JPH05262751A - Arylamide derivative - Google Patents

Abstract

PURPOSE:To provide a new compound having high blood platelet coagulation- inhibitory activity, vasodilative activity, and anti-hyperlipemic activity, thus useful for the treatment or prevention of various kinds of thrombosis, embolism, arteriosclerosis, and hypertension. CONSTITUTION:The objective compound of formula I [Ar is (halogen, alkyl, or alkoxy-substituted) phenyl, naphthyl, pyridinyl, furyl, etc.; X is CO or SO2; Y is 1,4-piperazinyl, 1,4-piperizinyl, etc.; Q is single bond or O; Z is 1-3C alkylene or dialkylmethylene; R<4> is OH or NH(CH2)mCOOH (m is 1-3)], e.g. 2-(4- benzenesulfonylpiperazinyl) beta-phenoxypropionic acid. The compound of the formula I can be obtained by reaction of a compound of formula II with a compound of formula A-Z-COOH in the presence of a base (e.g. NaOH) at 0-100 deg.C.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel arylamide derivative or a salt thereof, and a circulatory organ agent containing the same and having excellent platelet aggregation inhibitory action, vasodilatory action, antihyperlipidemic action and the like. It is a thing.

[0002]

BACKGROUND OF THE INVENTION Thromboxane A ₂ (hereinafter abbreviated as “TXA ₂ ”) is one of the metabolites of the arachidonic acid cascade, and its main actions are platelet aggregation and vasoconstriction. There is.

[0003] Therefore, TXA ₂ it is assumed that cause thrombosis and myocardial infarction by these effects, TXA ₂
Research on synthetic systems has been actively conducted. As a result, as agents that suppress TXA ₂ -based platelet aggregation, dazoxiben, OKY-0
46, CV4151, Dazmagre
1), OKA-1581, TXA ₂ synthase inhibitors such as R68070 and AH23848, GR32191, B
M13177, BM13505, SQ28668, IC
TXA ₂ receptor inhibitors such as I192605 have been developed.

However, the conventional TXA ₂ synthase inhibitor has been insufficient in suppressing thrombus formation in vivo, although it suppresses TXA ₂ production in vitro.

On the other hand, the TXA ₂ receptor inhibitor is considered to be effective in preventing thrombus formation because it suppresses direct platelet aggregation by TXA ₂ , but among the conventionally known TXA ₂ receptor inhibitors In addition to the excellent TXA ₂ receptor inhibitory action, there are drawbacks such as a transient TXA ₂ -like action, that is, side effects such as platelet aggregation-inducing action and vasoconstriction action.

[0006]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a circulatory organ agent having a strong platelet aggregation inhibitory action, vasodilatory action and antihyperlipidemic action.

[0007]

In such an actual situation, the present inventor has synthesized a large number of arylamide derivatives and, as a result of earnest research on their platelet aggregation inhibitory action, vasodilatory action and antihyperlipidemic action, The arylamide derivative represented by the following general formula (1) or a salt thereof has excellent platelet aggregation inhibitory action and vasodilatory action due to TXA ₂ receptor inhibitory activity, and further has antihyperlipidemic action and is safe The present invention has been completed with the finding that it is highly effective and is useful as a drug for various cardiovascular diseases such as thrombosis, myocardial infarction, arteriosclerosis, and hypertension.

That is, the present invention provides the following general formula (1):

[0009]

[Chemical 2]

The present invention provides an arylamide derivative represented by: or a salt thereof, and a circulatory organ agent containing the same.

The arylamide derivative of the present invention is represented by the above general formula (1). In the formula, the alkyl group is preferably a linear or branched chain having 1 to 6 carbon atoms, Examples are methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t
-Butyl group, n-pentyl group, i-pentyl group, n-hexyl group and the like are exemplified, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and an alkyl group substituted with a halogen atom. Examples thereof include a trifluoromethyl group and a 1,1,1-trifluoroethyl group, and examples of the carboxyalkyloxy group include a carboxymethyloxy group, a carboxyethyloxy group and a carboxypropyloxy group. Examples of the alkoxy group include those in which an enzyme atom is bonded to the alkyl group, examples of the alkenyl group include vinyl group, propenyl group, allyl group, branyl group, pentenyl group, and the like, and acylamino group includes formyl group. Amino group,
An acetamino group, a propionylamino group, a butyrylamino group, etc. are mentioned, and a methylene group, an ethylene group, a propylene group is mentioned as an alkylene group having 1 to 3 carbon atoms.

Examples of the salt of the arylamide derivative (1) include alkali metal salts, inorganic acid salts, organic acid salts and the like. More specifically, as the alkali metal salt,
Lithium salt, sodium salt, potassium salt, magnesium salt and the like can be mentioned, and as the inorganic acid salt, hydrochloride, sulfate,
Examples thereof include nitrates, hydrobromides, phosphates, and the like. Examples of organic acid salts include acetates, oxalates, citrates, malates, fumarates, maleates, succinates, and lactic acid. Examples thereof include salts, tartrates, methanesulfonates, benzenesulfonates and p-toluenesulfonates.

Specific examples of the compound (1) of the present invention include the following. 2- (4-benzenesulfonylpiperazinyl) β-phenoxypropionic acid 3- (4-benzenesulfonylpiperazinyl) β-phenoxypropionic acid 4- (4-benzenesulfonylpiperazinyl) β-phenoxypropionic acid 2- (4-benzoylpiperazinyl) β-phenoxypropionic acid 3- (4-benzoylpiperazinyl) β-phenoxypropionic acid 4- (4-benzoylpiperazinyl) β-phenoxypropionic acid 2- {4- (4 -Bromobenzenesulfonyl) piperazinyl} β-phenoxypropionic acid 3- {4- (4-bromobenzenesulfonyl) piperazinyl} β-phenoxypropionic acid 4- {4- (4-bromobenzenesulfonyl) piperazinyl} β-phenoxypropionic acid 2- {4- (4-bromobenzoyl) pi Piperazinyl} β
-Phenoxypropionic acid 3- {4- (4-bromobenzoyl) piperazinyl} β
-Phenoxypropionic acid 4- {4- (4-bromobenzoyl) piperazinyl} β
-Phenoxypropionic acid

2- (1-benzenesulfonylpiperidin-4-yl) β-phenoxypropionic acid 3- (1-benzenesulfonylpiperidin-4-yl)
β-phenoxypropionic acid 4- (1-benzenesulfonylpiperidin-4-yl)
β-phenoxypropionic acid 2- (1-benzoylpiperidin-4-yl) β-phenoxypropionic acid 3- (1-benzoylpiperidin-4-yl) β-phenoxypropionic acid 4- (1-benzoylpiperidin-4-yl) ) Β-phenoxypropionic acid 2- {1- (4-bromobenzenesulfonyl) piperidin-4-yl} β-phenoxypropionic acid 3- {1- (4-bromobenzenesulfonyl) piperidin-4-yl} β-phenoxy Propionic acid 4- {1- (4-bromobenzenesulfonyl) piperidin-4-yl} β-phenoxypropionic acid 2- {1- (4-bromobenzoyl) piperidine-4-
Yl} β-phenoxypropionic acid 3- {1- (4-bromobenzoyl) piperidine-4-
Yl} β-phenoxypropionic acid 4- {1- (4-bromobenzoyl) piperidine-4-
Il} β-phenoxypropionic acid

