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Salt and crystal forms of pyridopyridone derivatives

A technology of crystal form and hydrochloride, applied in the field of salt form of novel pyridopyridone derivatives, can solve the problems of large dose, obvious side effects in the gastrointestinal tract, difficult to penetrate the blood-brain barrier, etc.

Active Publication Date: 2022-03-04
CSTONE PHARM (SUZHOU) CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although many efforts have been made on the road to develop CDK4 / 6 inhibitors for the treatment of cancer and other diseases, only three drugs targeting this target (Palbociclib, Ribociclib, and Abemaciclib) have been marketed so far, and the indications are Only HR-positive / HER2-negative postmenopausal metastatic breast cancer
Although the clinical research of CDK4 / 6 inhibitors for lung cancer has progressed to Phase III clinical trials, there is still no drug on the market, so there is still an urgent need to develop novel, safer and more effective CDK4 / 6 that can treat a variety of cancers (including lung cancer) Inhibitor
On the other hand, although Palbociclib has been approved for marketing, it has been reported in the literature that its permeability is poor, and it is difficult to penetrate the blood-brain barrier, which is not conducive to the treatment of cancer with brain metastases, and Palbociclib also has severe bone marrow suppression toxicity; although the bone marrow of Abemaciclib Inhibitory toxicity is mild, but its gastrointestinal side effects are more obvious; compared with Palbociclib and Abemaciclib, Ribociclib is less effective, resulting in a larger clinical dosage

Method used

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  • Salt and crystal forms of pyridopyridone derivatives
  • Salt and crystal forms of pyridopyridone derivatives
  • Salt and crystal forms of pyridopyridone derivatives

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0108] Preparation of the crystal form of the compound of formula (I-2)

[0109] At 18°C, THF (2.8 L) and the compound of formula (I) (288.25 g, 528.09 mmol, 1.0 eq) were successively added into the reaction kettle, and heated to 40°C, the system was a little cloudy. The mixture was filtered while it was hot, and the filtrate was re-transferred to the reactor, and concentrated hydrochloric acid (39.60 ml, 0.9 equivalents) was slowly added dropwise to the reactor, then THF (280 ml) was added, and stirred at 40-45°C for 16 Hour. The reaction mixture was filtered, the filter cake was washed with THF (280 mL), and the filter cake was dried in a vacuum oven at 50° C. for 4 hours to obtain a crude product.

[0110] At room temperature of 12°C, the above crude product (257.16 g), EtOH (2.9 L) and water (145 ml) were successively added to the reaction kettle, and the reaction mixture was heated to 80°C (vigorous reflux), and the reaction system became clear. Heating was stopped and ...

Embodiment 1

[0112] Embodiment 1: the hygroscopicity research of the crystalline form of compound of formula (I-2)

[0113] Experimental conditions:

[0114] Instrument model: SMSDVS Advantage dynamic vapor adsorption instrument

[0115] Test conditions: Take a sample (10-15 mg) and place it in a DVS sample tray for testing.

[0116] DVS parameters:

[0117] Temperature: 25°C

[0118] Balance: dm / dt=0.01% / min (shortest: 10min, longest: 180min)

[0119] Drying: 120min at 0% RH

[0120] RH(%) test rung: 10%

[0121] RH (%) test step range: 0%-90%-0%

[0122] See Table 1-2 for the evaluation criteria of hygroscopicity.

[0123] Table 1-2

[0124] Hygroscopicity Classification Moisture absorption weight gain*(ΔW%) deliquescence Absorb enough water to form a liquid Very hygroscopic ΔW%≥15% Hygroscopic 15%>ΔW%≥2% slightly hygroscopic 2%>ΔW%≥0.2% No or almost no hygroscopicity ΔW%

[0125] Note: *Weight gain under moisture absorption at ...

Embodiment 2

[0128] Embodiment 2: the crystal form research of formula (I-2) compound

[0129] Weigh about 50 mg of the crystal form of the compound of formula (I) into different 1.5 mL glass vials, and add an appropriate amount of solvent or solvent mixture (see Table 1-3 below) to form a suspension or solution. After adding magnets, the above samples were placed on a magnetic heating stirrer (40° C.) for 2 days of testing.

[0130] Table 1-3

[0131] Numbering solvent crystal form 1 ethanol The crystal form of the compound of formula (I-2) 2 Acetonitrile The crystal form of the compound of formula (I-2) 3 acetone The crystal form of the compound of formula (I-2) 4 ethyl acetate The crystal form of the compound of formula (I-2) 5 Tetrahydrofuran The crystal form of the compound of formula (I-2)

[0132] It can be seen from the above table that under the solvent conditions of ethanol, acetonitrile, acetone, ethyl acetate and tetrah...

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Abstract

A salt form, crystal form and preparation method of a pyridopyridone derivative, specifically disclosing the hydrochloride of the compound of formula (I) and the crystal form of the hydrochloride, and also including the crystal form and the salt form in Application in the preparation of medicines for treating lung cancer and other cancers.

Description

[0001] Cross References to Related Applications [0002] This application claims the following priority: CN201810609544.6, the filing date is June 13, 2018. technical field [0003] The present invention relates to a salt form, a crystal form and a preparation method thereof of a novel pyridopyridone derivative, in particular to the hydrochloride of the compound of formula (I) and the crystal form of the hydrochloride. It also includes the application of the crystal form and salt form in the preparation of medicines for treating lung cancer and other cancers. Background technique [0004] The cell cycle refers to the continuous dynamic process experienced by cells that normally divide continuously from the end of the previous mitosis to the end of the next mitosis. Mammalian cell cycle consists of four phases: G1 phase (pre-DNA synthesis), S phase (DNA synthesis phase), G2 phase (late DNA synthesis phase) and M phase (mitosis phase). The M phase is followed by cytokinesis ...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D519/00A61K31/4965A61P35/00
CPCC07D519/00A61K31/4965A61P35/00C07D471/04
Inventor 徐招兵蔡进峰刘迎春宋宝慧施沈一姚婷胡利红丁照中
Owner CSTONE PHARM (SUZHOU) CO LTD
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