CN113698357A - Sulfadiazine derivative and application thereof in antitumor drugs - Google Patents

Sulfadiazine derivative and application thereof in antitumor drugs Download PDF

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CN113698357A
CN113698357A CN202111150453.9A CN202111150453A CN113698357A CN 113698357 A CN113698357 A CN 113698357A CN 202111150453 A CN202111150453 A CN 202111150453A CN 113698357 A CN113698357 A CN 113698357A
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sulfadiazine
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antitumor drugs
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杨金飞
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Conservation Xiamen Medical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/69—Benzenesulfonamido-pyrimidines
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

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

Description

Sulfadiazine derivative and application thereof in antitumor drugs
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to sulfadiazine derivatives, a preparation method thereof, and application of the sulfadiazine derivatives serving as a PD1/PD-L1 inhibitor in antitumor drugs.
Background
Statistically, lung cancer is the leading cause of cancer death worldwide because of its low survival rate. Non-small cell lung cancer accounts for 85% of lung cancer, with lung adenocarcinoma being the most common histological type of NSCLC. Traditional treatment options for patients remain limited, and recently, immunotherapy has emerged and has been in progress due to its superior efficacy. PD1/PDL1 immune checkpoint inhibitors have been developed and applied to the treatment of non-small cell lung cancer. PD1 is expressed by activated T cells, B lymphocytes and natural killer cells, and PDL1 is a PD1 ligand. PDL1 is expressed by T lymphocytes, epithelial cells, endothelial cells, tumor cells and other cells in the local tumor environment. The PD1 and PDL1 interaction inhibits T cell activation and helps tumor cells escape immune surveillance.
Currently, PD1/PD-L1 immune checkpoint inhibitors that have been used to treat NSCLC include nivolumab, pembrolizumab, atezolizumab and duvalumab. One study showed that pembrolizumab as a first line therapy significantly improved the overall survival of locally advanced or metastatic non-small cell lung cancer compared to traditional chemotherapy, without sensitizing to changes in epidermal growth factor receptor or alkaline phosphatase when PDL1TPS was 1% or greater. Treatment of non-small cell lung cancer patients with no driver mutations and high expression of PDL1 with Pembrolizumab is currently recommended as a first-line treatment regimen.
In conclusion, the research on the novel PD1/PD-L1 inhibitor with stronger specificity has great significance for the clinical immunotherapy of tumor drug patients.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a sulfadiazine derivative; and a preparation method of the derivative and application of the derivative as a PD1/PD-L1 inhibitor in antitumor immunotherapy drugs.
In order to achieve the purpose, the invention adopts the technical scheme that: the invention provides a sulfadiazine derivative shown in a general formula (I), and a geometric isomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof;
Figure BDA0003286845780000021
the R is1Or R2Selected from hydrogen, halogen, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Cycloalkyl, alkenyl, alkynyl or aryl.
The R is3Selected from hydrogen, C1-C6Alkoxy radical, C1-C6Single or multiple substitutions in the alkyl group.
The sulfadiazine derivative shown in the general formula (I) is selected from:
Figure BDA0003286845780000022
the term "alkyl" as used herein means straight or branched chainBranched alkyl, 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 reductive amination of the corresponding starting 4-substituted benzaldehyde and substituted sulfadiazine to give the target compound. Scheme 1 is as follows.
Figure BDA0003286845780000031
The sulfadiazine 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 Bruker ARX-400, and the mass spectrum is measured by Agilent 1100 LC/MS; all reagents used were analytically or chemically pure.
Example 1.
Figure BDA0003286845780000032
4-phenyl benzaldehyde (0.50g,2.74mmol) and sulfamonomethoxine (0.77g,2.74mmol) are dissolved in 1, 2-dichloroethane, then sodium borohydride acetate (2.33g,10.98mmol) is added in portions, the reaction is continued for 24h at room temperature, and the reaction is completed by TLC detection. 40mL of water was added, 30mL of dichloromethane was added for extraction, and the organic layer was washed with saturated brine and Na2SO4Dry overnight. Filtering to remove desiccant, evaporating under reduced pressure to remove solvent, and purifying the residue by silica gel column chromatography to obtain 0.67g with yield of 54.68％。
