JPH01100159A - Amide compound - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R1, R2 are lower alkyl, or incorporate along with N atom. to form 1-pyrrolidyl, piperidino; Ar is pyridyl, thienyl, furyl, pirazinyl) and its acid adduct. EXAMPLE:N-[4-[2-(Dimethylamino)ethoxy]benzyl]-2-pyrazinecarboxamide hydrochloride. USE:Digestive tract motion activator. PREPARATION:After the compound of formula II is converted into its acid chloride, anhydride, mixed anhydride, the derivative is allowed to react with a compound of formula III in the presence or in the absence of a base such as pyridine or sodium carbonate, in an inert organic solvent such as ether, benzene or DMF at 0 deg.C to the refluxing temperature of the solvent to give the compound of formula I.

Description

Detailed Description of the Invention - No. 1 The present invention relates to a novel amide compound represented by the following - Monana (I) and its pharmacologically acceptable acid addition salt, and these compounds are It has a ductal movement activating effect and is used in the medical field.

(In the formula, R and R2 each represent a lower alkyl group, or R1 and R2 together represent a 1-pyrrolidinyl group or a piperidino group together with the substituting nitrogen atom. Also, Ar represents a pyridyl group, a thienyl group, or a 1-pyrrolidinyl group or a piperidino group. group, furyl group, or pyrazinyl group.) LeΔ1 [No literature regarding the amide compound of the present invention was found, and
It is completely unknown that it has a gastrointestinal motility activating effect.

0i13. .

Decline in gastrointestinal motility function is one of the causes of unspecified gastrointestinal symptoms such as back discomfort and abdominal bloating. Therefore, in order to improve these symptoms, it is considered necessary to administer a drug that has a gastrointestinal motility activating effect. Drugs that have this type of effect include 4-amino-5-chloro-
N-[(2-diethylamino)ethyl]-2-methoxybenzamide [generic name: metoclopramide, The Merck Index, 10
Several drugs are known, including th edltlon and 6019, but they are not necessarily satisfactory in terms of medicinal efficacy and safety. Under these circumstances, the development of new gastrointestinal motility activators is desired in the medical field.

In view of the above-mentioned circumstances, the inventors of the present invention have conducted extensive research and have unexpectedly discovered a novel amide compound represented by the general formula (I) and a pharmacologically acceptable acid addition salt thereof. It was discovered that it has an excellent effect of activating gastrointestinal motility, and the present invention was completed.

In the compound represented by the general formula (I) of the present invention, the lower alkyl group represented by R and R2 includes methyl, ethyl, n-propyl, isopropyl, n-butyl,
Examples include isobutyl and tert-butyl groups.

The compound represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable acid addition salt as desired, or the base can be liberated from the generated acid addition salt.

Examples of pharmacologically acceptable acid addition salts of the compound represented by formula (I) of the present invention include mineral acid salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

Alternatively, acetic acid salts such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, oxalic acid, lactic acid, and tartaric acid may be mentioned.

The novel amide compound represented by the general formula (I) of the present invention can be produced as follows.

That is, a carboxylic acid compound represented by the following general formula (II) Ar-COOH(II) (wherein Ar represents the same meaning as above) is converted into a reactive derivative thereof (acid chloride, acid anhydride, mixed acid anhydride etc.), the general formula (III
) (In the formula, R and R2 have the same meanings as defined above.) It can be produced by reacting it with an amine compound represented by the following formula in an inert organic solvent in the presence or absence of a base.

Examples of the base used in the method of the present invention include pyridine, picoline, lutidine, collidine, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine potassium carbonate, sodium carbonate, and the like.

Furthermore, any inert organic solvent may be used in the method of the present invention as long as it does not inhibit the reaction.
For example, ether, benzene.

Examples include toluene, ethyl acetate, tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethylsulfoside, N,N-dimethylformamide, and the like. Further, the reaction is carried out at a temperature ranging from 0°C to the reflux temperature of the solvent used.

Incidentally, the amine compounds represented by the general formula (III), which are the starting materials in the method of the present invention, are new compounds except for some, and are produced as shown in the diagram below.

(III) (In the formula, R1 and R2 have the same meanings as defined above, and X represents a halogen atom.) A compound represented by the general formula (I) of the present invention, or a pharmacologically acceptable acid addition thereof Salt is usually packaged in capsules,
Tablets, fine granules, granules, syrups.

