CN113861130A - Biphenyl sulfanilamide thiadiazole derivative and application thereof in antitumor drugs - Google Patents

Biphenyl sulfanilamide thiadiazole derivative and application thereof in antitumor drugs Download PDF

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CN113861130A
CN113861130A CN202111151928.6A CN202111151928A CN113861130A CN 113861130 A CN113861130 A CN 113861130A CN 202111151928 A CN202111151928 A CN 202111151928A CN 113861130 A CN113861130 A CN 113861130A
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biphenyl
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sulphathiadiazoles
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杨金飞
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Conservation Xiamen Medical Technology Co ltd
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    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a biphenyl sulphathiadiazoles derivative, a preparation method thereof, and application of the biphenyl sulphathiadiazoles derivative as a PD1/PDL1 inhibitor in antitumor drugs. The invention provides a novel biphenyl sulphathiadiazoles derivative shown in a general formula (I), and a geometric isomer or pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. Experiments show that the biphenyl sulfonamide thiadiazole derivatives synthesized by the subject group have the prospect of developing antitumor drugs.

Description

Biphenyl sulfanilamide thiadiazole derivative and application thereof in antitumor drugs
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a biphenyl sulphathiadiazoles derivative, a preparation method thereof, and application of the biphenyl sulphathiadiazoles derivative as a PD1/PD-L1 inhibitor in antitumor drugs.
Background
Although we hope that the immune system will automatically treat cancer cells as "foreign", due to the unique and widely variable nature of tumor cells, a balance between the immune system and the tumor is often reached-tumor tolerance, and immune checkpoint dysregulation becomes one of the major causes of tumor tolerance. Immune checkpoints are a class of immunosuppressive molecules that can modulate the intensity and strength of immunity. The signaling pathway regulated by programmed cell death protein 1(PD-1) and its cognate ligand Programmed Death Ligand (PDLS) is of great interest in the development of anti-cancer drugs. Over-expression of the PD1 ligand in tumor cells suppresses the body's immune system, preventing the immune system from killing tumor cells. One of the basic ideas of tumor antibody therapy is to block PD1/PD-L1 protein-protein interaction (PPI), thereby activating the anti-tumor immune response of T cells and eliminating tumor cells. One of the basic ideas of tumor antibody therapy is to block PD1-PDL protein-protein interaction (PPI), thereby activating T cell anti-tumor immune response and eliminating tumor cells. One of the basic ideas of tumor antibody therapy is to block PD1/PD-L1 protein-protein interaction (PPI), thereby activating the anti-tumor immune response of T cells and eliminating tumor cells. Research shows that the application of monoclonal antibodies to the treatment of the advanced melanoma, the cell lung cancer (NSCLC) and the Renal Cell Carcinoma (RCC) causes lasting objective reaction, and compared with the traditional treatment, the survival time of the patient is obviously prolonged.
In conclusion, the research on novel PD1/PD-L1 inhibitor with stronger specificity is important for the clinical immunotherapy of tumor drug patients.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a biphenyl sulphathiadiazoles derivative; and a preparation method of the derivative and application of the derivative as a PD1/PD-L1 inhibitor in antitumor drugs.
