JPS62242675A - Piperazine acetamide derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel piperazine acetamide derivative useful as a therapeutic agent for urinary tract disorders, and a pharmacologically acceptable phosphoric acid addition salt thereof.

More specifically, the present invention relates to the general formula (I) (wherein R represents a lower alkyl group, R2 represents a phenyl group or a pyridyl group, and R3 represents a hydrogen atom or a lower alkoxy group). The present invention relates to a novel piperazine acetamide derivative represented by:

In the general formula (I) of the present invention, examples of the lower alkyl group represented by R include methyl, ethyl, propyl, butyl, etc., and examples of the pyridyl group represented by R2 include 2-pyridyl, 3-pyridyl, The 4-pyridyl group is methoxy, ethoxy,
Examples include propoxy groups.

Examples of the pharmacologically acceptable acid addition salts of the compound represented by the general formula (I) of the present invention include mineral acid salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and cationic acid; Examples include organic acid salts such as maleic acid, fumaric acid, citric acid, 7-euric acid, lactic acid, and tartaric acid.

The novel piperazine acetamide derivative represented by the general formula (I) of the present invention can be produced as follows.

That is, the compound represented by the general formula (I) according to the present invention is represented by the following general formula (n) (wherein R2 and R3 represent the same meanings as above, and X represents a halogen atom). and N represented by the following general formula (III) (wherein R1 represents the same meaning as above).
-alkylpiperazine in the presence of a solvent.

Solvents used in the method of the invention include, for example, benzene, toluene, pyridine, acetone, N, N-
Dimethylphoremamide, methanol.

Examples include ethanol and chloroform, and the reaction is carried out in a 1-room chamber at 4 degrees reflux of the solvent used.

The halogenoacetamide derivative represented by the general formula (II), which is the starting material in the method of the present invention, is also a new compound, and is produced as shown in the figure below.

(In the formula, R2* R3 and X represent the same meanings as above.

) Photoreactivity - The novel piperazine acetamide derivative represented by the general formula (I) and its pharmacologically acceptable acid addition salt produced in this way have an excellent micturition reflex suppressing effect. It is extremely useful as a therapeutic agent for urinary system disorders such as frequent urination and feeling of residual urine.

Hereinafter, the present invention will be explained by examples.

Reference example 1 2-chloroacetylamino-N-(2-pyridylmethyl)benzamide 2-amino-N-(2-pyridylmethylzamide 145
g and triethylamine 97 g chloroform 1450
108 g of chloroacetyl chloride was added dropwise to the +1 suspension under water cooling, and the mixture was stirred at room temperature.

Stir for 5 hours. The reaction solution is made alkaline by adding an aqueous sodium carbonate solution, and the precipitated crystals are collected by filtration.

The chloroform layer of the filtrate is separated, washed with water and dehydrated, and then the solvent is distilled off. The residue crystals and the previously obtained crystals were combined and recrystallized from methanol to give a melting point of 131-133.

142 g of pale yellow needles were obtained.

Elemental analysis value C1sHt4N302 Cl theoretical value C,
59.31; H, 4. G5; N, 13.83 experimental value
C. 59.18;H, 4.7G;N. 13.78 Reference Example 2 N-Benzyl-2-chloroacetylaminobenzamide Crystals obtained from 2-amino-N-benzylbenzamide in the same manner as in Reference Example 1 were recrystallized from ethanol,
Colorless needles with a melting point of 152-153' are obtained.

Elemental analysis value C16H15N2 02 Cl theoretical value C
, 63.47;H. 4.99;N. 9.25 Experimental value C, G3.39; H. 5. II; N, 9.1G Reference Example 3 2-chloroacetylamino-4,5-dimethoxy-N-
(Crystals obtained from 2-pyridylmethyl 2-amino-4,5-dimethoxy-N-(2-pyridylmethyl)benzamide in the same manner as in Reference Example 1 were recrystallized from chlorosim-ethanol 61 liquid, and the melting point A light colored powder crystal with an angle of 172-174° is obtained.

