JPS58225080A - Benzoylpiperazine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 is straight or branched 1-6C alkyl, 3-6C cycloalkyl, etc.; R2 is H or alkoxy; excluding the case that R2 is H and R1 is methyl) and its acid addition salt. EXAMPLE:1-Methyl-4-[4-(7-methoxy-1, 2, 3, 4-tetrahydro-1-naphthoyloxy) benzoyl]- piperazine. USE:It has chymotrypsin-inhibiting activity and is useful as a remedy for pancreatic diseases, etc. PROCESS:The compound of formula I can be prepared by esterifying the 4-substituted phenol of formula II with the tetrahydronaphthyl-carboxylic acid of formula III. The esterification is carried out, e.g. by reacting the reactive derivative of the compound of formula III (e.g. acid halide, acid anhydride, etc.) with the compound of formula II, or by reacting the compound of formula II with the compound of formula III in the presence of a dehydrating agent such as DCC.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a benzoylpiperazine derivative, and more particularly to a benzoylpiperazine derivative represented by the following general formula (I) and an acid addition salt thereof.

In the formula, Ro: linear or branched a 1-O, alkyl group, 0
3A-06 cycloalkyl group, 03-J: 36 cycloalkylalkyl group or pencil group, R2: hydrogen atom or alkoxy group.

However, the case where R2 is a hydrogen atom and R1 is a methyl group is excluded.

The present inventor has already discovered that the phenyl esters of the present invention have an excellent chymotrinosin inhibitory effect, and has filed a patent application (see Japanese Patent Application Laid-Open No. 158737/1983). Compounds similar to the above were prepared and their pharmacological effects were investigated. As a result, the novel penzoylbiperazone derivative represented by the general formula (1) and its acid addition salts have an even superior chymotrinosin inhibitory effect. They discovered this and completed the present invention.

Therefore, the present invention has unique uses based on the blocking effect of chymotrinosin, such as useful as a medicine for pancreatic disorders.
The present invention provides a compound of formula 1) and an acid addition salt thereof.

The compound of formula (1) of the present invention can be produced, for example, by esterifying a 4-substituted phenol (1) and a ketone hydronaphthylcarboxylic acid QII) according to the following reaction formula.

(III) (n) (Each symbol in the formula has the same meaning as above) The esterification reaction of compound (n) and (2) is carried out by a commonly used method. That is, a method of reacting a compound of formula (If) with a reactive conductor of the compound of formula (2), such as an acid halide, an acid anhydride, a mixed acid anhydride, an active ester, or an acid;
1) and a method in which the compound of formula 010 is reacted with dicyclohexylcarbodiimide in the presence of a dehydrating agent, etc. are employed as advantageous methods.

The compound (1) obtained in this way can be further processed by conventional methods such as inorganic acid salts such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid; acetic acid, zolopionic acid, maleic acid, fumaric acid, It can lead to organic acid salts such as tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

Next, the results of all measurements of the chymotrinosin inhibitory activity of the compounds of the present invention are shown.

[Measurement method]
[Refer to De Journal of Biochemistry 62.408 (1967)], a solution of the test compound in dimethyl sulfoxide 0.1-1 in water 0.1-
and Buffer # solution (0,1
M. Tris-HCl buffer; P) (s, o) 0, 1
ml of the bath solution was incubated for 10 minutes, mixed with 25 mM of acetyl-L-tyrosine ethyl ester, and reacted at 67°C for 60 minutes. Develop color by method, 5
The absorbance at 30 nm was measured and maintained. As a comparative compound to 1, chymotrinosin 151. The results using tosylphenylalanine chloromethyl ketone (comparative compound ■), known as an IW agent, are as in the first example.

Hereinafter, 1.°Margin 1st Example 1 1-Methyl-4-[4-(7-Medoxy1°2.3.
4-nato2hydro1-natutoyloxy)benzoyl]pipe2cine: 1-)f-4-(4-hydroxybenzoyl)bibe2
Cyclohexyl lupozoimide (4.91/l) was added to a solution of 4.4y gin 4.4y and 7-medoxy 1.2,3°4-tetrahydro-1-naphthylcarboxylic acid (4.949%) in acetonitrile 100+ILt, and the mixture was stirred overnight at room temperature. After removing the insoluble matter, it was evaporated under reduced pressure and added with 0.5N hydrochloric acid 50-
and washed with ethyl acetate. Water J@ was washed with a saturated sodium bicarbonate bath and extracted with ethyl acetate. After washing with water and drying, the solvent is distilled off to obtain a crude oil. This was mixed with a silica gel column methanol (bathing solvent: chloroform-methanol 30:1) made by A.
7.5711 of an oil is obtained.

When made into methanesulfonate according to a conventional method, the melting point is 15
6.2 g of thorny yellow needles at 0-151°C (yield: 61.
6%) is obtained.

Examples 2 to 7 Compounds shown in Table 2 were obtained by treatment in the same manner as in Example 1.
li f'1 ka no5. ■, (;1'i411 57 ++ reward 4t IFf
19 (l No. 109192 νji 2 Name of the invention
f'l, t-'s function 1i 1
Shin: I! ri] (1 (1/11, Fi 3-6-29, Ko-ku, Nagoya City, Henchi Prefecture, Otsu, Kowa Co., Ltd. Representative Takayasu Miwa 1st generation Misaki 13 6, ``Detailed Description of the Invention'' in the specification to be amended) ” Column 7, Contents of amendment (1) Specifications, page 7, line 14, “Examples 2 to 7” should be corrected to “Examples 2 to 9.”

■) Same, page 8, 2nd Table A, after Section A of Example 70, add the section of Examples 8 and 9 as shown in the appendix.

Claims (1)

[Claims] 1. A benzoylpiperazine derivative represented by the following general formula (I) and an acid addition salt thereof. In the formula, R]: straight chain or branched O1-06 alkyl group, 03
-C6 cycloalkyl group, 03-C6 cycloalkylalkyl group or benzyl group, R211 hydrogen atom or alkoxy group. However, the case where R2 is a hydrogen atom and R1 is a methyl group is excluded.