JPH01104041A - N-((2-oxo-1-pyrrolidinyl)acetyl)piperazine derivative, production thereof and remedy for senile dementia - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R is -SO2R<1> (R<1> is alkyl, phenylalkyl, amino, etc.) or -CONHR<2> (R<2> is amino, alkylamino, etc.)]. EXAMPLE:1-[(2-Oxo-1-pyrrolidinyl)acetyl]-4-(4-methoxybenzenesulfonyl)p iperazine. USE:An agent for senile dementia. PREPARATION:A compound expressed by formula II is reacted with a sulfonyl halide expressed by formula III (Hal is halogen) to afford the aimed compound expressed by formula I. The reaction is carried out by using a solvent, e.g. an aromatic solvent, such as benzene or toluene, or alkanols, such as methanol or ethanol. The reaction temperature is -20-100 deg.C, more preferably at -5-30 deg.C. The compound expressed by formula I is preferably orally or parenterally administered in about 0.01-20mg/kg daily dose in one or several divided portions.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to N-((2-oxo-1-pyrrolidinyl)acetylcopiperazine derivatives, methods for producing the same, and senile dementia drugs).

Conventionally, compounds useful for the treatment of this type of senile dementia include JP-A-58-174360.61 (06570, etc.). Very little was given.

The present inventors have proposed the following general formula (I): (wherein R represents -5o, R' or -CONHR", and R1 is alkyl, phenylalkenyl, amine, dimethylamino, a substituent aryl which may have or N
, S, or a six-membered heterocyclic group containing 0 heteroatoms; R1 represents amino, alkylamino, alkyl, or aryl which may have a substituent, respectively;
The present invention was completed based on the discovery that the compound represented by the following formula exhibits excellent effects as a drug for senile dementia.

The terms used in the above definition will be explained below.

Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, BeQ-butyl, inbutyl, tart-butyl, n-pentyl, impentyl, and the like.

Examples of phenylalkenyl include styryl, phenylpropenyl, phenylbutenyl, phenylpentenyl, and the like.

Examples of the aryl include phenyl, α-naphthyl, β-naphthyl, and the like.

Examples of the heterocycle include thienyl, furyl, pyridyl, pyrimidinyl, and the like.

Substituents that may be present on the aryl include the above-mentioned alkyl, alkoxy, halogen, acetylamino, nitro, and the like.

Examples of the halogen include chlorine, fluorine, bromine, and iodine. Examples of alkoxy include methoxy, ethoxy, and propoxy.

Compound (I) of the present invention can be mainly produced by the following production method.

(In the formula, X represents halogen, R', R'' and Ha
l has the same meaning as above. However, in Method B, R represents alkyl or optionally substituted aryl.

Compound (!a) is obtained by reacting artificial compound (II) with sulfonyl halide (II[) in a suitable solvent.

As the solvent, any inert organic solvent that dissolves the reaction reagents can be used, such as aromatic solvents such as benzene, toluene, and xylene, alkanols such as methanol, ethanol, and isobutypanol, dioxane, tetrahydrofuran, diethylene glycol, diethyl ether, Ethers such as sifthyl ether, dimethylformamide, dimethyl sulfoxide, etc. are used.

This reaction can also be accelerated by adding a tertiary amine such as triethylamine as an acceptor for hydrogen acid.

The reaction temperature used is -20 to 100°C, more preferably -5 to 30°C.

Compound (II) is reacted with isocyanate (IV) in a suitable solvent to obtain the target compound (Ib).

Examples of the solvent include methanol, ethanol, benzene, chloroform, dichloromethane, and carbon tetrachloride.

The reaction temperature used is -10°C to 100°C, more preferably around room temperature (1 to 30°C).

Method C (1) Compound (II) is reacted with phenyl halogenoformate (V) in a suitable solvent to obtain compound (VI).

As a solvent, methanol, ethanol, benzene, chloroform, dichloromethane, carbon tetrachloride, and as a deoxidizing agent, a base such as triethylamine is used.