2- (1-benzenesulfonylpiperidin-3-en-4-yl) β-phenoxypropionic acid 3- (1-benzenesulfonylpiperidin-3-ene-)
4-yl) β-phenoxypropionic acid 4- (1-benzenesulfonylpiperidin-3-ene-
4-yl) β-phenoxypropionic acid 2- (1-benzoylpiperidin-3-en-4-yl) β-phenoxypropionic acid 3- (1-benzoylpiperidin-3-en-4-yl) β-phenoxypropion Acid 4- (1-benzoylpiperidin-3-en-4-yl) β-phenoxypropionic acid 2- {1- (4-bromobenzenesulfonyl) piperidin-3-en-4-yl} β-phenoxypropionic acid 3 -{1- (4-bromobenzenesulfonyl) piperidin-3-en-4-yl} β-phenoxypropionic acid 4- {1- (4-bromobenzenesulfonyl) piperidin-3-en-4-yl} β- Phenoxypropionic acid 2- {1- (4-bromobenzoyl) piperidine-3-
En-4-yl} β-phenoxypropionic acid 3- {1- (4-bromobenzoyl) piperidine-3-
En-4-yl} β-phenoxypropionic acid 4- {1- (4-bromobenzoyl) piperidine-3-
En-4-yl} β-phenoxypropionic acid

2- (1-benzenesulfonyl-4-hydroxypiperidin-4-yl) β-phenoxypropionic acid 3- (1-benzenesulfonyl-4-hydroxypiperidin-4-yl) β-phenoxypropionic acid 4- ( 1-benzenesulfonyl-4-hydroxypiperidin-4-yl) β-phenoxypropionic acid 2- (1-benzoyl-4-hydroxypiperidine-4)
-Yl) β-phenoxypropionic acid 3- (1-benzoyl-4-hydroxypiperidine-4)
-Yl) β-phenoxypropionic acid 4- (1-benzoyl-4-hydroxypiperidine-4)
-Yl) β-phenoxypropionic acid 2- {1- (4-bromobenzenesulfonyl) -4-hydroxypiperidin-4-yl} β-phenoxypropionic acid 3- {1- (4-bromobenzenesulfonyl) -4- Hydroxypiperidin-4-yl} β-phenoxypropionic acid 4- {1- (4-bromobenzenesulfonyl) -4-hydroxypiperidin-4-yl} β-phenoxypropionic acid 2- {1- (4-bromobenzoyl) -4-Hydroxypiperidin-4-yl} β-phenoxypropionic acid 3- {1- (4-bromobenzoyl) -4-hydroxypiperidin-4-yl} β-phenoxypropionic acid 4- {1- (4-bromo) Benzoyl) -4-hydroxypiperidin-4-yl} β-phenoxypropionic acid

2- {4- (1-naphthalenesulfonyl)
Piperazinyl} phenoxyacetic acid 2- {4- (1-naphthalenesulfonyl) piperazinyl} β-phenoxypropionic acid 2- {4- (1-naphthalenesulfonyl) piperazinyl} γ-phenoxybutyric acid 3- {4- (1-naphthalenesulfonyl) Piperazinyl} phenoxyacetic acid 3- {4- (1-naphthalenesulfonyl) piperazinyl} β-phenoxypropionic acid 3- {4- (1-naphthalenesulfonyl) piperazinyl} γ-phenoxybutyric acid 4- {4- (1-naphthalenesulfonyl) Piperazinyl} phenoxyacetic acid 4- {4- (1-naphthalenesulfonyl) piperazinyl} β-phenoxypropionic acid 4- {4- (1-naphthalenesulfonyl) piperazinyl} γ-phenoxybutyric acid 2- {4- (1-naphthalenecarbonyl) Piperazinyl} phenoki Acetate 2- {4- (1-naphthalenecarbonyl) piperazinyl} β-phenoxypropionic acid 2- {4- (1-naphthalenecarbonyl) piperazinyl} γ-phenoxybutyric acid 3- {4- (1-naphthalenecarbonyl) piperazinyl} phenoxy Acetic acid 3- {4- (1-naphthalenecarbonyl) piperazinyl} β-phenoxypropionic acid 3- {4- (1-naphthalenecarbonyl) piperazinyl} γ-phenoxybutyric acid 4- {4- (1-naphthalenecarbonyl) piperazinyl} phenoxy Acetic acid 4- {4- (1-naphthalenecarbonyl) piperazinyl} β-phenoxypropionic acid 4- {4- (1-naphthalenecarbonyl) piperazinyl} γ-phenoxybutyric acid

2- {4- (2-naphthalenesulfonyl)
Piperazinyl} phenoxyacetic acid 2- {4- (2-naphthalenesulfonyl) piperazinyl} β-phenoxypropionic acid 2- {4- (2-naphthalenesulfonyl) piperazinyl} γ-phenoxybutyric acid 3- {4- (2-naphthalenesulfonyl) Piperazinyl} phenoxyacetic acid 3- {4- (2-naphthalenesulfonyl) piperazinyl} β-phenoxypropionic acid 3- {4- (2-naphthalenesulfonyl) piperazinyl} γ-phenoxybutyric acid 4- {4- (2-naphthalenesulfonyl) Piperazinyl} phenoxyacetic acid 4- {4- (2-naphthalenesulfonyl) piperazinyl} β-phenoxypropionic acid 4- {4- (2-naphthalenesulfonyl) piperazinyl} γ-phenoxybutyric acid 2- {4- (2-naphthalenecarbonyl) Piperazinyl} phenoki Acetate 2- {4- (2-naphthalenecarbonyl) piperazinyl} β-phenoxypropionic acid 2- {4- (2-naphthalenecarbonyl) piperazinyl} γ-phenoxybutyric acid 3- {4- (2-naphthalenecarbonyl) piperazinyl} phenoxy Acetate 3- {4- (2-naphthalenecarbonyl) piperazinyl} β-phenoxypropionic acid 3- {4- (2-naphthalenecarbonyl) piperazinyl} γ-phenoxybutyric acid 4- {4- (2-naphthalenecarbonyl) piperazinyl} phenoxy Acetic acid 4- {4- (2-naphthalenecarbonyl) piperazinyl} β-phenoxypropionic acid 4- {4- (2-naphthalenecarbonyl) piperazinyl} γ-phenoxybutyric acid

2- {1- (1-naphthalenesulfonyl)
Piperidin-4-yl} phenoxyacetic acid 2- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} β-phenoxypropionic acid 2- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} γ-phenoxybutyric acid 3- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} phenoxyacetic acid 3- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} β-phenoxypropionic acid 3- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} γ-phenoxybutyric acid 4- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} phenoxyacetic acid 4- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} β-phenoxypropionic acid 4- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} γ-phenoxybutyric acid 2- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} phenoxyacetic acid 2- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} β-phenoxypropionic acid 2- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} γ-phenoxybutyric acid 3- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} phenoxyacetic acid 3- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} β-phenoxypropionic acid 3- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} γ-phenoxybutyric acid 4- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} phenoxyacetic acid 4- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} β-phenoxypropionic acid 4- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} γ-phenoxybutyric acid 2- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} phenoxyacetic acid 2- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} β-phenoxypropionic acid 2- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} γ-phenoxybutyric acid 3- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} phenoxyacetic acid 3- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} β-phenoxypropionic acid 3- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} γ-phenoxybutyric acid 4- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} phenoxyacetic acid 4- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} β-phenoxypropionic acid 4- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} γ-phenoxybutyric acid

2- {1- (2-naphthalenecarbonyl)
Piperidin-4-yl} phenoxyacetic acid 2- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} β-phenoxypropionic acid 2- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} γ-phenoxybutyric acid 3- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} phenoxyacetic acid 3- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} β-phenoxypropionic acid 3- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} γ-phenoxybutyric acid 4- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} phenoxyacetic acid 4- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} β-phenoxypropionic acid 4- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} γ-phenoxybutyric acid 2- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} phenoxyacetic acid 2- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} β-phenoxypropionic acid 2- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} γ-phenoxybutyric acid 3- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} phenoxyacetic acid 3- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} β-phenoxypropionic acid 3- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} γ-phenoxybutyric acid 4- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} phenoxyacetic acid 4- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} β-phenoxypropionic acid 4- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} γ-phenoxybutyric acid 2- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} phenoxyacetic acid 2- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} β-phenoxypropionic acid 2- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} γ-phenoxybutyric acid 3- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} phenoxyacetic acid 3- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} β-phenoxypropionic acid 3- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} γ-phenoxybutyric acid 4- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} phenoxyacetic acid 4- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} β-phenoxypropionic acid 4- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} γ-phenoxybutyric acid

