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Thiophene amide ROCK (Rho-associated protein kinase) inhibitor as well as preparation method and application thereof

A technology of amide and thiophene carboxylic acid, applied in anti-inflammatory agents, non-central analgesics, respiratory diseases, etc., can solve problems such as insufficient cure diseases

Inactive Publication Date: 2018-06-29
FOSHAN SAIWEISI MEDICINE SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As current therapies are insufficient to cure the disease, we urgently need to seek new treatments

Method used

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  • Thiophene amide ROCK (Rho-associated protein kinase) inhibitor as well as preparation method and application thereof
  • Thiophene amide ROCK (Rho-associated protein kinase) inhibitor as well as preparation method and application thereof
  • Thiophene amide ROCK (Rho-associated protein kinase) inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The synthesis of embodiment 1 compound I-1

[0028]

[0029] Step 1. Synthesis of Compound IV

[0030] 2.07g (10mmol) of compound II and 0.85g (10mmol) of compound III were dissolved in 20mL of dry THF, stirred at room temperature, and 2.48g (12mmol) of N,N'-dicyclohexylcarbodiimide (DCC) and 0.1 g 4-dimethylaminopyridine (DMAP), after the addition was complete, the reaction mixture was stirred overnight at room temperature, and TLC tracking found that the reaction was complete. The reaction mixture was carefully poured into 200mL ice water, stirred, and washed with 50mL×3CH 2 Cl 2 After extraction, the extract phases were combined, washed successively with 100 mL of 1% dilute hydrochloric acid and 100 mL of 5% brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the residue was purified by silica gel column chromatography to obtain Compound IV, 2.41 g (...

Embodiment

[0039] Example compound 2 in vitro inhibition of ROCK analysis

[0040] Inhibition experiments were performed by the fluorescence polarization (FP) method using a commercially available ROCK IMAP kit from Molecular Devices (Product No. R8093) and essentially according to the protocol provided by the manufacturer. The S6 ribosomal protein-derived substrate used was (Fl)-AKRRRLSSLRA, also from Molecular Devices (product number R7184). Enzyme mix of ROCKα / ROCKII was obtained from Upstate Biotechnology (product number 14-451). Briefly, all compounds were screened in 384-well plates to determine enzyme inhibition at concentrations ranging from 100 μM to 0.1 nM using serial 3-fold dilutions. Y-27632 (commercially available from Tocris Corporation) was used as a reference (0.4 μM) in order to perform the experiments. 1 μL of compound solution (each concentration) to be tested in DMSO was placed in 2 μL of enzyme solution with 10 mM Tris-HCl, 10 mM MgCl2, 0.1% BSA, 0.05% NaN3, pH ...

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Abstract

The invention relates to the field of ROCK (Rho-associated protein kinase) inhibitors, in particular to a thiophene amide ROCK inhibitor, a preparation method thereof and an application to preparationof drugs for treating sexual dysfunction, inflammatory diseases, eye diseases, respiratory diseases and the like.

Description

technical field [0001] The present invention relates to the field of ROCK inhibitors. Specifically, the present invention relates to a ROCK inhibitor containing thiophene amide derivatives that produces a therapeutic effect on inhibiting ROCK, its preparation method, and its use in pharmaceuticals (such as sexual dysfunction, inflammatory diseases, ophthalmic diseases, etc.) and respiratory diseases, etc.). Background technique [0002] Serine / threonine protein kinase ROCK consists of two isoforms ROCK I and ROCK II in humans. ROCK I is encoded on chromosome 18, while ROCK II (also known as Rho kinase) is located on chromosome 12. Both have a molecular mass of about 160kD. The two (amino acid sequences) share 65% homology, and the homology of the kinase region is as high as 95%. Although their sequences are similar, their tissue distributions vary. The highest levels of expression of ROCK I are observed in heart, lung, and bone tissues, whereas ROCK II is mainly express...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/38A61P15/10A61P15/00A61P29/00A61P27/02A61P11/00
CPCC07D333/38
Inventor 蔡子洋
Owner FOSHAN SAIWEISI MEDICINE SCI & TECH
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