The reaction temperature used is -10 to 100°C, more preferably around room temperature.

(2) Compound (VI) obtained in (1) is added to amine (V
I) is reacted to obtain the target compound (Ib).

The reaction temperature is 50 to 150°C, more preferably
It is best to use a temperature around 100°C).

In addition to the above-mentioned methods A to C, methods for synthesizing the target compound (I) include the following methods.

(In the formula, R1 has the same meaning as above, and R3 has 1 to 1 carbon atoms.
(b) (VI) (■) [In the formula, R1 has the same meaning as above, Hal is /10 gen, and M is a metal atom (e.g., sodium, potassium, etc.) respectively. ] (C) Su(IX) (VI) (wherein, R
1 has the same meaning as above, and R4 represents hydroxy or halogen.) The raw material (I) is produced, for example, as shown in the following process formula.

(v) (X) (In the formula, R3 has the same meaning as above.) Examples of acidic acid salts include inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, and phosphoric acid, acetic acid, and citric acid. , salts of organic acids such as tartaric acid.

Compound (I) of the present invention can be administered orally or parenterally to humans or animals. For example, compound (I) is a tablet,
Orally as granules, powders, capsules, liquids, etc.
It is also administered parenterally as an injection or suppository. These preparations are prepared according to well-known methods using additives such as excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, suspending agents, dispersants, solubilizing agents, and preservatives. Manufactured.

Excipients include lactose, sucrose, starch, cellulose, sorbitol, etc.; binders include gum arabic, gelatin, polyvinylpyrrolidone, etc.; lubricants include:
Examples include magnesium stearate, talc, and silica gel. When the compound (I) of the present invention is used for the treatment of senile dementia, about 0.01 to 20 m/day
g/kg may be administered orally or parenterally in one or several doses.

Examples, reference examples, and formulation examples are shown below to illustrate embodiments of the present invention.

However, the abbreviations used in Examples, Reference Examples, and Tables shall have the following meanings.

Me=methimethi EBHx chill; 1-Pr: i
-propyl; n-Bu: rl-butyl; N
aHCOs: Sodium hydrogen suboxide, CHCl5
:Chloroform, HCC hydrochloric acid: AC niacetyl + MeO
H: methanol; CH, C1, dichloromethane;
EtOH: ethanol; EttO diether ether; EtsN: triethylamine [(2-year old
-pyrrolidinyl)acetylcopiperazine (II) 1.0
30g (4,88mIIIol) of CH, C1t 15
ml, and while stirring under water cooling, 1.108 g (5.36 m
mol) and Et, N O, 748 ml (5, 36 mmol)
1) was added, and the mixture was stirred at room temperature for 5 hours and 45 minutes. C in the reaction solution
After adding H and C1, the mixture was washed with dilute HCI, water, NaHCOs aqueous solution, and water in this order, and dried. The solvent was distilled off, the residue was subjected to silica gel column chromatography (silica gel: 91 g), and CHCl, -MeOH (30:
1-9:1 v/v). 1.63 g of crystals obtained from the eluted fractions were recrystallized with MeOH to obtain 339 g (yield near 2.0%) of the target compound x as prismatic crystals.

Elemental analysis: Calculated value as C1tH*5NsO*S (χ
): C, 53, 53i H, 6, 08; N, t
t, oz; S, 8.41 Actual value (X): C, 53,30; 1(, 6,06
iN, 10.97iS, 8.29 IR (Nujol): 3082. 1687.
1668. 1598. 1578°1498.14
58.1448.1408 am-'NMR (CDCI
, -CD, 0D=4:lv/v)'1; , 1.9-2
．． 2 (m, 2H), 2.41 (t,, C7Hz, 2
H), 3.03(br,4)1), 3.45
(t, J=7Hz, 2H), 3.61 (br.

4H), 3.89 (s, 3H), 4.04
(s, 2H), 7.05 (d.

J=10Hz, 28), 7.71 (d, J=10
Hz, 2H).