It is administered orally as a powder, injection, or suppository. These preparations can be manufactured by conventional methods by adding pharmacologically and pharmaceutically acceptable additives.

The main dosage for treatment patients depends on the patient's symptoms, but
Normally for adults, the daily dose is 1.0 to 1 by oral administration.
It is about 1.000 mg, and about 1.0 to 500 mg for parenteral administration.

The excellent effects discovered by the present invention will be explained below using test examples. Note that metoclopramide hydrochloride was used as a control compound.

Test Example 1 Guinea... IJW The ileum was removed from a Hartley male guinea pig (weighing around 450 g) and the length was 1.5-2. A sample of Oc+s was created. The specimens were suspended in a Krebs-Henseleit bath (37°C) aerated with a gas mixture of 95% 02 and 5% CO2, and rhythmic contractions were measured isotropically. The effect of the test compound was expressed as 100% of the contraction caused by 10-6M of acetate and lucorine. The results are shown in Table 1.

Table 1 Dose required to induce 50% contraction of the present acetylcholine Below, the present invention will be explained by reference examples and examples.
The invention is not limited to the specific details of these examples.

Reference Example 1 4-C2-(dimethylamino)ethoxy]benzaldehyde hydrohydroxybenzaldehyde 81.1 g (7)N.

To a solution of 2401 N-dimethylformamide, 138 g of potassium carbonate and 80 g of 2-dimethylaminoethyl chloride.
Add 7 g and 301 inpropyl ether and stir at 60° C. for 1.5 hours. After cooling, add 720+ sl of water to the reaction solution.
Pour into the solution and extract with chloroform. The chloroform layer is extracted with hydrochloric acid.

The aqueous layer is made alkaline with an aqueous sodium hydroxide solution and extracted with ethyl acetate. After washing and dehydrating the ethyl acetate layer,
The solvent is distilled off. The residue was distilled under reduced pressure and the boiling point was 142-14.
69.1 g of a colorless liquid at 4° C. (4 smog) are obtained.

Mass spectrum m/z: 193 (M) 1R spectrum ν (liquid film method) cm: 1G98 (C:0) NMR spectrum δ (cocI3) pp ugly: 2.
34(IliH,s), 2.7G(2H,t, J=E
iH2), 4.15 (28, t.

J=GHz), 7. (12(211,d, J=9)1z
), 7.82 (2H, d, J=9Hz), 9.87 (
IH, s) Reference Example 2 4-[2-(1-pyrrolidinyl)ethoxycobenzaldehyde 4-(2-bromoethoxy)benzaldehyde 2.29
1-42 g of pyrrolidine + 1.38 g of potassium carbonate and 81 g of N,N-dimethylformamide were added to 60°C.
Stir for 2 hours. After cooling, water was added and extracted with ethyl acetate. The ethyl acetate layer is extracted with hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and extracted with ethyl acetate.

After the ethyl acetate layer is washed with water and dehydrated, the solvent is distilled off.

The residue is distilled under reduced pressure to obtain 1.72 g of a colorless liquid with a boiling point of 170°C (511a+Hg).

Mass spectrum ■/z: 219 (M) IR spectrum ν (liquid film method) cll-1=.

1G9G(C:O) NMR spectrum δ (CDCl2) I) pI:
1.11i0-2.27 (4H1 intestine), 2.44-2.
80 (4H, m), 2.93 (2H, t, J:6Hz
), 4.19 (211, t + J: GHz), ? ,
Old (2H9d, J:9H2), 7.82 (2H, d
, J: 9Hz>, 9.87 (lH, s) According to the methods of Reference Examples 1 and 2, the compound of Reference Example 3 is obtained.

Reference example 3 4-(2-piperidinoethoxy)benzaldehyde Properties Colorless liquid Boiling point 180 to IE32°C (8 mmHg) Mass spectrum ts/z: 233 (M”) 1R spectrum
ν (liquid film method) C-2 1G94 (C:0) NMR spectrum δ (CDCl2) ppta:
1.12-1.76 [BH, m), 2.27-2.6I
(4) 11), 2.79 (2H, t, J: GHz), 4
．． 18 (2H, t, J: GHz), 7.00 (2H.

d, J: 9■Z), 7.82 (211, d, J: 982
), 8.87 (1■+s) Reference Example 4 4-C2-(dimethylamino)ethoxy]benzaldoxime 4-[2-(dimethylamino)ethoxy]benzaldehyde 154g and hydroxylamine hydrochloride 59.9g
g and ethanol 6001 and boil for 10 minutes.

