Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-14
2002-10-15
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S039000, C546S040000
Reexamination Certificate
active
06465479
ABSTRACT:
TECHNICAL FIELD
The present invention relates to certain pyridomorphinan compounds and more particularly to naltrexone-derived pyridomorphinan compounds. Compounds of the present invention exhibit high &dgr; antagonist potency. Moreover, compounds of the present invention possess &mgr; agonist characteristics. Compounds of the present invention are especially useful as analgesics for treating patients suffering from pain. Compounds of the present invention are also suitable for treating drug abuse including cocaine, methamphetamine and opioids such as morphine and heroin abuse. Also, compounds of the present invention can be used as immunomodulatory agents.
BACKGROUND OF INVENTION
Opioid receptors belong to the superfamily of G-protein coupled receptors that mediate the analgesic and other pharmacological actions of morphine and related opioid drugs. In the past, it was believed that only a single opioid binding site existed. The existence of at least three distinct subtypes of opioid receptors, designated up &mgr;, &dgr; and &kgr; receptors, in the central nervous system and periphery is now well established. Human &mgr;, &dgr; and &kgr; receptors have been cloned and have been shown to belong to the G protein-coupled receptor (GPCR) superfamily.
The existence of three distinct opioid receptor types, &mgr;, &dgr; and &kgr;, is confirmed by the recent cloning of these three opioid receptors from mouse, rat and human cDNAs. All three of the opioid receptor types are located in human brain or spinal cord tissues and each has a role in the mediation of pain. Opiates are used extensively for the treatment of pain and are the most effective analgesic agents available. Morphine and its analogues currently prescribed as potent analgesics are &mgr; selective ligands. The general administration of these medications is limited by side-effects such as respiratory depression, depression of gastrointestinal motility and development of tolerance and physical dependence.
The development of potent and selective antagonist and agonist ligands for each of these opioid receptor subtypes has been the goal of medicinal chemists for many years because of their potential usefulness as pharmacological tools and as therapeutic agents. Among the &mgr;, &dgr; and &kgr; receptors, the development of antagonist and agonist ligands acting through the &dgr; receptor has become the focus of research in recent years due to the therapeutic potential of opioid &dgr; ligands. Various studies suggest that &dgr; selective agonists could be potentially useful as analgesics devoid of side effects such as respiratory depression and physical dependence side effects. Selective antagonists of &dgr; receptors have been shown to display immunomodulatory effects as well as modulatory effects on the actions of drugs of abuse such as cocaine and methamphetamines. Moreover, recent studies using rodents have demonstrated that &dgr; opioid antagonists are capable of preventing the development of tolerance and dependence to &mgr; agonist such as morphine without interfering with the &mgr; opioid antinociception.
It has been found that a number of ligands synthetically derived from naltrexone display significant selectivity toward the &dgr; receptors. Among these, the indolomorphinan naltrindole is presently widely used as &dgr; selective antagonist ligand, and other ligands such as its 5′-isothiocyanate derivative, benzofuran analog, and (E)-7-benzylidenenaltrexone have been useful in the pharmacological characterization of &dgr; opioid receptor subtypes.
Continuing efforts exist for developing subtype selective nonpeptide opioid ligands.
SUMMARY OF INVENTION
The present invention relates to compounds represented by the following formula:
wherein each of Y, X and R is individually selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, aryl, halo, CF
3
and NO
2
provided that at least one of Y, X and R is other than hydrogen; and pharmaceutically acceptable salts thereof.
The present invention also relates to treating a patient suffering from pain which comprises administering to the patient a pain treating effective amount of at least one of the above compounds.
A further aspect of the present invention relates to treating a patient in need of an immunomodulatory agent which comprises administering to the patient an immunomodulatory effective amount of at least one of the above compounds.
A still further aspect of the present invention relates to treating a patient suffering from drug abuse which comprises administering an effective amount for treating drug abuse of at least one of the above compounds.
Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.
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patent: 5223507 (1993-06-01), Dappen et al.
patent: 5811400 (1998-09-01), Schiller
patent: WO 96/0255 (1996-02-01), None
Subramaniam Ananthan et al., Journal of Medicinal Chemistry, vol. 42, (18) pp. 3527-3538, Published Aug. 19, 1999.*
Ananthan et al., Opioid Receptor Ligands: Synthesis and Structure-Activity Relationships of 4'-Phenyl Pyrido-and Pyrimidoepoxymorphinans, 214thACS National Meeting, 1997.
Ananthan et al., Synthesis, Opioid Receptor Binding, and Biological Activities of Naltrexone-Derived Pyrido-and Pyrimidomorphinans,Journal of Medicinal Chemistry, vol. 42, No. 18, 1999: 3527-3538.
Ananthan et al., Synthesis and Opioid Receptor Binding Profiles of Phenyl Pyridomorphinans, 215thACS National Meeting, 1998.
Mathews et al., Lack of Antinociceptive Tolerance with SoRI 9409, An Opioid Mu Agonist/Delta Antagonist, Regional Meeting of Southwestern and Rocky Mountain Division of American Association for the Advancement of Sciences, 1999.
Mathews et al., Pharmacological Activities of Naltrexone-Derived Pyrido-and Pyrimidomorphinans, International Narcotics Research Conference, 1999, Abstract Mon41.
Connolly Bove & Lodge & Hutz LLP
Rotman Alan L.
Southern Research Institute
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