Examples 2 to 17 (In the formula, R' has the same meaning as defined above.) Reactions were carried out in the same manner as in Example 1 under the reaction conditions shown in Table 1 to obtain the target compound (I). Its physical properties are listed in Table 2.

(Left below) 700 mg (3,31 mmol) of ItL-(2-year-old xopisolysin-1-yl)acetylpiperazine was added to CHmClmlo.
, dissolved in 5 ml of methyl isocyanate under water cooling.
, 215 ml (3.64 mmol) was added thereto, and the mixture was returned to room temperature and stirred for 1 hour. After distilling off CH, C1, the precipitated crystals were washed with EtlO and collected by filtration.

Recrystallized from EtOH-Et, O to obtain the target substance (Ib-1
) 856 mg (yield, 96.3%) were obtained as colorless prism crystals.

Melting point: 203.0-205.0 ('C) Elemental analysis
(As C11H=.Naps) Calculated value (X): C
,53,72; H,7,51; N, 20.88 Actual value (1): c, 53.77; H,7,53i
N, 20.69IR (Nujol): 3347.
1681.1658.1620.1552°1492,
1469.1454.1411.1398 (am-'
) NMR (CDCIs-CDsOD:C1v/v)'8
．． 2.14 (q, J=7Hz, 2H)i 2.46
(t, J=7Hz, 2H); 2.77 (s, 3H);
3.37-3.60 (m, 10H); 4.13 (
(Ib) (In the formula, R1 has the same meaning as above.) In the same manner as in Example 18, the reaction was carried out under the reaction conditions shown in Table 3, and the purpose was Compound (rb) was obtained. Its physical properties are listed in Table 4.

(Space below) Example 23 (1) 5.026 g (23,790 mmol) of [(2-year-old xo-1-pyrrolidinyl)acetylcopiperazine]
Dissolved in 90 ml of HtCla, stirred with water cooling, and added 3.283 ml of chloroformic acid phenyl ester (26, 169 mmo
l) and EtsN 3 , 982 ml (28,549
mmol) was added. After 10 minutes, the mixture was brought to room temperature and stirred for 1 hour. The reaction solution was washed with dilute HCI, NaHCOa water, and water in this order, dried, and then the solvent was distilled off. Et the residue! After washing with O,
CHtCla - Et, recrystallized from O, melting point 185.0
7.7 tons of target substance as prism crystal at -186,0℃
og(Q)7. s%) was obtained.

Elemental analysis (c, as tHI lN5O4) Calculated value (X): C, 61,62; H, 6,39; N, 1
2.68 Actual value (X): C, 61,56F H, 6
, 40; N, 12.65IR (Nujol):
1722.1679.1661.1592.1494゜1460.1443.1419 crn-'IR(CH
Cl, ): 1719.1682.1664.15
94.1495°1461.1421 cm-' NMR (CDCIs): 8, 2.12 (quintet, J=7Hz, 2
H), 2.43(t, J=7Hz.

2H), 3.30-3.85 (m, 108), 4.
12(s, 2H).

7, OO~7.50 (m, 5H) (2) 1-phenoxycarbonyl-4-(2-year-old xo-1-pyrrolidinyl) acetylpiverazine 3.380 g (
10,200 mmol) to hydrazine hittler (1
00%) was added thereto, and the mixture was stirred at 90°C for 30 minutes.

The solution was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography (silicage gel 4: 273.9 g).
CHCl, -MeOH- concentrated ammonia water (32:6
: 1 v/v/v) solution to yield the title compound (I
b-6) 1.302 g (yield: 46.8%) was obtained as prism crystals.

m, p, : 164.0 to 166.0°C (i-propyl alcohol) Elemental analysis C+ +H+ *XNX I as N5Os・115H,O (X): C, 48, 41;
H, 7, 17F N, 25.66 actual value (X)
: C, ts, 3s; H, 7, i2; N, 25
．． 88IR (Nujol): 3200.1683.
1648.1510.1500゜1454, 1412
am-' NMR (CDCIs-CD5OD addition (C1v/v)'
S, 2.09 (quintat, 2H), 2.44
(t, 2H, J=7)1z).

