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Medicine containing liver-targeting specific ligand and thyroxine receptor agonist

A receptor agonist, thyroxine technology, applied in the field of biomedicine and targeted drugs, can solve the problems of thyroid hormone side effects and limited application

Active Publication Date: 2019-02-15
KYLONOVA (XIAMEN) BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, excessive thyroid hormone is prone to cause side effects, especially adverse reactions to the heart (including tachycardia and sudden death) and bone and muscle (Braverman LE et al., editors. Lippincott: The Thyroid 2000:515-517)
Due to these adverse effects of thyroid hormones, its further application in the treatment of non-alcoholic fatty liver disease is limited

Method used

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  • Medicine containing liver-targeting specific ligand and thyroxine receptor agonist
  • Medicine containing liver-targeting specific ligand and thyroxine receptor agonist
  • Medicine containing liver-targeting specific ligand and thyroxine receptor agonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0141] Example 1: Preparation of Drug 1 (Kylo-0101)

[0142] (1) Compound 1-1 generates compound 1-2 through the following chemical reaction:

[0143]

[0144] Weigh compound 1-1 (0.31g, 0.1mmol) and pour it into a synthesis tube, add pip / DMF (2ml / 8ml), nitrogen gas bubbles for 30-40min, then vacuum pump, then use DMF to wash compound 1-2, each time Use 10ml, wash 3 times, wash away pip and impurities generated by the reaction;

[0145] (2) Compound 1-2 generates compound 1-3 through the following chemical reaction:

[0146]

[0147] Weigh Dde-Lys(Fmoc)-OH (0.16g, 0.3mmol) and HBTU (0.114g, 0.3mmol) into the synthesis tube, add DMF (10mL) to dissolve the above solids, add DIPEA (55μL) and bubble nitrogen for 30- After 60 minutes, remove the reaction solution and wash the remaining solid compound 1-3 with DMF, each time using 10ml, and wash 3 times to remove HBTU, DIPEA and impurities generated by the reaction;

[0148] (3) Compound 1-3 generates compound 1-4 through t...

Embodiment 2

[0183] Example 2: Preparation of Drug 2 (Kylo-0102)

[0184] Compound 2-1 generates drug 2 (Kylo-0102) through the following chemical reaction, and the specific composition of the reactant is shown in Table 14:

[0185]

[0186]Add sodium methoxide / methanol (20mg / 5ml) solution to compound 2-1 (20mg, 0.0078mmol), set the shaker temperature at 30-35°C, rotate at 200r / min, shake for 30min, add 1mol / L HCl (5 -7 drops) to adjust the pH to 7, evaporate the solvent to dryness by rotary evaporator, water bath temperature 40-45°C, add ACN / water (0.2ml / 1.8ml) to dissolve the residue and load the sample, use the filler product name GE Resource15RPC (10ml ), the mobile phase is a mixture of water and acetonitrile (acetonitrile content 10% to 90%), purify, elute and collect all products, obtain 12mg of pure drug 2 (Kylo-0102) after freeze-drying, yield 71.1%, Such as figure 2 As shown, when the mass-to-charge ratio of Kylo-0102 is 1, the target product is 2201.55613 (1+), and when th...

Embodiment 3

[0187] Embodiment 3: the preparation method of drug 3 (Kylo-0103)

[0188] Compound 3-1 generates drug 3 (Kylo-0103) through the following chemical reaction, and the specific composition of the reactant is shown in Table 15:

[0189]

[0190] Add sodium methoxide / methanol (20mg / 5ml) solution to compound 3-1 (20mg, 0.0076mmol), set the shaker temperature at 30-35°C, rotate at 200r / min, shake for 30min, add 1mol / L HCl (5- 7 drops) adjust the pH to 7, evaporate the solvent to dryness using a rotary evaporator, the temperature of the water bath is 40-45°C, add ACN / water (0.2ml / 1.8ml) to dissolve the residue and load the sample, the product name of the filler is GE Resource15RPC (10ml) , the mobile phase was a mixture of water and acetonitrile (acetonitrile content 10% to 90%), purified, eluted and collected all products, and obtained 12.5 mg of pure drug 3 (Kylo-0103) after freeze-drying, with a yield of 72.7%. Such as image 3 As shown, when the mass-to-charge ratio of Kylo...

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Abstract

The invention provides a medicine structurally containing a liver-targeting specific ligand and a thyroxine receptor agonist. The liver-targeting specific ligand and the thyroxine receptor agonist areconnected by branched chains, connectors and connecting chains to form a novel medicine structure. Thyroxine receptors (TRs) are divided into two subtypes, namely TR-alpha and TR-beta, wherein the TR-beta is mainly expressed in the liver, and the TR-alpha is mainly expressed in the heart, the nervous system and the like. In some embodiments, the medicine provided by the invention is expected to have a liver-targeting effect and can specifically bring the thyroxine receptor agonist into the liver so as to prevent the thyroxine receptor agonist from entering the heart and other tissues, so thatside effects triggered by the effect of the thyroxine receptor agonist on the other tissues can be avoided and the therapeutic effect of the medicine on treatment of lipid metabolism disorders and related complications is maintained.

Description

technical field [0001] The present invention relates to the field of biomedicine, specifically to the field of targeted drugs, and more specifically to compounds for liver-targeted treatment of liver-derived diseases. Background technique [0002] The asialoglycoprotein receptor (ASGPR) in the liver is a receptor specifically expressed in hepatocytes and is a highly efficient endocytic receptor. Under physiological conditions in vivo, the secondary end of various glycoproteins exposed after enzymatic or acid hydrolysis of sialic acid is galactose residues, so the sugar specifically bound by ASGPR is galactosyl, so it is also called galactose-specific receptor . Monosaccharide and polysaccharide molecules such as galactose, galactosamine, and N-acetylgalactosamine have high affinity for it. The main physiological function of ASGPR is to mediate the clearance of asialoglycoprotein, lipoprotein and other substances in the blood, and it is closely related to the occurrence and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/54A61K47/61A61K31/198A61P1/16
CPCA61K47/549A61K47/61A61P1/16A61K31/198A61K31/44
Inventor 崔坤元
Owner KYLONOVA (XIAMEN) BIOPHARMA CO LTD
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