2- {1- (2-naphthalenesulfonyl)
Piperidin-3-en-4-yl} phenoxyacetic acid 2- {1- (2-naphthalenesulfonyl) piperidine-
3-en-4-yl} β-phenoxypropionic acid 2- {1- (2-naphthalenesulfonyl) piperidine-
3-en-4-yl} γ-phenoxybutyric acid 3- {1- (2-naphthalenesulfonyl) piperidine-
3-en-4-yl} phenoxyacetic acid 3- {1- (2-naphthalenesulfonyl) piperidine-
3-en-4-yl} β-phenoxypropionic acid 3- {1- (2-naphthalenesulfonyl) piperidine-
3-en-4-yl} γ-phenoxybutyric acid 4- {1- (2-naphthalenesulfonyl) piperidine-
3-en-4-yl} phenoxyacetic acid 4- {1- (2-naphthalenesulfonyl) piperidine-
3-en-4-yl} β-phenoxypropionic acid 4- {1- (2-naphthalenesulfonyl) piperidine-
3-en-4-yl} γ-phenoxybutyric acid 2- {1- (2-naphthalenecarbonyl) piperidine-
3-en-4-yl} phenoxyacetic acid 2- {1- (2-naphthalenecarbonyl) piperidine-
3-en-4-yl} β-phenoxypropionic acid 2- {1- (2-naphthalenecarbonyl) piperidine-
3-en-4-yl} γ-phenoxybutyric acid 3- {1- (2-naphthalenecarbonyl) piperidine-
3-en-4-yl} phenoxyacetic acid 3- {1- (2-naphthalenecarbonyl) piperidine-
3-en-4-yl} β-phenoxypropionic acid 3- {1- (2-naphthalenecarbonyl) piperidine-
3-en-4-yl} γ-phenoxybutyric acid 4- {1- (2-naphthalenecarbonyl) piperidine-
3-en-4-yl} phenoxyacetic acid 4- {1- (2-naphthalenecarbonyl) piperidine-
3-en-4-yl} β-phenoxypropionic acid 4- {1- (2-naphthalenecarbonyl) piperidine-
3-en-4-yl} γ-phenoxybutyric acid 2- {1- (2-naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} phenoxyacetic acid 2- {1- (2-naphthalenesulfonyl) -4-hydroxy Piperidin-4-yl} β-phenoxypropionic acid 2- {1- (2-naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} γ-phenoxybutyric acid 3- {1- (2-naphthalenesulfonyl) -4- Hydroxypiperidin-4-yl} phenoxyacetic acid 3- {1- (2-naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} β-phenoxypropionic acid 3- {1- (2-naphthalenesulfonyl) -4-hydroxy Piperidin-4-yl} γ-phenoxybutyric acid 4- {1- (2-naphthalenesulfonyl) -4-hydroxy Peridin-4-yl} phenoxyacetic acid 4- {1- (2-naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} β-phenoxypropionic acid 4- {1- (2-naphthalenesulfonyl) -4-hydroxypiperidine -4-yl} γ-phenoxybutyric acid

2- {1- (2-naphthalenecarbonyl)
-4-Hydroxypiperidin-4-yl} phenoxyacetic acid 2- {1- (2-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} β-phenoxypropionic acid 2- {1- (2-naphthalenecarbonyl)- 4-Hydroxypiperidin-4-yl} γ-phenoxybutyric acid 3- {1- (2-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} phenoxyacetic acid 3- {1- (2-naphthalenecarbonyl) -4- Hydroxypiperidin-4-yl} β-phenoxypropionic acid 3- {1- (2-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} γ-phenoxybutyric acid 4- {1- (2-naphthalenecarbonyl) -4 -Hydroxypiperidin-4-yl} phenoxyacetic acid 4- {1- (2-naphthalenecarbonyl)- -Hydroxypiperidin-4-yl} β-phenoxypropionic acid 4- {1- (2-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} γ-phenoxybutyric acid 2- {1- (1-naphthalenesulfonyl)- 4-Hydroxypiperidin-4-yl} phenoxyacetic acid 2- {1- (1-naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} β-phenoxypropionic acid 2- {1- (1-naphthalenesulfonyl) -4 -Hydroxypiperidin-4-yl} γ-phenoxybutyric acid 3- {1- (1-naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} phenoxyacetic acid 3- {1- (1-naphthalenesulfonyl) -4-hydroxy Piperidin-4-yl} β-phenoxypropionic acid 3- {1- (1-naphthalenesulfo Nyl) -4-hydroxypiperidin-4-yl} γ-phenoxybutyric acid 4- {1- (1-naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} phenoxyacetic acid 4- {1- (1-naphthalenesulfonyl) -4-Hydroxypiperidin-4-yl} β-phenoxypropionic acid 4- {1- (1-naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} γ-phenoxybutyric acid 2- {1- (1-naphthalenecarbonyl) ) -4-Hydroxypiperidin-4-yl} phenoxyacetic acid 2- {1- (1-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} β-phenoxypropionic acid 2- {1- (1-naphthalenecarbonyl) -4-Hydroxypiperidin-4-yl} γ-phenoxybutyric acid 3- {1- (1-naphthalenecal Nyl) -4-hydroxypiperidin-4-yl} phenoxyacetic acid 3- {1- (1-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} β-phenoxypropionic acid 3- {1- (1-naphthalenecarbonyl) ) -4-Hydroxypiperidin-4-yl} γ-phenoxybutyric acid 4- {1- (1-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} phenoxyacetic acid 4- {1- (1-naphthalenecarbonyl)- 4-Hydroxypiperidin-4-yl} β-phenoxypropionic acid 4- {1- (1-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} γ-phenoxybutyric acid

2- {1- (1-naphthalenesulfonyl)
-4-Hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid 3- {1- (1-naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid 4- {1- (1-Naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid 2- {1- (1-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxy Acetic acid 3- {1- (1-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid 4- {1- (1-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} α, α-Dimethylphenoxyacetic acid 2- {1- (2-naphthalenesulfonyl) -4-hydroxypiperidine-4-i } Α, α-Dimethylphenoxyacetic acid 3- {1- (2-naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid 4- {1- (2-naphthalenesulfonyl) -4- Hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid 2- {1- (2-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid 3- {1- (2- Naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid 4- {1- (2-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid 2- {4- (1-naphthalenesulfonyl) piperazinyl} β-phenylpropionic acid 2- {4- (1-naphthalene sulphone) Nyl) piperazinyl} γ-phenylbutyric acid 3- {4- (1-naphthalenesulfonyl) piperazinyl} β-phenylpropionic acid 3- {4- (1-naphthalenesulfonyl) piperazinyl} γ-phenylbutyric acid 4- {4- (1 -Naphthalenesulfonyl) piperazinyl} β-phenylpropionic acid 4- {4- (1-naphthalenesulfonyl) piperazinyl} γ-phenylbutyric acid 2- {4- (1-naphthalenecarbonyl) piperazinyl} phenylacetic acid 2- {4- (1 -Naphthalenecarbonyl) piperazinyl} β-phenylpropionic acid 2- {4- (1-naphthalenecarbonyl) piperazinyl} γ-phenylbutyric acid 3- {4- (1-naphthalenecarbonyl) piperazinyl} phenylacetic acid 3- {4- (1 -Naphthalenecarbonyl) piperazinyl} β-phenylpro On-acid 3- {4- (1-naphthalenecarbonyl) piperazinyl} γ-phenylbutyric acid 4- {4- (1-naphthalenecarbonyl) piperazinyl} phenylacetic acid 4- {4- (1-naphthalenecarbonyl) piperazinyl} β-phenylpropyi On-acid 4- {4- (1-naphthalenecarbonyl) piperazinyl} γ-phenylbutyric acid

