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Salt form of isoquinolinone compound as ROCK protein kinase inhibitor and preparation method thereof

A technology of compound and crystal form, which is applied in the field of salt form of isoquinolinone compound as a ROCK protein kinase inhibitor and its preparation, and can solve the problems of membrane permeability, pharmacokinetics, and druggability that need to be improved.

Pending Publication Date: 2022-06-21
GUANGZHOU OCUSUN OPHTHALMIC BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Patent WO2007026664A1 reports a series of compounds with inhibitory effect on ROCK kinase, such as the reference compound 2. This series of compounds has good enzyme activity, but they need to be improved in terms of membrane permeability, pharmacokinetics, and druggability.

Method used

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  • Salt form of isoquinolinone compound as ROCK protein kinase inhibitor and preparation method thereof
  • Salt form of isoquinolinone compound as ROCK protein kinase inhibitor and preparation method thereof
  • Salt form of isoquinolinone compound as ROCK protein kinase inhibitor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1: Preparation of crystal form of compound A of formula (II)

[0079]

[0080] first step

[0081] Turn on stirring and nitrogen protection, and sequentially add dichloromethane (8.6L), water (8.6L), and starting material 1-1 (575.34g) into the reaction kettle. Control the temperature in the reactor to be 10-15°C, add sodium bicarbonate (1289.36g), tetrabutylammonium hydrogen sulfate (133.87g) and starting material 1-2 (760.25g) to the reactor successively, control the internal temperature to 10-15°C and stirred for 2 hours. The reaction solution was allowed to stand for layers, and the organic phase was concentrated under reduced pressure until no fractions flowed out. The concentrated solution was transferred to a three-necked flask and the internal temperature was controlled to be 60-70°C and stirred for 12 hours, then cooled to room temperature naturally. The crude product was quickly filtered with silica gel and rinsed with dichloromethane until no pro...

Embodiment 2

[0092] Example 2: Preparation of compounds of formula (I)

[0093]

[0094] Compound 1-5 (2.2 g, 3.84 mmol) was dissolved in ethyl acetate (35 mL), to the reaction solution was added an ethyl acetate solution of hydrochloric acid (4 M, 20 mL) and stirred at 15° C. for 12 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8, extracted with ethyl acetate (60 mL×2), the organic phase was dried with anhydrous sodium sulfate (5 g), filtered, and the crude product obtained by concentrating under reduced pressure was subjected to high-efficiency solution Purification by gas chromatography (neutral system) affords the compound of formula (I). MS-ESI calculated value [M+H] + 470, the measured value is 470.1 H NMR (400MHz, CD 3 OD)δ=8.71(dd,J=1.4,8.0Hz,1H),8.24(dd,J=1.5,7.8Hz,1H),7.81(d,J=7.9Hz,1H),7.64(t,J= 7.9Hz, 1H), 7.54(d, J=0.9Hz, 1H), 7.09(s, 1H), 7.05(d, J=7.9Hz, 1H), 6.14(s, 2H), 3.77-3.62(m, 3H), 3.59-3.50(m, 1H),...

Embodiment 3

[0095] Example 3: Preparation of compound B crystal form of formula (II)

[0096] An appropriate amount of (II) Compound A crystal form was weighed into a sample bottle, and a certain volume of the solvent in Table 4 was added to prepare suspensions or solutions of different single solvents. After the suspension was continuously stirred at 50°C for 3 hours, the sample was filtered and the filtered solid was placed in a vacuum drying oven, and the residual solvent was removed by vacuum drying at 45°C.

[0097] Table 3 Preparation of crystal form of compound B of formula (II)

[0098] Numbering solvent Sample size solvent volume state Crystal form 1 isopropyl alcohol 100 2.0 suspension Form B 2 tetrahydrofuran 100 2.0 suspension Form B 3 Acetonitrile 101 2.0 suspension Form B 4 2-Butanone 100 2.0 suspension Form B 5 Ethyl acetate 101 2.0 suspension Form B

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Abstract

The invention discloses a salt form of an isoquinolinone compound serving as a ROCK protein kinase inhibitor and a preparation method of the salt form, and further discloses application of the salt form in preparation of drugs for treating glaucoma or intraocular hypertension diseases.

Description

technical field [0001] The invention relates to a salt form of an isoquinolinone-type compound as a ROCK protein kinase inhibitor and a preparation method thereof, and also includes the application of the salt form in the preparation of a medicine for treating glaucoma or ocular hypertension. Background technique [0002] RHO-associated kinase (ROCK), a serine / threonine protein kinase, is a downstream target effector molecule of RHO and is widely expressed in the human body. RHO-related protein kinase (ROCK) is involved in the regulation of myosin light chain (MLC) and is suitable for the treatment of vasodilation. ROCK kinase can also act on trabecular outflow tract cells, relax trabecular cells, and reduce the outflow resistance of aqueous humor. The latest research shows that ROCK kinase inhibitors can also promote the damage and repair of corneal endothelial cells, prevent fibrosis, and have great application prospects. [0003] Isoquinoline sulfonamide compounds are an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61P27/06A61P27/02
CPCC07D401/12A61P27/06A61P27/02C07B2200/13A61K31/4725C07B2200/11
Inventor 葛坚王延东刘奕志吴凌云尤旭肖哲明陈曙辉
Owner GUANGZHOU OCUSUN OPHTHALMIC BIOTECHNOLOGY CO LTD
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