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Difunctional molecular compound for inducing degradation of PD-L1 protein as well as preparation and application of difunctional molecular compound

A PD-L1, bifunctional molecule technology, applied in the field of bifunctional molecular compounds, can solve the problems of unsatisfactory efficacy of PD-L1 small molecule inhibitors, and achieve the effect of low onset dose of drugs

Pending Publication Date: 2022-06-03
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Most of the drugs currently used for tumor immunotherapy are monoclonal antibody drugs, mainly because the efficacy of PD-L1 small molecule inhibitors is not ideal

Method used

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  • Difunctional molecular compound for inducing degradation of PD-L1 protein as well as preparation and application of difunctional molecular compound
  • Difunctional molecular compound for inducing degradation of PD-L1 protein as well as preparation and application of difunctional molecular compound
  • Difunctional molecular compound for inducing degradation of PD-L1 protein as well as preparation and application of difunctional molecular compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0136] Example 1 Synthesis of intermediate compound Th-L2 (m=2)

[0137] In this embodiment, L is m is 2;

[0138] B is CRBN, then the synthetic route is:

[0139]

[0140] 58 mg of compound Th (thalidomide derivative, available for purchase) was placed in an eggplant-shaped flask, 3 mL of DMF was added, 50 mg of azido-2PEG-amine and 47 μL of DIPEA were added in sequence under stirring, and the reaction was carried out at 90 °C for 3-4 hours. Extracted with 30 mL of water and 30 mL of ethyl acetate, the organic layer was dried with anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by silica gel column chromatography, eluting with a gradient of petroleum ether-ethyl acetate 1:2 to 1:4 to obtain a yellow oil The compound was 33.2 mg, and the yield was 41%.

[0141] Th-L2, 1 H NMR (400MHz, CDCl 3 )δ9.06(br s,1H),7.49(t,J=7.8Hz,1H),7.09(dd,J=

[0142] 7.2, 2.0Hz, 1H), 6.93 (d, J=8.4Hz, 1H), 6.50 (t, J=5.6Hz, 1H), 4.96–4.92 (m, 1H)...

Embodiment 2

[0143] Example 2 Synthesis of Intermediate Compound M-L1 (m=1)

[0144] In this embodiment, B is MDM2;

[0145] In this embodiment, L is m is 1;

[0146]

[0147]320 mg of compound M was placed in an eggplant-shaped flask, 3 mL of DCM was added, 65 mg of azido-1PEG-amine, 132 μL of DIPEA, 74 mg of EDCI, and 92 mg of HOBt were successively added under ice bath, and the reaction was performed for 3-4 hours, and 30 mL of water and 30 mL of DCM were added for extraction. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 237.5 mg of a white solid, yield: 63.2%.

[0148] M-L1, 1 H NMR (600MHz, DMSO-d 6 )δ7.96(t,J=5.7Hz,1H),7.56–7.51(m,1H),7.17–

[0149] 7.14(m, 2H), 7.12(d, J=8.3Hz, 2H), 7.07–7.02(m, 2H), 6.98(d, J=8.0Hz, 2H), 6.62(d, J=7.3Hz, 2H) ), 5.66(d, J=9.7Hz, 1H), 5.58(d, J=9.7Hz, 1H), 4.72(hept, J=6.0Hz, 1H), 3.83(s, 4H), 3.76–3.67(m ,2H),3.65–3.55...

Embodiment 3

[0150] The synthesis of embodiment 3 intermediate compound V-2L

[0151] In the present embodiment, B is VHL;

[0152] In this embodiment, L is m is 1;

[0153]

[0154] 215 mg of compound V was placed in an eggplant-shaped flask, 3 mL of DCM was added, 57.5 mg of 3-azidopropionic acid, 132 μL of DIPEA, 74 mg of EDCI, 92 mg of HOBt were sequentially added under ice bath, and the reaction was carried out for 3-4 hours, and 30 mL of water and 30 mL of DCM were added for extraction. , the organic layer was dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 279 mg of a white solid, yield: 53%.

[0155] V-2L, 1 H NMR (600MHz, DMSO-d 6 )δ8.98(s, 1H), 8.57(t, J=6.0Hz, 1H), 8.12(d, J=9.4

[0156] Hz, 1H), 7.47–7.36 (m, 4H), 5.13 (d, J=3.6Hz, 1H), 4.58 (d, J=9.4Hz, 1H), 4.47–4.40 (m, 2H), 4.39–4.33 (m, 1H), 4.21 (dd, J=15.8, 5.5Hz, 1H), 3.69 (dd, J=10.5, 4.2Hz, 1H), 3.62 (dt, J=10.8...

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Abstract

The invention discloses a bifunctional molecular compound for inducing degradation of PD-L1 protein as well as preparation and application of the bifunctional molecular compound, and belongs to the technical field of chemical biology. Relates to a difunctional molecule compound for inducing degradation of PD-L1 protein as shown in a structural formula (I), a structural formula (II), a structural formula (III), a structural formula (IV) and a structural formula (V) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, the compound takes PD-L1 as a target protein binding ligand, can degrade PD-L1 protein in a targeted manner, can be used as a PD-L1 protein targeted degradation agent, and has a good application prospect through research. And a very potential treatment scheme can be provided for PD-L1 mediated infection, tumors, autoimmune diseases and / or other diseases. In the structural formula (I), B and L in each structural formula are described in the specification.

Description

technical field [0001] The invention belongs to the technical field of chemical biology, and in particular relates to a bifunctional molecular compound for inducing PD-L1 protein degradation and its preparation and application. The compound can degrade PD-L1 in A375 and B16 F10 cell lines and can increase the tumor-killing effect of T cells. Background technique [0002] Programmed cell death protein 1 ligand 1 (PD-L1, B7-H1, CD274) is a member of the B7 family of cell surface ligands that regulate T cell activation and immune responses. PD-L1 is structurally similar to B7 family members in that it contains extracellular IgV and IgC domains and a short cytoplasmic region. PD-L1 ligands bind to PD-L1 transmembrane receptors and inhibit T cell activation. Studies have shown that PD-L1 is expressed in tissues such as antigen-presenting cells, activated T cells, placenta, heart, and lung. In addition, PD-L1 is expressed in cells of many tumor types including melanoma, ovarian...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/454A61P35/00A61P37/02A61P19/02A61P17/00A61P5/00A61P1/16A61P13/12A61P31/12A61P31/14A61P31/20A61P31/22A61P31/16
CPCC07D401/14A61P35/00A61P37/02A61P19/02A61P17/00A61P5/00A61P1/16A61P13/12A61P31/12A61P31/14A61P31/20A61P31/22A61P31/16Y02P20/55Y02A50/30
Inventor 李华陈丽霞刘洋霍峻锋马志露
Owner SHENYANG PHARMA UNIVERSITY
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