JPH02207069A - Benzamide derivative - Google Patents

Abstract

NEW MATERIAL:A benzamide compound shown by formula I (R is group shown by formula II to formula V). EXAMPLE:N-[4-(1,2-Diethylpyrazolidinyl)]-2,3,5-trimethoxybenzamide hydrochloirde. USE:Useful as a motion promoter of digestive tube recovering reduction in motile function of digestive tube and eliminating unidentified complaint symptoms such as unpleasant feeling of stomach or feeling of distension of abdomen. PREPARATION:A compound shown by formula VI or a reactive derivative thereof is reacted with an amine shown by the formula H2NR in a proper solvent to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention provides a novel benzamide compound. have. Therefore, it is used as a medical drug in this field.

(Prior Art) Benzamide compounds have attracted attention as drugs that act on the central nervous system and exhibit excellent effects such as neuroleptic, sedative, antiemetic, and antiulcer effects.

Among this class of compounds, a compound called metoclopramide is used as a drug that promotes gastric motility and suppresses vomiting. In addition, a compound called sulpiride is being used in the treatment of duodenal ulcers and in the field of psychiatry.

Although these compounds are thought to exert distinctive effects by acting on the central nervous system, they sometimes cause extrapyramidal symptoms and endocrine dysfunction, resulting in undesirable effects. Sometimes.

When a drug does not act on the central nervous system and has a peripheral point of action, it is thought that undesirable symptoms that appear as side effects will be reduced, and from this point of view, drugs that exhibit only favorable effects are being sought. The application relating to trimethobenzamide as a gastrointestinal motility activator is attracting attention as a discovery of a new use for a known compound (Japanese Patent Laid-Open No. 64-9933).

(Problems to be Solved by the Invention) The present invention uses the following formula (1) to recover the decreased motor function of the gastrointestinal tract and eliminate indeterminate symptoms such as back discomfort and abdominal bloating. The present invention provides a novel drug.

0NHR It is made by That is, Expression (■) C:0OH H, Co OCR.

(Means for Solving the Problems) The compound provided by the present invention is reacted with an amine shown in the following manner in an appropriate solvent.

The reaction is carried out in a solvent that does not participate in the reaction, such as benzene, toluene, acetonitrile, tetrahydrofuran, dioxane, pyridine, triethylamine, dimethylaniline, etc. When the reaction is performed with the carboxyl group free, the condensing agent N,N'-dicyclohexyl is used. carbodiimide, 1,
It is preferable to use 1'-sulfinyldiimidazole, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, or the like.

When carrying out a reaction using a reactive derivative, it is preferable to use a reactive derivative such as an acid halide, a mixed acid anhydride with a carbonic acid monoester, or an active ester with p-nitrophenol. Alternatively, a method may be adopted in which the amine represented by 2〇 or N R is converted into a reactive derivative with thionyl chloride, phosphorus acid chloride, phosphorus oxychloride, etc., and this is reacted with the compound represented by formula (II). You can also do it.

Furthermore, since the compound provided by the present invention is a compound containing an amino group, acid addition salts are possible, but pharmacologically acceptable acid addition salts include hydrochloride, tartrate,
Examples include oxalate, lactate, methanesulfonate, and p-toluenesulfonate.

The thus obtained compound of the present invention is useful as it has the property of promoting gastrointestinal motility.

The effect of the obtained compound on the central nervous system and gastrointestinal motility was confirmed by the following method.

b) Antiemetic effect on apomorphine-induced emesis Adult male hybrids (body weight 7.0 to 10.0 kg) were used. Specimen 1m
g/kg subcutaneously and immediately fed with solid feed (Flare CCD).
-5) 50 was given. Thirty minutes later, apomorphine (S
ig + ia) O, 1 mg/kg was administered subcutaneously to determine whether or not apomorphine-induced emesis was suppressed.
Observation was made for 0 minutes. Those whose vomiting was suppressed are +;
Those that were not suppressed were marked -.

