JPS61233678A - Benzylpiperazine derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R1 is H or CH3; R2 is Cl, CH3, or phenyl which may be replaced with methoxy, etc.). EXAMPLE:4'-Chloromethyl-3,4,5-trimethoxybenzanilide. USE:An antiulcer. PREPARATION:An acid chloride shown by the formula R2COCl is reacted with an aminobenzoic ester in pyridine to give a compound shown by the formula II, which is reduced with aluminum lithium hydride in THF, and treated with thionyl chloride into a chlorine derivative and reacted with piperazine or N- methylpiperazine to give a compound shown by the formula I.

Description

Detailed Description of the Invention A. Industrial Application Field The present invention relates to the general formula (1) (wherein R is a hydrogen atom or a methyl group, and R7 is unsubstituted or one chloro atom at any position). , a methyl group, a methoxy group, an acetylamino group, or three groups in any position).

The compound (T) of the present invention has an anti-ulcer effect and is industrially useful as a pharmaceutical.

B. Conventional technology Many studies have been conducted on anti-ulcer drugs.

Conventionally, the mechanism of anti-ulcer action has been thought to be suppression of aggressive factors such as gastric juice and enhancement of protective factors such as mucus, and it is said that under normal conditions, a balance between these is maintained. It is being said.

1-Cyano-2-methyl-3-[2-[[(5-methylimidazol-4-yl)methyl]thio]ethyl]guanidine (generic name: cimetidine) (British patent 1,397
, No. 436, Special Publication No. 43832, Special Publication No. 1983-
No. 43833) is used to suppress gastric secretion and produce acid, and is cited as a representative example of the former, and many studies have been conducted on analogs thereof.

On the other hand, trans-4-[[[4-(aminomethyl)cyclohexyl]carbonyl]oxy]penzenopropanoic acid hydrochloride (-ship name: cetraxate hydrochloride)
The development of anti-ulcer drugs aimed at enhancing protective factors, such as No. 48978), is also actively underway.

The present inventors also discovered the present compound (1) with the aim of developing an anti-ulcer drug for the purpose of enhancing protective factors.

Means to solve the C1 problem: The clinical dose of cetraxate hydrochloride, which is used clinically as a protective factor-type anti-ulcer drug, is 200 mg at a time.
, is administered 3 to 1 time per day, which is relatively high.

In order to solve the problem of lowering the dosage, we discovered that many of the compounds with anti-ulcer activity have acid amide or ester bonds. The acid moiety was converted.

91 action Compound (I) of the present invention can be produced as follows.

[M W v That is, acid chloryl I' (TI) and aminobenzoic acid ester (R3 represents a lower alkyl group) are reacted in pyridine to form an amide compound (m), which is
・Reduced product (IV) was obtained with lithium aluminum hydride in Rowalan, and then the chloride (IV) was obtained with thionyl chloride in a solvent such as Hensen, chloroform, or dichloromethane.
), the target compound (1) can be obtained by boiling piperazine or N-methylpiperazine.

In addition, as shown in the figure below, compound (IV) is obtained by reacting acid chloride F'(r[) in the presence of a base, followed by treatment with a mineral acid to obtain an aldehyde compound (■), followed by methanol and ethanol. It can also be obtained by reduction with sulfur and lithium borohydride in a solvent such as.

E, Example 1, 8 g of anhydrous piperazine was dissolved in 100 ml of benzene, 3 g of 4'-chloromethyl-3,4°5-trimethoxybenzanilide was added thereto, and the mixture was heated in an external bath at about 80° C. for 1 hour. After that, it was concentrated to dryness under reduced pressure, water and 3 g of potassium carbonate were added to the residue, and extracted with chloroform. After distilling off the solvent under reduced pressure, dilute hydrochloric acid is added to the residue to make it acidic, and insoluble matter is filtered off.

The aqueous layer was made alkaline with potassium carbonate, extracted with chloroform, and dried (anhydrous potassium carbonate).

After that, the solvent was distilled off, and the residue was crystallized with ether, 2.5
g of 3.4.5-)dimethoxy-4-piperazinylmethylbenzanilide is obtained.

