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Unique Dual-Action Therapeutics

a dual-action, therapeutic technology, applied in the direction of biocide, application, drug composition, etc., can solve the problems of inability to independently liberate two moieties in vivo, adverse gastrointestinal effects of indomethacin and other nsaids either in prophylaxis or in therapy risks, allergic reactions, and sometimes severe ulcerations

Inactive Publication Date: 2012-01-12
RUTGERS THE STATE UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The chronic use of indomethacin and other NSAIDs either in prophylaxis or in therapy risks adverse gastrointestinal effects, renal toxicity, allergic responses, and occasionally severe ulcerations.
Although doubly functionalized with an NSAID and an anti-cholinergic, in this case the two moieties could not be independently liberated in vivo.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Materials and Methods

[0034]All reactants and solvents were of the highest purity commercial grade and were employed without further purification. The suppliers of uncommon reactants are indicated for those reactions and assays reported herein which employ a specialized reagent. All reactions were performed in oven-dried apparatus. 1H NMR and 13C NMR, spectra were recorded on a 500 MHz (Bruker) multinuclear spectrometer and chemical shifts are reported as ppm. All thin layer chromatography (TLC) was performed on Analtech silica gel plates (250 microns). Elemental analyses were performed at Quantitative Technologies (QTI), Inc. The 2-(2-methoxynaphthalene-6-yl)propanoic acid (naproxen) used in this work was the (S)-enantiomer. All other reagents were used as racemates.

Examples by METHOD A

[0035]By METHOD A, an NSAID converted to its acid chloride is coupled to 4-hydroxybenzaldehyde, the aldehyde reduced to a benzyl alcohol, and that alcohol condensed with an appropriate chloroformate (...

example 2

Preparation of 2-(4-Isobutylphenyl)propanoyl Chloride [ibuprofen acid chloride]

[0037]

[0038]A silicone oil bath was heated to 130° C. A reaction set-up was prepared consisting of a 200 mL round bottom flask with condenser and rubber septum-capped joints. After mixing the reactants as described below, the flask and contents were placed in the oil bath. Thionyl chloride (29.7 g, 0.25 mol) was added via glass syringe to 2-(4-isobutylphenyl)propionic acid (10.3 g, 0.05 mol) in dry toluene (60 mL) at room temperature under nitrogen atmosphere. The reaction mixture was then heated at 130° C. for 2.5 hr, removed from the oil bath, and allowed to cool to room temperature. The condenser walls were rinsed with 10 mL of toluene and the washing was added to the reaction mixture. The toluene and excess thionyl chloride were removed under reduced pressure and the light yellow liquid was held under vacuum pump for 45 min. This pale yellow-colored oil weighed (9.98 g) and represented a yield of 62% ...

example 3

Preparation of (S)-2-(2-Methoxynaphthalene-6-yl)propanoyl Chloride [naproxen acid chloride]

[0042]

[0043]By the method and equipment described in Example 2, 25.8 g (0.22 mol) of thionyl chloride was added via glass syringe to 10.0 g (0.043 mol) of (S)-2-(2-methoxynaphthalene-6-yl)propanoic acid (also known as naproxen) in 60 mL of dry toluene at room temperature under nitrogen atmosphere. The reaction mixture was then heated at 130° C. for 2.5 hr and worked up as described. Evaporation in vacuo began to precipitate a light yellow solid to which 40 mL of anhydrous hexane were added. The hexane and the suspended yellow solid were stirred vigorously under dry nitrogen atmosphere for 10 min and filtered to obtain, after vacuum drying, 9.85 g of light yellow acid chloride. Dry hexane was added (40 mL), and stirred for 10 min. under nitrogen. This crude product was stored in a nitrogen flushed glass vial and used for the coupling reaction without additional purification. The yield of 79%, f...

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Abstract

A new family of therapeutics which provides a controlled-release delivery platform for non-steroidal anti-inflammatory agents on an ester or an ester-carbonate backbone is disclosed herein. These agents are reversible inhibitors of acetylcholinesterase and are thus useful for clinical conditions benefiting from inflammation suppression and cholinergic intervention. These compounds are of the general formula wherein n=0, 1; X═C, Si, and N+ and NSAID=ibuprofen, naproxen, indomethacin and diclofenac. Other embodiments are also disclosed.

Description

[0001]This invention relates to a new class of reversible inhibitors of acetylcholinesterase (International Enzyme classification EC3.1.1.7) which serve simultaneously as pro-drugs capable of releasing non-steroidal anti-inflammatory agents (NSAIDs) by hydrolysis at either one or two chemically different hydrolytically-active loci.BACKGROUND OF THE INVENTION[0002]Inflammatory processes, often amenable to address by non-steroidal anti-inflammatories such as ibuprofen, naproxen, indomethacin and diclofenac, are inherent in the pathologies of multiple sclerosis, Alzheimer's disease, depression, amyotrophic lateral sclerosis, dementia, Parkinson's disease, and other neurodegenerative states. Several of these diseases are also independently characterized by perturbation of cholinergic balance and hence therapies combining cholinesterase inhibitors and inflammation mediators are believe to represent a dual benefit.[0003]The chronic use of indomethacin and other NSAIDs either in prophylaxi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/695C07C69/96A61P29/00C07D209/26A61K31/404C07F7/10A61K31/265
CPCA61K31/19A61K47/48023A61K31/405A61K31/196A61K47/54A61K47/55C07C2602/10C07F7/081A61K31/192C07D209/28A61P29/00A61K9/0014C07C69/96C07C229/42C07F7/0812
Inventor LASKIN, JEFFREYHECK, DIANEHUAN, MOU-TUANFABIO, KARINELACEY, C. JEFFREYYOUNG, SHERRIMOHANTA, PRAMODGUILLON, CHRISTOPHEHEINDEL, NED
Owner RUTGERS THE STATE UNIV
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