0.7g, 2.0mM) and isobutyric anhydride (1.0g, 6mM) in pyridine (10g)
The mixture was stirred at 80° C. for 5 hours. The reaction solution was concentrated to dryness,
Water (10d) was added to the residue, and the precipitated crude crystals were recrystallized from chloroform/ether to give colorless needles (0.5g).
, 59%).

Melting point 154-156℃ Elemental analysis value: C7゜C (%) as Ht+CeN5Os
H (%) N (%) Calculated value: 57.48. 5.79. 16.76 Experimental value: 57,20. 5.70: 16.97 Example-20 7-(3-chlorobenzyl)-2-methoxycarbonyl-3-methylamino-5-propyl-21(-pyrazolo[3,4-dcopyrimidine-4,G (514゜7l-1
)-dione 7-(3-chlorobennor)-3-methylamino-5-
Propylpyrazolo[3,4-dlpyrimidine-4,6(
511,71-1)-dione (1.0g, 2.9mM)
and triethylamine (1,2d, 8.6mM) were suspended in dioxane (50d), and methyl chloroformate (0,66d, 8.5mM) was added dropwise with stirring, followed by 2 hours at room temperature.
The mixture was stirred for 0 hours. The reaction solution was concentrated to dryness, and the residue was diluted with water (1
0-) was added, and the precipitated crude crystals were recrystallized from chloroform/methanol to give colorless crystals (1°0g, 8(i%)
I got it.

Melting point: 164-166°C Elemental analysis: c, tr. C (%) as C-N504
) l-1C%) N (%) Calculated value: 53.2
7. 4.97. 17.26 Experimental value: 53.44
．． 4.91. 17.43 Example-21 2-butyryl-7-(3-chlorobenzyl)-3-methylamino-5-propyl-2H-pyrazolo[3,4-d
Copyrimidine-4,6(5H,7H)-dione 7-(3-chlorobenzyl)-3-methylamino-5-
Propylpyrazolo[3,4-d]pyrimidine-4,6(
5H,71-1)-dione (0.7g, 2mM) and butyric anhydride (0.64g, 4a+M) were stirred in pyridine (10d) at 60<0>C for 27 hours. The reaction solution was concentrated to dryness,
The residue was purified by silica gel chromatography (leg, chloroform). The obtained crude crystals were recrystallized from acetone/isopropyl ether to give colorless needle crystals (0,6
3g, 75%) was obtained.

Melting point 1j2-153°C Elemental analysis value: C2°Ht 4 CQ N s Os as C (%) H (%) N (%) Calculated value: 57.48. 5.79. 18.76 Experimental value: 57.45. 5.78. 16.64 Example-22 7-benzyl-5-butyl-3-methylaminopyrazolo[3,4-d]pyrimidine-4,6(5H,71■)-
Dione ■-Benzy-3-butyl-6-hydrazinouracil (
4,0g, 13.9mM) and methylisothionate (2,857+11!, 41.7111M) in DMF (
50d) at 120° C. for 20 hours. Methanol (20 mL) was added and the resulting crystals were left to cool.
ME? ' / Recrystallized from methanol, colorless crystals (3,
0 g, 66%).

Melting point: 282-284°C Elemental analysis: Cl? C (%) as Ht+N aOt
I (%) N (%) Calculated value: 62
．． 37. 6.47. 21.39 Experimental value: 62.
60. 6.55. 21.32 Example-23 7-benzyl-5-butyl-3-dimethylaminopyrazolo[3,4-d cobyrimidine-4,6(51-[.

711)-dione l-benzyl-3-butyl-6-hydrazinouranor (
], Og, 3.5mM) in chloroform (30d) was added phosgeneiminium chloride (0.73g).

4.5mM) was added in small portions at room temperature, and then incubated at 50°C for 3 hours.
Stir for hours. The reaction solution was concentrated to dryness and the resulting brown slag was subjected to silica gel column chromatography (30
, chloroform) to give pale yellow crystals.

Recrystallization from 80% ethanol yields colorless needle crystals (0,6
1 g, 52%).

Melting point 17"1179℃ Elemental analysis value: C (%) r as C16HBNsOt
-r (%) N (%) Calculated value: 63.32. 6.79. 20.51 Experimental value: 63.39. a, g9; 20.43
Example-24 7-Hentru-5-butyl-2-methyl-3-methylamino-2H-pyrazolo[3,4-dlpyrimidine-4,
6(5I-I,7H)-dione 7-benzyl-5-butyl-3-methylaminopyrazolo[3,4-d cobyrimidine-4,6(5H,71()-dione (1,5g, 4
．． 58mM) was dissolved in DMF (50y=M), methyl iodide (0,48%, 6mM) and potassium carbonate (0,
82g, 6mM) was added thereto, and the mixture was left to stir at room temperature for 12 hours. The reaction solution was concentrated to dryness, and the resulting residue was dissolved in chloroform/
The extract was extracted with water, washed with chloroform, dried and condensed to solidify. Recrystallization twice from 80% ethanol gave colorless needles (0.88 g, 56%).

