Methods for treating neurodegenerative diseases

A neuron, pathogenic technology, applied in neurological diseases, neuromuscular system diseases, muscular system diseases, etc.

Inactive Publication Date: 2013-04-17
COYOTE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Depletion of TDP-43 by TARDBP siRNA in Neuro-2a cells also resulted in inhibition of the biological activity of the Rho family of small G proteins

Method used

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  • Methods for treating neurodegenerative diseases
  • Methods for treating neurodegenerative diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0260] Example 1: Synthesis of 5E, 9E, 13E-geranylgeranyl acetone

[0261] 01245-Trans isomer: 5E, 9E, 13E-Synthesis of geranylgeranyl acetone 1: 5-trans isomer: 5E, 9E, 13E-Synthesis of geranyl geranyl acetone 1 can Follow the steps outlined in Protocol 1 to complete.

[0262] plan 1

[0263]

[0264] 2E,6E-farnesyl alcohol 3 (where the geometry of the C2 and C6 positions have been fixed as trans or E) was designed and used as a commercially available Starting material for phyllogeranylacetone 1. The alcohol functional group of 2E,6E-farnesyl alcohol 3 was passed through phosphorus tribromide (PBr) in diethyl ether (EE) at 0 °C 3 ) or Ph in acetonitrile (ACN) 3 P and CBr 4 was converted to the corresponding bromide 4. The resulting bromide was then reacted with the carbanion (obtained from the reaction of ethyl acetoacetate 5 and sodium ethoxide) to yield the desired 5E,9E-farnesyl ketoester 6. Hydrolysis and decarboxylation of the resulting ketoester 6 using aqueou...

Embodiment 2

[0267] Example 2: Synthesis of 5-Z, 9E, 13E-geranylgeranyl acetone

[0268] Scenario 2

[0269]

[0270] 2E,6E-Farnesyl alcohol 3 (where the geometry of the C2 and C6 positions have been fixed as trans or E) was used as the commercially available 5Z,9E,13E-geranylgeranol The starting material for 2-methyl acetone. Farnesyl alcohol 3 reacted with phosphorus tribromide (PBr) in diethyl ether (EE) at 0 °C 3 ) or Ph in acetonitrile (ACN) 3 P and CBr 4 The reaction yielded the desired bromide 4, which subsequently reacted with the carbanion (obtained from the reaction of ethyl acetoacetate 5 and sodium ethoxide) to yield the desired 5E,9E-farnesyl ketoester 6. Hydrolysis and decarboxylation of the resulting ketoester 6 using aqueous 5N KOH yielded the desired 5E,9E-farnesylacetone 7, which was the basis for the synthesis of 5E,9E,13E-geranylgeranylacetone 1 and 5Z, One of the important intermediates of 9E, 13E-geranylgeranyl acetone 2.

[0271] To obtain a product with cis...

Embodiment 3

[0273] Example 3: Synthesis of 5Z, 9E, 13E-geranylgeranylacetone

[0274] 5 cis isomers: 5Z, 9E, 13E-geranyl geranyl acetone 2 Alternative synthetic methods: 5Z, 9E, 13E-geranyl geranyl acetone 2 Alternative synthetic methods can be as follows Scenario 3 is complete.

[0275] Option 3

[0276]

[0277] 5E,9E-Farnesylacetone 7 as an important intermediate can be used to generate an additional double bond in the cis-(Z)-direction. In one approach, the reaction of 5E,9E-farnesylacetone 7 with Wittig reagent 16 can generate conjugated ester 12 with cis-(Z)-geometry at the C2 position. Subsequent reduction of ester 12 by lithium aluminum hydride (LAH) yields the corresponding alcohol 13, which can then be converted to the corresponding bromide 14. Conversion of bromide 14 to ketoester 15, followed by hydrolysis and decarboxylation yields the desired 5-cis(Z)-isomer, 5Z,9E,13E,-geranylgeranylacetone (2).

[0278] In an alternative approach, the reaction of 5E,9E-farnesylaceto...

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Abstract

This invention relates to the 5-cis and 5-trans isomers of geranylgeranyl acetone, preferably such synthetic isomers, and pharmaceutical compositions containing such isomers. Other aspects of this invention relate to the use of geranylgeranyl acetone and its isomers in methods for inhibiting neural death, increasing neural activity, and increasing axon growth and cell viability. Geranylgeranyl acetone is a known anti-ulcer drug used commercially and in clinical situations. GGA has also been shown to exert cytoprotective effects on a variety of organs, such as the eye, brain, and heart.

Description

[0001] Cross References to Related Applications [0002] Pursuant to 35 U.S.C. §119(e), this application claims priority to U.S. Provisional Application No. 61 / 379,316, filed September 1, 2010, and U.S. Provisional Application No. 61 / 510,002, filed July 20, 2011 Priority, the entire contents of each of the aforementioned US provisional applications are hereby incorporated by reference. technical field [0003] The present invention generally relates to methods of inhibiting neurodeath and increasing neuronal activity using the compound geranylgeranylacetone (GGA), and compositions useful for these indications. The invention also relates to the cis and trans isomers of geranylgeranylacetone and mixtures of the various isomers of GGA and their therapeutic use. Background technique [0004] Geranylgeranylacetone is an acyclic isoprenoid compound with a retinoic acid skeleton, which has been shown to induce heat shock proteins in various types of expressed in the organization...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C49/203C07C43/15C07C45/65A61P25/28A61K31/121
CPCA61K9/10A61K31/121C07B2200/09C07C29/147C07C45/59C07C45/676C07C49/203C07C67/343A61P21/02A61P25/00A61P25/28C07C69/738C07C69/587C07C33/02C07C43/15C07C43/303C07C45/65
Inventor 本·A·巴雷斯诺基·纳卡亚马希罗阿基·塞里扎瓦安库什·B·阿加德
Owner COYOTE PHARMA
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