2- {4- (2-naphthalenesulfonyl)
Piperazinyl} β-phenylpropionic acid 2- {4- (2-naphthalenesulfonyl) piperazinyl} γ-phenylbutyric acid 3- {4- (2-naphthalenesulfonyl) piperazinyl} β-phenylpropionic acid 3- {4- (2- Naphthalenesulfonyl) piperazinyl} γ-phenylbutyric acid 4- {4- (2-naphthalenesulfonyl) piperazinyl} β-phenylpropionic acid 4- {4- (2-naphthalenesulfonyl) piperazinyl} γ-phenylbutyric acid 2- {4- ( 2-Naphthalenecarbonyl) piperazinyl} phenylacetic acid 2- {4- (2-naphthalenecarbonyl) piperazinyl} β-phenylpropionic acid 2- {4- (2-naphthalenecarbonyl) piperazinyl} γ-phenylbutyric acid 3- {4- ( 2-Naphthalenecarbonyl) piperazinyl} phenylacetic acid 3- {4- (2-naphthalenecarbonyl) piperazinyl} β-phenylpropionic acid 3- {4- (2-naphthalenecarbonyl) piperazinyl} γ-phenylbutyric acid 4- {4- (2-naphthalenecarbonyl) piperazinyl} phenylacetic acid 4- {4- (2-naphthalenecarbonyl) piperazinyl} β-phenylpropionic acid 4- {4- (2-naphthalenecarbonyl) piperazinyl} γ-phenylbutyric acid

2- {1- (1-naphthalenesulfonyl)
Piperidin-4-yl} phenylacetic acid 2- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} β-phenylpropionic acid 2- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} γ-phenylbutyric acid 3- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} phenylacetic acid 3- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} β-phenylpropionic acid 3- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} γ-phenylbutyric acid 4- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} phenylacetic acid 4- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} β-phenylpropionic acid 4- {1- (1-naphthalenesulfonyl) piperidine-
4-yl} γ-phenylbutyric acid 2- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} phenylacetic acid 2- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} β-phenylpropionic acid 2- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} γ-phenylbutyric acid 3- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} phenylacetic acid 3- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} β-phenylpropionic acid 3- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} γ-phenylbutyric acid 4- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} phenylacetic acid 4- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} β-phenylpropionic acid 4- {1- (1-naphthalenecarbonyl) piperidine-
4-yl} γ-phenylbutyric acid

2- {1- (2-naphthalenesulfonyl)
Piperidin-4-yl} phenylacetic acid 2- {1- (2-naphthalenesulfonyl) piperidine-
4-yl} β-phenylpropionic acid 2- {1- (2-naphthalenesulfonyl) piperidine-
4-yl} γ-phenylbutyric acid 3- {1- (2-naphthalenesulfonyl) piperidine-
4-yl} phenylacetic acid 3- {1- (2-naphthalenesulfonyl) piperidine-
4-yl} β-phenylpropionic acid 3- {1- (2-naphthalenesulfonyl) piperidine-
4-yl} γ-phenylbutyric acid 4- {1- (2-naphthalenesulfonyl) piperidine-
4-yl} phenylacetic acid 4- {1- (2-naphthalenesulfonyl) piperidine-
4-yl} β-phenylpropionic acid 4- {1- (2-naphthalenesulfonyl) piperidine-
4-yl} γ-phenylbutyric acid 2- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} phenylacetic acid 2- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} β-phenylpropionic acid 2- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} γ-phenylbutyric acid 3- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} phenylacetic acid 3- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} β-phenylpropionic acid 3- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} γ-phenylbutyric acid 4- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} phenylacetic acid 4- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} β-phenylpropionic acid 4- {1- (2-naphthalenecarbonyl) piperidine-
4-yl} γ-phenylbutyric acid 2- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} phenylacetic acid 2- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} β-phenylpropionic acid 2- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} γ-phenylbutyric acid 3- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} phenylacetic acid 3- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} β-phenylpropionic acid 3- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} γ-phenylbutyric acid 4- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} phenylacetic acid 4- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} β-phenylpropionic acid 4- {1- (1-naphthalenesulfonyl) piperidine-
3-en-4-yl} γ-phenylbutyric acid 2- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} phenylacetic acid 2- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} β-phenylpropionic acid 2- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} γ-phenylbutyric acid 3- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} phenylacetic acid 3- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} β-phenylpropionic acid 3- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} γ-phenylbutyric acid 4- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} phenylacetic acid 4- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} β-phenylpropionic acid 4- {1- (1-naphthalenecarbonyl) piperidine-
3-en-4-yl} γ-phenylbutyric acid

2- {1- (2-naphthalenesulfonyl)
-4-Hydroxypiperidin-4-yl} phenylacetic acid 2- {1- (2-naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} β-phenylpropionic acid 2- {1- (2-naphthalenesulfonyl)- 4-Hydroxypiperidin-4-yl} γ-phenylbutyric acid 3- {1- (2-naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} phenylacetic acid 3- {1- (2-naphthalenesulfonyl) -4- Hydroxypiperidin-4-yl} β-phenylpropionic acid 3- {1- (2-naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} γ-phenylbutyric acid 4- {1- (2-naphthalenesulfonyl) -4 -Hydroxypiperidin-4-yl} phenylacetic acid 4- {1- (2-naphthalenesulfonyl) -4-hydroxy Peridin-4-yl} β-phenylpropionic acid 4- {1- (2-naphthalenesulfonyl) -4-hydroxypiperidin-4-yl} γ-phenylbutyric acid 2- {1- (2-naphthalenecarbonyl) -4- Hydroxypiperidin-4-yl} phenylacetic acid 2- {1- (2-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} β-phenylpropionic acid 2- {1- (2-naphthalenecarbonyl) -4-hydroxy Piperidin-4-yl} γ-phenylbutyric acid 3- {1- (2-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} phenylacetic acid 3- {1- (2-naphthalenecarbonyl) -4-hydroxypiperidine- 4-yl} β-phenylpropionic acid 3- {1- (2-naphthalenecarbonyl) -4-hydroxypiperi Zin-4-yl} γ-phenylbutyric acid 4- {1- (2-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} phenylacetic acid 4- {1- (2-naphthalenecarbonyl) -4-hydroxypiperidine- 4-yl} β-phenylpropionic acid 4- {1- (2-naphthalenecarbonyl) -4-hydroxypiperidin-4-yl} γ-phenylbutyric acid

3- (4-Nicotinoylpiperazinyl) phenoxyacetic acid 3- {4- (3-pyridinesulfonyl) piperazinyl}
Phenylacetic acid 3- (4-nicotinoylpiperazinyl) phenylacetic acid 3- {1- (3-pyridinesulfonyl) piperidine-4
-Yl} phenoxyacetic acid 3- (1-nicotinoylpiperidin-4-yl) phenoxyacetic acid 3- {1- (3-pyridinesulfonyl) piperidine-4
-Yl} phenylacetic acid 3- (1-nicotinoylpiperidin-4-yl) phenylacetic acid 3- {1- (3-pyridinesulfonyl) piperidine-3
-En-4-yl} phenylacetic acid 3- (1-nicotinoylpiperidin-3-en-4-yl) phenylacetic acid

3- {1- (3-pyridinesulfonyl)-
4-Hydroxypiperidin-4-yl} phenoxyacetic acid 3- (1-nicotinoyl-4-hydroxypiperidine-
4-yl) phenoxyacetic acid 3- {1- (3-pyridinesulfonyl) -4-hydroxypiperidin-4-yl} phenylacetic acid 3- (1-nicotinoyl-4-hydroxypiperidine-
4-yl) phenylacetic acid

