Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-20
2004-04-20
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S363000, C544S364000, C544S365000, C544S360000, C544S368000, C544S369000, C544S370000, C544S371000, C544S372000, C544S376000, C544S379000, C544S389000, C544S390000, C544S391000, C544S284000, C544S353000, C544S355000, C544S356000, C544S357000, C544S235000, C514S354000, C514S356000, C514S357000, C514S405000, C514S400000, C206S570000
Reexamination Certificate
active
06723730
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates compounds that bind with high selectivity and high affinity to Vanilloid Receptors, especially Type I Vanilloid Receptors, also known as capsaicin receptors or VR1 Receptors. In an important aspect the invention provides capsaicin receptor, preferably human VR1 receptor, antagonists that are not capsaicin analogs (e.g., they do not contain a phenyl ring with two oxygen atoms bound to two adjacent ring carbons), are free of agonist activity, and exhibit an unprecedented level of affinity for the VR1 receptor. In another aspect, the invention provides aryl piperazines and related compounds that act as VR1 receptor ligands. In addition, this invention relates to such VR1 receptor ligands, high affinity antagonists and pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of diseases and other health-related conditions. Additionally this invention relates to the use of aryl piperazines and related compounds as tool for the analysis of VR1 receptors and as probes for the quantitative measurement and localization of VR1 receptors in cell and tissue samples.
2. Background
The sensation of pain can be triggered by any number of physical or chemical stimuli. In mammals, the peripheral terminals of a group of specialized small diameter sensory neurons, termed “nociceptors” mediate this response to a potentially harmful stimulus.
In efforts to discover better analgesics for the treatment of both acute and chronic pain, and to develop treatments for various neuropathic pain states, considerable research has been focused on the molecular mechanism of nociception. The response to heat, low extracellular pH (acidity), or capsaicin (the compound responsible for the hotness of hot peppers) is characterized by the persistent activation of nociceptors. It has been shown that both heat and capsaicin are capable of activating dorsal root ganglion and trigeminal ganglion neurons via an influx of cations. Additionally, moderately acidic conditions produce this response and can also potentiate the response of nociceptors to heat and capsaicin.
Capsaicin responses in isolated sensory neurons show dose-dependence and are also evoked by structural analogues of capsaicin that share a common vanilloid moiety. The term vanilloid receptor (VR) was coined to describe the neuronal membrane recognition site for capsaicin and such related irritant compounds. It was postulated that the VR is a nonselective cation channel with a preference for calcium. In 1989, resiniferatoxin (RTX), a natural product of certain
Euphorbia
plants, was recognized as an ultrapotent VR agonist. Specific binding of 3 H RTX provided the first unequivocal proof for the existence of a vanilloid receptor. The capsaicin response is competitively inhibited (and thereby antagonized) by another capsaicin analog, capsazepine and is also inhibited by the non-selective cation channel blocker ruthenium red. These antagonists bind to VR with no more than moderate affinity (i.e., with K
i
values of no lower than 140 uM).
Interest in characterizing VRs led to the cloning of a functional rat capsaicin receptor (VR1), from a rat dorsal root ganglion cDNA library. A human version of VR1 has also been described, and the term VR1 is used herein to refer to either or both.
The capsaicin receptor's channel opens in response to elevated temperatures (higher than about 45° C.). Capsaicin and related compounds, as well as protons are stimuli that lower the threshold channel opening, so that in the presence of any of these stimuli the capsaicin receptor can be opened even at room temperature.
Opening of the capsaicin receptor channel is followed by the release of inflammatory peptides from neurons expressing the receptor and other nearby neurons, increasing the pain response. After initial activation by capsaicin the capsaicin receptor undergoes a rapid desensitization, possibly via phosphorylation of intracellular sites of the receptor. Capsaicin and related VR1 agonist vanilloid compounds have enjoyed long pharmaceutical use as topical anaesthetics. While such compounds initially cause a strong burning sensation, receptor desensitization provides pain relief.
Localization of the capsaicin receptor in the dorsal root ganglion established this receptor as a leading target for analgesic discovery. Most currently marketed analgesic compounds act centrally, and often have side effects. Analgesic compounds that act peripherally are desirable for treating acute and chronic pain more effectively and with fewer side effects. Thus, compounds that interact with the capsaicin receptors, particularly antagonists of this receptor, which would not elicit the initial painful sensation of currently marketed capsaicin containing compounds, are desirable for the treatment of chronic and acute pain, itch, and urinary incontinence.
3. Description of Related Art
The vanilloid compounds capsaicin and Resiniferatoxin (RTX) act as potent and specific agonists of the capsaicin receptor. Capsazepine (which contains a phenyl ring with two oxygen atoms bound to two adjacent ring carbons and is therefore a capsaicin analog) acts as a moderate affinity competitive capsaicin receptor antagonist. Iodo-RTX is a capsaicin analog that has recently been reported to act as a high affinity antagonist. The inorganic dye, Ruthenium red, also antagonizes capsaicin responses of the receptor, albeit as a non-selective cation channel blocker. For an extensive review of vanilloid receptor ligands see Szallasi and Blumberg, (Pharmacological Reviews (1999) 51(3): 159-211).
SUMMARY OF THE INVENTION
This invention relates to VR1 receptor ligands, particularly VR1 receptor antagonists, and methods of using VR1 receptor antagonists for the treatment of neuropathic pain, peripheral-nerve-mediated pain, and pain, inflammatory and broncho-constriction symptoms resulting from exposure to capsacin-receptor-activating stimuli such as capsaicin and tear gas.
In one aspect the invention provides novel chemical compounds that act as capsaicin receptor modulatory agents, some of which exhibit antagonist potency greater than that of any previously described VR1 receptor antagonist. Compounds that act as capsaicin receptor antagonists and bind to capsaicin (preferably human VR1) receptors with K
i
values of less than 100 uM, as measured by a capsacin receptor binding assay, such as the assay given by Example 10, or that inhibit capsaicin activity in an assay for determination of capsaicin receptor antagonist effects (Example 11) with EC
50
values of less than or equal to 100 uM, are referred to herein as potent capsaicin receptor antagonists; such compounds that bind or antagonize with K
i
or EC
50
values of less than or equal to 10 uM are referred to herein as highly potent capsaicin receptor antagonists.
In an additional aspect, the invention provides methods of using the potent capsaicin receptor antagonist compounds of the invention for the treatment of symptoms resulting from exposure to painful capsaicin receptor activating stimuli. In particular, the invention provides methods of treating subjects who have been exposed to capsaicin or have been burnt by heat, light, tear gas, or acid exposure, the methods comprising administering to such subjects an effective amount of a potent capsaicin receptor antagonist, preferably a highly potent (high potency) capsaicin receptor antagonist, so that the subject's symptoms of pain or sensitivity are reduced. Preferred compounds of the invention provide pain relief without loss of consciousness, and preferably without sedation, in such subjects that is equal to or grater than the degree of pain relief that can be provided to such subjects by morphine without loss of consciousness. Highly preferred compounds provide such pain relief while causing only transient (i.e., lasting for no more than one half the time that pain relief lasts) or no sedation (see Example 16 for sedation assay). Subjects or patients referred to herein may be humans or
Bakthavatchalam Rajagopal
DeSimone Robert W.
Hodgetts Kevin J.
Hutchinson Alan
Krause James E.
Berch Mark L.
Habte Kahsay
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
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