In order to achieve the purpose, the invention adopts the technical scheme that: the invention provides a biphenyl sulphathiadiazoles derivative shown in a general formula (I), and a geometric isomer thereof or pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof;
Figure BDA0003287466720000021
the R is1、R2Or R3Selected from hydrogen, halogen, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Cycloalkyl, alkenyl, alkynyl or aryl.
Preferably, said R is1Or R2Selected from hydrogen, halogen, C1-C6Alkoxy or C1-C6An alkyl group.
Preferably, said R is3Is selected from C1-C6An alkyl group.
The biphenyl sulphathiadiazoles derivative shown in the general formula (I) is selected from the following components:
Figure BDA0003287466720000022
the term "alkyl" as used herein refers to a straight or branched chain alkyl group wherein C1-C6By a group is meant a moiety having 1 to 6 carbon atoms, i.e. the group contains 1,2, 3, 4, 5 or 6 carbon atoms.
The "alkoxy group" as referred to herein means an alkyl ether group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.
The compounds of formula I according to the present invention can be synthesized according to the method of scheme 1 by subjecting 4-substituted benzaldehyde, which is a corresponding starting material, and methyl-or ethyl-substituted sulfathiadiazole to a reductive amination reaction to obtain the target compound. Scheme 1 is as follows.
Figure BDA0003287466720000031
The biphenyl sulphathiadiazoles derivative can be used as a PD1/PD-L1 inhibitor and a clinical immunotherapy medicament for tumor patients.
Detailed Description
The following examples are intended to illustrate but not limit the scope of the invention. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by BrukeraRx-400, and the mass spectrum is measured by Agilent 1100 LC/MS; all reagents used were analytically or chemically pure.
Example 1.
Figure BDA0003287466720000032
4-Benzylbenzaldehyde (0.50g,2.74mmol) and sulfamethylthiadiazole (0.74g,2.74mmol) were dissolved in 1, 2-dichloroethane, and then sodium borohydride acetate (1.74g,8.23mmol) was added in portions, followed by reaction at room temperature for 2 daysAnd 8h, TLC detection shows that the reaction is finished. 40mL of water was added, 30mL of dichloromethane was added for extraction, and the organic layer was washed with saturated brine and Na2SO4Dry overnight. The drying agent was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.59g, yield 49.26%.
1H-NMR(400MHz,DMSO-d6)δ13.65(s,1H),7.74(d,J＝7.3Hz,2H),7.69(d,J＝8.5Hz,2H),7.50–7.46(m,4H),7.43-7.40(m,3H),7.31(s,1H),7.14(d,J＝8.5Hz,2H),4.32(s,2H),2.47(s,3H).ESI-MS m/z:437.1[M+H]+.
Example 2.
Figure BDA0003287466720000041
1H-NMR(400MHz,DMSO-d6)δ13.66(s,1H),7.69(d,J＝8.5Hz,2H),7.47(d,J＝7.8Hz,2H),7.40(d,J＝7.6Hz,2H),7.33–7.30(m,3H),7.16-7.14(m,4H),4.30(s,2H),2.48(s,3H),2.35(s,3H).ESI-MS m/z:451.1[M+H]+.
Example 3.
Figure BDA0003287466720000042
1H-NMR(400MHz,DMSO-d6)δ13.64(s,1H),7.71-7.69(m,3H),7.47(d,J＝7.8Hz,2H),7.43-7.40(m,3H),7.34-7.31(m,3H),7.12(d,J＝8.8Hz,2H),4.34(s,2H),2.48(s,3H),2.34(s,3H).ESI-MS m/z:451.1[M+H]+.
Example 4.
Figure BDA0003287466720000051
1H-NMR(400MHz,DMSO-d6)δ13.68(s,1H),7.66(d,J＝8.0Hz,2H),7.52–7.49(m,4H),7.42(d,J＝8.5Hz,2H),7.31(s,1H),7.14–7.11(m,4H),4.31(s,2H),2.46(s,3H).ESI-MS m/z:455.2[M+H]+.
Example 5.
Figure BDA0003287466720000052
1H-NMR(400MHz,DMSO-d6)δ13.61(s,1H),7.75-7.71(m,2H),7.69(d,J＝8.5Hz,2H),7.49-7.46(m,3H),7.40(d,J＝8.5Hz,2H),7.32-7.28(m,2H),7.11(d,J＝8.0Hz,2H),4.30(s,2H),2.47(s,3H).ESI-MS m/z:455.2[M+H]+.
Example 6.