3- {4- (2-furansulfonyl) piperazinyl} phenoxyacetic acid 3- {4- (2-furancarbonyl) piperazinyl} phenoxyacetic acid 3- {4- (2-furansulfonyl) piperazinyl} phenylacetic acid 3- {4- (2-furancarbonyl) piperazinyl} phenylacetic acid 3- {1- (2-furansulfonyl) piperidine-4-
Il} phenoxyacetic acid 3- {1- (2-furancarbonyl) piperidine-4-
Il} phenoxyacetic acid 3- {1- (2-furansulfonyl) piperidine-4-
Il} phenylacetic acid 3- {1- (2-furancarbonyl) piperidine-4-
Il} phenylacetic acid 3- {1- (2-furansulfonyl) piperidine-3-
En-4-yl} phenoxyacetic acid 3- {1- (2-furancarbonyl) piperidine-3-
En-4-yl} phenoxyacetic acid 3- {1- (2-furansulfonyl) -4-hydroxypiperidin-4-yl} phenoxyacetic acid 3- {1- (2-furancarbonyl) -4-hydroxypiperidine-4- Yl} phenoxyacetic acid 3- {1- (2-furansulfonyl) -4-hydroxypiperidin-4-yl} phenylacetic acid 3- {1- (2-furancarbonyl) -4-hydroxypiperidin-4-yl} phenylacetic acid 3- {1- (2-furansulfonyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid 3- {1- (2-furancarbonyl) -4-hydroxypiperidin-4-yl} α , Α-Dimethylphenoxyacetic acid

3- {1- (2-furansulfonyl) piperidin-3-en-4-yl} phenylacetic acid 3- {1- (2-furancarbonyl) piperidine-3-
En-4-yl} phenylacetic acid 3- {1- (3-pyridinesulfonyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid 3- {1- (4-pyridinesulfonyl) -4- Hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid 3- (1-isonicotinol-4-hydroxypiperidin-4-yl) α, α-dimethylphenoxyacetic acid

3- {4- (2-thiophenesulfonyl)
Piperazinyl} phenoxyacetic acid 3- (4-thenoylpiperazinyl) phenoxyacetic acid 3- {4- (2-thiophenesulfonyl) piperazinyl} phenylacetic acid 3- (4-thenoylpiperazinyl) phenylacetic acid 3- {1- (2-Thiophenesulfonyl) piperidine-
4-yl} phenoxyacetic acid 3- (1-thenoylpiperidin-4-yl} phenoxyacetic acid 3- {1- (2-thiophenesulfonyl) piperidine-
4-yl} phenylacetic acid 3- (1-thenoylpiperidin-4-yl) phenylacetic acid 3- {1- (2-thiophenesulfonyl) piperidine-
3-en-4-yl} phenoxyacetic acid 3- (1-thenoylpiperidin-3-en-4-yl}
Phenoxyacetic acid 3- {1- (2-thiophenesulfonyl) piperidine-
3-en-4-yl} phenylacetic acid 3- (1-thenoylpiperidin-3-en-4-yl)
Phenylacetic acid 3- {1- (2-thiophenesulfonyl) -4-hydroxy-piperidin-4-yl} phenoxyacetic acid 3- (1-thenoyl-4-hydroxypiperidine-4-
Yl) phenoxyacetic acid 3- {1- (2-thiophenesulfonyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid 3- (1-thenoyl-4-hydroxypiperidine-4-
Yl) α, α-Dimethylphenoxyacetic acid 3- {1- (2-thiophenesulfonyl) -4-hydroxypiperidin-4-yl} phenylacetic acid 3- (1-thenoyl-4-hydroxypiperidine-4-
Yl) phenylacetic acid

3- {4- (4-quinolinesulfonyl) piperazinyl} phenoxyacetic acid 3- {4- (4-quinolinecarbonyl) piperazinyl}
Phenoxyacetic acid 3- {4- (4-quinolinesulfonyl) piperazinyl}
Phenylacetic acid 3- {4- (4-quinolinecarbonyl) piperazinyl}
Phenylacetic acid 3- {1- (4-quinolinesulfonyl) piperidine-4
-Yl} phenoxyacetic acid 3- {1- (4-quinolinecarbonyl) piperidine-4
-Yl} phenoxyacetic acid 3- {1- (4-quinolinesulfonyl) piperidine-4
-Yl} phenylacetic acid 3- {1- (4-quinolinecarbonyl) piperidine-4
-Yl} phenylacetic acid 3- {1- (4-quinolinesulfonyl) -4-hydroxypiperidin-4-yl} phenoxyacetic acid 3- {1- (4-quinolinecarbonyl) -4-hydroxypiperidin-4-yl} phenoxy Acetic acid 3- {1- (4-quinolinesulfonyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid 3- {1- (4-quinolinecarbonyl) -4-hydroxypiperidin-4-yl} α, α-Dimethylphenoxyacetic acid 3- {1- (4-quinolinesulfonyl) -4-hydroxypiperidin-4-yl} phenylacetic acid 3- {1- (4-quinolinecarbonyl) -4-hydroxypiperidin-4-yl } Phenylacetic acid

3- {4- (2-indolecarbonyl)
Piperazinyl} phenoxyacetic acid 3- {1- (2-indolecarbonyl) piperidine-
4-yl} phenoxyacetic acid 3- {1- (2-indolecarbonyl) -4-hydroxypiperidin-4-yl} phenoxyacetic acid 3- {1- (2-indolecarbonyl) piperidine-
3-en-4-yl} phenoxyacetic acid 3- {1- (2-indolecarbonyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid

The arylamide derivative (1) of the present invention is
For example, it can be produced according to the following reaction formulas 1 to 5.

[0036]

[Chemical 3]

(Wherein A represents a halogen atom, R ⁷ represents an alkyl group, and Ar, X, Z and m have the same meanings as described above) That is, 1-arylpiperazine derivative (2) is substituted with an arylsulfonyl halide. Alternatively, an arylcarbonyl halide (3) is reacted to form a compound (4), which is demethylated to obtain a compound (5). Then the compound (5)
When the compound (6) is reacted with, the arylamide derivative (1a) of the present invention is obtained. Further, the amino acid derivative (7) is reacted with (1a) to give a compound (8), which is hydrolyzed to obtain the arylamide derivative (1) of the present invention.
b) is obtained.

Each reaction step will be described in detail below. The reaction of the 1-arylpiperazine derivative (2) with the arylsulfonyl halide or the arylcarbonyl halide (3) is
Tetrahydrofuran, benzene, toluene, ether,
0 in the presence of a base such as triethylamine or pyridine in a solvent inert to the reaction such as chloroform or methylene chloride
It is preferably carried out at a temperature of from ℃ to room temperature. Demethylation of the compound (4) is carried out by reacting ethanethiol / anhydrous aluminum chloride, boron trichloride, boron tribromide in a reaction inert solvent such as methylene chloride or chloroform at 0 ° C to room temperature, Pyridinium salt such as pyridine hydrochloride and 130 to 20
It is carried out by heating and melting at 0 ° C.

The reaction between the compound (5) and the compound (6) is
Sodium hydroxide, potassium hydroxide, sodium carbonate,
0 in the presence of a base such as potassium carbonate or sodium hydride
Performed at ~ 100 ° C.

The reaction of (1a) with the compound (7) is carried out in a solvent inert to the reaction such as methylene chloride, chloroform, tetrahydrofuran, benzene, toluene and ether in the presence of a base such as triethylamine and pyridine.
It is preferably carried out at 0 ° C to room temperature.

The compound (8) is hydrolyzed at room temperature in the presence of a base such as potassium hydroxide or sodium hydroxide in a mixed solvent of water, dioxane, alcohol or the like.

[0042]

[Chemical 4]

(Wherein Ar, X, A, Z, R ⁷ and m have the same meanings as described above) That is, 1-benzyl-4-piperidone (9) is reacted with arylmagnesium halide (10), Compound (1
1), dehydrated to obtain compound (12), and reduced to obtain 4-arylpiperidine derivative (13). Then, the compound (13) is reacted with an arylsulfonyl halide or arylcarbonyl halide (3) to form a compound (14), which is demethylated to obtain a compound (15). Further, by reacting the compound (15) with the compound (6), the arylamide derivative (1c) of the present invention can be obtained. Then, the amino acid derivative (7) is reacted with (1c) to give the compound (16), which is hydrolyzed to obtain the arylamide derivative (1d) of the present invention.