Oral) Effect on gastrointestinal motility in dogs A sample of 0.5 to 4
．． 0ff1g/)cg intravenously, or 1.0-2゜0■
/kg was orally administered, and the movements of the gastrointestinal tract were observed in the wild without anesthesia or under anesthesia. Evaluation of effects on gastrointestinal motility is as follows:
A strength of action comparable to that of metoclopramide was rated ++, a weaker effect was rated +, a stronger effect was ++++, and no effect was rated -.

c) Effect on guinea pig stomach specimens The stomach was removed from a guinea pig, and the sections from which the mucous membrane and serosa of the pylorus were removed were
The muscle was suspended in Krebs-Ringer solution in the direction of the circular muscle, and changes in tension were measured isometrically via a transducer.

Average shrinkage height when applying 10 μM of each sample (n=3
~5) was determined and used as an index of the strength of activity. The ionic contraction at high concentration was set as 1000, and the contraction due to the drug was calculated as a relative ratio.

2) Effect on gastric motility in rats without anesthesia using the Ba1loon method Rats (weighing 200 to 250 g) that had been fasted overnight were placed under light ether anesthesia, and a rubber Ba1loon was inserted into their stomachs.
Ba1loon-pressure transduc
Gastric motility was measured by the er method. Gastric motility was quantified as motility index using an integrator. The specimen was subcutaneously administered after the patient emerged from anesthesia and the ductal movement stabilized.

When metoclopramide and sulpiride were administered at 4s+g/kg, the values were 3.1 and 1.0, respectively.

EXAMPLES The present invention will be specifically explained by describing examples below.

Example 1 2, 3. 5-trimethoxybenzoic acid2. Dissolve OOg in 40 ml of tetrahydrofuran and cool with ice water r1-
Hydroxy-IH-benzotriazole 1°52g, N
, N'-dicyclohexylcarbodiimide 2.06g,
4-amino-1,2-diethylpyrazolidine 1.44g
were added one after another, and the mixture was stirred at room temperature for 14 hours.

After removing the insoluble matter, i! The mixture was concentrated, chloroform and water were added to the residue, acidified with hydrochloric acid, and the precipitate was separated by filtration.

The filtrate was left standing to separate chloroform Pi, water was added thereto, and the mixture was neutralized with potassium carbonate.

3.41 g of N-(4-(1,2-diethylpyrazolidinyl))-2,3,6-)rimethoxybenzamide was obtained from the chloroform layer.

3.41 g of the obtained compound was suspended in 5 ml of methanol, 5 ml of a 21% hydrogen chloride isopropyl ether solution was added under cooling, and further isopropyl ether was added, and the precipitate was dissolved in y! 2.45 g of N-(4-(1,2-diethylpyrazolidinyl))-2,3°5-trimethoxybenzamide hydrochloride was obtained.

mp, 124-126℃ (isopropanol) I
R(Nuj o I) cm-': 3540
, 3450. 3350. 2500°1670,
160O NMR (CDC13) δ (TMS, ppm)
:13, 5 (broad) 8, 8 1 (broad d) 7.12 (d) 6.64 (d) 5.0 (m) 3.92 (S) 3.86 (S) 3.81 (s ) 3, 8-2.8 (m) 1.32 (t) Antiemetic effect of apomorphine on vomiting: Effect on gastrointestinal motility in dogs 20 (4.0 mg/Kg i, v, under no anesthesia) Guinea pig specimen before removal Effect on: Effect on gastric motility in rats without anesthesia by 225Bat 1oon method: 1.2 Example 2 2, 3. 5-) Dissolve 1.00 g of rimethoxybenzoic acid in 20 ml of tetrahydrofuran, and add 0.76 g of 1-hydroxy-IH-benzotriazole under ice water 6, N, N.
' -Dicyclohexylcarbodiimide 1. 03g,
0.57 g of 1-(2-aminoethyl)pyronodine was successively added, and the mixture was stirred at room temperature for 21 hours.

After filtering off insoluble matter, the filtrate was concentrated, chloroform and water were added to the residue, the mixture was acidified with hydrochloric acid, and the precipitate was filtered off. The filtrate was left standing to separate the aqueous layer, neutralized by adding potassium carbonate, and then extracted with chloroform.

1.45 N-(2-(1-pyrrolidino)ethyl)-2,3,5-1rimethoxybenzamide from the chloroform layer
I got g.

1.45 g of the obtained compound was dissolved in 5 rnl of methanol, and while cooling, 5 ml of a 21% hydrogen chloride solution in isopropyl ether was added, followed by isopropyl ether, and N-(2-(1-pyrrolidino)ethyl) was separated as an oil. 1.19 g of -2,3,5-1rimethoxybenzamide hydrochloride was obtained.

