Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-07-22
2004-05-25
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S281000, C514S282000, C546S044000, C546S045000, C546S046000, C424S078290
Reexamination Certificate
active
06740641
ABSTRACT:
1. FIELD OF THE INVENTION
The present invention relates to glucoside and glucuronide derivatives of hydromorphone, dihydromorphine, and dihydroisomorphine and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising glucoside or glucuronide derivatives of hydromorphone, dihydromorphine, or dihydroisomorphine or a pharmaceutically acceptable salt thereof; and methods for treating or preventing pain in a patient comprising administering to a patient in need thereof a glucoside or glucuronide derivative of hydromorphone, dihydromorphine, or dihydroisomorphine or a pharmaceutically acceptable salt thereof.
2. BACKGROUND OF THE INVENTION
Morphine and its known derivatives are opiates, which have pain-relief properties and are therefore useful in the treatment of chronic and acute pain in humans and other mammals. For example, morphine, hydromorphone, diamorphone, and oxymorphone are widely used as analgesic agents to control pain. Other commonly used, but more mildly acting, analgesics include codeine, dihydrocodeine, and nalbuphine.
Morphine was first isolated in 1806 and remains an important drug for treatment of moderate to severe pain, such as pain caused by cancer or surgery (
T. Reisine and G. Pasternak, Opioid Analgesics and Antagonists, in Goodman and Gilman's The Pharmacological Basis of Therapeutics
521 (9th ed. 1996)). Although highly effective for relieving pain, presently used opiates may cause side effects (Id. at 536). In addition, the responses of individual patients to different opioids-purified alkaloids isolated from crude opium—can vary dramatically (Id. at 537). The mechanisms underlying this variation are not well understood (Id.). Furthermore, each opioid has a different potency, duration of action, and solubility (R. Twycross,
Opioids, in Textbook of Pain,
953-955 (3rd ed. 1994)).
Morphine and other clinically used opioids exert their analgesic effect by binding to neuronal opiod receptors. Neuronal opioid receptors are distributed throughout the nervous system and classified as mu (&mgr;), kappa (&kgr;) and delta (&dgr;) receptors. Each receptor class has a different binding affinity for each particular opioid. Opioid receptors work by activating an intracellular signaling pathway that decreases cyclic AMP, increases potassium efflux, and decreases calcium influx, thereby decreasing release of neurotransmitters (such as substance P) that are involved in the transmission of pain signals. Each receptor class achieves this effect using a different G-protein for signal transduction.
When bound to a particular ligand, each opioid-receptor class exerts a particular therapeutic effect. Ligand-bound mu receptors provide analgesia and euphoria. But ligand-bound kappa receptors are associated with paroxysm and diuresis and ligand-bound delta receptors are associated with dysphoria. Thus, opioids that bind selectively to mu receptors are preferable pain killers, since they avoid the undesirable side effects that result from binding to delta and kappa receptors. Morphine and other opioids can be selective mu-receptors binders, but only at low doses. Accordingly, there is a clear need in the art for mu-receptor binders that are more selective than morphine and other clinically used opioids, that have a higher therapeutic index for analgesia than morphine and other clinically used opioids, or that can be administered at doses larger than those for morphine and other clinically used opioids.
It is also known that glycoconjugates of opiates can exert pharmacological effects. For example, morphine-6-glucuronide, a glycoconjugate metabolite of morphine, is a more potent analgesic than morphine and morphine-3-glucuronide (G. J. Mulder,
Trends in Pharmacol. Sci.,
13(8):302-304 (1992) and Osborne et al.,
The Lancet
828 (1988)).
WO 97/21416 discloses a series of carbohydrate derivatives of biologically active opiates having at least one residue of carbohydrate per opiate molecule.
WO 98/54196 discloses sugar derivatives of opiate compounds comprising at least one sugar residue coupled with at least one opiate residue through an &agr;-glycosidic bond. The sugar derivatives of opiate compounds allegedly have analgesic properties.
WO 93/05057 discloses glucuronides of 4,5-epoxymorphinanes that are allegedly useful as analgesic agents and methods for their preparation.
M. Zheng et al., Xenobiotica, 32(5):427-439 (2002) discloses particular metabolites of hydromorphone.
There remains a clear need in the art for improved compounds, particularly mu-receptor-selective compounds, and methods for using them to treat or prevent pain.
Citation or identification of any reference in Section 2 of the application is not an admission that such reference is available as prior art to the application.
3. SUMMARY OF THE INVENTION
The present invention relates to 3-O-glucosylhydromorphone and pharmaceutically acceptable salts thereof.
The present invention also relates to 3-O-glucosyldihydroisomorphine and pharmaceutically acceptable salts thereof.
The present invention further relates to 6-O-glucosyldihydroisomorphine and pharmaceutically acceptable salts thereof.
The present invention still further relates to 3-O-glucosyldihydromorphine and pharmaceutically acceptable salts thereof.
The present invention still further relates to 6-O-glucosyldihydromorphine and pharmaceutically acceptable salts thereof.
The present invention still further relates to nordihydromorphine-3-glucuronide and pharmaceutically acceptable salts thereof.
The present invention still further relates to nordihydroisomorphine-3-glucuronide and pharmaceutically acceptable salts thereof.
The present invention still further relates to norhydromorphone-3-glucuronide and pharmaceutically acceptable salts thereof.
3-O-Glucosylhydromorphone, 3-O-glucosyldihydroisomorphine, 6-O-glucosyldihydroisomorphine, 3-O-glucosyldihydromorphine, 6-O-glucosyldihydromorphine, nordihydromorphine-3-glucuronide, nordihydroisomorphine-3-glucuronide, norhydromorphone-3-glucuronide, or pharmaceutically acceptable salts thereof (a “compound of the invention”) is useful for treating or preventing pain in a patient.
In one embodiment, the compounds of the invention are in isolated and purified form.
The invention also relates to pharmaceutical compositions comprising an effective amount a compound of the invention and a pharmaceutical acceptable carrier or vehicle. These compositions are useful for treating or preventing pain in a patient.
The invention further relates to methods for treating or preventing pain in a patient comprising administering to a patient in need of such treatment or prevention an effective amount of a compound of the invention.
The present invention may be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.
4. DETAILED DESCRIPTION OF THE INVENTION
4.1 Definitions
3-O-Glucosylhydromorphone has the structural formula (I):
3-O-Glucosyldihydroisomorphine has the structural formula (II):
6-O-Glucosyldihydroisomorphine has the structural formula (III):
3-O-Glucosyldihydromorphine has the structural formula (IV):
6-O-Glucosyldihydromorphine has the structural formula (V):
Nordihydromorphine-3-glucuronide has the structural formula (VI):
Nordihydroisomorphine-3-glucuronide has the structural formula (VII):
Norhydromorphone-3-glucuronide has the structural formula (VII):
As used herein, the term “isolated and purified” means isolated from another component or from other components of a naturally occurring source (such as a plant or animal cell, including a hepatocyte; cell culture; tissue; in vivo fluid including intracellular and extracellular fluid, including blood and plasma; and ex vivo fluid including sputum, urine, sweat, semen, menstrual fluid, and milk) or from a synthetic organic chemical reaction mixture, and processed through one or more purifying steps that separate the compound of the invention from other molecules associated with it. When isolated and purified, the
Gao Feng
Miotto Jahanara
Euro-Celtique S.A.
Jones Day
McIntosh III Traviss C.
Wilson James O.
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