Hereinafter, each reaction step will be described in detail. 1-
The reaction between benzyl-4-piperidone (9) and arylmagnesium halide (10) is carried out as a usual Grignard reaction in a solvent such as tetrahydrofuran or ether. The dehydration reaction of the compound (11) is carried out by heating under reflux in a solvent such as benzene or toluene in the presence of an acid such as sulfuric acid, p-toluenesulfonic acid or methanesulfonic acid.

The reduction of the compound (12) may be carried out by usual catalytic reduction, for example hydrogenation using palladium-carbon as a catalyst.

The reaction of the compound (13) with the arylamide derivative (1c) of the present invention is carried out by the reaction of the compound (2) of the reaction formula 1.
Can be carried out in the same manner as in the synthesis of compound (1a). Further, the reaction from (1c) to the arylamide derivative (1d) of the present invention is conducted by reacting the compound (1
It can be carried out by a method similar to the synthesis of b).

[0047]

[Chemical 5]

(In the formula, Ar, X, A, Z and m have the same meanings as described above, and R ⁸ represents an alkyl group.) That is, 1-benzyl-4-piperidone (9) is substituted with aryl magnesium halide (17). ) Is reacted with compound (1
8), which is reduced to obtain compound (19), which is reacted with arylsulfonyl halide or arylcarbonyl halide (3) to form compound (20), which is further hydrolyzed to obtain compound (21). Then, the compound (21) is reacted with the compound (6) to obtain the arylamide derivative (1e) of the present invention. Similarly, the compound (21) is reacted with the compound (24) and hydrolyzed to obtain the arylamide derivative (1e) of the present invention. Further, the compound (21) is dehydrated to obtain the compound (23)
When the compound (6) is reacted with this, the arylamide derivative (1f) of the present invention is obtained.

More specifically, in order to produce compound (18) by reacting 1-benzyl-4-piperidone (9) with arylmagnesium halide (17), compounds (9) to (11) of reaction formula 2 are used. May be carried out according to the method for obtaining The reduction reaction from compound (18) to (19) can be carried out according to the method of obtaining compounds (12) to (13) in the reaction formula 2.

The reaction of the compounds (19) to (20) can be carried out according to the reaction of the compounds (2) to (4) of the reaction formula 1, and the hydrolysis of the compound (20) and the compound (22) is performed. Can be carried out according to the reactions of the compounds (8) to (1b) in the reaction formula 1. Further, the reaction of the compounds (21) to (1e) and (22) can be carried out according to the reaction of the compounds (5) to (1a) of the reaction formula 1,
The dehydration reaction from the compound (21) to (23) is represented by reaction formula 2
Can be carried out according to the method of synthesizing the compounds (11) to (12) of the above, and the reaction of the compound (23) to (1f) is according to the method of synthesizing the compounds (5) to (1a) of the reaction formula 1. Can be done.

[0051]

[Chemical 6]

(In the formula, Ar, X, A, Z and R ⁸ have the same meanings as described above.) That is, bis (2-haloethyl) amine hydrochloride (26) was added to the arylaminocarboxylic acid derivative (25). The compound (28) is obtained by reacting the compound (27) with an arylsulfonyl halide or arylcarbonyl halide (3). Then, this is hydrolyzed to obtain the arylamide derivative (1 g) of the present invention. Each reaction step will be described in detail below. The reaction between the arylaminocarboxylic acid derivative (25) and bis (2-haloethyl) amine hydrochloride (26) is carried out in a solvent inert to the reaction such as tetrahydrofuran, benzene, toluene, ethanol and methanol such as triethylamine and pyridine. It is carried out under heating and reflux in the presence of a base.

The reaction of the compounds (27) to (28) can be carried out according to the reaction of the compounds (2) to (4) of the reaction formula 1, and the hydrolysis of (28) is performed by the compound of the reaction formula 1. It can be carried out according to the reactions of (8) to (1b).

[0054]

[Chemical 7]

(In the formula, Ar, X, A and Z have the same meanings as described above.) That is, the arylhalogeno derivative (29) was reacted with Mg to form a Grignard reagent (30), which was mixed with 1-benzyl-4. -Reacting with piperidone (9) to give compound (31). Then, this is hydrolyzed to form compound (32),
This is reduced to obtain compound (33). Further, by reacting with an arylsulfonyl halide or arylcarbonyl halide (3), the arylamide derivative (1h) of the present invention can be obtained.

Hereinafter, each reaction step will be described in detail. The Grignard reagent (30) can be prepared by heating the arylhalogeno derivative (29) with Mg in the presence of a catalytic amount of I _{2 in} a solvent inert to the reaction such as ether or tetrahydrofuran under reflux. The reaction of the compound (9) with the Grignard reagent (30) can be carried out by the same method as in the synthesis of the compounds (9) to (11) in the reaction formula 2.

Hydrolysis of the compound (31) may be carried out by usual acid hydrolysis, for example, adding dilute hydrochloric acid in ethanol and heating under reflux. The compound (32) can be reduced by hydrogenation using palladium hydroxide-carbon as a catalyst. Compound (3
The reaction from 3) to the arylamide derivative (1h) of the present invention can be carried out according to the reactions of (2) to (4) in the reaction formula 1.

The crude product of the arylamide derivative (1) of the present invention thus obtained is subjected to solvent extraction, recrystallization,
It can be purified by a conventional method such as column chromatography.

Next, the arylamide derivative (1) of the present invention
Shows the pharmacological action of.

1. Effect of prolonging bleeding time (in vivo) As an experimental animal, a group of 5 mice was used for the test. The test compounds shown in Table 1 below were orally administered, and
After a lapse of time, the tip of the tail was cut off, the mouse was immediately placed in a holder, and about 2 cm of the tip of the tail was vertically dipped in physiological saline at 37 ° C. The tail was raised and lowered at 15 second intervals and repeated until no bleeding occurred. The evaluation was performed by determining that there was a significant difference when an increase in bleeding time of 50% or more was observed compared to the control group, and determining the minimum effective dose (MED). The results are shown in Table 1.

[0061]

[Table 1]

2. Thromboxane A ₂ (TXA ₂ ) receptor antagonism (in vitro) The test was carried out using spirally cut rat aortic preparations. 0.1 μg / ml atropine, phentolamine,
A physiological saline solution containing mepyramine, cyproheptadine, 1 μg / ml propranolol and indomethacin was placed in a bath and heated to 37 ° C. The above specimen was suspended in this, and thromboxane agonist U-46619 (0.01 μm) was suspended.
(g / ml) was added to cause contraction. Then, the test compounds shown in Table 2 were added, and the minimum inhibitory concentration (M
IC). The results are shown in Table 2.

[0063]

[Table 2]

3. Cholesterol-reducing effect Experimental animals were fed a high cholesterol-choleic acid diet.
Six mice (3 mice per group) that were given daily for hypercholesterolemia were used. On the 6th and 7th days, the test compound was orally administered at half of the total dose. Then, after overnight fasting, the serum cholesterol concentration was measured, and those having a serum cholesterol concentration reduced by 15% or more compared with the control group were determined to have a significant difference. The minimum effective dose (MED) is shown in Table 3.

[0065]

[Table 3]

As described above, the arylamide derivative (1) of the present invention has an excellent bleeding time prolonging action, a platelet aggregation inhibiting action based on the thromboxane A ₂ receptor antagonistic action, a vasodilating action, and a cholesterol reducing action. is doing. In addition, the arylamide derivative (1) of the present invention was safe even if it was orally administered to mice at 300 mg / kg without death. When the arylamide derivative (1) of the present invention or a salt thereof is used as an agent for circulatory organ, the dose is
Although it varies depending on the weight, age, sex, administration method, physical condition, medical condition, etc. of the patient, about 10 to 200 mg per day is suitable for oral administration, and about 0.1 to 20 mg per day is suitable for parenteral administration.

The arylamide derivative (1) of the present invention is prepared by a conventional method in the form of tablets, granules, hard capsules, soft capsules, powders, fine granules, pills, suspensions, injections, suppositories, drops. Alternatively, it can be used as a pharmaceutical preparation of various dosage forms such as syrup.