Figure BDA0003287466720000053
1H-NMR(400MHz,DMSO-d6)δ13.60(s,1H),7.79(d,J＝7.5Hz,1H),7.69(d,J＝8.5Hz,2H),7.50–7.45(m,4H),7.40(t,J＝7.4Hz,1H),7.32(s,1H),7.25(t,J＝7.8Hz,1H),7.18-7.14(m,3H),4.32(s,2H),2.47(s,3H).ESI-MS m/z:455.1[M+H]+.
Example 7.
Figure BDA0003287466720000061
1H-NMR(400MHz,DMSO-d6)δ13.64(s,1H),8.10(d,J＝8.5Hz,2H),7.66–7.61(m,4H),7.46(d,J＝8.0Hz,2H),7.40(d,J＝7.8Hz,2H),7.32(s,1H),7.12(d,J＝8.2Hz,2H),4.32(s,2H),2.48(s,3H).ESI-MS m/z:471.1[M+H]+.
Example 8.
Figure BDA0003287466720000062
1H-NMR(400MHz,DMSO-d6)δ13.64(s,1H),7.76-7.71(m,2H),7.70(d,J＝8.2Hz,2H),7.49-7.44(m,3H),7.40(d,J＝8.5Hz,2H),7.33-7.28(m,2H),7.12(d,J＝8.4Hz,2H),4.31(s,2H),2.82(q,J＝7.1Hz,2H),1.22(t,J＝7.2Hz,3H).ESI-MS m/z:469.1[M+H]+.
Example 9.
Figure BDA0003287466720000063
1H-NMR(400MHz,DMSO-d6)δ13.66(s,1H),7.64(d,J＝8.0Hz,2H),7.53–7.49(m,4H),7.42(d,J＝8.4Hz,2H),7.30(s,1H),7.15–7.10(m,4H),4.30(s,2H),2.81(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H).ESI-MS m/z:469.1[M+H]+.
Example 10.
Figure BDA0003287466720000071
1H-NMR(400MHz,DMSO-d6)δ13.64(s,1H),7.64(d,J＝8.0Hz,2H),7.53–7.46(m,4H),7.40(d,J＝8.5Hz,2H),7.30(s,1H),7.12(d,J＝8.5Hz,2H),6.98(d,J＝8.4Hz,2H),4.30(s,2H),3.81(s,3H),2.82(q,J＝7.0Hz,2H),1.22(t,J＝7.2Hz,3H).ESI-MS m/z:481.1[M+H]+.
Example 11.
Figure BDA0003287466720000072
1H-NMR(400MHz,DMSO-d6)δ13.64(s,1H),7.78(d,J＝7.4Hz,1H),7.68(d,J＝8.2Hz,2H),7.51–7.46(m,4H),7.41(t,J＝8.4Hz,1H),7.34(s,1H),7.23(t,J＝7.4Hz,1H),7.18-7.14(m,3H),4.31(s,2H),2.80(q,J＝7.2Hz,2H),1.20(t,J＝7.4Hz,3H).ESI-MS m/z:469.1[M+H]+.
First, HTRF homogeneous time-resolved fluorescence technique.
The test principle is as follows: the HTRF PD-1/PD-L1 binding assay kit developed by Cisbio, Inc., the PD-1/PD-L1 binding assay was intended to measure the interaction between PD-1 and PD-L1 proteins. The interaction between Tag1-PD-L1 and Tag2-PD-1 was examined by using anti-Tag1-Europium (HTRF donor) and anti-Tag2-XL665 (HTRF acceptor). When the donor and acceptor antibodies are brought into proximity due to the close binding of PD-L1 and PD-1, excitation of the donor antibody induces a fluorescence resonance energy transfer ((FRET) towards the acceptor antibody, which in turn emits specifically at 665 nm. this specific signal is proportional to the extent of the PD-1/PD-L1 interaction.
The test method comprises the following steps: the compounds of the invention were tested for their inhibitory effect on PD-1/PD-L1, in accordance with the instructions. Dosing, control and negative control groups were preplaced in 384-well plates, with triplicate wells per group. Sequentially adding 4 mu L of LTag1-PD-L1 working solution and 4 mu L of Tag1-PD-1 working solution into each hole, and uniformly blowing and beating; then 2. mu.L of compound diluent is added into each well, mixed evenly and incubated for 15min at room temperature, Anti-Tag1-Europium and Anti-Tag2-XL665 are added into each well in sequence, the membrane is sealed and incubated for 2 h in dark, a Tecan microplate reader is used to read fluorescence values (Ex:320 nM; Em:620 and 665nM), and then the inhibition rate and the fitting IC are calculated50See table 1.
The compounds of Table 1 were tested for their inhibitory activity against PD-1/PD-L1 (IC 50).
Examples IC50(μM)
Example 1 5.6
Example 2 14.6
Example 3 24.9
Example 4 1.9
Example 5 0.26
Example 6 0.37
Example 7 2.7
Example 8 0.46
Example 9 0.68
Example 10 0.84
Example 11 0.95
The inhibition effect of the biphenyl sulphathiadiazoles derivative on PD-1/PD-L1 is determined by adopting HTRF (homogeneous phase time-resolved fluorescence) technical standard operation procedures, and the result shows that the compound has an obvious inhibition effect on PD-1/PD-L1.