After cooling, the precipitated crystals were collected by filtration and converted into hydrochloride with a melting point of 174~
191 g of pale yellow crystals at 175° C. are obtained. 1 water to this crystal
501 was added, made alkaline with potassium carbonate, and extracted with chloroform. After dehydration, the chloroform layer is
The solvent is distilled off. The residue was washed with isopropyl ether to obtain 157 g of colorless crystals. This is recrystallized from ethyl acetate to obtain colorless scales having a melting point of 95-96°C.

NMR spectrum δ (CDCl2) pp-22
．． 40 (8B, s), 2.80 (2B, t, J
: GHz), 4.21 (2H, t.

J=811Z), 6.88(211,d, J:9H2)
, 7.41 (2H, d, J=9Hz), 8.05 (Kame H, S), 10.50 (1■, br) Elemental analysis value C engineering, H engineering 6N202 Theoretical value C, 1i3.44; H, 7, 74; N
, 13.45 experimental value C, G3.28; H, 7,
71i N, 13.37 Compounds of Reference Examples 5 and 6 are obtained according to the method of Reference Example 4.

Reference example 5 4-[2-(1-pyrrolidinyl)ethoxycopenzaldoxime hydrochloride Properties Colorless platelet crystals (EtOH) Melting point 219-220.5°C NMR spectrum δ (CD30D) pPI '1
．． 84-2.14 (4B, m), 3.00-3.90 (
GH, Peng), 4.24-4.50 (2H, m), ? ,0
3 (2H, d, J: 9Hz), 7.56 (2H, d.

J=9H2), 8.03 (llI, s) elemental analysis value C
13H1BN20241 HC1 theoretical value C, 57, C
7i H, 7,07; N, 10.35 experimental value C,
57, 57; H,? , 15; N, IO, 25 Reference Example 6 4-(2-piperidinoethoxy)penzaldoquine hydrochloride Properties Colorless scaly crystals (EtOH) Melting point 224-225°C NMR spectrum δ (DMSO-d6) ppm
:1.0? -2,13(BH,l), 2.87-3.6
3 (GH, Peng), 4.47 (2H, t, J = 5.5Hz
), 7.01 (2H, d, J: 9Hz), 7.54 (
2H, d, J=9Hz), 8.0G (LH, s), 10
．． 88 (lLbr) Elemental analysis value C14H2ON202
e HC1 theoretical value C, 59,05; H, 7,4
3; N, 9.84 experimental value C, 58,74; H,
7,28; N, 9.64 Reference Example 7 4-C2-(dimethylamino)ethoxycopenzylamine 4-[2-(dimethylamino)ethoxycopenzaldoxime Suspension of 100 g of about 10% ammoniacal methanol 5001 Add 10.2 g of Raney nickel catalyst to the liquid. The mixture is hydrogenated at 30° C. and a pressure of 50 kg/cs+2. The catalyst is filtered off, and the filtrate is evaporated to remove the solvent. The residue was distilled under reduced pressure to obtain a boiling point of 142-144°C (8+
*mHg) 88.8 g of a colorless liquid are obtained.

Mass spectrum zen/z: 194 (M”) NMR
Spectrum δ (CDC13) ppm: 1.45
(2H, S) +2.32 (GH9s), 2.71 (2
H9t, J: GHz).

3.79 (2+1.s), 4.05 (2H, t, J=:
GHz), 6.88 (28, d.

J:9H2), 7.21 (2H, d, J:9H2) Compounds of Reference Examples 8 and 9 are obtained according to the method of Reference Example 7.

Reference Example 8 4-[2-(1-pyrrolidinyl)ethoxy]benzylamine Properties Colorless liquid Fluorescence point 163-165°C (3 aunHg) Mass spectrum m/z: 220 (M+) NMR spectrum δ (CDCl2) ppm: 1 .53 (2
H, br), 1.70-1.90 (4B, m), 2.5
0-2.75 (48, m), 2.89 (2H, t, J:
GHz), 3. ．． 79 (2H, s).

