Camptothecin derivative and ligand-drug conjugate thereof

A technology of camptothecin and derivatives, applied in the field of camptothecin derivatives and their ligand-drug conjugates, which can solve problems such as toxic side effects, increased aggregation of ADC, and shortened half-life

Pending Publication Date: 2022-05-10
SICHUAN BAILI PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Poor water solubility will lead to increased aggregation of ADC, which is easy to be endocytized by normal cells, resulting in toxic side effects or easier to be metabolized and shortened half-life

Method used

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  • Camptothecin derivative and ligand-drug conjugate thereof
  • Camptothecin derivative and ligand-drug conjugate thereof
  • Camptothecin derivative and ligand-drug conjugate thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0169] The preparation of conventional pharmaceutical compositions can be found in Chinese Pharmacopoeia.

[0170] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt of the ligand-drug conjugate of the present invention, or a salt of a compound described in the present invention, when such salt is used in a mammal It has safety and efficacy, and has proper biological activity. The ligand-drug conjugate compound of the present invention contains at least one carboxyl group, so it can form a salt with a base. Non-limiting examples of pharmaceutically acceptable salts include: sodium salt, potassium salt, calcium salt or magnesium salt, etc.

[0171] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt of the antibody-drug conjugate of the present invention, or a salt of a compound described in the present invention, which has Safety and effectiveness, and have appropriate biological ac...

Embodiment 1

[0178] Embodiment 1: Synthesis of Exitecan Chiral Isomer Compound 1

[0179]

[0180] Weigh compound SM-1 (N-(8-amino-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydronaphthalene-2-yl ) acetamide, purchased) (6.25g, 25.0mmol), SM-2((S)-4-ethyl-4-hydroxyl-7,8-dihydro-1H-pyranO[3,4-F ] indolezin-3,6,10(4H)-one (purchased) (7.25g, 27.5mmol), pyridinium p-toluenesulfonate (1.26g, 5.0mmol), add 500mL toluene, heat to reflux to separate water, After reacting for 5 hours, the reaction was monitored by HPLC until SM-2 was less than 10%, and the reaction was stopped. Cool down, concentrate under reduced pressure until the volume of the solution is only half, stir and crystallize in an ice-water bath for 2 h, filter, wash the filter cake three times with 30 mL of toluene, and dry in vacuum to obtain compound Ac-1: 10.68 g, 89%. LC-MS gave [M+H] + :478.2.

[0181] Ac-1 (10.68g, 22.5mmol), methanesulfonic acid (55mL), water (110mL) and toluene (55mL) were mixed in a 1L round bottom flask ...

Embodiment 2

[0182] Embodiment 2: the synthesis of compound 2

[0183]

[0184] Add compound 1 (in the form of trifluoroacetate) (100.0mg, 0.188mmol), glycolic acid (43.0mg, 0.565mmol), HATU (107.2mg, 0.282mmol), HOBt (38.1mg, 0.282mmol) and 5ml ultra-dry DMF, with a liquid seal on the bottle. The flask was stirred under an ice-water bath for 10 minutes, then DIEA (94uL, 0.565mmol) was added. The progress of the reaction was detected by TLC, and the reaction was about 3 h. After the reaction was complete, the reaction solution was sent to the preparation for separation. The preparation solution was concentrated in vacuo at 35° C. and freeze-dried to obtain 63.8 mg of white solid compound 2 with a yield of 69.7%. LC-MS results show [M+H] + : 493.9. 1 H NMR (400MHz, DMSO-d6) δ8.39 (d, J = 9.0Hz, 1H), 7.68 (d, J = 10.9Hz, 1H), 7.29 (s, 1H), 6.51 (s, 1H), 5.53 (dt,J=9.1,6.0Hz,1H),5.41(s,2H),5.12(d,J=19.1Hz,1H),4.92(d,J=18.9Hz,1H),3.99(s,2H) ,3.10(qt,J=16.7,6.1Hz,2H),2.29(d,J=1.8Hz,3H)...

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PUM

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Abstract

The invention discloses a camptothecin derivative and a ligand-drug conjugate of the camptothecin derivative. The invention discloses a better anti-tumor camptothecin ADC (Analog to Digital Converter) drug which has higher safety and effectiveness and can better meet clinical requirements.

Description

technical field [0001] The invention relates to a camptothecin derivative and its ligand-drug conjugate. Background technique [0002] Ligand-drug conjugate (ADC), as a new type of targeted drug, generally consists of three parts: antibody or antibody-like ligand, small molecule drug, and a linker that couples the ligand and drug. Antibody-drug conjugates use the specific recognition of antibodies to antigens to transport drug molecules to the vicinity of target cells and effectively release drug molecules to achieve therapeutic purposes. In August 2011, the US Food and Drug Administration (FDA) approved the new ADC drug Adecteis developed by Seattle Genetics for the treatment of Hodgkin's lymphoma and relapsed degenerative large cell lymphoma (ALCL) TM On the market, clinical application has proved the safety and effectiveness of such drugs. [0003] Camptothecin drugs, as anti-tumor small molecular compounds, are known to exhibit anti-tumor effects by inhibiting DNA topo...

Claims

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Application Information

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IPC IPC(8): C07D491/22C07K5/097C07K5/103C07K7/06A61K31/4375A61K38/06A61K38/07A61K38/08A61K47/64A61K47/68A61P35/00A61P35/02
CPCC07D491/22C07K7/06C07K5/1008C07K5/0821A61K47/64A61K47/6803A61P35/00A61P35/02C07B2200/07A61K38/00A61K47/68037A61K47/6855A61K47/6863A61K31/4375A61K47/68
Inventor 朱义万维李朱贵莉于天姿卓识杨秀娟
Owner SICHUAN BAILI PHARM CO LTD
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