To prepare a solid preparation, the arylamide derivative (1) of the present invention is added with an excipient, and if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, and a bulking agent. ,
It is preferable to prepare tablets, granules, powders, capsules, suppositories and the like by a conventional method after adding a coating agent, sugar coating agent and the like.
When preparing an injection, the arylamide derivative (1)
Is previously dissolved and dispersed in an aqueous carrier such as distilled water for injection,
It may be emulsified, or made into powder for injection and dissolved for use. The injection method includes intravenous administration,
Intraportal administration, intraperitoneal administration, intramuscular administration, subcutaneous administration and the like can be mentioned.

[0069]

The arylamide derivative of the present invention (1)
Has a strong effect of prolonging bleeding time, an inhibitory effect on thromboxane A ₂ receptor-based platelet aggregation and a vasodilatory effect, and an antihyperlipidemic effect. Various thrombosis such as arterial thrombosis and pulmonary thrombosis and pulmonary embolism, embolism such as peripheral vascular embolism, and
It is useful for treating and preventing cardiovascular diseases such as arteriosclerosis and hypertension.

[0070]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. Example 1 1- (4-chlorobenzenesulfonyl) -4- (3-methoxyphenyl) piperidine (Compound No. 34-10)

0.32 g (1.7 mmol) of 4- (3-methoxyphenyl) piperidine was added to anhydrous tetrahydrofuran 3
After dissolving in 0 ml and further adding triethylamine, p-chlorobenzenesulfonyl chloride 0.4 was added under stirring at room temperature.
g (1.9 mmol) was added in small portions. After stirring at room temperature for 5 hours, the solvent was evaporated under reduced pressure, the residue was redissolved in chloroform,
Washed with water. After drying over anhydrous Na ₂ SO ₄ , chloroform was distilled off under reduced pressure, and the residue was subjected to SiO ₂ column chromatography to obtain 0.47 g (yield 77%) of a colorless crystal target product from a fraction eluted with chloroform. ..

Example 2 1- (4-Chlorobenzenesulfonyl) -4- (3-hydroxyphenyl) piperidine (Compound No. 34-2) 1- (4-Chlorobenzenesulfonyl) -4- (3-methoxyphenyl) 0.47 g (1.3 mmol) of piperidine
Was dissolved in 15 ml of anhydrous methylene chloride, 0.60 ml (8.0 mmol) of ethanethiol and 0.50 g (3.8 mmol) of anhydrous aluminum chloride were added, and the mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, ice water was added to the residue, extracted with chloroform, and washed with water. Anhydrous N
After drying with a ₂ SO ₄ , chloroform was distilled off under reduced pressure to obtain 0.45 g (yield 99%) of the desired product as colorless crystals.

Example 3 1- (4-Chlorobenzenesulfonyl) -4- (3-hydroxyphenyl) piperidin-3-ene (Compound No. 34-8) 1- (4-Chlorobenzenesulfonyl) -4-hydroxy- 4- (3-hydroxyphenyl) piperidine 1.0
g (2.7 mmol) was dissolved in 100 ml of toluene, 0.1 g of p-toluenesulfonic acid monohydrate was added, and a Dean-Stark water separator was attached, and the mixture was stirred and refluxed for 10 hours. After the reaction was completed, toluene was distilled off to obtain 0.77 g of the desired product as a pale yellow oily substance.
(Yield 81%) was obtained.

Example 4 1- (4-chlorobenzenesulfonyl) -4-hydroxy-4- (3-hydroxyphenyl) piperidine (Compound No. 34-7) 4-hydroxy-4- (3-hydroxyphenyl) piperidine 2 0.3 g (12 mmol) was dissolved in 100 ml of anhydrous tetrahydrofuran and 2 ml of triethylamine (14.3 mm).
ol), 2.6 g (12 mmol) of p-chlorobenzenesulfonyl chloride was added little by little while stirring at room temperature. After stirring at the same temperature for 24 hours, the reaction mixture was evaporated under reduced pressure, the residue was dissolved in a mixed solvent of chloroform and methanol, and washed with water. After drying over anhydrous Na ₂ SO ₄ , the solvent was distilled off under reduced pressure and the residue was subjected to SiO ₂ column chromatography. The target substance 2.6 was obtained as colorless crystals from the fraction eluted with chloroform.
g (58% yield) was obtained.

The data of the compounds obtained in Examples 1 to 4 and the compounds prepared according to these Examples are shown in Table 4.
~ 7.

[0076]

[Table 4]

[0077]

[Table 5]

[0078]

[Table 6]

[0079]

[Table 7]

Example 5 [3- {4- (Chlorobenzenesulfonyl) piperazinyl} phenoxy] acetic acid (Compound No. 9) 0.45 g of 1- (4-chlorobenzenesulfonyl) -4- (3-hydroxyphenyl) piperazine ( 1.3 mmo
l) was dissolved in 20 ml of 5% aqueous sodium hydroxide solution, then 10 ml of 10% aqueous monochloroacetic acid solution was added, and the mixture was stirred under reflux. After 2 hours, 10 ml of 10% monochloroacetic acid was added, and the mixture was refluxed and stirred for 2 hours. Then, 20 ml of 5% aqueous sodium hydroxide solution and 10 ml of 10% monochloroacetic acid were added, and the mixture was refluxed and stirred for 2 hours. After the reaction was completed, the reaction mixture was acidified with diluted hydrochloric acid and extracted with chloroform. Anhydrous Na ₂ S
After drying with O _4, chloroform was distilled off under reduced pressure, and the residue was crystallized with ethyl acetate-petroleum ether to obtain 0.43 g (yield 81%) of the desired product as colorless crystals.

Example 6 [3- {4- (4-chlorobenzenesulfonyl) piperazinyl} phenoxy] acetic acid (3-carboxypropyl)
Amide (Compound No. 29) [3- {4- (4-chlorobenzenesulfonyl) piperazinyl} phenoxy] acetic acid (Compound No. 9) 1.0 g
(2.4 mmol) was dissolved in a mixed solution of 20 ml of anhydrous methylene chloride and 20 ml of anhydrous tetrahydrofuran, 0.60 g (3.7 mmol) of carbodiimidazole was added thereto, and the mixture was stirred at room temperature for 2 hours. Then triethylamine 0.50 ml
After (3.6 mmol) was added, 0.50 g (3.0 mmol) of γ-amino-n-butyric acid ethyl hydrochloride was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was distilled off under reduced pressure,
The residue was crystallized from ethanol-ether to obtain 1.14 g (yield 90%) of ethyl ester.

¹ H-NMR δppm (CDCl ₃ ): 1.24 (t, 3H), 1.88
(m, 2H), 2.36 (t, 2H), 3.20 (m, 8H), 3.44 (t, 2H), 4.14 (q,
2H), 4.46 (s, 2H), 6.52 (m, 3H), 6.84 (br, 1H), 7.24 (t, 1
H), 7.60 (d, 2H), 7.82 (d, 2H). 1.07 g (2.0 mmol) of the above crystal was added to dioxane 20.
Dissolve in a mixture of 20 ml of methanol and 20 ml of methanol, and add 0.5
An aqueous solution of sodium hydroxide N was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was acidified with diluted hydrochloric acid and extracted with chloroform. After drying over anhydrous Na ₂ SO ₄ , chloroform was distilled off under reduced pressure, and the residue was crystallized with ethyl acetate to obtain 0.84 g (yield 83%) of the desired product as colorless crystals.

Example 7 3- {1- (4-chlorobenzenesulfonyl) piperidin-4-yl} phenoxyacetic acid (Compound No. 21) 1- (4-chlorobenzenesulfonyl) -4- (3-hydroxyphenyl) piperidine 0.45g (1.3mmo
l) was dissolved in 30 ml of dioxane, to which 30 ml of 2N aqueous sodium hydroxide solution and 3.0 g of monochloroacetic acid (3
20 ml of an aqueous solution containing 1 mmol) was added, and the mixture was stirred under reflux for 2 hours. Further, 30 ml of a 2N aqueous sodium hydroxide solution and 20 ml of an aqueous solution containing 3.0 g (31 mmol) of monochloroacetic acid were added, and the mixture was refluxed and stirred for 2 hours. Then, the same amount of sodium hydroxide aqueous solution and monochloroacetic acid aqueous solution were added again, and the mixture was stirred under reflux for 2 hours. ..

