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Hepatoprotectant acetaminophen mutual prodrugs

Inactive Publication Date: 2011-10-27
ACORDA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017]In some embodiments, the invention embraces a compound comprising an acetaminophen moiety and a hepatoprotectant moiety, wherein the compound is capable of sufficiently decreasing liver damage in an individual relative to a molar equivalent of acetaminophen administered under the same conditions.
[0018]In some embodiments, the invention embraces a compound comprising an acetaminophen moiety and a hepatoprotectant moiety, wherein the compound is capable of sufficiently decreasing kidney damage (e.g., renal toxicity) in an individual relative to a molar equivalent of acetaminophen administered under the same conditions.
[0029]In another aspect, the present invention provides methods of delaying the onset of acetaminophen action in an individual, the method comprising administering to the individual an effective amount of a compound of any one of formulas I, II or III wherein the compound provides a slower onset of acetaminophen action as compared to acetaminophen. In another aspect, the present invention provides methods of delaying the onset of hepatoprotectant action in an individual, the method comprising administering to the individual an effective amount of a compound of any one of formulas I, II or III wherein the compound provides a slower onset of hepatoprotectant action as compared to the hepatoprotectant of the compound.

Problems solved by technology

However, it is well known that under certain conditions acetaminophen may be toxic to the liver (known as hepatotoxicity).
BMJ 1998; 316:1724-1725), which complicates the acetaminophen safety profile as it imparts a high degree of uncertainty in the toxic dose for a given patient.
However, NAC only has been shown to be effective at minimizing hepatic toxicity when administered within 8-10 hours of acute exposure to toxic blood levels of acetaminophen.

Method used

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Examples

Experimental program
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example 1

Synthesis of (S)-4-acetamidophenyl 2-amino-4-(methylthio)butanoate

[0168]

[0169]A white color milky suspension of L-methionine (3 g, 20 mmol) in THF (30 mL) and 10% NaOH solution (10 mL) was stirred for 30 min before turning into a clear colorless solution. To this Boc anhydride (6.58 g, 30.1 mmol) was added slowly over about 15 min at RT. The clear colorless solution was stirred further 12 h at RT. The reaction was monitored by TLC (DCM: MeOH (95:5 mL); TLC silica gel 60 F254 (Merck), detection with Ninhydrin solution (5% in Methanol); Rf values, product: 0.7, L-methionine: 0). After 12 h the clear colorless solution was turned to light brown color solution. This light brown color solution was evaporated under vacuum; a light brown color gummy material (thick oil) was obtained which was taken into ethyl acetate and water (60 mL: 10 mL); pH of the solution was adjusted to 6 by using 20% citric acid solution (15 mL). The light brown layer of ethyl acetate was separated and dried over s...

example 2

Synthesis of 2-acetamido-3-((2-acetamido-3-(4-acetamidophenoxy)-3-oxopropyl)disulfanyl)propanoic acid

[0172]

[0173]To a stirring milky suspension of N-Acetyl cysteine (0.2 g; 1.23 mmol) in DCM (5 mL) at 0° C. was added a catalytic amount of acetic acid followed by N-chlorosuccinimide (0.18 g; 1.35 mmol). The milky suspension was stirred at 0° C. for 30 min. In another round bottom flask, a milky suspension of 4-acetamidophenyl 2-acetamido-3-mercaptopropanoate (0.25 g; 1.23 mmol) in DCM (5.0 mL) and TEA (0.28 mL 2.45 mmol) was prepared and cooled to at 0° C. This milky suspension was added to the above N-Acetyl cysteine suspension. The resulting reaction mixture turned from milky suspension to a clear light orange solution within 15 min of 2.5 hours of stirring at 0° C. The reaction mixture was then evaporated under vacuum at 40° C. to yield light orange syrup, which was washed with diethyl ether (2×20 mL) and finally purified by preparative HPLC to generate a white crystalline solid ...

example 3

Synthesis of 3-((3-(4-acetamidophenoxy)-2-amino-3-oxopropyl)disulfanyl)-2-aminopropanoic acid dihydrochloride

[0174]

[0175]To a stirring colorless suspension of disulfide-linked cysteine (3,3′-disulfanediylbis(2-aminopropanoic acid), 5 g; 20.80 mmol) in THF (50 mL) was added 10% NaOH solution (25 mL) and stirred for 15 mints at RT. After 15 minutes, colorless suspension turned to a clear colorless solution, which was cooled to 0° C. and Boc anhydride (13.6 g; 62.42 mmol) was added. The reaction mass was warmed to RT and stirring continued for 12 hours. The reaction was monitored by TLC (methanol: dichloromethane (20:80); TLC silica gel 60 F254 (Merck); detection with λ 254 nm UV; Rf values, starting material: 0, boc-protected starting material: 0.2). After the reaction was completed, the reaction mixture was evaporated to dryness. The crude compound was taken into DI water (20 mL) and washed with ethyl acetate (50 mL). The ethyl acetate layer was removed and the aqueous layer was acid...

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Abstract

The present invention provides hepatoprotectant acetaminophen mutual prodrugs, which have an acetaminophen moiety covalently linked to a second moiety that may act as a hepatoprotectant against acetaminophen hepatotoxicity. Additionally, acetaminophen mutual prodrugs may have improved water solubility which may provide better suitability for parenteral and other dosage forms relative to administration of acetaminophen. Also provided are methods of treating a disease or condition that is responsive to acetaminophen (such as fever, pain and ischemic injury) using hepatoprotectant acetaminophen mutual prodrugs, as well as kits and unit dosages.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority benefit of U.S. Provisional Application No. 61 / 054,777, entitled “Hepatoprotectant Acetaminophen Mutual Prodrugs” filed May 20, 2008, the content of which is hereby incorporated by reference in its entirety as if it was set forth in full below.BACKGROUND OF THE INVENTION[0002]Acetaminophen (also known as paracetamol, and chemically known as N-(4-hydroxyphenyl)acetamide)) is a widely-used analgesic for the treatment of a variety of conditions related to pain. For example, acetaminophen is used to manage pain from surgery or traumatic injury, and pain produced by chronic inflammatory conditions such as osteoarthritis, rheumatoid arthritis, and lower back pain. In some cases acetaminophen is used to treat pain from mixed nociceptive / neuropathic etiologies, such as cancer or fibromyalgia. Acetaminophen also may have utility in the management of other conditions, such as myocardial injury (Spiler N M, Rork T H,...

Claims

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Application Information

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IPC IPC(8): A61K31/616C07D277/14C07H19/16A61K31/426A61K31/24A61K31/515A61K31/551A61K31/485A61K31/407A61K31/5415A61K31/522A61K31/4402A61K31/5513A61K31/5517A61P29/00C07C323/59
CPCA61K31/195A61K31/485A61K45/06A61K2300/00A61K31/216A61P25/00A61P25/04A61P29/00A61P29/02A61P39/00A61P43/00A61P9/00A61P9/10C07C233/01C07C233/07A61K9/0053C07C323/52
Inventor MUHAMMAD, NAWEEDBLEY, KEITH R.TOBIAS, JEFFREY
Owner ACORDA THERAPEUTICS INC
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