Camptothecin derivative and conjugate thereof

A derivative, camptothecin technology, applied in the field of camptothecin derivatives and their antibody-drug conjugates, can solve the problem of reducing the therapeutic index of ADC drugs

Pending Publication Date: 2020-12-25
SICHUAN BAILI PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, Daiichi Sankyo’s ADC drug with exitecan as the toxin designed for other targets such as Trop2 in subsequent clinical trials had to be reduced to the antibody-to-drug ratio: DAR=4 due to safety issues
The reduction in the number of conjugated drugs will reduce the therapeutic index of ADC drugs

Method used

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  • Camptothecin derivative and conjugate thereof
  • Camptothecin derivative and conjugate thereof
  • Camptothecin derivative and conjugate thereof

Examples

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preparation example Construction

[0259] The preparation of conventional pharmaceutical compositions can be found in Chinese Pharmacopoeia.

[0260] The term "carrier" used in the drug of the present invention refers to a system that can change the way the drug enters the human body and distributes the drug in the body, controls the release rate of the drug, and delivers the drug to the target organ. The drug carrier release and targeting system can reduce drug degradation and loss, reduce side effects, and improve bioavailability. For example, polymer surfactants that can be used as carriers can self-assemble and form various forms of aggregates due to their unique amphiphilic structure. Preferred examples are micelles, microemulsions, gels, liquid crystals, vesicles, etc. . These aggregates have the ability to entrap drug molecules, and at the same time have good permeability to the membrane, which can be used as excellent drug carriers.

[0261] The term "excipient" is an add-on in a pharmaceutical prepar...

Embodiment 1

[0287]

[0288] Synthesis of Compound 2:

[0289] Add 8mL of DMF to Ixitecan mesylate 1 (150.0mg, 282.4umol, prepared by the method disclosed in the patent application "EP0737683A1"), cool to 0°C in an ice-water bath, add 5 drops of triethylamine dropwise, adjust When the pH reached 7-8, 2 drops of benzyl bromide were added dropwise in an ice-water bath, and the temperature was raised to room temperature (25°C) to react for 1 hour. TLC monitored that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The obtained crude product was subjected to preparative high-performance liquid chromatography. Purified by method (acetonitrile / pure water system), collected the target peak, removed acetonitrile under reduced pressure, and lyophilized to obtain about 110 mg of compound 2, a yellow solid, with a yield of about 74%, MS m / z: [M+H] + 526.3.

[0290] Synthesis of compound 3:

[0291] At room temperature, sequentially add compound 2 (110...

Embodiment 2

[0299]

[0300] Synthesis of compound 7:

[0301] Add 4mL DMF to Ixitecan mesylate 1 (100.0mg, 188.3umol, prepared by the method disclosed in the patent application "EP0737683A1"), cool to 0°C in an ice-water bath, add triethylamine (105uL, 4eq ), added iodoethane (34uL, 1.5eq) dropwise in an ice-water bath, heated up to room temperature (25°C) and reacted for 4 hours, the reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by preparative high-performance liquid chromatography (acetonitrile / pure water system), collect the target peak, remove acetonitrile under reduced pressure, freeze-dry to obtain about 11 mg of compound 7, a yellow solid, and the yield is about 13%, MS m / z: [M+H] + 464.2.

[0302] Synthesis of Compound 8:

[0303] At room temperature, add compound 7 (10mg, 22umol) to a 25mL bottle, add 2mL DMF to dissolve, add DIPEA (8uL, 2eq) and benzyloxyacetyl chloride (8mg, 2eq) to the resulting solution in turn, ...

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Abstract

The invention discloses a camptothecin derivative for an antitumor drug and an antibody-drug conjugate of the camptothecin derivative. According to the invention, through a series of molecular structure modification, a better camptothecin antitumor drug is obtained, so that the camptothecin antitumor drug is more suitable for being used as an antibody coupling drug.

Description

technical field [0001] The invention relates to camptothecin derivatives and antibody-medicine conjugates used as antitumor medicine. Specifically, the present invention involves obtaining better camptothecin anti-tumor drugs through a series of molecular structure modifications, so as to be more suitable as antibody-conjugated drugs. Background technique [0002] Antibody-drug conjugate (antibody drug conjugate, ADC), as a new type of targeted drug, generally consists of three parts: antibody or antibody-like ligand, small molecule drug base, 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. Compared with traditional chemotherapy drugs, antibody-drug conjugates can precisely bind tumor cells and reduce the impact on normal cells [Mullard A, (2013) Nature Reviews Drug ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22A61K31/4375A61P35/00A61K47/68
CPCC07D491/22A61P35/00A61K47/6803A61K47/6889C07K5/1008A61K47/6855
Inventor 朱义万维李卓识张伟张宜英胥涛
Owner SICHUAN BAILI PHARM CO LTD
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