Melting point 146-148℃ Elemental analysis value: C (%) as Ctsl-1t3NsOt
H (%) N (%) Calculated value: 63.32. 6.79. 20.51 experimental value + 63.55. 6.86: 20.29 Example-25 5-butyl-7-(4-methoxybenzyl)-3-methylaminopyrazolo[3,4-d]pyrimidine-4,6(
5H,7II)-dione 3-butyl-6-hydrazino-1-(tl-methoxybenzyl)uracil (2,0 g, 6.3 mM) and methylisothiocyanate (1,36td, 20 mM) in DMF
' (20M1.) and stirred at 120°C for 20 hours.

After adding ethanol (20y4) and leaving it to cool, the precipitated crystals were recrystallized from DMF'/ethanol to give colorless crystals (
1.2 g, 53%) was obtained.

Melting point: 292-294°C Elemental analysis: C+al-1tsN so C
(%) H (%) N (%) Calculated value・60.49. 6.49. 19.59 experimental value + 60.58. 6.49. 19.54 Example-26 5-butyl-7-(4-chlorobenzyl)-3-methylaminopyrazolo[3,4-d]pyrimidine-4゜6 (
51-1,7H)-dione 3-butyru-1-(4-chlorobenzyl)-6-hydrazinouracil (3,0 g, 9.3 mM) and methylisothiocyanate (2,0 rJ, 29 mM) were dissolved in DMF' ( 3
The mixture was stirred at 120° C. for 20 hours. Add ethanol (20+J), leave to cool, and precipitate crystals I)
Recrystallization from M P /ethanol gave pale yellow crystals (
1.91 g, 57%) was obtained.

Melting point: 291-294°C Elemental analysis: CI7!1t. As Cf2N50, C(
%) [-1(%) N(%) Calculated value: 56.
43. 5.57. 19.36 Experimental value: 56.5
1; 5.49. 19.22 Example-27 5-Butyl-3-methylamino-7-(2-nitrobenzyl)pyrazolo[3,4-d]pyrimidine-4,6(5
DMF' (40s
112) The solution was stirred at 120°C for 20 hours. Add ethanol (20d), leave to cool, and DM the precipitated crystals.
Recrystallized from F/ethanol to give colorless needle crystals (2.0g
, 45%).

Melting point 〉300℃ Elemental analysis value: C, 7H,. C as N a O4 (%)
I-((%)N(%) Calculated value: 54.83. 5.41. 22.57 Experimental value: 54.89: 5.31. 22.43 Example-28 5-butyl-3-methylamino -7-(4-nitrobenzyl)pyrazolo[3,4-d]pyrimidine-4,6(5
H,7H)-dione 3-butyl-6-hydrazino-! -(4-Nitrobenzyl)uracil (1,7 g, 5 mM) and methylisothiocyanate (0,7y4.10 mM) in DMr;' (20
7n1. ) for 20 hours at 120°C. Add ethanol (20d) and leave to cool to obtain crystals.
Recrystallization from MF/ethanol gave pale yellow crystals (0,6
1 g, 32%).

Melting point 277-279°C Elemental analysis value: C (%) as C+t14roNa04
H (%) N (%) Calculated value: 54.83. 5.41 22.57 Experimental value: 54.8G, 5. , IL, 22.51
Example-29 5-butyl-3-methylamino-7-(2-pennolaminoethyl)pyrazolo[3,4-d]pyrimin-4,
6(5H,7H)-dione 5-butyl-7-(2-chloroethyl)-3-methylaminopyrazolo[3,4-d]pyriminone-1゜6(5
11,7H)-dione (0.6g, 2mM) and hensylamine (0.661n1.6mM) were heated to reflux in dioxane (20yJ) for 20 hours. When the silica obtained by concentration to dryness under reduced pressure was placed in ice water, colorless crystals were obtained. The obtained crystals were dissolved in IN-hydrochloric acid, insoluble materials were filtered off, and 1N aqueous ammonia was added to the filtrate to precipitate crystals. Recrystallization from DMF/methanol/water gave colorless needles (0.32 g, 43%).

