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EP4 receptor antagonist and PD-1 inhibitor combined and used for treating cancer

A receptor antagonist, PD-1 technology, applied in the field of biomedicine, can solve the problems of low objective response rate and high death toll

Inactive Publication Date: 2019-10-29
SHANGHAI YUYAO BIOTECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the current immune checkpoint inhibitors have many shortcomings in the treatment of cancer, especially malignant tumors, such as low objective response rate for advanced solid tumors (generally, objective response rate <30%); induce a variety of lethal side effects , including colitis, neurotoxicity, pneumonia, hepatitis, hypophysitis, nephritis, adrenalitis, and heart disease, these factors cause the largest number of deaths and are the most fatal side effects

Method used

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  • EP4 receptor antagonist and PD-1 inhibitor combined and used for treating cancer
  • EP4 receptor antagonist and PD-1 inhibitor combined and used for treating cancer
  • EP4 receptor antagonist and PD-1 inhibitor combined and used for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0252] Example 1-1, (S)-4-(1-(2-(3,5-difluorobenzyl)-4,7-dihydro-5H-thieno[2,3-c]pyran- Preparation of 3-formamido)ethyl)benzoic acid (YJ132)

[0253]

[0254] Tetrahydro-4H-pyran-4-one (2.00g, 20.0mmol), ethyl cyanoacetate (2.50g, 22.0mmol) and sulfur (704mg, 22.0mmol) were dissolved in 30.0mL ethanol, and then added to the solution Morpholine (1.74 g, 20.0 mmol) was added to it, and stirred overnight at 50°C. Use TLC to detect the reaction. After the reaction is completed, the reaction solution is extracted with ethyl acetate and water, the upper organic phase is evaporated to dryness, and purified by column chromatography to obtain a light yellow solid, namely 2-amino-5,7-dihydro-4H - Thieno[2,3-c]pyran-3-carboxylic acid ethyl ester (4.29 g, 94% yield). Dissolve ethyl 2-amino-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (900 mg, 4.0 mmol) in 1.5M HCl (20.0 mL) at room temperature Stir for 20 min, then lower the temperature to 0 °C under ice bath conditions, add NaN...

Embodiment 1-2

[0255] Example 1-2, (S)-4-(1-(2-(3-methoxybenzyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3 -Formamido) ethyl) the preparation of benzoic acid (YJ133)

[0256]

[0257] Using the same reaction route as the preparation of compound YJ132, replacing 3,5-difluorobenzaldehyde with 3-methoxybenzaldehyde, compound YJ133 was finally obtained (the yield of the last step reaction was 90%). 1 H NMR (500MHz, DMSO-d 6 )δ12.84(s,1H),8.75(d,J=8.0Hz,1H),7.94–7.85(m,2H),7.51–7.43(m,2H),7.20–7.11(m,1H),6.80 –6.67(m,3H),5.17(p,J=7.1Hz,1H),4.63(s,2H),3.86–3.78(m,2H),3.69(s,3H),2.62(s,2H), 1.43(d,J=7.1Hz,3H).

Embodiment 1-3

[0258] Example 1-3, 3-((2-(3-(trifluoromethyl)benzyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide Base) the preparation of methyl) benzoic acid (YJ134)

[0259]

[0260] Using the same reaction scheme as for the preparation of compound YJ132, substituting 3,5-difluorobenzaldehyde for 3-trifluoromethylbenzaldehyde and methyl (S)-4-(1-aminoethyl)benzoate for 3-(Aminomethyl)benzoic acid methyl ester, compound YJ134 was finally obtained (the yield of the last step reaction was 92%). 1 H NMR (500MHz, DMSO-d 6 )δ12.94(s,1H),8.85(d,J=8.0Hz,1H),7.90(s,1H),7.61(s,1H),7.69–7.32(m,6H),4.73(s,2H ),4.51–4.41(m,2H),4.31(s,2H),3.81–3.70(m,2H),2.62(s,2H).

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Abstract

The invention provides an EP4 receptor antagonist and a PD-1 inhibitor combined and used for treating cancer. The invention provides the product combination, including a first medicine composition (i)and a second medicine composition (ii), the first medicine composition contains a first active ingredient (a) which is the EP4 receptor antagonist and an acceptable vector on pharmacy, the second medicine composition contains a second active ingredient (b) which is the PD-1 inhibitor, and an acceptable vector on the pharmacy; and the medicine compositions of the first medicine composition and thesecond medicine composition are different, or the same. According to the product combination, malignant tumor can be treated synergistically.

Description

technical field [0001] The present invention relates to the field of biomedicine, in particular to the combination of EP4 receptor antagonist and PD-1 inhibitor for the treatment of cancer. Background technique [0002] Cancer has become one of the most terrifying killers threatening human life and health. According to the 2018 "Global Cancer Report" released by the International Agency for Research on Cancer (IARC), there will be 18.1 million new cancer cases worldwide in 2018, and about 9.6 million people will die of cancer. cancer, and its morbidity and mortality are increasing year by year. According to the report, my country ranks first in the world in terms of cancer incidence and mortality. Among them, the number of new cases in my country accounted for 3.804 million cases and the number of deaths accounted for 2.296 million cases. [0003] Following surgical treatment, radiotherapy and chemotherapy drug treatment, the development of tumor immunotherapy represented b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04C07D333/78C07D333/68C07D333/80A61K31/381A61K31/4436A61K31/4365A61K45/06A61P35/00
CPCC07D495/04C07D333/78C07D333/68C07D333/80A61K45/06A61P35/00
Inventor 章涵堃卢伟强刘明耀杨俊杰于薇薇彭世鸿
Owner SHANGHAI YUYAO BIOTECH LTD
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