Crystal or amorphous substance of steroid derivative fxr agonist, preparation method and use thereof

一种结晶、溶剂的技术，应用在药物化学领域，能够解决无法激活小鼠和人类FXR、内源性FXR配基自然性不确定等问题

Active Publication Date: 2021-06-25
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds fail to activate mouse and human FXR, making the nature of the endogenous FXR ligand uncertain

Method used

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  • Crystal or amorphous substance of steroid derivative fxr agonist, preparation method and use thereof
  • Crystal or amorphous substance of steroid derivative fxr agonist, preparation method and use thereof
  • Crystal or amorphous substance of steroid derivative fxr agonist, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] The preparation of embodiment 1 formula I compound

[0095] The preparation of step 1-1 formula 3 compound

[0096]

[0097] Methanol (33 L) was added to a 50 L reaction kettle at 25 degrees Celsius, substrate 2 (3.330 kg, 8.23 ​​mol) was added to the reaction kettle, and p-toluenesulfonic acid monohydrate (156.6 g, 0.823 mol) was added , the reaction was heated to 60 °C and stirred at this temperature for 12 hours. TLC monitored the reaction, showing disappearance of starting material. HPLC showed about 100% product formation. The reaction solution was cooled to room temperature, then the pH value was adjusted to about 9 with saturated sodium bicarbonate solution, and the solution was spin-dried to obtain the crude product. The crude product was dissolved in ethyl acetate (30 L), followed by saturated sodium bicarbonate solution (9 L), water (9L), washed with saturated brine (9L). The organic phase was spin-dried to obtain the product. The product is brown oily...

experiment example 1

[0135] The solid stability test of experimental example 1 crystal A

[0136] Investigate crystal A under the following conditions: 1) 40°C (open), 2) 60°C (open), 3) room temperature / 92.5%RH (open), 4) room temperature / 75%RH (open), 5 ) 40°C / 75%RH (open), 6) solid stability at 60°C / 75%RH (open). The room temperature is selected from 20°C to 30°C.

[0137] Weigh an appropriate amount of crystal A sample and place it on the bottom of the glass sample bottle, and spread it into a thin layer. The samples placed under all the above conditions were sealed with aluminum foil, and some small holes were punched on the aluminum foil to ensure that the samples could fully contact with the ambient air. Samples were taken on the 5th and 10th day for XRPD detection, and the test results were consistent with the initial The detection results were compared, and it was found that the crystal forms of the samples did not change.

experiment example 2

[0138] The solid stability test of experimental example 2 crystal B

[0139] Investigate crystal B under the following conditions: 1) room temperature / 92.5% RH (open), 2) room temperature / 75% RH (open), 3) 40°C / 75%RH (open), 4) 60°C / 75 Solid stability in % RH (open). The room temperature is selected from 20°C to 30°C.

[0140] Weigh an appropriate amount of crystal B sample and place it on the bottom of the glass sample bottle, and spread it into a thin layer. The samples placed under all the above conditions were sealed with aluminum foil, and some small holes were punched on the aluminum foil to ensure that the samples could fully contact with the ambient air. Samples were taken on the 5th and 10th day for XRPD detection, and the test results were consistent with the initial The detection results were compared, and it was found that the crystal forms of the samples did not change.

[0141] The solid stability test of the solid amorphous of the compound shown in Experiment...

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Abstract

Steroid derivative FXR agonist (Formula I) crystal or amorphous substance, and preparation method thereof, crystal composition and pharmaceutical composition containing the crystal or amorphous substance, and their preparation for treating or preventing FXR related The purposes in the medicine of this kind of disease.

Description

technical field [0001] The application belongs to the field of medicinal chemistry, in particular, the application relates to the crystalline or amorphous substance of the steroid derivative FXR agonist, the crystalline composition comprising the crystal or the amorphous substance, the pharmaceutical composition, and their medical use . Background technique [0002] Farnesoid X receptor (FXR) is an orphan nuclear receptor initially identified from a rat liver cDNA library (BM. Forman, et al., Cell 81:687-693 (1995)), which is related to insect molting Hormone receptors are closely related. FXR is a member of the nuclear receptor family of ligand-activated transcription factors that includes steroid, retinoid, and thyroid hormone receptors (DJ. Mangelsdorf, et al., Cell 83:841-850 (1995)). Northern and in situ analysis showed that FXR is abundantly expressed in liver, intestine, kidney and adrenal gland (BM. Forman, et al., Cell 81: 687-693 (1995) and W. Seol, et al., Mol. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J43/00A61K31/58A61P1/16A61P3/04A61P3/06A61P3/10A61P9/10A61P13/02
CPCA61K31/58A61P1/16A61P3/04A61P3/06A61P3/10A61P9/10A61P13/02C07J43/003C07B2200/13
Inventor 李小林肖华玲李鹏贺海鹰李卫东
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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