4.10(2■, t, J:fil(Z), Ili, 88
(2■, d, J=9Hz), 7.22 (2H, d, J
:9Hz) Reference Example 9 4-(2-piperidinoethoxy)benzylamine Properties Colorless liquid Boiling point 185-190°C (6mdg) Mass spectrum m/z: 234 (M”) NMR
Spectrum δ (CDCl2) 1)I)l'1.
30-1.90 (8H, m), 2.4O-2JO (4H
, m), 2.7G (21j, t, J=8Hz), 3
．． 79<21,s), 4.09(2B,t,J
: GHz), 8.8B (28, d, J=9■z),
7.21 (2H, d, J: 9 Hz) Example I N-C4-[2-(dimethylamino)ethoxy]benzyl]-2-pyrazinecarboxamide hydrochloride pyrazinecarboxylic acid 1.15 g of chloroform lQa+
0.94 g of triethylamine in suspension under water cooling and stirring
and 1.01 g of ethyl chlorocarbonate were sequentially added dropwise. After stirring at the same temperature for 30 minutes, 4-[2-(dimethylamino)
1.50 g of ethoxycopenzylamine was added dropwise while stirring while cooling with water. Stir the mixture for 15 hours. After distilling off the solvent under reduced pressure, 10% hydrochloric acid is added to the residue. The aqueous layer was washed with ethyl acetate, made alkaline with potassium carbonate, and extracted with ethyl acetate. After the ethyl acetate layer is washed with water and dehydrated, the solvent is distilled off. The residue was washed with cyclohexane to give light green crystals 1. Get OOg. This is converted into a hydrochloride salt by a conventional method and recrystallized from ethanol to obtain colorless needle crystals with a melting point of 191-192°C.

1R spectrum p (KBr) c+e:
111iB4(C:0) NMR spectrum δ (DMSO-d6) pl)l
'2.81 (61, S), 3.44 (211, t, J
:5.5H2), 4.37(21(.

t, J=5.5Hz), 4.47(2■, d, J:
8.5Hz), 6.95 (20°d, J29H2), 7
．． 31 (2H, d, J: 9Hz), 8J9 (II, dd
.

J: 2.5, 1.5H2), 8.83(l) I, d, J
:2.5H2), 9.09(IH,br), 9.18(
IH, d, J=1.5Hz) Elemental analysis value C16H20
N402 @HCI theoretical value C,57,08i H
, Ili, 28; N, 1G, l1i3 experimental value C,
5B, 92 i H, 8,42; N, lG, 54 Example 2 N-[4-[2-(dimethylamino)ethoxycopenzyl]-2-furancarboxamide hydrochloride 4-[2-(dimethylamino) ) ethoxy]benzylamine2. To a solution of 1.4 g of OOg and 1.14 g of triethylamine in 101 chloroform was added 1.47 g of 2-furancarboxylic acid chloride (1.2 g of 2-furancarboxylic acid
(Adjusted from 7g and 2゜00g of thionyl chloride in a conventional manner)
Add. After stirring the mixture at room temperature for 30 minutes, the two solvents were distilled off under reduced pressure. Add 10% hydrochloric acid to the residue and wash with ethyl acetate.

The aqueous layer is made alkaline with potassium carbonate and extracted with ethyl acetate. After the ethyl acetate layer is washed with water and dehydrated, the solvent is distilled off. The residue was washed with a mixture of isobropyle-ethyl-hexane to obtain 2.76 g of light gray crystals. This was converted into a hydrochloride by a conventional method, and recrystallized from ethanol, with a melting point of 16.
2.70 g of colorless needles having a temperature of 0-161° C. are obtained.

IR spectrum v (KBr) cra-':
1G42(C:O) NMR spectrum δ (DMSO-d6) pI)I
n '2.81 (Ili■, s), 3.45 (2H,
t, J=5Hz), 4.3G (2B.

d, J=BHz), 4.37 (2H, t, J:5■z)
, 8.58 (IH, dd.

J:3. ．． 5.2Hz), 6.94 (2B, d, J: 9
Hz), 7.12 (IH.

dd, J: 3.5, 1Hz),? , 27 (2H, d, J
:9Hz), 7.78 (IH, dd, J:2.IH2)
, 8.72 (IH, br) elemental analysis value C16H2ON
20341HC1 theoretical value C, 59, 17; H, B
, 52; N, 8.82 experimental value C, 59,02;
H, G, GG; N, 8.40 According to the method of Examples 1 and '2, the compounds of the following examples are obtained.

