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Novel dicarboxylic acid linked amino acid and peptide prodrugs of opioids and uses thereof

A technology of opioids and prodrugs, applied in the field of amino acid and peptide prodrugs, can solve problems such as unstable systemic utilization

Inactive Publication Date: 2012-07-11
SHIRE PLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There remains a need in the treatment of severe pain with opioids for products that retain all of the inherent pharmacological advantages of opioids, but avoid their major limitations: (1) induce adverse GI side effects, including chronic constipation; and (2) Low and unstable systemic availability following oral dosing

Method used

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  • Novel dicarboxylic acid linked amino acid and peptide prodrugs of opioids and uses thereof
  • Novel dicarboxylic acid linked amino acid and peptide prodrugs of opioids and uses thereof
  • Novel dicarboxylic acid linked amino acid and peptide prodrugs of opioids and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0114] Conventional techniques for the preparation / isolation of individual enantiomers, if necessary, include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or salts) using, for example, chiral high pressure liquid chromatography (HPLC). or racemates of derivatives).

[0115] Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, such as an alcohol, or in case the compound of formula (I) contains an acidic or basic moiety, a base or acid , such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixtures can be separated by chromatography and / or fractional crystallization and one or both diastereoisomers converted into the corresponding pure enantiomers by methods well known to the skilled person.

[0116] The chiral compounds of the present invention (and their chiral precursors) can be obtained in enantiomerically enriched form by chromatography, usually HPLC, on an...

Embodiment 1

[0787] Example 1 - General route to the synthesis of amino acid or peptide dicarboxylic acid conjugates of opioids

[0788] Schemes 1 (alcohol esters) and 2 (enol esters) below give two general routes for the synthesis of dicarboxylic acid-linked amino acid or peptide conjugates of opioids as their HCl or TFA salts. These synthetic routes are illustrated using a succinic acid linker. However, this applies to all dicarboxylic acid linkers of the invention.

[0789]

[0790] Scheme 1 - Route of dicarboxylic acid-linked amino acid opioid prodrugs (alcohol esters)

[0791]

[0792] Scheme 2 - Route of dicarboxylic acid-linked amino acid opioid prodrugs (enol esters)

[0793] The compounds listed in Table 8 can be prepared by these methods using meprotamol and valine as examples of hydroxy opioids and amino acids, respectively. It should be understood that other opioids can readily be substituted for meprotamol for conjugation to the various prodrug moieties described he...

Embodiment 2-

[0803] The synthesis of embodiment 2-oxycodone-[succinyl-(S)-valine] enol ester

[0804] Scheme 3 gives the general synthetic route of oxycodone-[succinyl-(S)-valine] ester.

[0805]

[0806] Scheme 3 - Synthesis of oxycodone-[succinyl-(S)-valine] enol ester from activated succinyl-(S)-valine ester

[0807] Synthesis of (N-hydroxysuccinimide)-succinyl-(S)-valine-O-tert-butyl ester in detail described

[0808] A solution of N,N-dicyclohexylcarbodiimide (958 mg, 4.64 mmol) in ethyl acetate (15 mL) was added to succinyl-(S)-valine- O-tert-butyl ester (1.21 g, 4.42 mmol) and N-hydroxysuccinimide (560 mg, 4.86 mmol). The reaction was stirred at 50 °C for 2 hours. The resulting mixture was cooled to room temperature and filtered through celite. The filtrate was washed twice with saturated aqueous sodium bicarbonate (50 mL), water (50 mL) and brine (50 mL), dried (MgSO 4 ) and concentrated to give the desired (N-hydroxysuccinimide)-succinyl-(S)-valine-O-tert-butyl ester...

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Abstract

The present invention concerns dicarboxylic acid linked amino acid and peptide prodrugs of opioid analgesics and pharmaceutical compositions containing such prodrugs. Methods for providing pain relief, decreasing the adverse GI side effects of the opioid analgesic and increasing the bioavailability of the opioid analgesic with the aforementioned prodrugs are also provided. In one embodiment, prodrugs having the amino acid side chains of valine, leucine, isoleucine and glycine; and mono-, di-and tripeptides thereof are provided.

Description

field of invention [0001] The present invention relates to the use of dicarboxylic acid-linked amino acid and peptide prodrugs of opioid analgesics, including oxycodone, codeine, and dihydrocodeine, to treat pain, minimizing the pain associated with the administration of the parent compound. Adverse gastrointestinal (GI) side effects and improved pharmacokinetics of individual opioids. Background of the invention [0002] Proper treatment of pain continues to represent a major challenge to patients and healthcare professionals. Optimal pharmacotherapy of pain requires selection of an appropriate analgesic that achieves rapid efficacy with minimal side effects. Full agonist opioid analgesics provide perhaps the most important option in the management of nociceptive pain and remain the gold standard of treatment. However, misuse and abuse of opioids is a widespread problem and may prevent physicians from prescribing these drugs. [0003] While providing good pain relief, op...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/485A61K31/55C07D223/04C07D489/02A61P23/00
CPCA61K31/485C07D223/04C07D489/02A61K31/55A61P1/00A61P23/00A61P25/04A61P25/36A61P43/00
Inventor 理查德·富兰克林伯纳德·T·戈尔丁罗伯特·G·泰森
Owner SHIRE PLC
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