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Macrocycles with antioxidant and neuroprotective activities

A technology for compounds, epoxides, used in antioxidant and neuroprotective products to solve problems such as failure

Pending Publication Date: 2021-12-21
INST BIOMAR SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Confusingly, studies in some animal models of human diseases (in rodents) associated with oxidative stress have yielded very promising results, with some of these antioxidant pharmacological strategies subsequently in clinical trials fail in

Method used

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  • Macrocycles with antioxidant and neuroprotective activities
  • Macrocycles with antioxidant and neuroprotective activities
  • Macrocycles with antioxidant and neuroprotective activities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0213] Embodiment 1: the fermentation of HT-09B-VENT-WQ002

[0214] stock culture :

[0215] Pure cultures of HT-09B-VENT-WQ002 were stored frozen at -70°C in 20% glycerol.

[0216] Inoculum :

[0217] 40 mL of a well-grown agar culture inoculated in a 250 mL shake flask containing 2% oat flour, 2% malt extract, 0.01% KH 2 PO 4 , 0.005% MgSO 4 and tap water and cultured at 24°C on a rotary shaker (200rpm). Flasks were incubated for 48 hours and used as the first stage inoculum.

[0218] fermentation :

[0219] 250 mL of the same medium was inoculated in a 2L Erlenmeyer flask with 10% of the first stage inoculum. Fermentation was carried out on a rotary shaker (200 rpm) for 7 days at 24°C. The production of Compound I can be monitored by HPLC or any other method with sufficient sensitivity.

Embodiment 2

[0220] Example 2: Generation of Compound I and GKK1032

[0221] The fermentation broth (4L) of the fungus HT-09B-VENT-WQ002 was filtered through celite, and the mycelial cake was extracted twice with 2L of EtOAc / MeOH (3:1) mixture. The resulting suspension was filtered and partitioned between EtOAc and water. The organic layer was dried and the crude extract (3.1 g) was fractionated by VFC (vacuum flash chromatography) on silica gel, eluting with a stepwise gradient of hexane / EtOAc / MeOH. Fractions 7-8 (eluted with EtOAc and EtOAc / MeOH 9:1, 0.4 g) were applied to a silica gel column and flash chromatographed by elution with a hexane / EtOAc gradient. Fraction 11 (eluted with hexane / EtOAc 6:4, 32 mg) was finally passed through semi-preparative reverse phase HPLC (Agilent Prep 1100 HPLC, 5-μg C18 column; 30x100 mm; gradient eluted with 40-100 aqueous MeOH 25 Minutes, flow rate is 21.6mL / min, UV detection at 200nm) purification to obtain 19mg of compound I (Rt: 17.64min). Fractio...

Embodiment 3

[0227] Example 3: Generation of Compounds of Formula (I) or (II)

[0228] Using the adsorption resin XAD-1180 as the stationary phase and EtOAc / MeOH 3:1 as the mobile phase, the fermentation broth (8 L) of the fungus HT-09B-VENT-WQ002 was subjected to solid-phase extraction. LCMS allowed the isolation of Compound I (106 mg, 96% purity), GKK1032 (3.5 mg, 70% purity), pyrrocidine A (15.8 mg, 77% purity), pyrrocidine B (5.63 mg, 94% purity) and GKK-1032A2 (7.67 mg, 53% purity).

[0229] Five additional fermentations were performed (total volume 49.5 L) and 3 g of GKK1032 were isolated. Subjecting this compound to various reactions, mainly with low molecular weight organometallics, acids, bases, alkylating agents, and reducing agents, produces 14 compounds that are structurally related to Compound I:

[0230]

[0231]

[0232] Compound CL0652 was prepared as follows:

[0233] Dissolve 13 mg of compound GKK1032 in 10 mL of CH 2 Cl 2 and 1mL CH 3 CN. Then add 2 teaspoon...

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Abstract

Compounds of general formula wherein the wavy bond ~ is either a double bond or the epoxide, or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, for use in the treatment of diseases associated with oxidative stress.

Description

technical field [0001] The present invention relates to macrocyclic compounds, pharmaceutical compositions containing them and their use as antioxidant and neuroprotective products. Background technique [0002] Histopathological examination of biopsies or autopsies has revealed that a considerable number of human chronic and acute diseases are associated with biochemical signs of oxidative stress. Oxidative stress defines an abnormal condition in which cells cannot effectively eliminate the endogenous formation of reactive oxygen species and reactive nitrogen species (collectively called RONS) ( JP, et al. Adv. Drug Deliv. Rev. 61:1299-1315, 2009). RONS (including one or more of the following: hydrogen peroxide or H 2 o 2 , superoxide anion or O 2 ·- , nitric oxide or · NO, peroxynitrite anion or ONOO - , hydroxyl radical or · OH, etc.) are physiologically synthesized molecules that play important cellular signaling roles; however, RONS are inherently unstable and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/407A61K9/00A61P25/28A61P39/06
CPCA61K31/407A61P25/28A61P39/06A61P9/10C07D491/08C07D491/18C12P17/18
Inventor A·费尔南德斯·梅达德M·D·L·A·维努埃萨·纳瓦罗J·M·桑切斯·洛佩兹J·P·博拉诺斯·赫尔南德兹M·D·L·A·阿尔梅达·帕拉E·费尔南德斯·桑切斯
Owner INST BIOMAR SA