Elemental analysis value C17H18N3 G4 Cl theoretical value C
．． 5G. +3;H. 4.99;N. 11.55 Experimental value C, 55.95; H, 5. Ql;N. 11.3
5 Example 1 4-Methyl-N-[2-(2-pyridylmethylaminocarbonyl)phenyl-1-piperazineacetamide.
136 g of fumarate 2-chloroacetylamino-N-(2-pyridylmethyl)benzamide and 87 g of l-methylpiperazine
．． A solution of 4 g of N,N-dimethylformamide in 1380 ml is stirred at room temperature for 18 hours. Add water to the reaction solution, make it acidic with hydrochloric acid, and wash with ethyl acetate. The aqueous layer is made alkaline with an aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer is washed with saturated brine, dehydrated, and then the solvent is distilled off. The residue was converted into a fumarate salt according to a conventional method, and recrystallized from methanol to give a melting point of 153-154.
122 g of a light yellow prism product of 50°C was obtained.

Elemental analysis value C20H25N502/C4H404 theoretical value C, 59, G2; H, G, 05; N, 14.48
Experimental values C, 59,50iH, G, Off; N, 14.
48 Example 2 2.80 g of 4-methyl-N-(2-pennolaminocarbonylphenyl)-1-piperazineacetamide fumarate N-benzyl-2-chloroacetylaminobenzamide and 1.39 g of 1-methylpiperazine. N,
Add 28ml of N-dimethylformamide solution to 18ml at room temperature.
Stir for an hour. Thereafter, the extraction residue obtained by processing in the same manner as in Example 1 is converted into a fumarate salt according to a conventional method. Recrystallized from methanol, melting point 213-21 B' (D colorless W1
Piece 1, 50g'.

obtain.

Elemental analysis value C21G26 H402・3/2C4H4
04 theoretical value C, 59,99; H, 5,97: N, I
O, 3G experimental value C, 59, 79; H, 8, 29; N,
10.21 Example 3 N-[4,5-dimethoxy-2-(2-pyridylmethylaminocarbonyl)phenyl-4-methyl-1-piperazineacetamide hydrochloride 2-chloroacetylamino-4,5-dimethoxy- 2゜00g of N-(2-pyridylmethyl)benzamide and 0.8g of 1-methylpiperazine
3g of N.

Add 20 ml of N-dimethylformamide solution to 36 ml at room temperature.
Stir for an hour. Thereafter, the extraction residue obtained by processing in the same manner as in Example 1 is converted into a hydrochloride according to a conventional method. Recrystallized from methanol to give 1.57 g of colorless needles, melting point 234-238'.
get.

Elemental analysis value C22H29N 504・2HC1・l/
2H20 Theoretical value C, 51, 87; H, G, 33iN, 13.
75 experimental value C, 51, 88; H, Ili, 40; N,
13.44 Example 4 4-ethyl-N-[2-(2-pyridylmethylaminocarbonyl)phenyl]-1-piperazineacetamide.
Fumarate 2-chloroacetylamino-N-(2-pyridylmethyl)benzamide2. OOg and 1-ethylpiperazine 1
．． 13 g of N,N-dimethylformamide was then treated in the same manner as in Example 1, and the resulting residue was converted into a fumarate salt in accordance with a conventional method. 11) Crystallize from ethanol,
Color-containing plate-like product 1 with a melting point of 167-168''.

Obtain 89g.

Elemental analysis value C21 H27N5 02・C4H404
Theoretical value C, 6G. 35iH. lli. 28;N.
14.08 Experimental value C, GO. 05;H, 6.4
9; N, eyes. 04 Patent applicant Hokuriku Pharmaceutical Co., Ltd. Amendment (spontaneous)
-February 7, 1988 Director General of the Japan Patent Office Yu Yu 71 Road Department 1Pi Indication 1988 Patent Application No. 86047 2 Name of the invention Piperazine acetamide derivative 3 Capturing person/Relationship with reverse sex Patent Subject of Applicant's 4th correction Column 5 Supplement for "Detailed Description of the Invention" in Description 3 + Contents of E (+) Description 3 No. 2 [The statement "phosphoric acid" in the 17th line above 1 has been corrected to "phosphoric acid" do.