Recrystallized from chloroform-ether. Colorless prismatic crystal.

mp 154-156°.

NMR (CDC13') δ: t, 76 (IH, s), 2
．． 29-2.48 (4tl, m), 2.76-2.95
(411, m), 3.44 (2tl, s), 3°85 (
61-1, S), 3.88 (3H, S), 7.04 (2
11,s), 7.27(2+1.A2B, type d
, J=9.011z), 7.55(211,A2-B
2type d, J=9.0llz), 8.03(Il
l, br s).

Dihydrochloride: Recrystallized from methanol-water. Colorless uncinate crystals, m
p 214. -218°.

The raw material 4'-chloromethyl-3,4°5-trimethoxybenzanilide was synthesized as follows.

8.3 g of ethyl p-aminobenzoate to 100 m of pyridine
1, and 13 g of 3.4.5-trimethoxybenzoyl chloride was added under water cooling.

After stirring at room temperature for 1 hour, water was added to the reaction solution and extracted with chloroform. After washing with water, wash with dilute hydrochloric acid, then with aqueous sodium carbonate solution, and dry (magnesium sulfate).

The solvent was distilled off and the crystals were washed with ether to obtain 17 g of 4'-ethoxycarbonyl-3,4,5-1-rimethoxybenzanilide. Recrystallized from ethanol-ether, colorless prism product, mp 11B-121°.

Next, 8.5 g of this was mixed with 1.5 g of lithium aluminum hydride and 120 g of dry tetrahydrofuran under water cooling.
Add to suspension of m1.

After that, let it come to room temperature and stir for 40 minutes. Then, it was decomposed by pouring it into dilute hydrochloric acid, extracted with dichloromethane, washed with water, and dried (magnesium sulfate).

The solvent was distilled off and the crystals were washed with ether to give 4'-hydroxymethyl-3,4,5-)rimethoxybenzanilide 7.
I got g. Recrystallized from methanol-ether to give colorless needles, mp 161-164°.

Next, dissolve 6g of this in 100ml of chloroform,
At room temperature, 0.5 ml of pyridine and 5 g of thionyl chloride were added dropwise and stirred for 1 hour. After that, water was added to the reaction solution for extraction, and the chloroform layer was washed with an aqueous potassium carbonate solution and dried (magnesium sulfate). The solvent was distilled off to obtain 1:5 g of 4'-chloromethyl-3.4.5-)rimethoxybenzanili in the form of pale yellow needle-like crystals. Recrystallized from benzene-ether, colorless needles, mp 154-157°.

The following compounds were synthesized in the same manner as in Example 1.

2. From 4-ethoxycarbonyl-4-methoxybenzanilide (recrystallized from dichloromethane-ether, colorless lateral crystals, mp 180-182°), 4'-hydroxylmethyl-4-methoxybenzanilide (recrystallized from dichloromethane) Crystallized, colorless needles, mp 160-
1 (33°), 4'-chloromethyl-4-methoxybenzanilide (recrystallized from dichloromethane-ether, colorless flakes, mp 171-173°) to give 4-methoxy-4-(4 -Methylpiperazinylmethyl)benzanilide (recrystallized from dichloromethane-ether to give colorless shingles, mp 173-175°).

NMR (CDCI3) δ: 2.27 (311, S),
2.33-2.62 (811, m), 3.45 (2+1
．． S), 3.84 (311, S), 6.90 (2+1.
A, mouth, type d, J=9.011z), 7.25
(211, A2131type d.

J=9.0llz), 7.52(211, A2B2ty
ped, J=9.0tlz), 7.78(2)1. A
, B, type d, J=9.0IIz), 7.80(
III, br s).

Dihydrochloride: Recrystallized from methanol-water to give colorless sword crystals, m
p 215-218°.

