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Neuroprotective and neuro-restorative iron chelators and monoamine oxidase inhibitors and uses thereof

A compound, alkoxy technology, applied in the field of novel multifunctional neuroprotective compounds

Inactive Publication Date: 2013-09-11
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] One of the major problems with the use of chelating agents as antioxidant drugs is the limited transport of these ligands or their metal complexes across cell membranes or other biological barriers

Method used

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  • Neuroprotective and neuro-restorative iron chelators and monoamine oxidase inhibitors and uses thereof
  • Neuroprotective and neuro-restorative iron chelators and monoamine oxidase inhibitors and uses thereof
  • Neuroprotective and neuro-restorative iron chelators and monoamine oxidase inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] Example 1. Synthesis of 5-[(methyl-2-propyn-1-ylamino)methyl]-8-quinolinol (M30)

[0124] The M30 described herein was synthesized as follows:

[0125]

[0126] Reagents: (a) HCl (32%), HCHO (37%), 0~rt; (b) N-methylpropargylamine, (Me 2 CH) 2 NEt, CHCl 3 , rt.

[0127] In water at 0°C, 14.6 g (0.1 mol) of 8-quinolinol, 16 mL of 32% HCl, and 16 mL (0.1 mL) of 37% formaldehyde were mixed with hydrogen chloride gas for 6 h. The solution was allowed to stand at room temperature for 2 hours without stirring. The resulting yellow solid was collected on a filter, washed with 90% ethanol and dried under vacuum to give 5-chloromethyl-8-quinolinol HCl salt A (19.0 g, 98%): 1 H NMR (250MHz, CDCl 3 , δ) 5.32 (s, 2H), 7.53 (m, 1H), 7.85 (m, 2H), 8.12 (m, 1H), 9.12 (m, 1H), 9.28 (m, 1H).

[0128] in 50mL CHCl 3 , 5-chloromethyl-8-quinolinol HCl salt A (2.707 g, 11.8 mmol) and diisopropylethylamine (DIPEA; 2.1 mL, 20.4 mmol, 2 eq) were mixed, and N- Methyl-N-propargylamin...

Embodiment 2

[0129] Example 2. Synthesis of Ester M30

[0130] The ester M30 described herein was synthesized as follows:

[0131]

[0132]A solution of 1 eq M30 and 1 eq triethylamine (TEA) in tetrahydrofuran (THF) under nitrogen atmosphere by dropwise addition of 1 eq corresponding acid chloride in THF (eg, R=-CH3, acetyl chloride) solution treatment. After completion (TLC or HPLC analysis), the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The crude product was purified by crystallization or column chromatography.

[0133] In this way, the following esters can be prepared, having at the 8-position of the group: -OCOCH 3 , -OCOCH 2 CH 3 , -OCOCH(CH 3 )CH 2 CH 2 CH 3 , -OCOCH 2 CH(CH 3 ) 2 , -OCOCH 2 Cl, -OCOCH 2 OCH 3 , -OCOCH 2 CH 2 OCH 2 CH 3 , -OCOCH=CH 2 , -OCOC(CH 3 )=CH 2 , -OCOCH=CH(CH 3 ), -OCOCH=CHPh, -OCOCH 2 CH 2 CH=CH 2...

Embodiment 3

[0134] Example 3. Synthesis of amino acid esters of M30

[0135] The M30 amino acid esters described herein were synthesized as follows:

[0136]

[0137] Using the procedure of Song, et al. (J.Med.Chem., 2005, 48, 1274-1277), t-Butoxycarbonyl (Boc) protected amino acid (5eq), N,N'-cyclohexylcarbodioxide imine (DCC; 5eq) and 4-dimethylaminopyridine (DMAP: 0.5eq) were reacted with M30 (1eq) in dry 4-dimethylaminopyridine (DMAP: 0.5eq) at room temperature 24h. The reaction was filtered and the DMF was vacuum dried. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography. In the case of aspartic acid and glutamic acid, the t-butyl protected beta and gamma carboxylic acids, respectively, were utilized. The purified product was treated with trifluoroacetic acid (TFA): dichloromethane (DCM) [1:1]. After 4 h, the solvent was removed in vacu...

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Abstract

8-Hydroxy-quinoline derivatives and 8-ethers, 8-esters, 8-carbonates, 8-acyloxymethyl, 8- phosphates, (phosphoryloxy)methyl, and 8-carbamates derivatives thereof are described that exhibit iron chelation, neuroprotective, neurorestorative, apoptotic and / or selective MAO-AB inhibitory activities.

Description

technical field [0001] The present invention relates to novel multifunctional neuroprotective compounds, in particular quinoline derivatives and residues with iron chelator function that confer anti-apoptotic and neuroprotective functions, and brain MAO inhibition (preferably in liver and small intestine) with little or no MAO inhibition). Background technique [0002] Iron is known to enhance the production of highly reactive and toxic hydroxyl groups, thereby stimulating oxidative damage. Iron is associated with many diseases, disorders and conditions because humans have no physiological means to eliminate excess iron. Examples of such diseases, disorders and conditions include hereditary hemochromatosis and thalassemia, which were initially treated with deferoxamine (DFO), a naturally occurring siderophore (introduced in the early 1960s), It was later replaced by the orally active iron chelator deferiprone (L1), and more recently by the orally active drug deferasirox. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/26C07D215/28C07D215/32A61K31/47A61P25/00
CPCA61P1/00A61P3/10A61P7/00A61P9/00A61P17/06A61P19/02A61P21/02A61P25/00A61P25/14A61P25/16A61P25/28A61P27/02A61P27/06A61P29/00A61P31/14A61P33/06A61P43/00C07D215/26C07D215/28C07D215/32C07D405/06A61K31/47
Inventor V·R·小祖拉夫斯基D·M·斯道特T·J·尼茨M·B.H.·尤蒂姆O·韦瑞伯
Owner VARINEL
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