3, 20-3.80 (m, 108), 4.11 (s
, 2H) (blank below) Reference example perazine methyl 2-oxo-1-pyrrolidine acetate 18.
piperazine 19.778 to f33g (115mmol)
g<230 mmol) and heated at 100° C. for 2 hours and 20 minutes. Excess piperazine was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and CHCl
s -MaOH- concentrated ammonia water (32:4:0.5
It was eluted with a mixture of ~32:6:IV/V/V). The eluted fractions were concentrated under reduced pressure to obtain 16.856 g (yield: 69.1%) of the target product as crystals.

m, p,: 116.0-117.0°C (i-propanol-Et, O) Elemental analysis C. Calculated value as HtNso* (%): C, 56,85; H, 8,11; N
, 19.89 actual value C%): C, 56,74;
H, s, os; N, 19.75IR (Nujol)
: 3295.1676, 1642.1488.14
63°1451.1436.1408 am-'NMR
(CDC1,): 8.1.87 (br, s, 1) I Disappeared with addition of CD5OD>, 1.95-2.25 (m, 2H), 2.4
3(t,, J=7Hz, 2H), 3.84(t.

J=6Hz, 4H), 3.4-3.6 (m, 6H)
, 4.10 (s, 2H) The test equipment was an acrylic resin box (30 x 30
m), with a white wooden plate (10×
I used one with 10x10x1 placed on it.

- Groups of 10 SD male mice (4-5 weeks old) were
Divide into groups, the first group received the solvent as a control group, and the second group received the solvent as a control group.
Groups were orally administered 5 and 50+ ng/kg of the test drug, respectively, and after 60 minutes were placed on the plate, and when lowered onto the grid floor, a current of 3 mA was applied for 5 seconds. 5 more
~10 minutes later, 30 mA to both eyes, 1 m5ec,
Electric convulsions were induced by applying a 100 Hz square wave for 0.2 seconds, and the animals were immediately returned to their home cages. After 24 hours, the mouse was placed on the plate in the test device again and the latency to fall to the floor was measured. Since mice exhibiting amnestic symptoms immediately descend to the floor, the anti-amnestic effect can be observed as a prolongation of the latency. In Table 5, the latency time (median value) of the compound-treated group is expressed as a percentage change when the latency time (median value) of the solvent control group is set as 100. Comparison between vehicle control group and drug treated group Mann-1Jh
This was done using itnay's U test.

Table 5 silver 1

Claims (5)

[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R is -SO_2R^1 or -CONHR^2
, R^1 is alkyl, phenylalkenyl, amino, dimethylamino, aryl which may have a substituent, or N
, S or O; R^2 represents amino, alkylamino, alkyl or aryl which may have a substituent, respectively. ) or its acid addition salt. (2) A senile dementia drug containing the compound according to claim 1 or an acid addition salt thereof. (3) The method for producing the compound according to claim 1, which comprises reacting the compound represented by formula (II) with a sulfonyl halide represented by general formula (III). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) Hal-SO
_2R^1(III) (wherein R^1 is alkyl, phenylalkenyl, amino, dimethylamino, aryl which may have a substituent, or a five- or six-membered atom containing N, S or O heteroatom) Heterocyclic group; Hal represents a halogen.) (4) The method for producing a compound according to claim 1, characterized in that the compound represented by formula (II) is reacted with an isocyanate ester represented by general formula (IV). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) R^2NCO
(IV) (In the formula, R^2 represents alkyl or aryl which may have a substituent.) (5) The compound represented by formula (II) is reacted with halogenoformic acid phenyl ester (V) to obtain compound (VI), which is then reacted with amine (VII). Method of manufacturing compounds. X-COO-Ph(V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI) R^2NH_2(VII) (In the formula, Ph is phenyl, X is halogen, R^2 is amino, alkylamino, alkyl or Each represents an aryl which may have a substituent.)