Histone acetyltransferase activators and uses thereof

a technology of histone acetyltransferase and activator, which is applied in the field of histone acetyltransferase activator, can solve the problems of poor candidates for therapeutics, unfavorable physicochemical characteristics of compounds used in cns diseases, and unproductive cholinesterase inhibitors, so as to reduce inclusion bodies and improve the effect of amyloid beta plaques

Inactive Publication Date: 2017-06-29
THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides a method for reducing inclusion bodies in subjects with neurodegenerative diseases, such as Alzheimer's disease, by administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. The compound can reduce the levels of beta-amyloid peptides, native and phosphorylated Tau proteins, native and phosphorylated alpha-synuclein, lipofuscin, cleaved TARDBP (TDB-43), or a combination thereof. The method can be applied to subjects with abnormally elevated levels of amyloid beta plaques and various neurodegenerative diseases.

Problems solved by technology

Currently available therapies for AD are palliative and do not cure the disease.
However, as AD progresses, the brain loses less acetylcholine, thereby rendering cholinesterase inhibitors unproductive as treatment for AD.
HAT activators have been reported, but many are neither soluble nor membrane permeant, which makes them poor candidates for therapeutics.
However, these compounds suffer from unfavorable physicochemical characteristics for use in CNS diseases.

Method used

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  • Histone acetyltransferase activators and uses thereof
  • Histone acetyltransferase activators and uses thereof
  • Histone acetyltransferase activators and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0243]

Methyl 2-Methoxy-6-Methylbenzoate, 4

[0244]A vigorously mixture of 1-methoxy-2,3-dimethylbenzene (1, 1.34 mL), Copper (II) Sulfate pentahydrate (2.5 g) and potassium peroxodisulfate (8.1 g) in acetonitrile / water 1:1 (70 mL) was heated at reflux for 6 h. The reaction was cooled to room temperature and was extracted with dichloromethane (3 times). The organic layer was dried over Na2SO4, filtered and evaporated to produce the desired liquid product (2) suitable for further reaction without purification. A solution of 2 (1.50 g) and sulfamic acid (1.30 g) in water (22.5 mL) and THF (11.2 mL) was stirred at room temperature and after 5 min a solution of NaClO2 (1.180 g) in water (5 mL) was added. The reaction was stirred at room temperature for 1 h and then was extracted with ethyl acetate. The organic layer was separated and extracted with NaOH 1M. The aqueous solution was acidified with HCl 6N and extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered a...

example 2

[0248]

2-ethoxy-6-hydroxybenzoic acid, 8

[0249]NaOH 1N (6 mL) was added dropwise to a solution of ethyl 2-ethoxy-6-hydroxybenzoate (7, 1 g) in ethanol (3 mL). The reaction was refluxed for 2 h and then concentrated and extracted with water and dichloromethane (3 times). The aqueous solution was separated and acidified to pH=1 to obtain the precipitation of the product (660 mg, yield: 76%), which was filtrated and washed with water. C9H10O4, MS-ESI: [M+H]+=183 m / z. 1H-NMR: (CDCl3, 300 MHz) δ 1.57 (t, 3H, Jv=7.2 Hz, —CH2CH3), 4.32 (q, 2H, Jv=7.2 Hz, —CH2CH3), 6.47 (d, 1H, Jo=8.4 Hz, H-5), 6.71 (d, 1H, Jo=8.4 hz, H-3), 7.39 (t, 1H, Jo=8.4 Hz, H-4), 11.60 (s, 1H, C(═O)OH), 12.16 (s, 1H, OH).

N-(4-chloro-3-(trifluoromethyl)phenyl)-2-ethoxy-6-hydroxybenzamide, 9

[0250]N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (900 mg) was added gradually to a solution of 8 (660 mg) and 4-chloro-3-(trifluoromethyl)aniline (780 mg) in dichloromethane (5 mL) at 0° C. The reaction was stirred a...

example 3

[0254]

2-Bromo-6-Fluorobenzoic Acid, 11

[0255]A solution 2-bromo-6-fluorobenzonitrile 10 in KOH 1M (25 mL) was stirred to reflux for 2 day. The reaction was cooled to room temperature and the HCl concentrate was added to pH=2-3. The aqueous solution was extracted with ethyl acetate (3 times). The organic layer was separated, dried and evaporated to obtain the desired product (126 mg, yield: 95%). C7H4BrFO2, MS-ESI: [M−H]−=218 m / z. 1H-NMR: (CDCl3, 400 MHz) δ 7.14 (t, 1H, Jo=8.4 Hz, H-4), 7.29-7.35 (m, 1H, H-3), 7.45 (d, 1H, H-5).

2-bromo-N-(4-chloro-3-(trifluoromethyl)phenyl)-6-fluorobenzamide, RP106

[0256]N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl, 74 mg) was added to a solution of 11 (65 mg) in dichloromethane (0.5 mL) at 0° C., and then 4-chloro-3-(trifluoromethyl)aniline (64 mg) was added. The solution was stirred at room temperature for 24 h. The solvent was evaporated and the residue was crystalized from methanol (55 mg, yield: 47%). C14H7BrClF4NO, MS-ESI...

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Abstract

The invention provides compounds and compositions comprising compounds that modulate histone acyl transferase (HAT). The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and / or accumulations of alpha-synuclein as well as cancer by administering a compound that modulates HAT to a subject.

Description

[0001]This application claims the benefit of and priority to U.S. Provisional Application No. 61 / 972,571, filed on Mar. 31, 2014 and U.S. Provisional Application No. 62 / 023,715, filed on Jul. 11, 2014, each of which is incorporated herein by reference.[0002]All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.[0003]This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights.BACKGROUND O...

Claims

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Application Information

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IPC IPC(8): A61K31/536C07D265/22C07C237/40A61K31/166C07C235/64C07D209/38C07D209/34A61K31/403C07D265/26C07C235/42
CPCA61K31/536C07D265/26C07D265/22C07C237/40C07C235/42A61K2121/00C07D209/38C07D209/34A61K31/403A61K31/166C07C235/64A61P25/14A61P25/16A61P25/20A61P25/28A61P35/00A61P35/02A61P43/00C07D209/46
Inventor ARANCIO, OTTAVIODENG, SHIXIANLANDRY, DONALD W.FIORITO, JOLEPURGATORIO, ROSAO'CONNOR, OWEN ANTHONYAMENGUAL, JENNIFER EFFIE
Owner THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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