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Nitrophenyl ether compounds, and preparation methods, pharmaceutical compositions and application thereof
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A technology of nitrophenyl ethers and compounds, which is applied in the field of nitrophenyl ether compounds, their preparation, pharmaceutical composition and application, and can solve problems such as difficulty in preparation and purification, side effects, and inability to be administered orally
Active Publication Date: 2020-05-22
CHINA PHARM UNIV +1
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Abstract
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[0007] However, PD-1 / PD-L1 monoclonalantibody drugs also have obvious shortcomings, such as easy to cause excessive activation of T cells, causing immune-related side effects, and cannot be administered orally, poor compliance, and difficult to prepare and purify, resulting in high price. Expensive etc.
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Embodiment 1
[0078] Synthesis of (3-nitro-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-L-serine (1)
[0079]
[0080] Synthesis of ethyl 2-methyl-3-bromobenzoate (1A)
[0081] Dissolve 2-methyl-3-bromobenzoic acid (10.0g, 46.5mmol) in ethanol (50mL), slowly drop into 20mL SOCl under ice-cooling 2 , After dropping, place it in an oil bath and heat at 70°C and stir for 2 hours. Cool, add 200 mL of water, extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrousmagnesiumsulfate, filter with suction, and concentrate under reduced pressure to obtain 1A, which is directly put into the next reaction.
[0083] 1A (4.0 g, 16.5 mmol), phenylboronic acid (3.0 g, 24.7 mmol) and potassium acetate (4.8 g, 49.4 mmol) were added to 30 mL of DMF and 8 mL of water, and Pd(dppf)Cl was added 2 (1.2g, 1.7mmol), reacted at 90°C for 12h under nitrogen protection, suction filt...
Embodiment 2
[0094] Synthesis of (3-nitro-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-L-threonine (2)
[0095]
[0096] Referring to the method of Example 1, the L-serine methyl ester hydrochloride in Example 1 was replaced with L-threonine methyl ester hydrochloride to obtain a white solid with a yield of 51%. MS(EI) m / z 449.1[M-H] - ; 1 H NMR (300MHz, DMSO) δ8.05 (d, J = 2.0Hz, 1H), 7.83-7.76 (m, 1H), 7.62-7.54 (m, 1H), 7.47 (dd, J = 14.8, 8.0Hz, 4H), 7.39(d, J=7.2Hz, 1H), 7.32-7.26(m, 3H), 7.20(d, J=7.8Hz, 1H), 5.35(d, J=7.9Hz, 2H), 4.00- 3.93(m,2H),3.16(d,J=5.6Hz,1H),2.20(s,3H),1.16(d,J=6.3Hz,2H).
Embodiment 3
[0098] Synthesis of (3-nitro-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-L-proline (3)
[0099]
[0100] Referring to the method of Example 1, the L-serine methyl ester hydrochloride in Example 1 was replaced with L-provinyl methyl ester hydrochloride to obtain a white solid with a yield of 50%. MS(EI) m / z 445.1[M-H] - ; 1 H NMR (300MHz, DMSO) δ8.06(s, 1H), 7.82(d, J=7.2Hz, 1H), 7.62(d, J=8.9Hz, 1H), 7.48(dd, J=16.4, 7.8Hz ,3H),7.38(t,J=7.2Hz,1H),7.30(dd,J=6.8,4.6Hz,3H),7.22(d,J=6.8Hz,1H),5.37(s,2H),4.31 (d,J=13.3Hz,1H),4.10(d,J=12.7Hz,1H),3.87(s,1H),3.27(s,2H),2.93(d,J=8.6Hz,1H),2.21 (s,3H),1.93(s,2H),1.82(s,1H).
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Abstract
The invention discloses nitrophenyl ether compounds, and preparation methods, pharmaceutical compositions and application thereof, belonging to the field of medicines. The invention particularly relates to the nitrophenyl ether compounds with structural characteristics of a general formula (I) which is described in the specification, stereoisomers, metabolites, metabolic precursors, prodrugs, solvates, crystals or pharmaceutically acceptable salts of the nitrophenyl ether compounds, the preparation methods of the nitrophenyl ether compounds, and application of the nitrophenyl ether compounds and the stereoisomers, the metabolites, the metabolic precursors, the prodrugs, the solvates, the crystals and the pharmaceutically acceptable salts thereof as PD-1 / PD-L1 inhibitors. Pharmacological experiment results show that the compounds disclosed by the invention have remarkable inhibition activity on PD-1 / PD-L1 protein-protein interaction and can effectively inhibit PD-1 / PD-L1 mediated tumorimmune escape, so the compounds can be used for preparing inhibitors with the activity of inhibiting PD-1 / PD-L1 and can be used as immune checkpoint inhibitors for immunotherapy of tumors.
Description
technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to a class of nitrophenyl ether compounds or their stereoisomers, pharmaceutically acceptable salts, crystals, and solvents as PD-1 / PD-L1 protein-protein interaction inhibitors Compounds or prodrugs, their preparation methods, pharmaceutical compositions containing these compounds, and uses of these compounds or compositions in the treatment of diseases related to PD-1 / PD-L1-mediated immunosuppression, such as cancer. Background technique [0002] Immune escape is a fundamental feature of malignant tumors. Under normal physiological conditions, the body's immune system can recognize foreign molecules and clear them in time. But for cancer patients, due to the low immunity of the body and the special biological characteristics of tumor cells, tumor cells can escape the recognition and killing of the immune system through various mechanisms, and finally survive and develop in th...
Claims
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