Melting point 198-200℃ Elemental analysis value: C18H28N110 t (%)
11 (%) N (%) Calculated value: 61.60. 1.08: 22.69
Experimental Detective: 61.51. 6.8? , 22.58
Example-30 7-(2-benzyloxyethyl)-5-butyl-3-
Methylaminopyrazolo[3,4-d]pyrimidine-4,
6(5H,7H)-dione 1-(2-benzyloxyethyl)-3-butyl-6-
Hydrazinouracil (2.1g, 6.3mM) and methylisothiocyanate (1.36g, 20mM) were added to DMP.
(20 nJ) at 120° C. for 20 hours. 50
% methanol (20d) was added and the resulting crystals were recrystallized from DMF/methanol/water to give pale yellow crystals (0.94 g, 40%).

Melting point 214-216°C Elemental analysis value: C (%) I ((%) N (%) as Cle ) I t s N s Oa Calculated value: 61.44. 6. F8: 1 g, 85
Experimental value: 61.42. 6.53. 19.09 Example-31 5-butyl-3-ethylamino-7-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidine-, i,
G (5H,71()-dione 3-butyl-6-hydrazino-1-(4-methoxybenzyl)uracil (0,6
4g, 2mM) and ethyl isothiocyanate (0,53
6+IIM) was stirred in DMF (6+IIM) at 90°C for 14 hours and then at 110°C for 14 hours. Water (2 kinds) was added to the reaction solution, and the crystals obtained by cooling were added to DMF.
/ethanol/water to give colorless needle crystals (0,5
2g, 70%) was obtained.

Melting point 234-236℃ Elemental analysis value: C+sH! C (%) as SN so 3
H (%) N (%) Calculated value: 61.44. 6.78. 18.86 Experimental value: 61.35. 6.93. 18.77 Example-32 7-(4-aminobenzyl)-5-butyl-3-methylaminopyrazolo(3,4-cD pyrimidine-11,-6
(5H,7H)-dione hydrochloride 5-butyl-3-methylamino-7-(4-nitrobenzyl)pyrazolo[3,4-d]bilimine-4.6 (
5I-1,7H)-dione (Ig, 2.6mM) was suspended in concentrated hydrochloric acid (5-) and ethanol (2,5+14) and added to stannous chloride (3,75g) in ethanol with stirring at room temperature. The solution (5 years old) was added dropwise. The mixture was left stirring at room temperature for 24 hours and concentrated to dryness. The residue was dissolved in hot water and left to cool to give yellow crystals (0.42 g, 46%).

Melting point 〉31O℃ Elemental analysis value: C+7Ht2NaO*・1. I C12・
C (%) I ((%) N (%) as 1/2HffiO Calculated value: 52.64. 6.24. 21.67 Experimental value: 52.4 g, 5.73. 21.35 Formulation example Compound of the present invention (1), for example, memory disorder, emotional disorder 1
When used as a therapeutic or preventive drug for behavioral abnormalities, it can be used, for example, in the following formulations.

11 tablets (1) 7-(3-chlorobenzyl)-3-methylamino-5-propylpyrazolo[3,4-d]pyrimidine-4
, 6(51(,71-1)-dione 20a+g (2) Lactose 35B (3) Cornstarch 150mg (4) Microcrystalline cellulose 30mg (5)° Magnesium stearate 5mg 40mg (1), (2), (3) and 2/3 of (4) and (5)
After mixing 172, it is granulated. The remaining (4) and (
5) is added to the granules and pressure molded into tablets.

2. Capsule (1) 7-benzyl-3-methylamino-5-propylpyrazolo[3,4-d]pyrimidine-4゜6(5H,7
H)-Dione 20mg (2) Lactose
100D (3) Microcrystalline cellulose
70mg (4) Magnesium stearate
10mg00mg After mixing 172 of (1), (2), (3) and (4), granulate it. The remaining (4) is added to the granules and the whole is encapsulated in a gelatin capsule.

Effect of the Invention Experimental Example 1 The nootropic effect (memory impairment improving effect) of the compound (1) of the present invention was investigated by the passive avoidance test shown below. 5
A week-old male mouse is first placed in a light room of a passive avoidance learning device consisting of two rooms, light and dark. Mice naturally move quickly to dark rooms. 0 from the darkroom floor when moving
．． A current of 5 milliamperes is applied to the mouse for 3 seconds under conditions of no escape. The mice remember the electric shock for several weeks. The formation of this memory was impaired by the following operations, and the effect of the compound (1) of the present invention on this memory impairment was investigated. That is, immediately after applying an electric shock, the mouse was placed in a 4Q glass container filled with carbon dioxide gas, and when breathing stopped, the mouse was removed and spontaneous breathing was restored by artificial respiration. This action causes the mouse to forget that it received an electric shock.

