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Cyclic dinucleotide analogues, pharmaceutical composition of analogues and applications of analogues and pharmaceutical composition

A technology of cyclic dinucleotides and analogues, applied in drug combinations, sugar derivatives, sugar derivatives, etc.

Pending Publication Date: 2020-03-31
SHANGHAI DE NOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, there have been many cyclic dinucleotide analogues with agonistic effects on the STING signaling pathway published (WO2014 / 093936, WO2014 / 189805, WO2014 / 189806, WO2016 / 120305, WO2016 / 145102, WO2017 / 027645, WO2017 / 075477,WO2017 / 093933,WO2017 / 123657,WO2017 / 123669,WO2017 / 161349,WO2017 / 186711,WO2018 / 009466,WO2018 / 009648,WO2018 / 009652,WO2018 / 045204,WO2018 / 060323,WO2018 / 065360,WO2018 / 098203, WO2018 / 100558), but there is no STING agonist on the market as a drug

Method used

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  • Cyclic dinucleotide analogues, pharmaceutical composition of analogues and applications of analogues and pharmaceutical composition

Examples

Experimental program
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Effect test

Embodiment 1

[0380] Embodiment 1: the synthesis of intermediate 1-8

[0381]

[0382]

[0383] Step 1: Suspend adenosine (50g, 187mmol) in acetic acid / sodium acetate (pH=4.0, 0.5M, 1L) buffer, slowly add liquid bromine (60g, 374mmol) dropwise, keep the system temperature below 10°C, After the addition was complete, the reaction system was stirred at room temperature for 48 hours. Add saturated aqueous sodium bisulfite solution to the reaction solution, remove excess bromine, adjust pH to neutral with aqueous sodium hydroxide solution (1M), cool in an ice-water bath, stir for 2 hours, precipitate solid, filter, collect solid, Intermediate 1-1 (29 g) was obtained after vacuum drying. m / z:[M+H] + 346.0 / 348.0.

[0384] Step 2: Intermediate 1-1 (10g, 28.9mmol) was suspended in methanol (100mL), sodium methoxide (9.36g, 173mmol) was added, the reaction system was refluxed and stirred for 5 hours, concentrated under reduced pressure to remove methanol, and the residue was dissolved in me...

Embodiment 2

[0390] Embodiment 2: the synthesis of compound 1-p1, 1-p2, 1-p3 and 1-p4

[0391]

[0392] Step 1: Intermediate 1-8 (2.85mmol) was dissolved in dry acetonitrile (15mL), concentrated under reduced pressure to remove the solvent, and the above operation was repeated twice. The last time left 10mL of acetonitrile, and No. 4 molecular sieves (0.8g) were added. Compound 1-9 (CAS No: 104992-55-4, 3.3g, 3.42mmol) was dissolved in dry acetonitrile (15mL), and then concentrated under reduced pressure to remove the solvent. After repeating twice, 5mL of acetonitrile remained for the last time. At 0°C, the acetonitrile solution of compound 1-9 was slowly added dropwise to the acetonitrile solution of compound 1-8, and the resulting reaction system was stirred at room temperature for 0.5 hours, and then N,N-dimethyl-N'- (3-Thio-3H-1,2,4-dithiazol-5-yl)formamidine (DDTT, 697mg, 3.42mmol) was added to the reaction liquid and stirred for 40 minutes. Molecular sieves were removed by filtr...

Embodiment 3

[0402] Example 3: Synthesis of Intermediates 2-8 and 2-9

[0403]

[0404] Step 1: Under nitrogen protection, add N,O-bistrimethylsilylacetamide (BSA, 13.6g, 116mmol) to 7-aminothiazolo[4,5-d]pyrimidin-2(3H)-one (synthetic The method refers to J.Med.Chem.1990, 33, 407-415 Compound 28) (6.5g, 38.7mmol) and tetraacetyl ribose (11g, 46.4mmol) in acetonitrile (120mL) solution, reflux for 1 hour. After the reaction solution was cooled to room temperature, trimethylsilyl trifluoromethanesulfonate (TMSOTf, 17.2 g, 77.4 mmol) was added to the above reaction solution, and reflux was continued for 48 hours. After the reaction solution was cooled to room temperature, slowly add saturated aqueous sodium bicarbonate solution to the above reaction solution, extract with ethyl acetate (150mL×3), combine the organic phases and wash with water, separate the organic phases and dry them with anhydrous sodium sulfate, filter, After concentration, the residue was purified by Flash column chrom...

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PUM

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Abstract

The invention discloses cyclic dinucleotide analogues, a pharmaceutical composition of the analogues and applications of the analogues and the pharmaceutical composition. The cyclic dinucleotide analogs (I), an isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt of the analogs have a structure shown in the specification. The cyclic dinucleotide analogs provided by the invention can be used as regulators of stimulator of interferon genes (STIG) and related signaling pathways, and can effectively treat and / or alleviate multiple types of diseases, including but not limited to malignant tumors, inflammation, autoimmune diseases and infectious diseases; and in addition, the STING regulators can also be used as vaccine adjuvants.

Description

technical field [0001] The invention relates to a cyclic dinucleotide analogue, its pharmaceutical composition and its application as a STING agonist and activation of the STING pathway. Background technique [0002] Interferon gene stimulator STING (Stimulator of Interferon Genes), also known as T1MEM173, MITA, MPYS and ERIS, is an important signaling molecule in innate immune signaling. The protein encoded by this gene contains 5 transmembrane structures. It plays an important regulatory role in the process of immune response related to bacterial infection. As a pattern recognition receptor, STING can detect and recognize exogenous nucleic acid in the cytoplasm and activate signal transduction pathways related to type I interferon responses. In addition, studies have shown that STING participates in the regulation of apoptosis signals by interacting with type II major histocompatibility complex (MHCII). Studies of human tumors with spontaneous T cell infiltration have sh...

Claims

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Application Information

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IPC IPC(8): C07H19/213C07H19/23C07H1/00A61K31/7076A61K31/7084A61K31/7064A61K31/708A61K45/06A61P35/00A61P37/06A61P31/14A61P31/18A61P31/20A61K39/39A61P19/02A61P17/06A61P35/02
CPCC07H19/213C07H19/23C07H1/00A61P35/00A61P37/06A61P31/14A61P31/18A61P31/20A61K39/39A61P19/02A61P17/06A61P35/02A61K2039/55511A61K2039/5152A61K39/0011A61K31/7076A61K31/708A61K31/7084A61K45/06A61P31/12A61P37/00C07H21/02C07H21/00A61K2300/00C12N15/113A61P31/00
Inventor 仝朝龙秦平刘凤涛王景录邓晓磊郭洪利陈大为高大新
Owner SHANGHAI DE NOVO PHARMA
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