(2) Add the following text between the bottom line of the 6th page of the specification and the first line of the 7th page.

"Reference Example 4 2-chloroacetylamino-N-(3-pyridylmethyl)benzamide 2-amino-N-(3-pyridylmethyl)benzamide was prepared in the same manner as in Reference Example 1, melting point 231-234"
Obtain pale yellow crude crystals of (decomposition).

Since the crystal is unstable, it is used in the next reaction without purification.

IR spectrum (KBr method) Cm-1:169G (C:
0), 1635 (C:O) NMR spectrum (CDCI
3 solutions) δ: 4.12 (2H, s), 4.80 (2H
, d, J=GHz).

7.05 (III, t-d, J near, 5.IH2).

7.15-7.77 (SR, Peng), 8.40-8.55
(3H, m).

11.7F (IH, br) MS spectrum mHz: 305,303 (M”, l:
3) Reference Example 5 2-chloroacetylamino-N-(4-pyridylmethyl2-amino-N-(4-pyridylmethyl)benzamide was prepared in the same manner as in Reference Example 1, with a melting point of 238 to 242°.
(decomposition) to obtain crude yellow crystals.

Since the crystal is unstable, it is used in the next reaction without purification.

IR spectrum (KBr method) c+s-': 1G50 (
C:O) NMR spectrum (CDCI3 solution) δ: 4, 1G (2
■Is), 4. fi[i(211, d, J:llil
lZL7, Ol-]J5 (6H. Zen), 8.43-84
3 (3H, Peng).

11,74 (lH.br) MS spectrum yr/z: 305,303 (M, 1
:3) J(3) Specification S, page 7, line 14, "Recrystallize from methanol" is changed to "F[crystallize from methanol. Dry the obtained crystals with hot air at 80" for 4 hours. By doing so, it is corrected to ``.

(4) Add the following sentence between the bottom line of page 7 of specification 3 and the first line of the top plan of page 8.

The fumarate anhydride described in 1. is allowed to absorb moisture overnight at room temperature with a humidity of 80% to obtain a -hydrate.

Sex wand colorless prism product Melting point: 153-154.

Elemental analysis value C20 H25 N502 ・C4H4
04 ・H20 theoretical value C, 57.48; H, G. 2
3; N, 13.9G experimental value C. 57.35;H
, 8.37; N, 13.90J (5) Specification No. 10
Add the following sentence α from the 8th line onward on the page.

“Example 5 4-Methyl-N-[2-(3-pyridylmethylaminocarbonyl)phenyl]-1-piperazineacetamide oxalate 2-chloroacetylamino-N-(3-pyridylmethyl)benzamide 3.50 g A solution of 1.84 g of 1-methylpiverazine in N.N-dimethylformamide 35-1 was stirred at room temperature for 42 hours.Then, the extraction residue obtained by the same treatment as in Example 1 was re-diluted with ethyl acetate. A pale yellow prism product 1.Bog is crystallized and has a melting point of 74-78°.

This product is converted into an oxalate salt according to a conventional method, and recrystallized from methanol to obtain a colorless prism product having a melting point of 186-1896.

Elemental analysis value C2oH25N502/C2H204 theoretical value C, 57,76; H, 5,95; N, 15
．． 31 Experimental value C, 5F, 32; H, G, I8;
N, 15.03 Example 6 4-Methyl-N-[2-(4-pyridylmethylaminocarbonyl)phenyl]-1-piperazineacetamide.
3.00 g of oxalate 2-chloroacetylamino-N-(4-pyridylmethyl)benzamide and 1-methylpiperazine
．． A solution of 41 g of N,N-dimethylformamide 301 is stirred at room temperature for 17 hours. Thereafter, the extraction residue obtained by processing in the same manner as in Example 1 is converted into oxalate according to a conventional method. 11) Crystallization from ethanol yields 1.44 g of pale yellow flakes with a melting point of 147-150''.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 represents a lower alkyl group, R_2 represents a phenyl group or pyridyl group, and R_3 represents a hydrogen atom or a lower alkoxy group. ) A piperazine acetamide derivative represented by: and a pharmacologically acceptable acid addition salt thereof.