3.4-ethoxycarbonyl-4-methylbenzanilide (recrystallized from dichloromethane-ether to give colorless gold 1
crystalline form, mp 19B-201'), 4'-hydroxylmethyl-4-methylbenzanilide (recrystallized from dichloromethane-ether, colorless flaky crystals, mp
154-156°), 4'-chloromethyl-4-methylbenzanilide (recrystallized from dichloromethane-needle, pale yellow needle crystals, mp 163-166°), 4-methyl-4'-(4 -Methylpiperazinylmethyl)benzanilide (recrystallized from dichloromethane-ether to give colorless needles, mp 163-165@).

NMR (CDCI3) δ: 2.27 (311, S),
2.40 (311, s), 2.30-2.57 (811
, m), 3.45 (211, s), 7.22 (2If,
A2B2type d, J=9.0l-1z), 7.2
5 (2t1.A2.Bltype d.

J”9.01lz), ?-53(2H* A2ex
type d, J"9.0112), 7.71 (2H
, A2B2type d, J=9.0Hz), 7.80
(IH, br S).

Dihydrochloride: Recrystallized from methanol-acetone, colorless prism product, mp 200-210° (d).

4.2-chloro-47-chloromethylbenzanilide (
Recrystallized from dichloromethane-ether to give colorless sword crystals,
mp 14.1-143'), 2-chloro-4'
-(4-methylpiperazinylmethyl)benzanilide (
Recrystallization from dichloromethane-ether gave a colorless prism product (mp 176-178°).

NMR (CDC+3) δ: 2.26 (311, s),
2.30-2.57 (811, m), 3.45 (211
, S), 7.15-7.74 (811, m), 8.02
(11I, br s).

Dihydrochloride: Recrystallized from methanol-acetone, colorless cylindrical crystals, mp 215-218°.

5. 2-Chloro-4'-biperazinylmethylpenzanilide (recrystallized from dichloromethane-ether, colorless prism product mp132-134°) was obtained from 2-chloro-4-chloromethylbenzanilide.

NMR (CDC+3) δ: 1.72 (III, br
s), 2°27-2.48 (411, m), 2.71
-2.92 (4H, m), 3.43 (2+1.S)7.
17-7.73 (8H, m), 8.21 (III, br
S).

Dihydrochloride: Recrystallized from methanol-ether, colorless nail-shaped crystals, mp 179-184°.

6.3 from 3'-hydroxymethyl-3,4,5-)rimethoxybenzanilide (recrystallized from dichloromethane-ether, colorless prism product, mp121-1236)
7-Chloromethyl-3,4゜5-trimethyl-xybenzanilide (recrystallized from dichloromethane-ether, colorless needle crystals, mp 176-178°) to give 3,4
．． 5-trimethoxy-3'-(4-methylpiperazinylmethyl)benzanilide (pale yellow oil) was obtained.

NMR (CDC13) δ: 2.25 (3H, s),
2.33-2.57 (811, m), 3.46 (2+1
．． s), 3.87 (411, s), 6.97-7°12
[3H, m, 7.05 (211, S)], 7.17-7
．． 33 (IH, m)], 7.43-7. (+7(2tl
, m), 8.00 (111, br S).

Dihydrochloride: Recrystallized from methanol-ether to give colorless spirate crystals, mp 17B-181'.

In addition, 3'-hydroxymethyl-3,4,5-trimethoxybenzanilide' is 3'-formyl-3°4.5-)
Rimethoxybenzanilide (recrystallized from methanol-ether, colorless needles, mp 128-1306) was obtained by reduction with sodium borohydride in methanol.

3.4.5-) Liftoxy-3-huupiverazinylmethylbenzanilide (pale yellow oil) was obtained from 7.3'-chloromethyl-3,4,5-)rimethoxybenzanilide.

NMR (CDC+3) δ: 2.2B-2.55 (41
1, m), 2.68-2.97 (411, ■), 3.4
3 (2H, s), 3.85 (611, S), 3.87 (
311, S), 7.00-7. IO[311,m, ?
, 08(2N,s)], 7°13-7.35(ill,
m), 7.43-7.68 (211, m), 8.28
(III, brS).

Dihydrochloride: Recrystallized from methanol-ether, colorless needles, mp 175-177'.

8. 4'-Chloromethyl-4-methoxybenzanilide to 4-methoxy-4'-piperazinylmethylhenzanilide (recrystallized from chloroform, colorless needles, mp
175-178°) was obtained.

