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Compounds and methods for the treatment of neurodegenerative diseases

a neurodegenerative disease and compound technology, applied in the field of compound and method for the treatment of neurodegenerative diseases, can solve the problems of brain damage, memory loss, language problems, and interfering with a person's daily life and activities, and achieve the effects of preventing brain damage, preventing brain damage, and preventing brain damag

Inactive Publication Date: 2019-09-05
RESILIO THERAPEUTICS LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes compounds and methods to treat neurodegenerative diseases in humans. These compounds are made from an ingredient called DFMO and its prodrugs. These compounds may help to protect or restore nerve cells in the brain that are affected by these diseases. The technical effect of this patent is to provide new tools to treat neurodegenerative diseases.

Problems solved by technology

Dementia is the loss of cognitive functioning—thinking, remembering, and reasoning—and behavioral abilities, to such an extent that it interferes with a person's daily life and activities.
Her symptoms included memory loss, language problems, and unpredictable behavior.
Although we still don't know how the Alzheimer's disease process begins, it seems likely that damage to the brain starts a decade or more before clinically measurable problems become evident.
Abnormal deposits of proteins form amyloid plaques and tau tangles throughout the brain, and once-healthy neurons begin to work less efficiently.
Over time, neurons lose their ability to function and communicate with each other, and eventually they die.
By the final stage of Alzheimer's, damage is widespread, and brain tissue has shrunk significantly.

Method used

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  • Compounds and methods for the treatment of neurodegenerative diseases
  • Compounds and methods for the treatment of neurodegenerative diseases
  • Compounds and methods for the treatment of neurodegenerative diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-Acyloxyalkoxycarbonyl Derivative of DFMO

[0081]

Methylation of DFMO:

[0082]To MeOH (50 mL) is added acetyl chloride (7.14 mL, 10 eq) after stirring for 30 minutes, DFMO (0.01 mole) is added. Stirring is continued for 48 hours. After concentration under vacuum, ethyl acetate (500 mL) is added and the contents neutralized (pH=7.2) with saturated NaHCO3. The organic layer is separated, dried and then concentrated under vacuum to afford the methyl ester of DFMO.

Prodrug 1:

[0083]To a solution of the DFMO methyl ester (1 mmole) in DMF (5 mL) is added triethyl amine (3 mmole) followed by the addition of chloromethyl chloroformate (2.1 mmole). The contents are stirred for 16 hours to afford the intermediate 1A. To the intermediate 1A, is then added sodium acetate (4 mmole). After stirring for another 20 hours, ethyl acetate (100 mL) and brine (100 mL) is added. The organic layer is separated, dried with magnesium sulfate and then concentrated under vacuum to afford Prodrug 1 (Formula (II) whe...

example 2

(Oxodioxolenyl)Methyl Carbamate Prodrug

[0084]

Intermediate 2A

[0085]To 0.05 g of DFMO in acetonitrile (5 mL) is added Hunigs base (400 μL, 2.3 mmole) followed by the addition of di-tert-butyl dicarbonate (250 μL). The contents are stirred overnight (20 hours). After adding DCM (1 mL) and sonicating, additional Di-tert-butyl dicarbonate is added (100 uL) and then after 15 minutes methanol (1 mL) was added. The mixture is stirred for 3 hours after which thin layer chromatography showed one spot. Concentration under vacuum, add ethyl acetate (15 mL) and ice and acidify to pH=4. Extract, dry (MgSO4) and then concentrate under vacuum and purify using isocratic 10% MeOH in DCM to afford Intermediate 2A (100 mg). ESI (M+Na) (405.2)

Intermediate 2B

[0086]To 65 mg (0.00017 mole) of the Intermediate 2A acid in THF / MeOH (9:1) (1 mL) cooled to 0° C. is added TMS diazomethane (170 μL, 2 eq). The mixture is warmed to RT (room temperature) and then stirred for an hour. Acetic acid (200 μL) is added an...

example 3

[0089]

[0090]To 0.1 mmole of the methyl ester of DFMO in DCM (10 mL) cooled to 0° C. is added a 20% solution of phosgene in toluene (0.21 mmole) in the presence of triethylamine (3 eq). After stirring for 24 hours to form the intermediate 3A, 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (0.5 mmole) is then added. Stirring is continued for 24 hours. To the reaction is then added water (5 mL) and then 1 N HCl (5 mL). The organic layer is then separated, dried with sodium sulfate and then concentrated under vacuum to afford Prodrug 3 (Formula (II) where Q1 and Q3 are —C(═O)OCH2-5-methyl-1,3-dioxol-2-one, Q2 and Q are H and Q5 is —CH3).

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Abstract

Novel compounds of formula (II) are disclosed. Compounds of formula (II) comprise ornithine derivatives or compounds that can metabolize under physiological conditions to ornithine. The pH and plasma stability of compounds of formula (II) is also described. Also disclosed are methods for the treatment of neurodegenerative diseases such as Alzheimer's Disease using compounds of formula (II).

Description

CLAIM FOR PRIORITY[0001]This application claims the benefit of priority to U.S. Provisional Application No. 62 / 415,590, filed Nov. 1, 2016, which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION[0002]Alzheimer's disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills, and eventually even the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear after age 60. Estimates vary, but experts suggest that as many as 5.1 million Americans may have Alzheimer's disease.[0003]Alzheimer's disease is the most common cause of dementia among older people. Dementia is the loss of cognitive functioning—thinking, remembering, and reasoning—and behavioral abilities, to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when...

Claims

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Application Information

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IPC IPC(8): C07C229/26A61P35/00A61P25/28C07D317/38
CPCC07C229/26C07D317/38A61P25/28A61P35/00A61P25/00A61K45/06C07D317/40C07C271/22
Inventor TAVARES, FRANCIS XAVIERVITEK, MICHAEL PETER
Owner RESILIO THERAPEUTICS LLC