Therefore, we conducted a memory recovery test the next day. That is,
The mouse was reintroduced into the light room of the passive avoidance learning device, and the time taken to move to the dark room was measured.

The mice forgot that they had received the electric shock and returned to the dark room after 10 to 20 seconds. On the other hand, the mice administered with the compound (1) of the present invention recovered their memory and either did not try to move to the dark room or took a long time to move even if they did. Therefore, the effect of the test compound was determined by the average time the mice remained in the light room during this test (8 mice per group). This was investigated by comparing with the group). The results were expressed as percent change when the average value in the control group was set as 100 (Table 1).

The test compound was administered as a 5% gum arabic suspension intraperitoneally 30 minutes before the test, or orally 0 minutes before the test.

Table 1 shows the memory impairment improving effect (improving effect on passive avoidance response disorder caused by carbon dioxide inhalation) of representative compounds of the compounds (I) of the present invention.

Table 1: Relief from passive avoidance response disorder caused by carbon dioxide inhalation:
Statistically significant differences (P<0.05) are indicated.

Experimental Example 2 Wistar rats that had been sufficiently trained in an 8-way radial maze were used. The rat was placed in the device and allowed to take food freely until the fourth choice. Immediately after the fourth choice, the rat was removed from the device, and after a certain delay time was inserted, the rat was returned to the device and allowed to continue with the fifth choice and beyond. Ta. Number of correct responses in the 5th to 8th choices (number of times the arm with food remaining was selected) and number of errors until all food was taken (number of times the arm that had already taken food was selected again)
was measured. If the delay time is within 4 hours, rats will show a high number of correct responses and a small number of errors.

In this experiment, 7 to 12 rats were used per group, and immediately after the fourth selection, the rats were removed from the apparatus and treated with scopolamine 0,
5 mg/kg was administered intraperitoneally, and 1 hour later, the fifth and subsequent treatments were continued. The test compound was administered intraperitoneally at 10 mg/kg at the same time as scopolamine.

As shown in Table 2, the spatial memory of rats was significantly inhibited by scopolamine administration, which induced a significant decrease in the number of correct responses and an increase in the number of errors. Compound obtained in Example 6 (
When compound 6) was administered, an ameliorating effect on spatial memory impairment caused by scopolamine was observed, with a significant increase in the number of correct responses and a decrease in the number of errors.

Table 2 Note 1 for spatial memory impairment caused by scopolamine
) The number of correct responses and errors are expressed as standard error of the mean.

Note 2) Indication: indicates a statistically significant difference (p<o, ot) when compared with the physiological saline control group.

Note 3) +: Indicates a statistically significant difference (P<0.1) when compared with the scobolamine control group.

Note 4) ++ indicates a statistically significant difference (P<0.05) when compared with the scopolamine control group.

Experimental Example 3 A male Wistar rat was used whose olfactory bulbs on both sides were removed by suction. 30x3 with grid floor
Using a step-down passive avoidance device, a 30x7x4゜5cn+ vinyl chloride platform was installed in one corner of a 0x30cm box.A rat placed on the platform descended to the grid floor, and at the same time an electric current of 0.6 mA for 1 second was applied. Shocked. Similar trials were repeated at 1 minute intervals, and the avoidance time for the rat to descend from the platform to the grid floor was measured. Trials were repeated up to 10 times until the rat avoided on the platform for more than 180 seconds. Using 8-10 rats per group,
The test compound was administered intraperitoneally at 20 mg/kg one hour before the start of the test. The rat is 18 on the platform
The average number of attempts required to demonstrate avoidance for 0 seconds or more is as shown in Table 3. Compared to the sham-operated group, a marked increase in the number of trials required to acquire an avoidance response was observed in the olfactory bulbectomy control group administered with physiological saline. When Compound 6 was administered, a marked and significant improving effect was observed on the impaired acquisition of passive avoidance responses in olfactory bulbectomized rats.

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 represents an optionally substituted aryl or heteroaryl group, R^2 represents a lower alkyl group, and R ^3 and R^4 each represent hydrogen or a lower alkyl group, R^5 represents hydrogen, a lower alkyl group or an acyl group, and X represents a lower alkylene group which may contain a heteroatom. The broken line indicates that there are two double bonds in the pyrazole ring, and R^5 is bonded to either the 1st or 2nd position] or a salt thereof.