IR(Neat)am-': 3380, 2B20. 2500. 1670 Apomorphine antiemetic effect on vomiting: Effect on gastrointestinal motility in dogs: + (3.0 mg/Kg i, v, under anesthesia) Effect on guinea pig specimens before removal: 254 Gastric motility in rats without anesthesia using the Balloon method Effect on: 1.0 Example 3 2, 3. 5-) Dissolve 1.00 g of rimethoxybenzoic acid in 20 ml of tetrahydrofuran, add 1-hydroxy-I H-benzotriazole 0° 76 g% N under ice water 4
, N'-dicyclohexylcarbodiimide 1.03g
, 0.65 g of 1-(2-aminoethyl)morpholine were sequentially added, and the mixture was stirred at room temperature for 15 hours.

After filtering off insoluble matter, the filtrate was concentrated, chloroform and water were added to the residue, the mixture was acidified with hydrochloric acid, and the precipitate was filtered off. The filtrate was left standing to separate the aqueous layer, neutralized by adding potassium carbonate, and then extracted with chloroform.

1.52 N-(2-(1-morpholino)ethyl)-2,3,5-)rimethoxybenzamide from the chloroform layer
I got g.

1.52 g of the obtained compound was dissolved in 5 ml of methanol, and 21% hydrogen chloride isopropyl ether filtrate was added under cooling.
5 ml of t6i was added, furthermore isopropyl ether was added, and the precipitate was collected by filtration to obtain 1.12 g of N-(2-(1-morpholino)ethyl)-2,3,5-trimethoxybenzamide hydrochloride. Ta.

mp, 128-131°C IR (Nujol) cm-': 3380.2
460, 1655, 1610 Le J emetic effect on apomorphine emesis: Effect on guinea pig excised stomach specimen: 62
Effect on gastric motility in rats without anesthesia by Bal 1oan method: 1,6 Example 4 N-(1-ethyl-2-pyrrolidinylmethyl)-2-nitro3. 5. 6-drimethoxybenzamide 4.
00g was dissolved in a mixture of 40 ml of acetic acid and 40 ml of acetic anhydride, and 5% Pd-C (50% wet > 0.80 g
was added and hydrogenated at room temperature and pressure.

After filtering off the catalyst, the solvent was distilled off. Chloroform and water were added to the residue, acidified with hydrochloric acid to separate the aqueous layer, neutralized by adding potassium carbonate, and extracted with chloroform.

3.80 g of N-(1-ethyl-2-pyrrolidinylmethyl)-2-7cetylamino-35.6i-)dimethoxybenzamide was obtained from the chloroform layer.

mp, 153-155℃ (Toluene) IR (Nu
j o 1) am-':3300, 1
670. 1650/NMR (CDC13)
δ (TMS, ppm): 8, 0 (bro
ad s)8, 8 (broad t)
6.50 (s) 3, 9-1.3 (m) 3.86 (S) 3.76 (s) 2.07 (s) 1.07 (t) Antiemetic effect of apomorphine on vomiting: According to Ba1loon method Effect on gastric motility in rats without anesthesia: 1.2 Example 6 2-(butan-2-one-3-yl)oxy-3°5-
1.50 g of dimethoxybenzoic acid in 2 ml of tetrahydrofuran
Dissolve in 5 ml of ice water and add 0.1-hydroxy-IH-hensitriazole. 94g, N.

N'-dicyclol\xylcarbodiimide 1.27g1
0679 g of 2-7minomethyl-1-ethylpyrrolidine was successively added, and the mixture was stirred at room temperature for 14 hours.

After filtering off insoluble matter, the filtrate was concentrated, chloroform and water were added to the residue, the mixture was acidified with hydrochloric acid, and the precipitate was filtered off. The filtrate was neutralized with potassium carbonate, and N-(1-
Ethyl-2-pyrrolidinylmethyl)-2-(butane-2
2.14 g of -on-3-yl)oxy-3,5-dimethoxybenzamide were obtained.

2.14 g of the obtained compound was dissolved in 2.5 ml of chloroform, and 2.5 ml of 16.3% hydrogen chloride isopropyl ether solution was added under cooling.
1.49 g of 1-ethyl-2-pyrrolidinylmethyl)-2-(butan-2-one-3-yl)oxy-3,5-dimethoxybenzamide hydrochloride was obtained.

