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US-12624017-B2 - Salt form of isoquinolinone type compound as rock inhibitor and preparation method therefor

US12624017B2US 12624017 B2US12624017 B2US 12624017B2US-12624017-B2

Abstract

Disclosed is a salt form of an isoquinolinone type compound as a ROCK protein kinase inhibitor and a preparation method therefor, and use of the salt form in the preparation of a medicament for treating glaucoma or ocular hypertension is further included.

Inventors

  • Jian Ge
  • Yandong Wang
  • Yizhi Liu
  • Lingyun Wu
  • Xu You
  • Zheming XIAO
  • Shuhui Chen

Assignees

  • GUANGZHOU OCUSUN OPHTHALMIC BIOTECHNOLOGY CO., LTD.
  • OCUSUN OPHTHALMIC PHARMACEUTICAL (GUANGZHOU) CO., LTD.

Dates

Publication Date
20260512
Application Date
20230621
Priority Date
20201221

Claims (16)

  1. 1 . A crystal form of a compound of formula (II), wherein an X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at the following angles of 2θ:3.30±0.20°, 6.33±0.20°, 6.55±0.20°, 10.62±0.20°, 12.57±0.20°, and 13.11±0.20°.
  2. 2 . The crystal form according to claim 1 , wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following angles of 2θ:3.30±0.20°, 6.33±0.20°, 10.62±0.20°, 12.57±0.20°, 13.11±0.20°, 17.85±0.20°, 18.51±0.20°, and 20.99±0.20°.
  3. 3 . The crystal form according to claim 1 , wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following angles of 2θ:3.30±0.20°, 6.33±0.20°, 6.55±0.20°, 10.62±0.20°, 12.57±0.20°, 13.11±0.20°, 14.20±0.20°, 16.37±0.20°, 17.85±0.20°, 18.51±0.20°, 19.56±0.20°, 20.99±0.20°, 25.53±0.20°, and 26.35±0.20°.
  4. 4 . The crystal form according to claim 3 , wherein the X-ray powder diffraction pattern having characteristic diffraction peaks at the following angles of 2θ:3.30°, 6.33°, 6.55°, 10.62°, 12.57°, 13.11°, 14.20°, 16.37°, 17.85°, 18.51°, 19.56°, 20.99°, 25.53°, and 26.35°.
  5. 5 . The crystal form according to claim 4 , wherein: the crystal form is crystal form A, and analysis data of the X-ray powder diffraction pattern is listed below: angles Interplanar Relative of 2θ distance Intensity intensity No. (°) (Å) (count) (%) 1 3.30 26.76 348.60 43.99 2 6.33 13.95 779.58 98.38 3 6.55 13.50 475.77 60.04 4 10.62 8.33 562.38 70.97 5 12.57 7.04 226.50 28.58 6 13.11 6.76 792.44 100.00 7 14.20 6.24 122.94 15.51 8 16.37 5.42 178.19 22.49 9 17.85 4.97 228.61 28.85 10 18.51 4.79 198.30 25.02 11 19.56 4.54 192.79 24.33 12 20.99 4.23 232.26 29.31 13 25.53 3.49 170.02 21.46 14 26.35 3.38 149.03 18.81.
  6. 6 . The crystal form according to claim 1 , wherein a differential scanning calorimetry curve of the crystal form has an endothermic peak with an onset at 235.9° C.±3.0° C.
  7. 7 . The crystal form according to claim 1 , wherein a thermogravimetric analysis curve of the crystal form shows a weight loss up to 7.70% at 160.0-3.0° C.
  8. 8 . A crystal form of a compound of formula (II), wherein an X-ray powder diffraction pattern has characteristic diffraction peaks at the following angles of 2θ:12.12±0.20°, 16.48±0.20°, 16.95±0.20°, 17.94±0.20°, and 21.87±0.20°.
  9. 9 . The crystal form according to claim 8 , wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following angles of 2θ:9.69±0.20°, 12.12±0.20°, 16.48±0.20°, 16.95±0.20°, and 21.87±0.20°.
  10. 10 . The crystal form according to claim 8 , wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following angles of 2θ:9.69±0.20°, 12.12±0.20°, 16.48±0.20°, 16.95±0.20°, 17.94±0.20°, 19.23±0.20°, 20.37±0.20°, and 21.87±0.20°.
  11. 11 . The crystal form according to claim 10 , wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following angles of 2θ:4.80±0.20°, 9.69±0.20°, 12.12±0.20°, 14.61±0.20°, 16.48±0.20°, 16.95±0.20°, 17.94±0.20°, 19.23±0.20°, 20.37±0.20°, 21.87±0.20°, 27.53±0.20°, 28.72±0.20°, and 33.61±0.20°.
  12. 12 . The crystal form according to claim 8 , wherein a differential scanning calorimetry curve of the crystal form has an endothermic peak with an onset at 239.5±3.0° C.
  13. 13 . The crystal form according to claim 8 , wherein a thermogravimetric analysis curve of the crystal form shows a weight loss up to 1.30% at 200.0±3.0° C.
  14. 14 . A preparation method for a crystal form B of a compound of formula (II), comprising: (a) adding a crystal form A of the compound of formula (II) into a solvent to form a suspension; and (b) stirring the suspension at 50° C. for 3 h, filtering, and drying, an X-ray powder diffraction pattern of the crystal form A of the compound of formula (II) has characteristic diffraction peaks at the following angles of 2θ: 1.30±0.20°, 6.33±0.20°, 6.55±0.20°, 10.62±0.20°, 12.57±0.20°, and 13.11±0.20°; an X-ray powder diffraction pattern of the crystal form B of the compound of formula (II) has characteristic diffraction peaks at the following angles of 2θ: 9.12±0.20°, 16.48±0.20°, 16.95±0.20°, 17.94±0.20°, and 21.87±0.20°; wherein the solvent is selected from the group consisting of isopropanol, tetrahydrofuran, acetonitrile, 2-butanone, and ethyl acetate.
