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Indole derivative having piperidine ring

a technology of piperidine and indole, which is applied in the field of indole derivatives having piperidine rings, to achieve the effect of superior binding affinity to a 5-ht1a receptor and superior clinical action to treat or prevent lower urinary tract symptoms

Inactive Publication Date: 2005-11-17
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0030] Under such circumstances, the present inventors have conducted intensive studies. As a result, they have found that a compound described below, which shows binding affinity to a 5-HT1A receptor and has an antagonistic effect against receptor, has excellent inhibitory effect on the accentuation of urinary reflex caused by superior brain injury and is useful as an agent for treating or preventing lower urinary tract symptoms, and particularly, increased urinary frequency or urinary incontinence, thereby completing the present invention.

Problems solved by technology

However, a compound, which has a superior binding affinity to a 5-HT1A receptor and an antagonism to the receptor, and which is able to exhibit superior clinical action to treat or prevent lower urinary tract symptoms, and particularly, symptoms regarding urinary storage has not yet been found.

Method used

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  • Indole derivative having piperidine ring
  • Indole derivative having piperidine ring
  • Indole derivative having piperidine ring

Examples

Experimental program
Comparison scheme
Effect test

production example 1

Synthesis of 1-(piperidin-4-yl)-1H-indole-6-carboxamide

[0602]

(1) Synthesis of methyl 1-(1-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxylate

[0603] 44.3 g of methyl 3-amino-4-(2,2-dimethoxyethyl)benzoate synthesized according to the publication (Tetrahedron Letters, Vol. 37, No. 34, pp. 6045-6048) and 64.9 g of benzyl 4-oxo-1-piperidinecarboxylate were dissolved in 485 ml of acetic acid, followed by stirring at room temperature. Approximately 20 minutes later, 58.9 g of sodium triacetoxyborohydride was added to the reaction solution. Then, the reaction solution was further stirred for 2 hours. Thereafter, 485 ml of water was added to the reaction solution, and the obtained mixture was heated to a temperature between 100° C. and 115° C. Approximately 3 hours later, the reaction solution was cooled, and then concentrated under a reduced pressure. Thereafter, water and ethyl acetate were added thereto, so as to separate an organic layer. The obtained organic layer was washed wit...

production example 2

Synthesis of N-methyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide

[0611]

(1) Synthesis of N-methyl-1-(1-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxamide

[0612] 2.00 g of 1-(1-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxylic acid was dissolved in 20 ml of tetrahydrofuran, and 1.03 g of 1,1′-carbonylbis-1H-imidazole was then added thereto. The obtained mixture was stirred at room temperature for 1.5 hours, and 4.11 ml of a 40% methylamine aqueous solution was added thereto. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate aqueous solution, a saturated ammonium chloride aqueous solution, and a saturated sodium chloride solution. Thereafter, the organic layer was dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, and the residue was then purified by NH silica gel column chro...

production example 3

Synthesis of 3-amino-4-(2,2-dimethoxyethyl)benzamide

[0616]

(1) Synthesis of 3-nitro-4-methylbenzamide

[0617] 20.0 g of 3-nitro-4-methylbenzoic acid was dissolved in 400 ml of tetrahydrofuran. Thereafter, 21.5 g of 1,1′-carbonyldiimidazole and 0.1 ml of dimethylformamide were added thereto. The obtained mixture was stirred for 45 minutes. Thereafter, 20 ml of 28% ammonia water was added thereto, followed by stirring at room temperature for 24 hours. After completion of the reaction, the reaction solution was concentrated under a reduced pressure, and the residue was separated into 600 ml of ethyl acetate and 200 ml of water. The organic layer was separated, and then washed with 200 ml of 2 N hydrochloric acid, 100 ml of water, 100 ml of a saturated sodium bicarbonate aqueous solution, and 100 ml of a saturated sodium chloride solution. It was then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the filtrate was concentrated under a reduced press...

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Abstract

The present invention relates to a compound represented by the following formula, a pharmacologically acceptable salt thereof, or a use thereof as a pharmaceutical: wherein R1 and R2 are substituents adjacent to each other, and together with two carbon atoms to each of which they attach, form a 5- to 7-membered non-aromatic carbocyclic group or the like, which may be substituted by 1 to 4 substituents selected from (1) an oxo group, (2) a hydroxyl group, and the like; R3 represents a hydrogen atom or the like; and R6 represents a hydrogen atom or the like. It is an object of the present invention to discover an agent for treating or preventing lower urinary tract symptoms, and particularly symptoms regarding urinary storage, which has a superior strength of binding to a 5-HT1A receptor and an antagonism to the receptor.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims priority date under the Paris Convention based on Japanese Patent Applications No. 2004-142437 filed in Japan on May 12, 2004, the contents of which are hereby incorporated by reference. BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates to a compound having ability to bind to a serotonin 1A receptor, and a use thereof as a pharmaceutical. More specifically, it relates to an agent for treating or preventing lower urinary tract symptoms. [0004] 2. Description of the Related Art [0005] In the periphery system, serotonin exhibits effects of smooth muscle relaxation, platelet aggregation, and gastrointestinal tract function regulation. On the other hand, in the central nervous system, serotonin functions as a neurotransmitter and is deeply associated with the motor system, perceptive system, physiological functions such as body temperature regulation, sleep, feeding behav...

Claims

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Application Information

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IPC IPC(8): A61K31/454A61K31/4725A61K31/536A61K31/55A61K31/553A61P13/02A61P13/10A61P43/00C07D401/04C07D401/14C07D405/14C07D413/14C07D417/14C07D491/08
CPCC07D401/04C07D401/14C07D491/08C07D413/14C07D417/14C07D405/14A61P1/00A61P1/04A61P1/08A61P1/12A61P13/00A61P13/02A61P13/10A61P15/00A61P15/08A61P15/10A61P25/00A61P25/06A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P25/32A61P25/34A61P25/36A61P43/00
Inventor SUZUKI, YUICHIITO, KOICHISASAKI, ATSUSHIUENO, KOSHISAKAI, MIYUKIISHIHARA, HIROKIKUBOTA, ATSUHIKO
Owner EISIA R&D MANAGEMENT CO LTD
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