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US-11702400-B2 - Salt types, crystal forms, and preparation methods for benzopyrazole compounds as RHO kinase inhibitors

US11702400B2US 11702400 B2US11702400 B2US 11702400B2US-11702400-B2

Abstract

Salt types, crystal forms, and preparation methods for benzopyrazole compounds as RHO kinase inhibitors. Specifically, disclosed are hydrochloride and acetate of compounds of formula (I) and crystal forms thereof, as well as application of the salt types and the crystal forms in preparation of RHO inhibitor drugs.

Inventors

  • WU LINGYUN
  • XIAO ZHEMING
  • JIANG CHUNYAN
  • LI JIAN
  • CHEN SHUHUI

Assignees

  • MEDSHINE DISCOVERY INC

Dates

Publication Date
20230718
Application Date
20201016
Priority Date
20191018

Claims (13)

  1. 1. A crystal form A of the hydrochloride having a structure shown in formula (II-1), wherein, the X-ray powder diffraction pattern thereof measured by Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 14.77±0.20°, 20.50±0.20°, 22.38±0.20° and 24.15±0.20°;
  2. 2. The crystal form A as defined in claim 1 , wherein, the X-ray powder diffraction pattern thereof measured by Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 10.22±0.20°, 13.36±0.20°, 14.77±0.20°, 18.69±0.20°, 20.50±0.20°, 22.38±0.20°, 24.15±0.20° and 25.03±0.20°.
  3. 3. The crystal form A as defined in claim 2 , wherein, the X-ray powder diffraction pattern thereof measured by Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.38°, 9.32°, 10.22°, 13.36°, 14.77°, 15.21°, 18.69°, 20.50°, 21.69°, 22.08°, 22.38°, 24.15°, 24.58°, 25.03°, 26.28°, 27.13°, 28.15°, 29.44°, 30.15°, 31.49°, 32.1°, 32.69°, 35.17° and 38.51°.
  4. 4. The crystal form A as defined in claim 2 , wherein, the XRPD pattern thereof is shown in FIG. 1 .
  5. 5. The crystal form A as defined in claim 4 , wherein, the differential scanning calorimetry curve thereof has an endothermic peak with an onset at 245.2° C.±3° C.
  6. 6. A preparation method of the crystal form A as defined claim 1 , comprising the following steps: 1) adding a compound of formula (I-1) to an organic solvent and stirring at an appropriate temperature; 2) filtering under reduced pressure, collecting filter cake; 3) vacuum drying the filter cake.
  7. 7. The preparation method as defined in claim 6 , wherein, the organic solvent is ethanol; or, the appropriate temperature is 25° C.; or, the stirring time is 10-12 hours.
  8. 8. A crystal form B of the acetate having a structure shown in formula (II-2), wherein, the X-ray powder diffraction pattern thereof measured by Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.18±0.20°, 12.37±0.20°, 17.08±0.20°, 21.22±0.20° and 24.88±0.20°;
  9. 9. The crystal form B as defined in claim 8 , wherein, the X-ray powder diffraction pattern thereof measured by Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.18±0.20°, 11.94±0.20°, 12.37±0.20°, 17.08±0.20°, 20.76±0.20°, 21.22±0.20°, 22.01±0.20° and 24.88±0.20°.
  10. 10. The crystal form B as defined in claim 9 , wherein, the X-ray powder diffraction pattern thereof measured by Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.18°, 10.57°, 11.94°, 12.37°, 12.94°, 13.93°, 16.22°, 17.08°, 17.93°, 18.30°, 19.47° 20.34°, 20.76°, 21.22°, 21.58°, 22.01°, 22.25°, 23.06°, 24.07°, 24.46°, 24.88°, 25.28°, 25.69°, 25.99°, 26.66°, 27.03°, 28.85°, 29.54°, 31.14°, 31.88°, 32.48°, 33.70°, 34.43°, 35.54°, 36.33°, 37.89°, and 39.67°.
  11. 11. The crystal form B as defined in claim 9 , wherein, the X-ray powder diffraction pattern thereof is shown in FIG. 4 .
  12. 12. A preparation method of the crystal form B as defined in claim 8 , comprising the following steps: 1) dissolving a compound of formula (I) in an organic solvent, then adding acetic acid and stirring; 2) filtering under reduced pressure, collecting filter cake; 3) vacuum drying the filter cake.
  13. 13. The preparation method as defined in claim 12 , wherein, the organic solvent is ethyl acetate.