IR(Neat)cm-': 3440.2660. 1730, 1650°1600
．． 1536. 1355 NMR (CDC13) δ (TMS, ppm) 12, 1
(br, IH)9.03
(br, IH) 7, 1-6. 5 (m
2H) 4.8 (m IH) 4,
1-1. 9 (m 20H) 1, 7-1. 2
(rn, 6H) Antiemetic effect of apomorphine on vomiting: Effect on guinea pig specimen before removal: 279 Examples
6 Dissolve 1.50 g of 2-chloro-6-nitro-3,5-1 methoxybenzoic acid in 20 ml of tetrahydrofuran, add 0.0 g of l-hydroxy-IH-benzotriazole and add ice water.
93g, N,N'-dicyclohexylcarbodiimide 1. 27g, 1-(2-aminoethyl)
0.71 g of pyrrolidine was added one after another, and the mixture was stirred at room temperature for 19 hours.

After filtering off insoluble matter, the mixture was washed with N,N-dimethylformamide, the filtrate and the washing liquid were combined and concentrated, and the residue was acidified with salt M and the precipitate was filtered off.

The filtrate was allowed to stand still to separate the aqueous layer, and after washing with toluene,
Neutralized with potassium carbonate.

2.04 g of N-(2-(1-pyrrolidino)ethyl-2-chloro-6-nitro-3,5-simethoxybenzamide) was obtained from the chloroform layer.

2.04 g of the obtained compound was suspended in 10 ml of methanol, and 5 ml of a 16.3% hydrogen chloride isobutylene ether solution was added under cooling, and the precipitate was collected by filtration to give N-(2-(1
-pyrrolidino)ethyl2-chloro-6-nitro-3
, 1.69 g of 5-dimethoxybenzamide hydrochloride was obtained.

mp, 199-202°C (dec,) (Itanol/methanol) IR (NujOI)e+m-': 31B0, 2620.16B0, 1530°35O NMR (DMSO-da) δ (TMS, ppm) 11.
4 (broad) 9.19 (broad t) 7.06 (s) 4.02 (s) 3.98 (S) 3,9-1.7 (m) Antiemetic effect of apomorphine on vomiting: Gastrointestinal motility in dogs Effect on: +++ (0.25 B/g i, v, under no anesthesia) Effect on guinea pig specimen before removal: 421 Example 7 2-Nitro-3-hydroxy-5-methoxybenzoic acid 4
．． Dissolve 30 g in 83 ml of tetrahydrofuran and add 1-hydroxy-IH-benzotriazole under ice water treatment.
18g, N,N'-dicyclohexylcarbodiimide4. 37 g of N,N-diethylethylenediamine and 2.15 g of N-diethylethylenediamine were sequentially added thereto, and the mixture was stirred at room temperature for 14 hours.

Insoluble matter was filtered off, washed with methanol, the filtrate and washing liquid were combined and concentrated, chloroform was added to the residue, and continuous extraction was performed using a Soxhlet extractor. Concentrate the extract to N-(N,N
-diethylaminoethyl)-2-nitro-3-hydroxy-5-methoxybenzamide (6.20 g) was obtained. 6.20 g of the obtained compound was suspended in 80 ml of water,
40 ml of IN-hydrochloric acid was added and insoluble matter was filtered off. The filtrate was concentrated to dryness to give N-(N,N-diethylaminoethyl)-
3.80 g of 2nitro-3-hydroxy-6-methoxybenzamide hydrochloride was obtained.

mp, 197-198.5°C (ethanol) I
R(Nu j o l) am-': 335
0. 2700. 1670. 16101520
, 1335 NMR (DMS O-d 6) δ (TMS,
p p m>10, 7 (broad) 9, 08 (broad t) 6.81 (s) 3.83 (s) 3, 8-2.9 (m) 1.26 (t) Antiemetic for apomorphine emesis Effect: Effect on rat gastrointestinal motility under non-anesthesia by Ba1loon method = 0.9

Claims (1)

[Claims] 1 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Numerical formulas, chemical formulas, Benzamide compound represented by ▼, ▲Mathematical formula, chemical formula, table, etc.▼