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Efficient and stable small molecule agonist of v [gamma] 9v delta 2t cells

A C2-C10, selected technology, applied in the field of phosphoantigen agonists, can solve the problems of ambiguity, unfavorable pharmacokinetic properties of phosphoantigen, weak reactivity of phosphoantigen, etc.

Inactive Publication Date: 2019-04-19
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although the role of Vγ9Vδ2 T cells in the treatment of cancer (including infectious diseases) is clear, but because the cells only account for 2-10% of the total T lymphocytes in human blood, and the mechanism of small molecule activation of γδT cells is not yet clear, human-derived It is difficult to establish a mouse model, the widespread presence of IPP in tumor cells makes γδT cells less reactive to phosphoantigens, and the currently developed phosphoantigens have unfavorable pharmacokinetic properties. got a lot of questions

Method used

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  • Efficient and stable small molecule agonist of v [gamma] 9v delta 2t cells
  • Efficient and stable small molecule agonist of v [gamma] 9v delta 2t cells
  • Efficient and stable small molecule agonist of v [gamma] 9v delta 2t cells

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0436] Example 1: Preparation of TH-Z 132

[0437]

[0438] Step 1: Dissolve 3.9mmol (0.328g) of isoprene monooxide in 3mL of ethyl acetate, add CuCl successively 2 (3.9mmol, 0.672g) and LiCl (3.9mmol, 0.672g) and heated to 80℃ to react for 1h, cool, add 0.15g of ice, then filter the insoluble matter, separate the organic phase, and extract the aqueous phase with n-hexane Several times, combine the organic phases and use MgSO 4 Dry, spin-dry and purify by silica gel column to obtain 2-methyl-4-chloro-2-butenal (1.95 mmol, 0.230 g), yield: 50%.

[0439] Step 2: Dissolve 2-methyl-4-chloro-2-butenal (0.84mmol, 0.1g) in 3mL tetrahydrofuran and place it at 0°C, then add NaBH in batches 4 The reaction was monitored at any time until the raw materials disappeared completely, and a small amount of water was added to quench the reaction. Then it was extracted with ethyl acetate multiple times, the organic phases were combined and spin-dried, sampled, separated and purified to obtain 2-methy...

Embodiment 2

[0444] Example 2: Preparation of TH-Z 456

[0445]

[0446]

[0447] Example 2 was prepared by a method similar to Example 1, except that tris(tetra-n-butylammonium) monochloromethyl diphosphate was used as the raw material in the third step.

[0448] TH-Z 456 characterization data:

[0449] 1 H NMR(400MHz, D 2 O)δppm 5.63(t,J=6.2Hz,1H),4.56(dd,J 1 =J 2 =7.4Hz,2H),4.0(s,2H),3.8(dd,J 1 =J 2 = 15.4Hz, 1H), 1.70(s, 3H). 31 P NMR(162MHz, D 2 O)δppm 13.99(d,J=9.0Hz,1P), 9.31(d,J=9.0Hz,2P).

Embodiment 3

[0450] Example 3: Preparation of TH-Z 455

[0451]

[0452]

[0453] Example 3 was prepared in a similar manner to Example 1, except that tris(tetra-n-butylammonium) monofluoromethylene diphosphate was used as the raw material in the third step.

[0454] TH-Z 455 characterization data:

[0455] 1 H NMR(400MHz, D 2 O)δppm 5.61(t,J=6.6Hz,1H), 4.64(dd,J 1 =J 2 =12.2Hz,1H),4.54(dd,J 1 =J 2 =7.28Hz 2H), 3.98(s, 2H), 1.68(s, 3H). 31 P NMR(162MHz, D 2 O)δppm 12.86(dd,J 1 =11.2Hz, J 2 =62.5Hz,1P),7.52(dd,J 1 = 11., J 2 = 58.0Hz, 2P).

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Abstract

The invention relates to a formula (I) compound as an efficient and stable small molecule agonist of v [gamma] 9v delta 2t cells, wherein the groups are defined in the specification and the claims. The present invention also relates to pharmaceutical compositions containing the formula (I) compound and use thereof in the treatment of proliferative diseases.

Description

Technical field [0001] The present invention relates to a phosphorous antigen agonist for the proliferation of Vγ9Vδ2 T cells. Background technique [0002] Vγ9Vδ2 T cells are a common subtype of γδ T cells. Compared with another subtype of T cells and αβ T cells that can only sense polypeptide antigens, Vγ9Vδ2 T cells do not rely on antigen processing and tissue phase presented by antigen presenting cells. Capacitive antigen (MHC) limitation, so that it can detect and respond to non-polypeptide antigens, such as some small molecule phosphorous antigens. At present, clinical trials have evaluated the effectiveness and safety of γδT cell-based immunotherapy on solid tumors including multiple myeloma, non-Hodgkin’s lymphoma, prostate cancer, kidney cancer and lung cancer, so phosphorus Antigen stimulation of Vγ9Vδ2 T cells for tumor therapy has become a research hotspot. [0003] Two types of agonists have been developed: (1) Direct phosphorous antigens, mainly intermediates in iso...

Claims

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Application Information

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IPC IPC(8): C07F9/09C07F9/38C07F9/40C07F9/58C07F9/6506C07F9/6518C07F9/6524C07F9/655A61P35/00A61K31/675A61K31/665A61K31/662A61K31/661
CPCA61P35/00C07F9/091C07F9/094C07F9/3808C07F9/4071C07F9/4078C07F9/6524C07F9/6552Y02P20/55
Inventor 张永辉李丽平周晓英杨芸芸
Owner TSINGHUA UNIV
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