Compound suitable for the treatment of synucleopathies

Inactive Publication Date: 2014-12-11
NEUROPORE THERAPIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016]It turned out that the organic heteroaromatic compounds according to the present invention having formula (I) specifically block the formation of propagating dimers and toxic SYN

Problems solved by technology

However, patients with PD also develop non-motor symptoms such as memory and olfactory deficits that result from the degeneration of other neu

Method used

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  • Compound suitable for the treatment of synucleopathies
  • Compound suitable for the treatment of synucleopathies
  • Compound suitable for the treatment of synucleopathies

Examples

Experimental program
Comparison scheme
Effect test

Example

Example 1

[0085]The chemical synthesis of the compounds having formula (I) as defined above is exemplified by the synthesis of the compound having the following structure:

[0086]The synthesis scheme is depicted in FIG. 8.

1. Synthesis of 2-piperazinyl-thiazole-5-carboxylic acid 2

[0087]2-Bromothiazole carboxylic acid 1 (1 g; 4.8 mmol) and piperazine (6.2 g; 72 mmol; 24 equiv.) were dissolved in dioxane, K2CO3 (3.32 g; 24 mmol; 5 equiv.) was added and the suspension was refluxed overnight. The solvent was removed at the rotary evaporator, the residue dissolved in ethanol, filtered and recrystallized. The crude product was dried at the oil pump and directly used in the following step.

2. Protection of 2 with Boc

[0088]Crude 1, triethylamine (24 mmol; 3.4 ml) and di-tert-butyl-dicarbonate (14.4 mmol; 3.14 g) were dissolved in methanol and refluxed overnight. The solvents were removed at the rotary evaporator and the residue was chromatographed over a short silica gel column.

[0089]Yield of 3:...

Example

Example 2

The Compounds of Formula Ia

[0100]

may be prepared by the methods of known chemical reactions and procedures, some from starting materials which are well known in the art.

Example

Example 3

[0101]To screen the effectiveness and ideal doses for the HAOC (Heteroaromatic organic compounds) of the present invention at blocking SYN aggregation two sets of assays can be utilized. The first set involves in vitro assays in cell free and cell based systems and the second includes in vivo studies in transgenic mouse models of PD.

[0102]In the present example the following HAOC, denominated as NPT200-5, was used:

[0103]The objective is to identify with the in vitro assays a positive response by demonstrating a 50% effect in 2 out of the 3 assays at a 1 μM dose.

[0104]1. In Vitro Assays of SYN Aggregation and Toxicity

[0105]The in vitro studies include the following: i) effects on SYN oligomers in a cell free immunoblot assay of SYN aggregation; ii) effects on SYN accumulation and neurite outgrowth in neuronal cultures infected with a LV-SYN construct; and iii) effects on SYN oligomers in neuronal cultures infected with a LV-SYN construct.

[0106]For this purpose, recombinant S...

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Abstract

The present invention relates to certain heteroaromatic compounds of Formula (Ia), or pharmaceutically acceptable salts thereof, and uses of such compounds in the treatment of synucleopathies.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 13 / 516,543, filed Aug. 28, 2012, which is a U.S. National Phase Application of International Application No. PCT / US2010 / 060862, filed Dec. 16, 2010, which claims priority to U.S. Provisional Application No. 61 / 287,082, filed Dec. 16, 2009, the entire contents of each of which is incorporated herein by reference in their entireties.BACKGROUND OF THE INVENTION[0002]The present invention relates to compounds suited to be used to treat and / or prevent synucleopathies.[0003]Protein misfolding and aggregation into toxic oligomers has been linked with the neurodegenerative process in Alzheimer's Disease (AD), Parkinson's Disease (PD) and other age-associated neurological disorders. Together, AD and PD affect over 10 million people in the US and Europe alone. In PD and related conditions such as Dementia with Lewy bodies (DLB), Parkinson's Disease Dementia (PDD), and Multiple System A...

Claims

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Application Information

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IPC IPC(8): C07D417/14C07D403/14C07D413/14
CPCC07D417/14C07D403/14C07D413/14A61P21/02A61P25/00A61P25/14A61P25/16A61P25/28C07D403/12C07D413/12C07D417/12C07D473/00C07D487/04A61K31/519
Inventor MASLIAH, ELIEZERROCKENSTEIN, EDWARD M.WRASIDLO, WOLFGANGTSIGELNY, IGOR FLINT
Owner NEUROPORE THERAPIES
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