After completion of the reaction, dilute hydrochloric acid was added to the reaction mixture to make it acidic, extracted with chloroform, washed with water, and dried with anhydrous Na ₂ SO _4.
Dried in. Chloroform was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate-petroleum ether to obtain 0.44 g (yield 83%) of the desired product as colorless crystals.

Example 8 3- {1- (4-chlorobenzenesulfonyl) piperidin-3-en-4-yl} phenoxyacetic acid (Compound No. 26) 1- (4-chlorobenzenesulfonyl) -4- (3- Hydroxyphenyl) piperidine-3-ene 0.43 g
(1.2 mmol) was dissolved in 30 ml of dioxane and added to 2
30 ml of an aqueous solution of sodium hydroxide N and 20 ml of an aqueous solution containing 3.0 g (31 mmol) of monochloroacetic acid were added, and the mixture was stirred under reflux for 2 hours. Thereafter, the reaction was carried out in the same manner as in Example 7 to obtain 0.42 g (yield 84%) of the target product as colorless crystals.

Example 9 3- {1- (4-chlorobenzenesulfonyl) -4-hydroxypiperidin-4-yl} phenoxyacetic acid (Compound No. 25) 1- (4-chlorobenzenesulfonyl) -4-hydroxy-4 -(3-hydroxyphenyl) piperidine 0.4
7 g (1.3 mmol) was dissolved in 30 ml of dioxane, to which was added 30 ml of 2N aqueous sodium hydroxide solution and 20 ml of an aqueous solution containing 3.0 g (31 mmol) of monochloroacetic acid, and 2
The mixture was stirred under reflux for an hour. Thereafter, the reaction was carried out in the same manner as in Example 7 to obtain 0.45 g (yield 81%) of the target product as colorless crystals.

Data for Examples 5-9 and the compounds prepared according to these Examples are shown in Tables 8-15.

[0088]

[Table 8]

[0089]

[Table 9]

[0090]

[Table 10]

[0091]

[Table 11]

[0092]

[Table 12]

[0093]

[Table 13]

[0094]

[Table 14]

[0095]

[Table 15]

Example 10 3- {1- (4-bromobenzoyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxyacetic acid (Compound No. 60) {1- (4-bromobenzoyl) -4 801 mg of-(2-hydroxyphenyl) -4-hydroxypiperidine was added to 4.00 g (20.5 ml) of ethyl α-bromoisobutyrate in the presence of 1.20 g (8.68 mmol) of potassium carbonate at an external temperature of 100 ° C for 9 hours. It was stirred. After completion of the reaction, the reaction mixture was cooled, water was added, and the mixture was extracted with chloroform. Then, after drying with mirabilite, chloroform and residual ethyl α-bromoisobutyrate were distilled off under reduced pressure to give 3- {1- (4-bromobenzoyl) -4-hydroxypiperazin-4-yl} α, α-dimethylphenoxyethyl acetate. Oily substance 9
Yield 02 mg (86.4%).

The 3- {1- (4
-Brombenzoyl) -4-hydroxypiperidine-4
-Yl} α, α-dimethylphenoxyethyl acetate 78 mg
Is dissolved in a mixed solution of 5.0 ml of methanol and 5.0 ml of dioxane, and further 5.0% of 1N aqueous sodium hydroxide solution
ml was added and the mixture was stirred for 1 hour at room temperature. After the reaction was completed, diluted hydrochloric acid was added to make the liquid acidic, and the mixture was extracted with chloroform and dried with sodium sulfate. Then, chloroform was distilled off under reduced pressure, and the obtained crystals were pulverized with a mixed solvent of ether and petroleum ether to give 3- {1- (4-bromobenzoyl) -4-hydroxypiperidin-4-yl} α, α-dimethylphenoxy. 63 mg (85%) of colorless crystals of acetic acid were obtained.

Example 11 3- {4- (4-bromobenzenesulfonyl) piperazinyl} phenylacetic acid (Compound No. 36) Ethyl 3-aminophenylacetate 480 mg (2.68 mmo)
l), bis (2-chloroethyl) amine hydrochloride 480 mg
(2.70 mmol) and triethylamine 0.50 ml
(3.61 mmol) was added to methanol, and the mixture was stirred under reflux for 100 hours. After completion of the reaction, the reaction mixture was distilled off under reduced pressure,
An aqueous solution of sodium hydrogencarbonate was added to the residue to make it weakly alkaline, followed by extraction with chloroform, drying with sodium sulfate, and evaporation under reduced pressure. Then, the residual oily substance is treated with silica gel 30.
column chromatography using 10 g
The MeOH / CHCl ₃ eluate was distilled off under reduced pressure, and 3- (1-
350 mg of piperazinyl) phenyl ethyl acetate oil
(52.7%) was obtained.

220 g (0.887 mm) of ethyl 3- (1-piperazinyl) phenylacetate thus obtained.
ol) was dissolved in 20 ml of anhydrous tetrahydrofuran, 0.50 ml (3.61 mmol) of triethylamine was further added, and 300 mg (1.17 mmol) of p-bromobenzenesulfonyl chloride was added little by little with stirring at room temperature.
Then, the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with water and dried on sodium sulfate. Then, chloroform was distilled off under reduced pressure, and 3-
There were obtained 414 mg (quantitative) of ethyl {4- (4-bromobenzenesulfonyl) piperazinyl} phenylacetate.

The 3- {4- (4
-Bromobenzenesulfonyl) piperazinyl} phenylethyl acetate 414 mg (0.887 mmol) in dioxane 1
Dissolve in a mixed solvent of 0 ml and 10 ml of methanol, and add 1 more
A normal aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, diluted hydrochloric acid was added to make the liquid acidic, and the mixture was extracted with chloroform and dried with sodium sulfate. Then, chloroform was distilled off under reduced pressure, and the obtained crystals were pulverized with a mixed solvent of ether and petroleum ether to give 325 mg (83.5%) of colorless crystals of 3- {4- (4-bromobenzenesulfonyl) piperazinyl} phenylacetic acid. Got

According to the methods of Examples 5 to 11, the following Table 1
6-The compound (1) of the present invention shown in Table 24 was produced. These data are shown in the same table.

[0102]

[Table 16]

[0103]

[Table 17]

[0104]

[Table 18]

[0105]

[Table 19]

[0106]

[Table 20]

[0107]

[Table 21]

[0108]

[Table 22]

[0109]

[Table 23]

[0110]

[Table 24]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location A61K 31/495 ABN 7252-4C ABR ACB C07D 209/30 9283-4C 209/42 9283-4C 211 / 22 9165-4C 211/34 9165-4C 211/52 9165-4C 211/70 9165-4C 211/96 9165-4C 213/71 213/82 215/36 215/48 295/16 A 307/38 307/54 333/18 333/24 401/06 209 8829-4C 211 8829-4C 401/12 209 8829-4C 211 8829-4C 405/06 211 8829-4C 405/12 211 8829-4C 409/06 211 8829-4C 409 / 12 211 8829-4C (72) Inventor Hidehiko Kamiya 2-2-21-404 Azuma, Narita-shi, Chiba (72) Inventor Hiroyuki Mizuno 1-24-19 Hiyoshidai, Tomisato-cho, Inba-gun, Chiba (72) Inventor Kuraishi Tadayuki 2-5-4 Kasumi, Narashino City, Chiba Prefecture

Claims (2)

[Claims] 1. The following general formula (1): An arylamide derivative represented by or a salt thereof. 2. A circulatory organ preparation containing the arylamide derivative or the salt thereof according to claim 1 as an active ingredient.