Description

The present application is a National Stage of International Application No. PCT/CN2020/121388, filed on Oct. 16, 2020, which claims priority of the Chinese Patent Application No. CN201910993446.1 filed on Oct. 18, 2019, the contents of which are incorporated herein by reference in their entireties. TECHNICAL FIELD The present disclosure relates to a salt type, a crystal form and a preparation method thereof for benzopyrazole compounds as RHO kinase inhibitors, specifically relates to a hydrochloride and an acetate of a compound of formula (I), and a crystal form thereof, and also includes a use of the salt type and crystal form in the manufacture of RHO inhibitor medicaments. BACKGROUND RHO associated kinase (abbreviated as ROCK), a serine/threonine protein kinase, is a downstream target effector molecule of RHO and is widely expressed in human body. RHO associated kinase (ROCK) is involved in the regulation of myosin light chain (MLC) and is suitable for vasodilatory therapy. New research supports the involvement of ROCK kinase in the regulation of immune response and fibroblast activation in TH17 cells, which may extend the indications for pulmonary diseases such as pulmonary fibrosis and asthma, and further indications include autoimmune diseases. ROCK kinase family includes two subtypes, ROCK1 and ROCK2. ROCK2 kinase is related to inflammation and fibrosis. Selective ROCK2 inhibitor does not cause vasodilation at high concentration in vitro vasodilation experiment, which can reduce cardiovascular side effects. Although the embryo mortality rate of ROCK1 knockout mice is not high, most of them die from cytoskeleton variation caused by MLC phosphorylation reduction after birth, while 90% of ROCK2 knockout mice die in embryonic stage, but there is no difference between surviving mice and wild type mice, so selective inhibition of ROCK2 activity may have higher safety. Therefore, selective ROCK2 kinase inhibitors can avoid cardiovascular side effects of drugs. KD025 (WO2006105081A1, WO2008054599A1, WO2010104851A1 and WO2014055996A1) is an oral selective inhibitor of ROCK2 kinase developed by Kadmon Company. Studies have shown that KD025 represents a novel mechanism to treat idiopathic pulmonary fibrosis (IPF) by inhibiting fibrosis-regulating proteins such as RHO kinase. The trigger for idiopathic pulmonary fibrosis (IPF) may be muscle damage. The body response to injury involves the reorganization of the actin cytoskeleton in a variety of cells (e.g., epithelial cells, fibroblasts, endothelial cells, and macrophages), while the assembly of actin filaments and the contraction of actomyosins are regulated by RHO kinase family proteins (including ROCK1 and ROCK2) guidance. Previous studies have shown that RHO kinase family proteins can be activated in the lungs of IPF patients and animal models of this disease, and RHO kinase inhibitors can prevent the tissue fibrosis process in these models and induce the established fibrosis to subside. At present, the Phase II clinical trial of moderate to severe psoriasis has been completed, and KD025 is in the Phase II clinical research stage of idiopathic pulmonary fibrosis (IPF) treatment. WO2014134388A1 and WO2016028971A1 also disclose a class of compounds with structural general formula as shown in formula (a) and formula (b), which can also be used in the treatment of cardiovascular diseases, neuropathological diseases, tumors, autoimmune diseases, pulmonary fibrosis, inflammatory diseases, etc. Content of the Present Invention The present disclosure provides a hydrochloride of a compound of formula (I), having the structure shown in formula (I′) wherein, n is 1.6-2.4, and the carbon atoms with “*” are chiral carbon atoms, which exist in a (R) or (S) single enantiomer form or a (R) or (S) single enantiomer-rich form. In some embodiments of the present disclosure, the n is 1.9, 2.0 or 2.1. In some embodiments of the present disclosure, the hydrochloride has the structure shown in formula (I-1), wherein, the carbon atom with “*” is a chiral carbon atom, which exists in a (R) or (S) single enantiomer form or a (R) or (S) single enantiomer-rich form. In some embodiments of the present disclosure, the hydrochloride has the structure shown in formula (II-1), In some embodiments of the present disclosure, the X-ray powder diffraction (XRPD) pattern measured by Cu Kα radiation of a crystal form A of the hydrochloride has characteristic diffraction peaks at the following 2θ angles: 14.77±0.20°, 20.50±0.20°, 22.38±0.20° and 24.15±0.20°. In some embodiments of the present disclosure, the X-ray powder diffraction pattern measured by Cu Kα radiation of the crystal form A of the hydrochloride has characteristic diffraction peaks at the following 2θ angles: 10.22±0.20°, 13.36±0.20°, 14.77±0.20°, 18.69±0.20°, 20.50±0.20°, 22.38±0.20°, 24.15±0.20°, and 25.03±0.20°. In some embodiments of the present disclosure, the X-ray powder diffraction pattern measured by Cu Kα radiation of the