Claims (5)

1. The biphenyl sulphathiadiazoles derivative is characterized in that the structural formula of the derivative is as follows:
Figure FDA0003287466710000011
wherein, R is1、R2Or R3Selected from hydrogen, halogen, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Cycloalkyl, alkenyl, alkynyl or aryl.
2. The biphenyl sulfonamide thiadiazole derivative according to claim 1, wherein R is represented by1Or R2Selected from hydrogen, halogen, C1-C6Alkoxy or C1-C6An alkyl group.
3. The biphenyl sulfonamide thiadiazole derivative according to claim 1, wherein R is represented by3Is selected from C1-C6An alkyl group.
4. The biphenyl sulphathiadiazoles derivative according to claim 1, wherein said derivative is selected from the group consisting of:
Figure FDA0003287466710000012
5. the biphenyl sulfanilamide thiadiazole derivative according to any one of claims 1 to 4 as a PD1/PDL1 inhibitor as a clinical immunotherapy drug for tumor patients.
CN202111151928.6A 2021-09-29 2021-09-29 Biphenyl sulfanilamide thiadiazole derivative and application thereof in antitumor drugs Withdrawn CN113861130A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009129267A2 (en) * 2008-04-14 2009-10-22 The Board Of Regents Of The University Of Texas System Small molecule inhibitors of the pleckstrin homology domain and methods for using same
CN103664878A (en) * 2012-09-12 2014-03-26 山东亨利医药科技有限责任公司 Hetero-aromatic ring and derivative type tyrosine kinase inhibitor thereof
WO2015054662A1 (en) * 2013-10-10 2015-04-16 Eastern Virginia Medical School 4-((2-hydroxy-3-methoxybenzyl)amino) benzenesulfonamide derivatives as 12-lipoxygenase inhibitors
WO2016210296A1 (en) * 2015-06-26 2016-12-29 Dana-Farber Cancer Institute, Inc. 4,6-pyrimidinylene derivatives and uses thereof
CN110325531A (en) * 2016-12-09 2019-10-11 泽农医药公司 Benzsulfamide and its purposes as therapeutic agent

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009129267A2 (en) * 2008-04-14 2009-10-22 The Board Of Regents Of The University Of Texas System Small molecule inhibitors of the pleckstrin homology domain and methods for using same
CN103664878A (en) * 2012-09-12 2014-03-26 山东亨利医药科技有限责任公司 Hetero-aromatic ring and derivative type tyrosine kinase inhibitor thereof
WO2015054662A1 (en) * 2013-10-10 2015-04-16 Eastern Virginia Medical School 4-((2-hydroxy-3-methoxybenzyl)amino) benzenesulfonamide derivatives as 12-lipoxygenase inhibitors
WO2016210296A1 (en) * 2015-06-26 2016-12-29 Dana-Farber Cancer Institute, Inc. 4,6-pyrimidinylene derivatives and uses thereof
CN110325531A (en) * 2016-12-09 2019-10-11 泽农医药公司 Benzsulfamide and its purposes as therapeutic agent

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