1H-NMR(400MHz,DMSO-d6)δ11.36(s,1H),8.39(s,1H),7.74(d,J＝7.3Hz,2H),7.64(d,J＝8.8Hz,2H),7.49–7.45(m,4H),7.43-7.40(m,3H),7.31(s,1H),7.14(d,J＝8.4Hz,2H),6.30(s,1H),4.32(s,2H),3.80(s,3H).ESI-MS m/z:447.1[M+H]+.
Example 2.
Figure BDA0003286845780000041
1H-NMR(400MHz,DMSO-d6)δ11.34(s,1H),8.38(s,1H),7.62(d,J＝8.4Hz,2H),7.52–7.49(m,4H),7.41(d,J＝8.2Hz,2H),7.31(s,1H),7.14-7.11(d,J＝8.4Hz,4H),6.31(s,1H),4.31(s,2H),3.81(s,3H).ESI-MS m/z:465.1[M+H]+.
Example 3.
Figure BDA0003286845780000042
1H-NMR(400MHz,DMSO-d6)δ11.34(s,1H),8.39(s,1H),7.74-7.70(m,2H),7.64(d,J＝8.8Hz,2H),7.49-7.46(m,3H),7.41(d,J＝8.2Hz,2H),7.31-7.27(m,2H),7.12(d,J＝8.0Hz,2H),6.29(s,1H),4.30(s,2H),3.82(s,3H).ESI-MS m/z:465.1[M+H]+.
Example 4.
Figure BDA0003286845780000051
1H-NMR(400MHz,DMSO-d6)δ11.38(s,1H),8.39(s,1H),7.78(d,J＝7.8Hz,2H),7.64(d,J＝8.8Hz,2H),7.50–7.46(m,4H),7.41(t,J＝7.0Hz,1H),7.31(s,1H),7.24(t,J＝7.6Hz,1H),7.16-7.14(m,3H),6.31(s,1H),4.30(s,2H),3.82(s,3H).ESI-MS m/z:465.1[M+H]+.
Example 5.
Figure BDA0003286845780000052
1H-NMR(400MHz,DMSO-d6)δ11.35(s,1H),8.38(s,1H),7.62(d,J＝8.4Hz,2H),7.47(d,J＝7.8Hz,2H),7.40(d,J＝7.6Hz,2H),7.33-7.31(m,3H),7.17-7.14(m,4H),6.32(s,1H),4.33(s,2H),3.78(s,3H),2.35(s,3H).ESI-MS m/z:461.1[M+H]+.
Example 6.
Figure BDA0003286845780000053
1H-NMR(400MHz,DMSO-d6)δ11.34(s,1H),8.36(s,1H),7.70-7.65(m,3H),7.46(d,J＝7.4Hz,2H),7.42-7.39(m,3H),7.34-7.31(m,3H),7.15(d,J＝8.6Hz,2H),6.30(s,1H),4.30(s,2H),3.81(s,3H),2.24(s,3H).ESI-MS m/z:461.1[M+H]+.
Example 7.
Figure BDA0003286845780000061
1H-NMR(400MHz,DMSO-d6)δ11.35(s,1H),8.39(s,1H),8.06(d,J＝8.4Hz,2H),7.64–7.60(m,4H),7.48(d,J＝8.0Hz,2H),7.40(d,J＝7.8Hz,2H),7.31(s,1H),7.14(d,J＝8.2Hz,2H),6.31(s,1H),4.30(s,2H),3.78(s,3H).ESI-MS m/z:481.1[M+H]+.
Example 8.
Figure BDA0003286845780000062
1H-NMR(400MHz,DMSO-d6)δ11.36(s,1H),8.38(s,1H),7.92(s,1H),7.67-7.64(m,3H),7.56(d,J＝7.4Hz,2H),7.46(d,J＝8.2Hz,2H),7.41(d,J＝7.6Hz,2H),7.31(s,1H),7.12(d,J＝8.0Hz,2H),6.31(s,1H),4.31(s,2H),3.78(s,3H).ESI-MS m/z:516.1[M+H]+.
Example 9.
Figure BDA0003286845780000063
1H-NMR(400MHz,DMSO-d6)δ11.34(s,1H),8.40(s,1H),7.64(d,J＝8.6Hz,2H),7.54(d,J＝8.0Hz,2H),7.47(d,J＝7.8Hz,2H),7.42(d,J＝7.4Hz,2H),7.31(s,1H),7.12(d,J＝8.2Hz,2H),6.88(d,J＝8.0Hz,2H),6.30(s,1H),4.33(s,2H),3.81(s,6H).ESI-MS m/z:477.2[M+H]+.
Example 10.
Figure BDA0003286845780000071
1H-NMR(400MHz,DMSO-d6)δ11.16(s,1H),7.66(d,J＝8.6Hz,2H),7.53–7.48(m,4H),7.42(d,J＝8.0Hz,2H),7.32(s,1H),7.14-7.10(d,J＝8.4Hz,4H),6.36(s,1H),4.32(s,2H),2.44(s,3H),2.38(s,3H).ESI-MS m/z:463.1[M+H]+.
Example 11.
Figure BDA0003286845780000072
1H-NMR(400MHz,DMSO-d6)δ11.44(s,1H),7.68(d,J＝8.2Hz,2H),7.54(d,J＝7.8Hz,2H),7.48(d,J＝7.6Hz,2H),7.43(d,J＝7.6Hz,2H),7.35(s,1H),7.14(d,J＝8.0Hz,2H),6.92(d,J＝8.2Hz,2H),6.02(s,1H),4.33(s,2H),3.81(s,6H),3.76(s,3H).ESI-MS m/z:507.1[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, a PD-1/PD-L1 binding assay, was designed 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 tight 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. therefore, compounds that block the PD-1/PD-L1 interaction will result in a reduction in the HTRF signal.
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.
Table 1 Compounds were tested for inhibitory Activity (IC) against PD-1/PD-L150)。
Examples IC50(μM)
Example 1 6.8
Example 2 4.7
Example 3 0.28
Example 4 0.64
Example 5 12.5
Example 6 8.9
Example 7 1.6
Example 8 0.47
Example 9 24.6
Example 10 10.6
Example 11 31.5
The inhibition effect of the sulfadiazine derivative on PD-1/PD-L1 is determined by adopting an HTRF (homogeneous time-resolved fluorescence) technical standard operating program, and the result shows that the compound has an obvious inhibition effect on PD-1/PD-L1.

Claims (3)

1. The sulfadiazine derivative is characterized in that the structural formula of the derivative is as follows:
Figure FDA0003286845770000011
wherein, R is1Or R2Selected from hydrogen, halogen, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Cycloalkyl radicalsAn alkenyl, alkynyl or aryl group;
the R is3Selected from hydrogen, C1-C6Alkoxy radical, C1-C6Single or multiple substitutions in the alkyl group.
2. The sulfadiazine derivative of claim 1, wherein the sulfadiazine derivative is selected from the group consisting of:
Figure FDA0003286845770000012
3. sulfadiazine derivatives according to any one of claims 1-2 as inhibitors for clinical immunotherapy of patients with tumors.
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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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Application publication date: 20211126