Camptothecin drugs and antibody conjugates thereof

A technology for camptothecin and antibody drugs, which can be used in drug combinations, anti-tumor drugs, pharmaceutical formulations, etc., and can solve problems such as narrow treatment windows

Pending Publication Date: 2020-09-22
SICHUAN BAILI PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Exitecan has not been successfully marketed as a single chemotherapy drug, and it is speculated that it is related to its high cell activity, resulting in a narrow therapeutic window

Method used

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  • Camptothecin drugs and antibody conjugates thereof
  • Camptothecin drugs and antibody conjugates thereof
  • Camptothecin drugs and antibody conjugates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] The synthesis of embodiment 1 compound 2

[0059]

[0060] Dissolve compound 1 (exitecan mesylate, purchased) (40mg, 75.3mmol, 1.0eq) and L-lactic acid (10mg, 113.0 mmol, 1.5eq) in dry 5mL DMF, then add PyBop (58.8mg , 113.0 mmol, 1.5 eq) and DIEA (15.7 uL, 113.0 mmol, 1.5 eq). After stirring at room temperature for 3 hours, TLC detected that the reaction was complete, quenched with water, extracted with dichloromethane (10 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography. Compound 2 (30.9 mg, 81.1%) was obtained. LC-MS: [M+H]+: 508.2. 1H NMR (400Mz, CDCl3 / CD3OD): 0.91-0.94 (3H, m), 1.32-1.39 (3H, m), 1.71-1.83 (2H, m), 2.31(3H,s),2.78-3.02(2H,m),3.16-3.26(2H,m), 4.27-4.35(1H,m),4.81-4.92(1H,m),5.15-5.24(2H,m ), 5.49-5.76 (2H, m), 7.52 (1H, d, J = 12.0Hz), 7.58 (1H, s), 7.75 (1H, d, J = 12.0Hz).

Embodiment 2

[0061] The synthesis of embodiment 2 compound 4

[0062]

[0063] Add compound 3 to a 500mL single-necked bottle: N-fluorenylmethoxycarbonyl-glycyl-glycine (10g, 28.2mmol, 1.0eq), lead tetraacetate (17.5g, 55.3mmol, 1.4eq), 200mL dry tetrahydrofuran and 67mL Toluene, stirred evenly, under nitrogen protection, heated to 85°C for 2.5h. TLC monitoring, after the raw material reacted, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 4 (8.7 g, 83.7%)).

Embodiment 3

[0064] The synthesis of embodiment 3 compound 5

[0065]

[0066] Add compound 3 (500mg, 1.4mmol, 1.0eq), p-toluenesulfonic acid monohydrate (26mg, 0.1mmol, 0.1eq) and 10mL THF into a 25mL single-necked bottle, stir well, cool down to 0°C, and then slowly add L - Benzyl lactate (1.2g, 7.0mmol, 5eq), warmed up to room temperature after the addition was complete. TLC monitoring, after the reaction was completed, a saturated NaHCO3 solution was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by a reverse-phase column to obtain compound 5 (400 mg, 60.3%). 1H NMR (400 Mz, CDCl3): 1.39 (3H, d, J = 6.8Hz), 3.78 (2H, t, J = 4.0Hz), 4.17-4.27 (2H, m), 4.42 (2H, d, J = 4.0Hz), 4.72-4.85(2H,m), 5.11-5.58(2H,m), 5.43(1H,s), 7.06(1H,t,J=8.0Hz), 7.25-7.33(6H,m), 7.38 (2H, t, J = 8.0Hz), 7.57 (2H, d, J = 8.0Hz), 7.75 (2H, d, J = 8.0Hz).

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Abstract

The invention discloses camptothecin drugs and antibody conjugates thereof. The inventor designs a series of anti-tumor exatecan active derivatives on the basis of comprehensive understanding of ADC drugs, and experiments prove that newly designed anti-tumor molecular compounds show good anti-tumor activity in the experiments.

Description

technical field [0001] The invention relates to camptothecin drugs and their antibody drug conjugates used as antitumor drugs. Background technique [0002] As a new type of targeted drug, antibody-drug conjugate (ADC) 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22A61K31/4375A61P35/00A61K47/68
CPCA61K47/6835A61P35/00C07D491/22
Inventor 朱义万维李卓识秦文芳张勇
Owner SICHUAN BAILI PHARM CO LTD
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