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Antibody-drug-conjugate, and intermediate, preparation method and application thereof

An antibody-conjugated drug and antibody technology, applied in the field of biotechnology and medicine, can solve the problem of single type of antibody-conjugated drug

Pending Publication Date: 2020-12-29
TAIZHOU FUDAN-ZHANGJIANG PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is to overcome the single defect of existing antibody-conjugated drugs, and provide an antibody-conjugated drug, its intermediate, preparation method and application

Method used

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  • Antibody-drug-conjugate, and intermediate, preparation method and application thereof
  • Antibody-drug-conjugate, and intermediate, preparation method and application thereof
  • Antibody-drug-conjugate, and intermediate, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0103] Preparation Example 1 Preparation of DS-8201a linker-drug conjugate GGFG-Dxd

[0104] The compound GGFG-Dxd (structure as follows) was synthesized according to the known method reported in WO2015146132A1, ESI-MS m / z: 1034.5 (M+H), 1 H-NMR (400MHz, DMSO-d 6 )δ8.61(t, J=6.4Hz, 1H), 8.50(d, J=8.5Hz, 1H), 8.28(t, J=5.1Hz, 1H), 8.11(d, J=7.5Hz, 1H) ,8.05(t,J=5.7Hz,1H),7.99(t,J=5.9Hz,1H),7.77(d,J=11.0Hz,1H),7.31(s,1H),7.25–7.16(m, 5H), 6.98(s, 2H), 6.51(s, 1H), 5.59(dt, J=7.4, 4.1Hz, 1H), 5.41(s, 2H), 5.20(s, 2H), 4.64(d, J =6.1Hz,2H),4.53–4.40(m,1H),4.02(s,2H),3.74–3.37(m,8H),3.18–3.00(m,2H),3.04–2.97(m,1H), 2.77(dd,J=13.5,9.4Hz,1H),2.38(s,3H),2.19(dd,J=14.9,8.5Hz,2H),2.11–2.05(m,2H),1.86(dd,J= 14.0,6.7Hz,2H),1.45(s,4H),1.20–1.14(m,2H),0.87(t,J=7.1Hz,3H).

[0105]

Embodiment 1

[0106] The synthesis of embodiment 1 compound DX01

[0107]

[0108] Synthesis of step 1 compound IIIC:

[0109] Commercially available compound IIIA (5.58g, 10mmol) and commercially available IIIB (3.16g, 10mmol) were mixed in 100mL of anhydrous N, N-dimethylformamide, HATU (1.14g, 3.0mmol) was added, three Ethylamine 10mL, react at room temperature for 2h. After the reaction was complete, the solvent was distilled off under reduced pressure, and the crude product was purified by silica gel column chromatography [chloroform:methanol=10:1 (v / v)] to obtain the title compound IIIC (7.71g, yield 90%), ESI-MS m / z : 857.1 (M+H).

[0110] Synthesis of step 2 compound IIID:

[0111] Compound IIIC (7.71 g, 9 mmol) was dissolved in dichloromethane, 9 mL of trifluoroacetic acid was added, and reacted at room temperature for 0.5 h. After the reaction was completed, the solvent was distilled off under reduced pressure, and the crude product was purified by silica gel column chromat...

Embodiment 2

[0121] Synthesis of DX02, DX03, DX04

[0122]

[0123] Referring to Example 1, in step 1, compound IIIA was reacted with different commercially available amino fragments, and the subsequent steps were the same as in Example 1 to finally obtain compounds DX02-DX04.

[0124] Compound DX02: light yellow powder, ESI-MS m / z: 1164.3 (M+H); Compound DX03: light yellow powder, ESI-MS m / z: 1199.5 (M+H); Compound DX04: light yellow powder, ESI - MS m / z: 1169.2 (M+H).

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PUM

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Abstract

The invention discloses an antibody-drug conjugate, and an intermediate, a preparation method and an application thereof. The invention discloses an antibody-coupled-drug, the general structural formula of which is Ab -(L3-L2-L1-D) m. The antibody-coupled-drug can realize wide application of cytotoxic drugs, especially application of camptothecin in the ADC field, to treat tumor patients resistantto microtubule ADC.

Description

technical field [0001] The invention belongs to the fields of biotechnology and medicine, and in particular relates to an antibody-coupled drug, its intermediate, preparation method and application. Background technique [0002] Antibody-drug conjugate (ADC) is one of the hot spots in the pharmaceutical industry in recent years. Due to the unsatisfactory clinical efficacy of many antibody drugs, many industry giants are increasingly turning their attention to ADC drugs. At present, four ADC drugs have been approved for marketing in foreign countries. On May 17, 2000, the FDA approved Pfizer's Gemtuzumab Ozogamicin (trade name Mylotarg) for the treatment of acute myeloid leukemia (AML) patients with first relapse, over 60 years old, CD33+, not suitable for cytotoxic chemotherapy, although the drug It was withdrawn from the market in 2010, but it was re-listed in 2017. In the same year, Pfizer's Inotuzumab ozogamicin (trade name Besponsa) was also approved by the FDA for the...

Claims

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Application Information

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IPC IPC(8): A61K47/68A61K47/65A61P35/00
CPCA61K47/6873A61P35/00A61K47/65A61K47/6803
Inventor 鲍彬郭青松高贝张一帆邱雪飞杨彤沈毅珺张文伯
Owner TAIZHOU FUDAN-ZHANGJIANG PHARM CO LTD