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Water-soluble acetaminophen analogs

a technology of acetaminophen and analogs, applied in the field of water-soluble acetaminophen analogs, can solve the problems of affecting and affecting the development of effective therapeutic acetaminophen beyond oral dosage forms, so as to delay the onset of acetaminophen action and slow the onset of acetaminophen

Inactive Publication Date: 2011-09-01
ACORDA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016]In another aspect, the present invention provides methods of delaying the onset of acetaminophen action in an individual, the methods comprising administering to the individual an effective amount of an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein the compound provides a slower onset of acetaminophen action as compared to acetaminophen.

Problems solved by technology

However, the use of certain opioids is often accompanied by significant adverse side-effects (e.g., respiratory depression, biliary spasm, constipation, sedation, addiction and abuse potential and post-operative nausea and vomiting, etc.) which make them less desirable.
The alternative use of NSAIDs, however, impairs blood clotting (in addition to the side effects previously mentioned), which is highly undesirable in post-operative settings which require active wound healing and blood clotting.
Despite a desire for an acetaminophen dosage form suitable for parenteral administration, development of effective therapeutic acetaminophen beyond oral dosage forms has been limited.
However, this acetaminophen derivative is reportedly not readily amenable to chemical and / or enzymatic hydrolysis (and thus not amenable to clinical use) as it requires alkaline phosphatase and about 15 hours in vitro to yield the desired acetaminophen drug from the derivative (see Chemical and Pharmaceutical Bulletin 29 (2): 577-580, 1981).
These products are not optimal clinical solutions either because of their tolerance profile or administration requirements.

Method used

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  • Water-soluble acetaminophen analogs
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  • Water-soluble acetaminophen analogs

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of (4-acetamidophenoxy)methyl dihydrogen phosphate

N-(4-(methylthiomethoxy)phenyl)acetamide

[0106]

[0107]To a stirred ash-colored suspension of sodium hydride (1.9 g; 75.49 mmol) in hexamethylphosphoramide (HMPA; 25 mL) cooled to 0° C., a solution of acetaminophen (10 g; 66.22 mmol in 35 mL of HMPA) was added slowly in about 15 minutes. The ash-colored suspension changed to a light-brown clear solution after 15 minutes of stirring. The reaction mixture was stirred for an additional 20 minutes at 0° C. Then chloromethyl methyl sulfide (7.67 g; 79.47 mmol) was slowly added to the reaction mixture over about 10 minutes. There was no color change in reaction mixture. The reaction mixture was slowly warmed to room temperature and stirring continued for 3 hr. Rf values of starting material and product, in a methanol:dichloromethane solvent system (3:97) on TLC silica gel 60 F254 (Merck) detected at λ 254 nm, were 0.4, and 0.6, respectively. The reaction mixture was quenched with sa...

example 2

Synthesis of Sodium (4-acetamidophenoxy)methyl phosphate

[0112]

[0113]To a stirring milky suspension of (4-acetamidophenoxy)methyl dihydrogen phosphate (20 mg; 0.076 mmol) in ethyl acetate (5 mL), a solution of sodium-2-ethyl hexanoate (25 mg; 0.15 mmol) in ethyl acetate (2 mL) was added. The reaction suspension was stirred for 3 h. The milky suspension turned to a white solid after one hour, which was filtered, washed with ethyl acetate (3×15 mL) and ether (3×20 mL) to yield 10 mg (50% yield) of product as a white solid (melting range: 206-209° C.). 1H NMR (400 MHz, DMSO): δ 9.8 (s, 1H), 7.41 (d, 2H, J=10.8 Hz), 6.96 (d, 2H, J=11.6 Hz), 5.26 (d, 2H, J=10.4 Hz), 1.97 (s, 3H).

example 3

Solubility of Acetaminophen Analogs

[0114]Solubility of (4-acetamidophenoxy)methyl dihydrogen phosphate and its disodium salt is listed in Table. 1.

TABLE 1Solubility of Acetaminophen ProdrugsSolubilitySoluteSolvent(mg / mL)(4-Water145acetamidophenoxy)methyldihydrogen phosphateSodium (4-Water160acetamidophenoxy)methylphosphate

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Abstract

The present invention provides water-soluble acetaminophen prodrugs and formulations which may be suitable for parenteral administration. Methods of treating a disease or condition responsive to acetaminophen (such as fever and / or pain) using the acetaminophen prodrugs, as well as kits, unit dosages, and combinations with additional pharmaceutical agent(s) are also provided.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority benefit of U.S. Provisional Application No. 61 / 054,774, entitled “Water-Soluble Acetaminophen Analogs” 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 (USAN) or paracetamol (INN) (chemically known as N-(4-hydroxyphenyl)acetamide) is an antipyretic and analgesic commonly used to manage fever of any etiology, minor and severe pains (including post-operative pain) and a variety of aches. Acetaminophen is well tolerated and lacks many of the undesired effects of other analgesics, such as non-steroidal anti-inflammatory drugs (NSAIDs) or types of cyclooxygenase (COX) inhibitors (e.g., stomach lining irritation, adverse effects on platelets and renal function, fetal ductus arterious closure complications and Reye's syndrome).[0003]Acetaminophen has also been shown to be effective in pr...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/664C07F9/22A61P25/04A61P29/00
CPCC07F9/091A61K31/661A61P25/00A61P25/04A61P25/28A61P29/00A61P29/02A61P43/00A61P9/00A61P9/10A61K9/0019A61K45/06C07F9/094
Inventor MUHAMMAD, NAWEEDBLEY, KEITH R.
Owner ACORDA THERAPEUTICS INC
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