Novel cyclic dinucleotide derivative and antibody-drug conjugate thereof

An antibody drug and conjugate technology, applied in the field of antibody drug conjugates and cyclic dinucleotide derivatives, can solve the problem of no specific examples of conjugates, no confirmed anti-tumor effects of conjugates, no records Problems such as conjugate examples

Pending Publication Date: 2021-04-27
DAIICHI SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Patent Document 14 describes a conjugate containing an immunostimulatory compound, an antibody structure, and a linker, but does not describe a specific example of a conjugate using a STING agonist as an immunostimulatory compound
Patent Document 26 describes a conjugate in which a CDN having a specific structure is bound to an antibody via a linker, but does not describe an example of in vivo administration of the conjugate, and the antitumor effect of the conjugate has not been confirmed

Method used

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  • Novel cyclic dinucleotide derivative and antibody-drug conjugate thereof
  • Novel cyclic dinucleotide derivative and antibody-drug conjugate thereof
  • Novel cyclic dinucleotide derivative and antibody-drug conjugate thereof

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0616] In the preparation of the above-described sugar chain-reconstituted antibody, concentration of the antibody aqueous solution, concentration measurement, and buffer exchange can be performed according to the common procedures A to C described later.

[0617] In addition, the azide sugar chain oxazoline body of SG type was synthesized according to the method described in WO2018 / 003983. As an example, [N 3 -PEG(3)] 2 The synthesis method of -SG(10)-Ox (compound 1-10 described in WO2018 / 003983) is shown in the following formula.

[0618]

[0619] The azidosugar chain oxazoline body of MSG type was also synthesized according to the method described in WO2018 / 003983. As an example, [N 3 The synthesis method of -PEG(3)]-MSG1(9)-Ox (compound 1-11 described in WO2018 / 003983) is shown in the following formula.

[0620]

[0621] Method E: Conjugation of antibodies and drugs (sugar chain coupling 1)

[0622]

[0623] (In the formula, the two asterisks (*) on the left ...

Embodiment 1

[0732] Example 1: Synthesis of CDN1

[0733] (5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R)-7-(6-amino-9H-purin-9-yl)-15,16-dihydroxy-2,10-bis(mercapto)- 14-(6,7,8,9-tetrahydro-2H-2,3,5,6-tetraazabenzo[cd]azulene-2-yl)octahydro-2H, 10H, 12H-5,8 - A bridge - 2λ 5 , 10λ 5 - Furo[3,2-l][1,3,6,9,11,2,10]pentoxabisphosphine cyclotetradecyne-2,10-dione

[0734]

[0735] [synthesis path]

[0736]

[0737] (Process 1)

[0738] 7-{2-O-[tert-butyl(dimethyl)silyl]-3,5-O-(di-tert-butylsilyl)-β-D-ribofuranosyl}-5- Iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0739] In the N,N-dimethylformamide (10 mL) solution of 5-iodo tuberculin (1.0 g) known in the literature (Tetrahedron 2007, 63, 9850-9861), slowly dropwise at 0°C After di-tert-butylsilylbis(triflate) (1.24 mL), the mixture was stirred at the same temperature for 30 minutes. After adding imidazole (868 mg) at 0°C, the temperature was raised to room temperature and stirred for 30 minutes. At room temperature, tert-butyldimethylsil...

Embodiment 2

[0797] Example 2: Synthesis of CDN2

[0798] (5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R)-7-(6-amino-9H-purin-9-yl)-15,16-dihydroxy-2,10-bis(mercapto)- 14-(6,7,8,9-tetrahydro-2H-2,3,5,6-tetraazabenzo[cd]azulene-2-yl)octahydro-2H, 10H, 12H-5,8 - A bridge - 2λ 5 , 10λ 5 - Furo[3,2-l][1,3,6,9,11,2,10]pentoxabisphosphine cyclotetradecyne-2,10-dione

[0799] (Diastereomer 4 of Compound 1 described in Example 1)

[0800]

[0801] [synthesis path]

[0802]

[0803] (Process 1)

[0804] N-benzoyl-3'-O-[tert-butyl(dimethyl)silyl]-2'-O-[hydroxy(oxo)-λ 5 -phosphino]adenosine

[0805] Commercially available (ChemGenes) N-benzoyl-5'-O-[bis(4-methoxyphenyl)(phenyl)methyl]-3'-O-[tert-butyl(dimethyl )silyl]-2'-O-{(2-cyanoethoxy)[bis(prop-2-yl)amino]phosphino}adenosine (962 mg) in the same manner as in Example 1, Step 7 Method The reaction was carried out to give the title compound in acetonitrile. The acetonitrile solution was used directly in the next reaction.

[0806] (Process ...

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PUM

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Abstract

The invention is to develop a novel CDN derivative that has a STING agonist activity, and a therapeutic agent and / or method for treating a disease related to a STING agonist activity by using the novel CDN derivative. Additionally, to develop a therapeutic agent and / or method for treating a disease related to a STING agonist activity that is capable of delivering the novel CDN derivative to a target cell or a target organ. According to the present invention, a novel CDN derivative that has a strong STING agonist activity, and an antibody-CDN derivative conjugate that comprises the novel CDN derivative are provided.

Description

technical field [0001] The present invention relates to a cyclic dinucleotide derivative having a new structure with STING agonist activity, and an antibody drug conjugate formed by combining the novel cyclic dinucleotide derivative and an antibody against a target cell via a linker compounds, pharmaceutical compositions containing the antibody-drug conjugates, and the like. Background technique [0002] STING (Stimulator of Interferon Genes: interferon gene-stimulating protein) is a transmembrane-type adaptor protein located in the endoplasmic reticulum (Non-Patent Document 1). STING functions as a central molecule for natural immune activation in mammals and is the front line against entry of pathogens such as bacteria and viruses. Activation of STING is known to be caused by multiple cytoplasmic DNA sensors sensing exogenous and intrinsic DNA signals. Among cytoplasmic DNA sensors, cGAS (Cyclic GMP-AMP Synthase: cyclic GMP-AMP synthase) is considered to be an important ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/68A61K31/7084A61K47/65A61P35/00A61P35/02A61P43/00C07H21/02C07K16/00
CPCA61P35/00A61P35/02A61P43/00A61K47/6889A61K47/6807A61K47/6855A61K47/6849A61K47/6835A61K31/7084A61K47/65A61K47/68C07H21/02C07K16/00C07K16/32A61K47/545
Inventor 津田敏史田渊俊树渡边秀昭小林宏行石崎雅之原香生子和田悌司荒井雅巳
Owner DAIICHI SANKYO CO LTD
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