Example 3 N-[4-[2-(dimethylamino)ethoxycobenzylconicotinamide Properties Colorless prism product (AcOEt-Et20) Melting point
85.5-86℃ IR spectrum v (KBr) cm-1:165
2 (C=0) NMR spectrum δ (coc13) ppm: 2
．． 31 (IEH, S), 2.71 (2H, t, J: 5.
5H2), 4.04 (2H.

t, J=5.5Hz), 4.55(2H, d, J=5.
5Hz), 6.85 (IH.

br), 8.87 (2H, d, J=8.5Hz), 7
．． 10-7.40(3)1. m).

8.11 (II, dt, J: 8.2Hz), 8.6G (
IH, dd, J: 5.2Hz).

8.95 (IH, d, J=2Hz) Elemental analysis value C17H21N302 Theoretical value C, C8,21; H, 7,07; N, 1
4.04 Experimental value C, C8,02; H, 7,03;
N, 14.01 Example 4 N-[4-[2-(dimethylamino)ethoxycopenzyl-2-thiophenecarboxamide Properties Colorless needle crystals (AcOEt) Melting point 98-99°C IR spectrum v (KBr) am, 1G1
8(C:0) NMR spectrum δ (CDCl2) I)pm
'2.33 (G11.s), 2.71 (2■, t, J:
5.5Hz), 4.05 (2H.

t, J=5.5! Iz), 4.54 (211, d, J:
5.5Hz), 6.15 (IH.

br), 6.89 (21, d, J: 9Hz), 7.04
(In, dd, J=5.3.5Hz), 7.211i (
2 [1, d, J: 9Hz), 7.35-7.50 (2H
9) Elemental analysis value C16H2ON202 S theoretical value C,8
3,13i H,G,G2 i N, 9.20 Experimental value C, 113,25i H, 6,57; N, 9.2
7 Example 5 N-[4-[2-(1-pyrrolidinyl)ethoxy]penzylconicotinamide Properties Pale yellow liquid mass spectrum -/z: 325 (M”) IR spectrum ν (liquid film method) cm-1: 1G48(C:O
) NMR spectrum δ (CDC13) pp ■: 1.
60-2.00 (4H, m), 2.44-2.76 (4
0, ugly), 2.87 (211, t, J=6H2), 4.
07 (2H, t, J: 6H2), 4.53 (2H, d.

J:5.5Hz), 8.84(2H,d, J:911
2), 7.02 (lH, br).

7.23 (2H, d, J: 9Hz), 7.28 (1B,
ddd, J: 8.5°0.5Hz), 8. lo(IH,
dt, J:8. +, 5Hz), 8J2 (IH.

dd, J:5.1.5)1z), 8.94(IH, dd
, J:1.5,0.5Hz) Example 6 N-[4-(2-piperidinoethoxy)benzyl]-2
-Thiophenecarboxamide Properties Colorless needle crystals (AcOEt) Melting point 114.5-115°C 1R spectrum v (KBr) cta:
IGIG(C:O) NMR spectrum δ (CDC13) 1)l)l
'1.20-1.94 (GH, +s), 2.32-2.
64 (4H, m), 2.75 (2H, t, J:GH
z), 4.08 (2H, t, J: GHz), 4.5
2 (2H.

d, J:5, s■Z), 6.33 (IH, br)
, 6.8G (2H,d, J=9Hz), 7.04(I
H, dd, J: 5.4Hz), 7.25 (2H, d, J
:9Hz), 7.44 (IH, dd, J: 5.IHz)
, 7.50 (IH, dd.

J: 4.1Hz) Elemental analysis value C19H24N 202 S theoretical value C,
1li6.25; H, 7,02; N, 8.13
Experimental value C, GG, 19 i H, 8, 98; N,
7.98 A novel amide compound represented by the general formula (I) of the present invention,
and its pharmacologically acceptable acid addition salts have excellent gastrointestinal motility activating effects and are extremely useful as agents for improving various gastrointestinal symptoms associated with decreased gastrointestinal motility. It is.

Patent applicant: Hokuriku Pharmaceutical Co., Ltd.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ - represents a pyrrolidinyl group or a piperidino group; and Ar represents a pyridyl group, a thienyl group, a furyl group, or a pyrazinyl group), and a pharmacologically acceptable acid addition salt thereof.