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Inhibitors of rho associated coiled-coil containing protein kinase

A technology of R12 and R13, which can be used in medical preparations containing active ingredients, drug combinations, cardiovascular system diseases, etc., and can solve problems such as hindering the penetration of small molecule inhibitors

Pending Publication Date: 2020-06-12
KADMON CORP LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the blood-brain barrier (BBB), although playing a key role in brain homeostasis, also significantly hinders the penetration of most small molecule inhibitors

Method used

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  • Inhibitors of rho associated coiled-coil containing protein kinase
  • Inhibitors of rho associated coiled-coil containing protein kinase
  • Inhibitors of rho associated coiled-coil containing protein kinase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0305] All solvents and reagents were commercially available and used as received. Recorded on the Bruker instrument (300MHz or 400MHz) in the deuterated solvent 1 H NMR spectrum. Chemical shifts are given in ppm and coupling constants are given in Hertz. By flash chromatography using 220-400 mesh silica gel or by reverse phase HPLC with CH 3 CN / water was used as solvent to purify all final compounds. Thin layer chromatography was performed on silica gel 60F-254 (0.25 nm thickness) plates. Visualization was accomplished with UV light and / or 10% phosphomolybdic acid in ethanol. Nominal (low resolution) mass spectra were acquired on a Waters LCT or Applied Biosystems API 3000 mass spectrometer. High resolution mass spectra (HRMS) were acquired on Waters LCT or Agilent TOF mass spectrometers. All other LC-MS experiments were performed on an Agilent 1100HPLC coupled to an Agilent single quadrupole mass spectrometer. Compound purity was determined by LC-MS at wavelengths of ...

Embodiment 2

[0342] N-(1H-indazol-5-yl)-2-(methylamino)-2-phenylacetamide

[0343]

[0344] The reaction was carried out according to general scheme A. The final residue was purified by reverse phase preparative HPLC to afford N-(lH-indazol-5-yl)-2-(methylamino)-2-phenylacetamide (80%) as an off-white solid. 1 H NMR (400MHz, CD 3 OD) δ8.34 (s, 1H), 8.27 (s, 1H), 7.68-7.65 (m, 2H), 7.60-7.53 (m, 5H), 5.1 (s, 1H), 2.69 (s, 3H). MS (ES+) m / e 281.1 (M+H).

Embodiment 3

[0346] N-(1H-indazol-5-yl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0347]

[0348] The reaction was carried out according to general scheme A. The final residue was purified by reverse-phase preparative HPLC to give N-(1H-indazol-5-yl)-1,2,3,4-tetrahydroquinoline-3-carboxamide (23% ). 1 H NMR (400MHz, MeOD-d 3 )δ13.75(s,1H),10.84(s,1H),8.94(s,1H),8.80(s,1H),8.26(m,2H),7.71(m,2H),7.28(m,2H ), 6.63(s,1H), 4.21(m,1H), 3.97(m,1H), 3.65(m,3H). MS(ES+)m / e293.1(M+H) + .

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Abstract

The invention relates to inhibitors of ROCK1 and / or ROCK2. Also provided are methods of inhibiting ROCK1 and / or ROCK2 that are useful for the treatment of disease.

Description

technical field [0001] The present invention relates to inhibitors of ROCK1 and / or ROCK2. Also provided are methods of inhibiting ROCK1 and / or ROCK2, which are useful in the treatment of diseases. Background technique [0002] Rho-related coiled-coil-containing protein kinase (ROCK) is a member of the serine / threonine kinase family. Two isoforms, ROCK1 and ROCK2, have been identified. Both isoforms are activated by the GTP-bound form of Rho GTPase and, when activated, phosphorylate a variety of downstream substrates. ROCK plays an important role in many cellular processes including smooth muscle cell contraction, cell proliferation, adhesion and migration. As such, ROCK inhibitors have potential therapeutic applicability in a variety of pathological conditions including, for example, asthma, cancer, erectile dysfunction, glaucoma, insulin resistance, renal failure, pulmonary hypertension, neuronal degeneration, and bone mass porosis. [0003] ROCK is a key intracellular...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/416C07D231/56A61P9/00A61P25/28
CPCA61P9/00A61P25/28C07D231/56C07D401/12C07D403/12A61P19/04
Inventor E.斯库卡斯K.G.刘J-I.金M.V.波于洛夫斯基莫日根张静雅
Owner KADMON CORP LLC
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