Camptothecin-analogue crystal forms and preparing method and application thereof

A technology of crystal form and diffraction peak, which is applied in the field of crystal form of camptothecin derivatives and its preparation, can solve problems such as major adverse reactions and poor solubility of camptothecin, and achieve the effect of ensuring safety

Inactive Publication Date: 2017-03-29
SICHUAN SINO INNOVATION BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] Camptothecin is a class of alkaloids isolated from the leaves of Camptotheca acuminate, which can exhibit anticancer activity by inhibiting topoisomerase I, but camptothecin is poorly soluble and has a large Adverse reactions, in order to overcome this defect, technicians in the field of pharmacy have successfully developed a variety of camptothecin derivatives with clinical application value, such as topotecan, irinotecan

Method used

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  • Camptothecin-analogue crystal forms and preparing method and application thereof
  • Camptothecin-analogue crystal forms and preparing method and application thereof
  • Camptothecin-analogue crystal forms and preparing method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] 5.5 g of starting material (S)-5-amino-4,11-diethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b] Quinoline-3,14(4H,12H)dione was dissolved in 200ml of dichloromethane, evaporated to dryness under reduced pressure at 40°C, added 170mL of n-heptane, spin-dried under reduced pressure at 40°C, and added 170mL of n-heptane again The alkane was spin-dried under reduced pressure at 40°C to obtain a solid product with a yield of 100%. The number is HSSYO-001-3S 20131224-02, and its XRPD is as follows Figure 5 or its partial enlargement Image 6 shows that the obtained solid is (S)-5-amino-4,11-diethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2 -b] Form A of quinoline-3,14(4H,12H)dione.

Embodiment 2

[0066] 1.0 g of the starting material (S)-5-amino-4,11-diethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b] Quinoline-3,14(4H,12H)dione was dissolved in 100ml of a mixed solvent of tetrahydrofuran and methanol with a volume ratio of 1:1, added 100mL of n-heptane, stirred and precipitated, filtered and dried to obtain a solid product with a yield of 71 %. The code is HSSYO-001-3-THF-MeOH-Ht. Its DSC such as figure 2 As shown, it shows that Form A has endothermic peaks at 260.43°C and 267.86°C. Its XRPD as figure 1 , Figure 5 or its partial enlargement Image 6 As can be seen from the figure, it and the product obtained in Example 1 are both crystal form A.

Embodiment 3

[0068] 1.0 g of the starting material (S)-5-amino-4,11-diethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b] Quinoline-3,14(4H,12H)dione was dissolved in 100ml of a mixed solvent of tetrahydrofuran and methanol with a volume ratio of 1:3, added 200mL of water, stirred to separate out, filtered and dried to obtain a solid product with a yield of 70% . No. HSSYO-001-3-THF-MeOH-H 2 O, its XRPD as Figure 5 or its partial enlargement Image 6 As can be seen from the figure, it and the products obtained in Example 1 or Example 2 are both crystal form A.

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Abstract

The invention provides camptothecin-analogue crystal forms and a preparing method and application thereof. The crystal forms include the crystal form A and the crystal form B, wherein in the crystal form A, Cu-K alpha radiation is adopted, and an X-ray powder diffraction spectrum of the crystal form A is characterized by comprising characteristic diffraction peaks at the portions corresponding to 2theta values of 6.95+ / -0.2 degrees, 10.35+ / -0.2 degrees, 15.15+ / -0.2 degrees, 15.85+ / -0.2 degrees and 23.25+ / -0.2 degrees; the crystal form B comprises characteristic diffraction peaks at the portions corresponding to 2theta values of 7.70+ / -0.2 degrees, 10.55+ / -0.2 degrees, 11.20+ / -0.2 degrees, 12.00+ / -0.2 degrees and 19.50+ / -0.2 degrees. The crystal form A has the quite-high crystal form stability, and the crystal form B has the good crystal form stability.

Description

technical field [0001] The present invention relates to a crystal form of a camptothecin derivative, in particular to a crystal form of a camptothecin derivative and a preparation method and application thereof. Background technique [0002] Camptothecin is a class of alkaloids isolated from the leaves of Camptotheca (Camptotheca acuminate), which can inhibit topoisomerase I and show anticancer activity, but camptothecin is poorly soluble and has a large Adverse reactions, in order to overcome this defect, those skilled in the pharmaceutical field have successfully developed a variety of camptothecin derivatives with clinical application value, such as topotecan and irinotecan. For topotecan, the FDA approves it for the treatment of ovarian cancer, cervical cancer and small cell lung cancer; for irinotecan, it is approved for the treatment of colon cancer. [0003] CN102574866A discloses a class of camptothecin derivatives, which have good anti-proliferative activity on var...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22A61K31/4745A61P35/00
CPCC07D491/22C07B2200/13
Inventor 王裕军邹振运干玉娟倪瑛朱鸿龙凯
Owner SICHUAN SINO INNOVATION BIOTECH CO LTD
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