Compounds, compositions and methods for the treatment of synucleinopathies

Inactive Publication Date: 2007-11-29
PROTEOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0028] In a sixth aspect, this invention is a method of treatment of Aβ, IAPP, other amyloids, and α-synuclein or NAC fibrillogenesis, in an in vitro environment. The method includes the step of administering into the in vitro environment a therapeutically effective amount of a compound of this invention. Preferably the compound is selected from the groups described below with respect to their activity against Aβ, IAPP, and NAC.
[0029] In another aspect, this invention is a method of treating the formation, deposition, accumulation, or persistence of α-synuclein/NAC fibrils, comprising treating the fibrils with an effective amount of the compounds of this inve

Problems solved by technology

Fibrillar Aβ amyloid deposition in Alzheimer's disease is believed to be detrimental to the patient and eventually leads to toxicity and neuronal cell death, characteristic hallmarks of Alzheimer's disease.
In Alzheimer's disease, Parkinson's and “systemic” amyloid diseases, there is currently no cure or effective treatment, and the patient usually dies within 3 to 10 years from disease onset.
For most of these amyloidoses, there is no apparent cure or effective treatment and the consequences of amyloid deposition can be detr

Method used

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  • Compounds, compositions and methods for the treatment of synucleinopathies
  • Compounds, compositions and methods for the treatment of synucleinopathies
  • Compounds, compositions and methods for the treatment of synucleinopathies

Examples

Experimental program
Comparison scheme
Effect test

example 1

3,4,3′,4′-Tetrahydroxybenzoin

Compound 1; DC-0001

Bis(3,4-methylenedioxy)benzoin

Compound 1B; DC-0001B

[0118]

[0119] A solution of piperonal (5 g) in ethanol (6.5 ml) was treated with a solution of potassium cyamide (0.5 g) in water (5 ml), then refluxed for 5 h. The resultant precipitate was filtered off, washed with water then crystallized from ethanol to give DC-0001B (2.24 g, 45%) as an off white crystalline solid. 1H-NMR (CDCl3) 7.52 (1H, dd, J 2, 8 Hz), 7.39 (1H, d, J 2 Hz), 6.73-6.82 (4H, m), 6.02 (2H, s), 5.91 (2H, m), 5.76 (1H, d, J 6 Hz) and 4.51 (1H, d, J 6 Hz).

[0120] M / z 287 ((M−CH)−, 100%).

Bis(3,4-methylenedioxy)benzil

[0121] A mixture of copper acetate (20 mg), ammonium nitrate (660 mg) and DC-0001B (2 g) in aq. acetic acid (80%, 10 ml) were refluxed together for 90 minutes. The mixture was cooled then poured into water (100 ml) and the product extracted into ethyl acetate (2×100 ml), dried and evaporated in vacuo to give a yellow gum. Trituration from ethanol gave b...

example 2

3,4,3′,4′-Tetrahydroxydiphenylmethane

Compound 3; DC-0003

[0132]

Bis(3,4-methylenedioxyphenyl)methanol

[0133] To a solution of piperonal (0.75 g) in solution in dichloromethane (25 ml) was added dropwise 3,4-(methylenedioxy)phenylmagnesium bromide (5 ml, 1M solution in toluene / THF). The mixture was stirred at room temperature overnight, then poured onto water, extracted with dichloromethane, dried and evaporated in vacuo to give the crude alcohol as a brown gum. Purification by column chromatography over silica gel eluting with ethyl acetate in CH2Cl2 (10 to 20%) gave the pure alcohol as a white gum (1.18 g, 87%).

[0134]1H-NMR (CDCl3) 6.7-6.8 (6H, m), 5.93 (4H, s), 5.66 (1H, bs) and 2.18 (bs).

Bis(3,4-methylenedioxyphenyl)methane

Compound 3B; DC-0003B

[0135] A solution of the alcohol (2.61 g) in methanol (25 ml) / tetrahydrofuran (30 ml) was shaken with Pd(OH)2 / C (20%, 100 mg) under an atmosphere of hydrogen for 12 hours. The mixture was filtered through Celite, then the solvents remove...

example 3

1,2-bis(3,4-dihydroxyphenyl)ethane

Compound 4; DC-0004

[0142]

1,2-bis-(3,4-dihydroxyphenyl)ethane

Compound 4; DC-0004

[0143] A solution of the tetrahydroxybenzil (see Example 1) (70 mg) in methanol (10 ml) with palladium hydroxide on carbon (20%, 10 mg) was stirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered through Celite, and the solvents removed in vacuo to give an orange gum. Separation by column chromatography over silica gel eluting with 20% ethyl acetate in dichloromethane gave DC-0004 as an off white gum (43 g, 68%).

[0144]1H-NMR ((CD3)2CO) 7.73 (4H, bs), 6.80 (2H, d, J 8 Hz), 6.79 (2H, d, J 2 Hz), 6.62 (2H, dd, J 2, 8 Hz) and 2.79 (4H, s).

[0145] M / z 245 ((M−H)+, 100%).

[0146] HPLC (Method 2) 31.7 minutes.

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Abstract

Bis- and tris-dihydroxyaryl compounds and their methylenedioxy analogs and pharmaceutically acceptable esters, their synthesis, pharmaceutical compositions containing them, and their use in the treatment of synucleinopathies, such as Parkinson's disease, and the manufacture of medicaments for such treatment.

Description

RELATED APPLICATIONS [0001] This application is a continuation in part of U.S. application Ser. No. 10 / 452,851 filed May 30, 2003 which claimed priority under 35 USC 119(e) to: (1) U.S. Provisional Application No. 60 / 385,144, filed May 31, 2002, (2) U.S. Provisional Application No. 60 / 409,100, filed Sep. 9, 2002, (3) U.S. Provisional Application No. 60 / 412,272, filed Sep. 20, 2002, (4) U.S. Provisional Application No. 60 / 435,880, filed Dec. 20, 2002, and (5) U.S. Provisional Application No. 60 / 463,104, filed Apr. 14, 2003. The entire contents of all of these applications are incorporated by reference into this application.TECHNICAL FIELD [0002] This invention relates to bis- and tris-dihydroxyaryl compounds and their methylenedioxy analogs and pharmaceutically acceptable esters, their synthesis, pharmaceutical compositions containing them, and their use in the treatment of amyloid diseases, especially Aβ amyloid disease, such as observed in Alzheimer's disease, IAPP amyloid di...

Claims

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Application Information

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IPC IPC(8): A61K31/165A61K31/045A61K31/135A61K31/36A61K31/16C07C39/15C07C39/16C07C39/17C07C69/017
CPCC07C39/15C07D491/08C07C39/17C07C69/017C07C215/50C07C217/32C07C233/56C07C235/24C07C235/38C07C235/52C07C235/54C07C235/56C07C235/74C07C235/76C07C273/1827C07C275/34C07C275/40C07D207/16C07D211/74C07D213/30C07D213/69C07D213/85C07D221/08C07D221/18C07D231/06C07D241/08C07D263/38C07D265/38C07D295/096C07D295/192C07D311/60C07D317/50C07D317/54C07D317/58C07D317/60C07D317/66C07D317/68C07D333/16C07D405/14C07D407/14C07D409/14C07D413/14C07D451/06C07D471/04C07D487/08C07C39/16
Inventor ESPOSITO, LUKECUMMINGS, JOELHUDSON, MICHAELSNOW, ALAN
Owner PROTEOTECH
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