Novel indazole derivative

A technology of indazole and compound, applied in the field of novel indazole derivatives or their salts, to achieve excellent Rho kinase inhibitory effect

Inactive Publication Date: 2006-11-15
UBE IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] However, there is no specific disclosure about the indazole derivatives of the present invention in any of the above-mentioned documents

Method used

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Examples

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preparation example Construction

[0300] The production method of the synthetic intermediate of the compound of the present invention will be described in detail in the following Examples [Production Items].

[0301] In order to show the usefulness of the compounds of the invention, the Rho kinase inhibitory effect of the compounds of the invention was evaluated. Its detailed description is shown in the following example [pharmacological test items (Rho kinase inhibitory activity evaluation test)], based on Journal of biological chemistry issued in 1999, volume 274, page 32418 [J.Biol.Chem., 274, 32418 ( 1999)], the method of Beiyuan et al. and the method of commercially available active type ROCK II [upstatebiotechnology, Catalog No. 14-338, (5Unit / 50ml] attached instruction manual), the Rho kinase inhibitory activity of the compound of the present invention was carried out. Evaluation. As a result, it was found that the compound of the present invention has an excellent Rho kinase inhibitory effect and is ve...

reference example 1

[0315] Synthesis of 1-bromo-4-(1-cyano-1-methylethyl)benzene (reference compound 1-1)

[0316]

[0317] In a solution containing 100g (510mmol) of 4-bromophenylacetonitrile in 1500ml of N,N-dimethylformamide, under an argon flow, 45g (1100mmol) of sodium hydride (60 % mineral oil dispersion). Then, 95 ml (1500 mmol) of iodomethane was added dropwise with stirring at 0°C, and stirred at 10°C for 1 hour.

[0318] After the reaction was completed, the reaction solution was slowly poured into 900 g of saturated ammonium chloride aqueous solution, and 500 ml of water was added, followed by extraction with 2000 ml of ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 110 g of the title compound as a dark brown oil. (Yield: 96%)

[0319] Rf value: 0.78 (n-hexane:ethyl acetate=1:1 (V / V)).

[0320] MS (CI, m / z): 224, 226 (M + +1).

[0321] 1 H-NMR (CDCl 3 ,...

reference example 2

[0352] Synthesis of 4-(1-aminocarbonyl-1-methylethyl)-1-bromobenzene (reference compound 2-1)

[0353]

[0354] In 1000ml of toluene solution containing 100g (450mmol) of 1-bromo-4-(1-cyano-1-methylethyl)benzene (reference compound 1-1), under argon flow, while stirring, at room temperature 250 g (1800 mmol) of potassium trimethylsiliconate (purity: 90%) was added, and stirred for 4.5 hours under heating and reflux.

[0355] After the reaction, the reaction solution was cooled to room temperature, and 500 ml of water was added dropwise. After stirring the mixed solution at room temperature for 25 minutes, the resulting solid was filtered. The above solid was washed with 400 ml of water to obtain 99 g of the title compound as a white powder. (Yield: 92%)

[0356] Melting point: 139-141°C.

[0357] Rf value: 0.23 (n-hexane:ethyl acetate=1:1 (V / V)).

[0358] MS (CI, m / z): 242, 244 (M + +1).

[0359] 1 H-NMR (CDCl 3 , δppm): 1.56 (s, 6H), 5.18 (brs, 1H), 5.52 (brs, 1H)...

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Abstract

To prepare a novel indazole derivative useful as a medicine and to find out a new pharmacological activity of the derivative. The compound is represented by the general formula [I] and has excellent Rho-kinase inhibitory activity. In the formula, ring X is a benzene ring or pyridine ring; R<1> and R<2> each is hydrogen or alkyl; R<3> and R<4> each is halogeno, hydrogen, OH, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, aryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, carboxy, hydrocarbonyl, alkylcarbonyl, etc.; and R<5> is halogeno, hydrogen, OH, alkoxy, aryloxy, alkyl, or aryl. These groups may be substituted.

Description

technical field [0001] The present invention relates to novel indazole derivatives or salts thereof useful as medicines. The indazole derivatives of the present invention have Rho kinase inhibitory activity and are useful as therapeutic agents for diseases related to Rho kinase, for example, eye diseases such as glaucoma. Background technique [0002] Rho, a low molecular weight GTP-binding protein, is activated by signals generated by various cell membrane receptors. Activated Rho exerts smooth muscle contraction, cell morphological changes, cell movement, cell division, intercellular adhesion, platelet aggregation, leukocyte aggregation, and cancer cell infiltration through the Rho kinase information transmission system and actomyosin information transmission system. Molecular switching of various cellular phenomena such as deterioration. [0003] In addition, the aforementioned cellular phenomena are known to be associated with hypertension, angina pectoris, asthma, per...

Claims

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Application Information

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IPC IPC(8): C07D231/56A61K31/416A61K31/4439A61P27/06A61P43/00C07D401/04
CPCC07D231/56C07D401/04C07D403/04C07D413/04A61P11/00A61P15/00A61P27/02A61P27/06A61P29/00A61P35/00A61P43/00A61P9/00
Inventor 楸原昌彦小森健一砂本秀利西田洋松木雄中岛正秦野正和木户一贵原英彰
Owner UBE IND LTD
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