NMR (CDC13) δ: 2.27-2.48 (411
, m), 2.74-2.95 (411, m), 3.44
(2H, S), 3.84 (4H, S), 6.90 (21
1, A, B, type d, J=9.0Hz), 7.2
4 (21+, A, +32 type d, j: 9.0H
2), 7.53 (211, A2B, type d, J=
9.0H2) 1.7.78 (211, A, B2type
d, J=9.011z), 7.80(Iff, br
s) Dihydrochloride: Recrystallized from methanol-water, colorless prism product, mp 242-24.5°.

(2)-1 The pharmacological effects of the synthesized compounds were investigated.

Compound A: 3.4.5-)liftoxy-4-piperazinylmethylbenzanilide (compound of Example 1) Compound B: 2-chloro47-biperazinylmethylbenzanilide (compound of Example 5) Compound C-nidimethicin (anti-ulcer drug that suppresses aggressive factors) Salt-dead ulcers - Wistar strain Al1 rats (200-24,0g
) After fasting for 24 hours, the test drug was orally administered (51/K
g) After 30 minutes, 5 ml/Kg of 0.6N hydrochloric acid was orally administered. Thereafter, the animals were dehydrated and fasted, and their stomachs were removed 1 hour later. The length (mm) of each ulcer that occurred in the glandular stomach was measured, and the total per animal was taken as the ulcer coefficient.

The results are shown in Table 1.

Table 1 After fasting Wistar male rats (200-240 g) for 24 hours, the test drug was orally administered (5 m3/d), and 30 minutes later, 5 ml/kg of absolute ethanol was orally administered to them. Thereafter, the animals were dehydrated and fasted, and their stomachs were removed 1 hour later. The length (mm) of each ulcer that occurs in the glandular stomach is determined as 1, and the total length per animal is if! It was taken as the tumor coefficient.

The results are shown in Table 2.

Table 2 After fasting male Wistar rats (200-240 g) for 24 hours, the abdomen was opened under ether anesthesia to expose the stomach. Add 20% acetic acid 0.02 to the submembranous tissue at the bifurcation of the gastric body and pylorus.
m1 was injected with a microsyringe and the abdomen was opened. The test drug was orally administered twice a day for 14 consecutive days starting from the 1st day after surgery.

The day after the final administration, the rats were killed by buffing, the stomach was removed, and 5 ml of ethanol was injected. The major axis and minor axis of each ulcer opening were measured, and the product (mm2) thereof was taken as the ulcer coefficient.

The results are shown in Table 3.

Table 3 Wistar male rats (200-240g) were fasted for 24 hours and then the test drug was orally administered (5m/-).
After 0 minutes, indomethacin (25 mg/kg) was orally administered (5 ml/g in 0.5% gum arabic powder suspension). Thereafter, the animals were dehydrated and fasted, and their stomachs were removed 7 hours later. The length (mm) of each ulcer that occurred in the glandular stomach was measured, and the total per animal was taken as the ulcer coefficient.

The results are shown in Table 4.

Table 4 Wistar rats (280-300 g) were used for experiments under urethane (1.5 g/kg, subcutaneous) anesthesia. After laparotomy, hydrogen gas clearance was performed in the mucosa of the anterior wall of the gastric body. The electrode was inserted and fixed, and the indifferent electrode was placed subcutaneously in the hind leg.A cannula for blood removal was placed in the carotid artery, and the body weight was 100 g.
Blood was removed by rapidly aspirating 1.5 ml of blood per sample. The test drug was administered into the femoral vein immediately after blood removal. Before blood removal and after drug administration 0°25.0.5.1.1.5.2.2.5.3
After some time, gastric mucosal blood flow was measured by electrolytic hydrogen gas clearance method.

The results are shown in Table 5.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ represents a phenyl group substituted with a group, an acetylamino group or three methoxy groups, and a group -NHCOR_2
indicates an arbitrary position for the group ▲ which includes mathematical formulas, chemical formulas, tables, etc. ▼. ) A benzylpiperazine derivative represented by