  15. 15 . A method for treating glaucoma or ocular hypertension, comprising: administrating the compound according to claim 1 to a subject in need thereof.
  16. 16 . A method for treating glaucoma or ocular hypertension, comprising: administrating the compound according to claim 8 to a subject in need thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of International Application No. PCT/CN2021/140206, filed on Dec. 21, 2021, which claims priority to Chinese Application No. 202011521011.6, filed on Dec. 21, 2020. The disclosures of the aforementioned applications are hereby incorporated by reference in their entireties. TECHNICAL FIELD The present disclosure relates to a salt form of an isoquinolinone type compound as a ROCK inhibitor and a preparation method therefor, and also includes a use of the salt form in the preparation of a medicament for treating glaucoma or ocular hypertension. BACKGROUND Rho-associated kinase (ROCK), a serine/threonine protein kinase, is a downstream effector molecule of RHO and widely expressed in the human body. ROCK is involved in the regulation of myosin light chain (MLC). It is suitable for the treatment of vasodilation. ROCK can also act on trabecular outflow tract cells to decrease the resistance to the outflow of aqueous by relax trabecular cells. Recent research shows that ROCK inhibitors can also promote the repair of corneal endothelial cells and prevent fibrosis, which has great application prospects. Isoquinoline sulfonamide compounds are an important class of ROCK inhibitors. Fasudil and K-115 (WO2006057397A1), which have been launched at present, are both isoquinoline sulfonamide compounds. Fasudil, as a novel drug with extensive pharmacological effects, is a RHO kinase inhibitor, which expands blood vessels by increasing the activity of myosin light chain phosphatase, reduces the tension of endothelial cells, improves the microcirculation of brain tissue without producing or aggravating cerebral steal. And at the same time, it can antagonize inflammatory factors, protect nerves, resist apoptosis, and promote nerve regeneration. However, the approval of K-115 has very wide potential applications, including glaucoma, ocular hypertension, diabetic retinal damage complications, age-related macular degeneration, corneal damage, recovery after cataract and glaucoma surgery, etc., and may be further expanded to systematic drugs. WO2007026664A1 reported a series of compounds with ROCK inhibitory effects, such as control compound 2, which have good enzymatic activity, but need to be improved in terms of membrane permeability, pharmacokinetics, druggability and other aspects. The present disclosure reports a class of similar compounds that have been structurally modified and have significantly improved properties in this regard SUMMARY The present disclosure provides a compound of formula (II), The present disclosure further provides a crystal form A of the compound of formula (II), with an X-ray powder diffraction pattern having characteristic diffraction peaks at the following angles of 2θ: 6.33±0.20°, 10.62±0.20°, and 13.11±4.20°, In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following angles of 2θ: 3.30±0.20°, 6.33±0.20°, 6.55±0.20°, 10.62±0.20°, 12.57±0.20°, and 13.11±0.20°. In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following angles of 2θ: 3.30±0.20°, 6.33±0.20°, 10.62±0.20°, 12.57±0.20°, 13.11±0.20°, 17.85±0.20°, 18.51±0.20°, and 20.99±0.20°. In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following angles of 2θ: 3.30±0.20°, 6.33±0.20°, 6.55±0.20°, 10.62±0.20°, 12.57±0.20°, 13.11±0.20°, 14.20±0.20°, 16.37±0.20°, 17.85±0.20°, 18.51±0.20°, 19.56±0.20°, 20.99±0.20°, 25.53±0.20°, and 26.35±0.20°. In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form A is substantially as shown in FIG. 1. In some embodiments of the present disclosure, the X-ray powder diffraction pattern analysis data of the crystal form A is as shown in Table 1. TABLE 1The X-ray powder diffraction pattern analysis data ofthe crystal form A of the compound of formula (II)anglesInterplanarRelativeofdistanceIntensityintensityNo.2θ(°)(Å)(count)(%)13.3026.76348.6043.9926.3313.95779.5898.3836.5513.50475.7760.04410.628.33562.3870.97512.577.04226.5028.58613.116.76792.44100.00714.206.24122.9415.51816.375.42178.1922.49917.854.97228.6128.851018.514.79198.3025.021119.564.54192.7924.331220.994.23232.2629.311325.533.49170.0221.461426.353.38149.0318.81 In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form A is obtained using a Cu-Kα radiation source. In some embodiments of the present disclosure, a differential scanning calorimetry curve of the crystal form A has an endothermic peak with an onset at 235.9±3.0° C. In some embodiments of the present disclosure, the differential scanning calorimetry curve of the crystal form A is substantially as shown in FIG. 2. In some embodiments of the