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Novel thiophenediamine derivative having urea structure

A compound, low-level technology, applied in the directions of medical preparations containing active ingredients, organic chemistry, drug combinations, etc., to achieve the effect of changing the shape of trabecular cells and reducing intraocular pressure

Inactive Publication Date: 2011-04-27
SANTEN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no specific description of novel thiophenediamine derivatives having a urea structure

Method used

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  • Novel thiophenediamine derivative having urea structure
  • Novel thiophenediamine derivative having urea structure
  • Novel thiophenediamine derivative having urea structure

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0165] The production method of the compound of the present invention can be roughly classified into the methods shown below, and the method can be appropriately selected according to the type of the substituent.

[0166] 1) Compound (I) of the present invention can be prepared according to Synthetic Route 1. That is, the compound (I) of the present invention can be obtained by treating the compound (II) in an organic solvent such as methanol in the presence of an acid such as hydrogen chloride-ethyl acetate at 0°C to room temperature for 30 minutes to 24 hours.

[0167] Synthetic pathway 1

[0168]

[0169] Compound (IIa, R 2 =H) can be prepared according to synthetic route 1-1. That is, the compound can be obtained by reacting compound (III) and isocyanate (IV) in an organic solvent such as dichloromethane at 0° C. to room temperature for 30 minutes to 24 hours.

[0170] Synthetic pathway 1-1

[0171]

[0172] Compound (III) can be prepared according to Synthetic R...

reference example 1

[0200] 3-amino-4-tert-butoxycarbonylaminothiophene (reference compound 1-1)

[0201] Under ice cooling, di-tert-butyl dicarbonate ( 0.16g, 0.72mmol), stirred overnight at room temperature. Water (40 mL) was added to the reaction liquid, followed by extraction with ethyl acetate (30 mL, twice). The organic layer was washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title reference compound (87 mg) as a brown solid. (Yield 58%)

[0202] [Table 1]

[0203]

reference example 2

[0205] N-(4-tert-butoxycarbonylaminothiophen-3-yl)-5-methoxycarbonylpyridine-2-carboxamide (reference compound 2-1)

[0206] To 3-amino-4-tert-butoxycarbonylaminothiophene (reference compound 1-1, 0.68g, 3.2mmol), 5-methoxycarbonylpyridine-2-carboxylic acid (0.64g, 3.5mmol) and N-form HATU (1.3 g, 3.5 mmol) was added to a solution of morpholine (0.70 mL, 6.4 mmol) in DMF (20 mL), and stirred overnight at room temperature. Water (0.30 L) and ethyl acetate (0.40 L) were added, and the insoluble matter was filtered to obtain the title reference compound (0.50 g) as a pale yellow solid. Furthermore, the filtrate was separated into layers, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the precipitated solid was filtered with ethyl acetate (30 mL) to obtain the title reference compound (0.30 g) as a pale yellow solid. (Yield 67%)

[0207] [Table 2]

[0208]

[0209] Hereinafter, reference compound 2-2 ...

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Abstract

The present invention is related to study on synthesis of a novel thiophenediamine derivative having a urea structure and finding of a pharmacological action of the derivative. Specifically, the present invention provides a compound represented by formula (1) or a salt thereof. In the formula, R1 and R2 may be the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl group or the like; R3 represents a hydroxy group, an optionally substituted lower alkoxy group, an optionally substituted lower cycloalkyloxy group or the like; R4 and R5 may be the same or different and each represents a halogen atom, a lower alkyl group, a hydroxy group or the like; X represents an optionally substituted lower alkylene group or the like; Y represents a single bond, an optionally substituted lower alkylene group or the like; W1-W2 represents N-CH, CH-N or the like; and l and m may be the same or different and each represents 0, 1 or the like.

Description

technical field [0001] The present invention relates to a novel thiophenediamine derivative having a urea structure or a salt thereof useful as a medicine. The derivative has histone deacetylase inhibitory activity, and is expected to be used as a preventive and / or therapeutic agent for diseases for which histone deacetylase inhibitors are effective. In addition, the derivative also has both a morphological change effect on trabecular cells and an effect on lowering intraocular pressure, and is also useful as a preventive and / or therapeutic agent for diseases related to aqueous humor circulation and / or intraocular pressure. Background technique [0002] The chromosomal DNA of eukaryotes is wound around core histones, namely histones H2A, H2B, H3, H4, etc., to form a basic structure called a nucleosome. In addition, the chromatin structure is formed by the assembly of the nucleosome structure. The post-translational modification of histone is closely related to the constitu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/36A61K31/381A61K31/4436A61K31/4439A61K31/444A61K31/496A61K31/5377A61P1/00A61P1/04A61P1/16A61P3/10A61P7/00A61P7/06A61P9/00A61P9/10A61P11/02A61P11/06A61P13/12A61P17/00A61P17/06A61P19/02A61P21/00A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/28A61P27/02A61P27/06A61P27/14A61P29/00A61P31/04A61P31/10A61P31/12A61P33/00A61P35/00A61P37/02A61P37/06A61P37/08A61P43/00C07D407/12C07D409/12C07D409/14C07D417/14
CPCC07D409/12C07D333/36A61P1/00A61P1/04A61P1/16A61P1/18A61P11/00A61P11/02A61P11/06A61P13/08A61P13/10A61P13/12A61P15/00A61P15/08A61P15/14A61P17/00A61P17/06A61P19/00A61P19/02A61P21/00A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/28A61P27/00A61P27/02A61P27/06A61P27/14A61P29/00A61P31/00A61P31/04A61P31/10A61P31/12A61P31/22A61P33/00A61P33/02A61P33/06A61P35/00A61P35/02A61P37/02A61P37/06A61P37/08A61P43/00A61P5/14A61P5/38A61P7/00A61P7/06A61P7/10A61P9/00A61P9/04A61P9/10A61P3/10
Inventor 茂木宽幸田岛久嗣三品纪子山崎裕辅米田信次渡边克彦藤河顺子山本实
Owner SANTEN PHARMA CO LTD
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