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Fluorene derivative

A technology of derivatives and compositions, applied in the field of fluorene derivatives, can solve problems such as undisclosed compounds, fatigue, and insufficient clinical effects

Inactive Publication Date: 2006-10-04
ASTELLAS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Specific prophylactic agents clinically used in some countries include Ca antagonists (eg, lomerizine, flunarizine, etc.), serotonin antagonists (eg, phenthiazine, methysergide, etc.), β-class Adrenaline blocking agents (such as propranolol, etc.), however, it is reported that they all have many side effects, and have not obtained sufficient clinical effects so far
[0004] Among the above-mentioned preventive agents, phenthiazine, which is a serotonin antagonist, has a higher efficacy than other agents, but there is a problem in finding that its effective dose causes side effects such as fatigue, drowsiness, dizziness, and weight gain (J. Neurol. (1991) 238, S45-S52)
However, the derivative has a ring group as R 3 , no compounds having the fluorene structure as R are disclosed in said application

Method used

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Examples

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Embodiment

[0171] The compounds of the present invention will be described in detail below with reference to Examples. In this connection, since novel compounds are also included in the starting compounds for the compounds of the present invention, the preparation methods of these compounds are illustrated in Reference Examples.

[0172] Reference example 1-a

[0173] Under heating, 4-bromoisophthalic acid diethyl ester is reacted with 2-methylphenylboronic acid, sodium carbonate and tetrakis(triphenylphosphine)palladium in toluene-ethanol-water under heating to obtain 2' -Diethyl methylbiphenyl-2,4-dicarboxylate. FAB-MS: 313(M+H) + .

[0174] Reference example 1-b

[0175] A solution of diethyl 2'-methylbiphenyl-2,4-dicarboxylate in ethanol was treated with 1M sodium hydroxide to obtain 2'-methylbiphenyl-2,4-dicarboxylic acid. FAB-MS: 257(M+H) + .

[0176] Reference example 1-c

[0177] 5-Methyl-9-oxo-9H-fluorene-2-carboxylic acid is prepared by heating 2'-methylbiphenyl-2,4-dic...

reference example 2

[0179] 3'-methylbiphenyl-2,4-dicarboxylic acid was treated in the same manner as in Reference Example 1-c, and the resulting solid was heated in ethanol in the presence of concentrated sulfuric acid for esterification. After the reaction treatment, separation and purification were carried out by silica gel column chromatography to obtain ethyl 6-methyl-9-oxo-9H-fluorene-2-carboxylate [FAB-MS: 267 (M+H) + ] and ethyl 8-methyl-9-oxo-9H-fluorene-2-carboxylate [FAB-MS: 267 (M+H) + ].

reference example 3

[0181] In the same manner as in Reference Example 1-a, ethyl 3-chloro-2'-formylbiphenyl-4-carboxylate was prepared from ethyl 4-bromo-2-chlorobenzoate and 2-formylphenylboronic acid ester. FAB-MS: 288(M) + .

[0182] At room temperature, make ethyl 3-chloro-2'-formylbiphenyl-4-carboxylate with sodium perchlorate, sodium dihydrogenphosphate and 2-methyl-2-butene in tert-butanol-acetonitrile- Reaction in water to produce 3'-chloro-4'-(ethoxycarbonyl)biphenyl-2-carboxylic acid. FAB-MS: 305(M+H) + .

[0183] Afterwards, in the same manner as Reference Example 1-c and Reference Example 2, 1-chloro-9-oxo-9H-fluorene-2-carboxylic acid ethyl ester [FAB-MS: 287 (M+H) + ] and ethyl 3-chloro-9-oxo-9H-fluorene-2-carboxylate [FAB-MS: 287 (M+H) + ].

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Abstract

This invention relates to a novel fluorene derivative having a characteristic structure in which guanidino group or the like functional group is linked to the fluorene structure via carbonyl group, or a salt thereof. The compound of the invention has an advantage in that it has high affinity for serotonin receptor subtypes, particularly for 5-HT 2B receptor and 5-HT 7 receptor, and shows excellent pharmacological effects in comparison with the conventional compounds which have only one of the antagonistic activities of 5-HT 2B receptor and 5-HT 7 receptor, this is useful as a prophylactic antimigraine agent having high safety and excellent effect.

Description

technical field [0001] The present invention relates to fluorene derivatives useful as medicaments, especially as prophylactic agents against migraine. Background of the invention [0002] Migraine is a disorder of recurrent, throbbing headaches that occur intensely on one or both sides of the head and last from a few hours to about 3 days. This pathological state of migraine is thought to be exacerbated by the following attack mechanism. First, the dural blood vessels are contracted once by the action of 5-HT (serotonin) or similar neurotransmitters, and then relax again. In this case, inflammation is increased by releasing CGRP or similar vasoactive peptides and plasma proteins, so cause headaches. [0003] Drugs for migraine are classified into preventive agents and therapeutic agents. The purpose of the former is to reduce the frequency of attacks by continuously administering this agent prophylactically before the onset of the disease, and the purpose of the latter i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C279/22A61K31/166A61K31/343A61K31/351A61K31/352A61K31/357A61K31/385A61K31/41A61K31/4168A61K31/4196A61K31/421A61K31/426A61K31/438A61P25/06A61P43/00C07D221/20C07D233/88C07D249/08C07D257/04C07D263/28C07D277/18C07D277/28C07D307/94C07D309/06C07D309/22C07D311/96C07D317/72C07D339/06C07D207/20C07D209/54C07D209/96C07D211/70C07D233/50C07D249/14C07D257/06C07D303/06C07D305/14C07D309/20C07D317/12C07D319/14C07D327/04C07D335/04
CPCC07D277/18C07D305/14C07D263/28C07D207/20A61K31/357C07D233/50C07D209/96A61K31/426C07D211/70C07D319/14C07D317/12C07D307/94A61K31/4168C07D249/14A61K31/438C07D335/04A61K31/421C07D209/54A61K31/385C07D303/06C07D339/06A61K31/351C07D311/96A61K31/166C07D309/20A61K31/41C07D257/06A61K31/343A61K31/352C07D221/20C07D309/06A61K31/4196C07C279/22C07D327/04A61P25/06A61P43/00
Inventor 山田弘美板鼻弘恒森友纹子松澤崇穗原田幸一郎藤安次郎古贺祐司奥誠岡崎利夫阿久沢忍渡边俊博
Owner ASTELLAS PHARMA INC
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