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Monomethyl fumarate-carrier conjugates and methods of their use

A technology of monomethyl fumarate and conjugates, which can be used in drug combinations, pharmaceutical formulations, active ingredients of esters, etc., and can solve the problem of underutilization of small molecules

Inactive Publication Date: 2021-10-08
FLAGSHIP PIONEERING INNOVATIONS V INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although therapeutic options to date utilizing the small mammalian biota have largely focused on probiotics (e.g., live microorganisms) as active agents, combinations of small molecules that exploit bidirectional communication remain largely underutilized.

Method used

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  • Monomethyl fumarate-carrier conjugates and methods of their use
  • Monomethyl fumarate-carrier conjugates and methods of their use
  • Monomethyl fumarate-carrier conjugates and methods of their use

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0377] Preparation of conjugates

[0378] Compounds can be prepared using synthetic methods and reaction conditions known in the art. Optimum reaction conditions and reaction times may vary with the reactants used. Solvents, temperatures, pressures and other reaction conditions can be selected by one of ordinary skill in the art unless otherwise indicated.

[0379] Glycoside Preparation Strategy #1: (Substitution)

[0380] plan 1

[0381]

[0382] In Scheme 1, a polyacylated sugar, compound 1, is treated with monomethyl fumarate compound 2 in a suitable solvent, optionally in the presence of a catalyst, wherein n represents an integer from 1 to 3, m Represents an integer from 0 to 1, and R is equal to C1-10 alkyl. Suitable catalysts include pyridine, dimethylaminopyridine, trimethylamine, and the like. The catalyst may be used in an amount ranging from 0.01 to 1.1 equivalents relative to Compound 2. Suitable solvents include dichloromethane, ethyl acetate, diethyl eth...

Embodiment 1

[0468] Example 1: Preparation of Exemplary Conjugates of the Invention

[0469]

[0470] Compound 1: Fumaric acid ((2S,3S,4R,5R,6S)-6-methyl-3,4,5-tris(propionyloxy)tetrahydro-2H-pyran-2-yl)methyl base ester

[0471] at 20°C in N 2 Downward [(2S,3R,4R,5S)-6-hydroxy-2-methyl-4,5-di(propionyloxy)tetrahydropyran-3-yl]propionate (0.5g, 1.50 mmol, 1 equiv) and (E)-4-methoxy-4-oxo-but-2-enoic acid (234.87 mg, 1.81 mmol, 1.2 equiv) in THF (5 mL) were added in one portion DCC (620.82 mg, 3.01 mmol, 2 equiv) and DMAP (91.90 mg, 752.23 μmol, 0.5 equiv) in . The mixture was stirred at 20 °C for 12 h. LC-MS indicated complete consumption of [(2S,3R,4R,5S)-6-hydroxy-2-methyl-4,5-bis(propionyloxy)tetrahydropyran-3-yl]propionate , and a main peak with the expected m / z was detected. The reaction mixture was filtered and concentrated under reduced pressure to yield a residue. The residue was purified by preparative HPLC (water + 0.04% (v / v) HCl / MeOH) and fumaric acid ((2S,3S,4R,5R,6S...

Embodiment 2

[0708] Example 2: In vitro DMPK degradation assay

[0709] The conjugates disclosed herein may be stable at a range of physiological pH levels and may be activated by enzymes present in the local microenvironment at the desired site of action (e.g., in the gastrointestinal tract, such as in the stomach, small intestine, or large intestine). ) are selectively cut. Conjugates were tested for chemical stability over a range of pH levels as well as their ability to degrade in representative in vitro systems. Data for selected conjugates are shown below.

[0710] Assay 1. Stability of the conjugates in simulated gastric fluid (SGF). This assay was used to assess the stability of the conjugates in the stomach.

[0711] By dissolving 2 g of sodium chloride in 0.6 L of ultrapure water ( Millipore Sigma, Darmstadt, Germany) to prepare media. The pH was adjusted to 1.6 with 1N hydrochloric acid, and then the volume was adjusted to 1 L with purified water.

[0712] 60mg FaSSIF pow...

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Abstract

Disclosed are conjugates of monomethyl fumarate and a carrier group or aminocarrier group, or a pharmaceutically acceptable salt thereof. In the conjugates, monomethyl fumarate acyl is covalently bonded to the carrier group or aminocarrier group through a carbon-oxygen bond that is cleavable in vivo. The carrier group may include a core, e.g., a monosaccharide, a sugar acid (e.g., acid monosaccharide), a sugar alcohol, or a catechin polyphenol. The aminocarrier group may include a core, e.g., an aminomonosaccharide. The carrier group or aminocarrier group may include, e.g., at least one short chain fatty acid acyl, at least one tryptophan analogue, at least one ketone body, or at least one preketone body. Also disclosed are pharmaceutical compositions containing the conjugates and methods of their use.

Description

technical field [0001] The present invention relates to conjugates of monomethyl fumarate with a carrier or an amino carrier group. The invention also features compositions comprising the conjugates and methods of using the conjugates. Background technique [0002] Mammalian microbiomes can communicate bidirectionally with mammalian host systems. Although therapeutic options to date utilizing the small mammalian biota have largely focused on probiotics (eg, live microorganisms) as active agents, combinations of small molecules that exploit bidirectional communication remain largely underutilized. [0003] There is a need for pharmaceutical applications that take advantage of the advantages of small molecule based conjugates. Contents of the invention [0004] The present invention provides a conjugate composed of monomethyl fumarate and a carrier group or an amino carrier group, a pharmaceutical composition containing them, as well as regulating autoimmune markers in a s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/225A61K47/54A61P25/00A61P37/02
CPCA61K47/54A61P37/02A61P25/00A61K47/549A61K31/191A61K31/7008A61K31/194A61K31/7004A61K47/55A61K47/542A61K47/60A61K31/22A61P25/28A61P37/06A61K31/225
Inventor J·P·小凯西D·A·贝里J·E·亚历山大T·布里格斯L·巴克宾德D·S·古纳塞克拉A·卡马利萨维斯塔尼M-J·金B·兰特A·梁K·努德尔S·C·佩克C·罗斯S·J·泰勒K·亚苏达
Owner FLAGSHIP PIONEERING INNOVATIONS V INC
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