Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-13
2002-11-26
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S085000, C544S337000, C544S358000, C544S359000, C544S360000, C544S383000, C544S386000
Reexamination Certificate
active
06486165
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to compounds, to processes of their preparation, to pharmaceutical compositions containing them and to their medical use as agonists at kappa opioid receptors.
The present invention also relates to compositions and method for the treatment and/or prevention of itch, also known as pruritus, which has many causes. The compositions, which are formulated for topical and systemic administration, contain kappa opiate receptor agonists that are substantially devoid of central nervous system effects, and, thus, have very little, if any potential for producing side effects associated with centrally acting kappa opiate receptor agonists.
2. Reported Developments
A) Kappa (&kgr;)-receptor Agonists as Analgesics
Opium and its derivatives are potent analgesics that also have other pharmacological effects, and exert their effects by interacting with high-affinity receptors.
It has been shown by investigators that there are at least three major opioid receptor types in the central nervous system (hereinafter CNS) and in the periphery. These receptors, known as mu (&mgr;), delta (&dgr;) and kappa (&kgr;), have distinct pharmacological profiles, anatomical distributions and functions. [See, for example: Wood, P. L.,
Neuropharmacology
, 21, 487-497, 1982; Simon, E.,
J Med. Res. Rev
., 11, 357-374, 1991; Lutz et al.,
J. Recept. Res
. 12, 267-286; and Mansour et al.,
Opioid I
, ed. Herz,. A. (Springer, Berlin) pp. 79-106, 1993.] The &dgr; receptors are abundant in CNS and mediate analgesia, gastrointestinal motility and various hormonal functions. The &mgr; receptors bind morphine-like drugs and mediate the opiate phenomena associated with morphine, including analgesia, opiate dependence, cardiovascular and respiratory functions, and several neuroendocrine effects.
The &kgr; receptors have a wide distribution in CNS and mediate a spectrum of functions including the modulation of drinking, water balance, food intake, gut motility, temperature control and various endocrine functions. They also produce analgesia. [See, for example: Leander et al.,
J. Pharmacol. Exp. Ther
. 234, 463-469, 1985; Morley et al.,
Peptides
4, 797-800, 1983; Manzanares et al.,
Neuroendocrinology
52, 200-205, 1990; and Iyengar et al.,
J. Pharmacol. Exp. Ther
., 238, 429-436, 1986.]
Most clinically used opioid analgesics such as morphine and codeine act as &mgr; receptor agonists. These opioids have well-known, undesirable and potentially dangerous dependence forming side effects. Compounds which are &kgr;-receptor agonists act as analgesics through interaction with &kgr; opioid receptors. The advantage of these agonists over the classical &mgr; receptor agonists, such as morphine, lies in their ability to cause analgesia while being devoid of morphine-like behavioral effects and addiction liability.
A large number of classes of compounds which act as agonists at &kgr; opioid receptors have been described in the art including the following illustrative classes of compounds.
U.S. Pat. No. 4,065,573 discloses 4-amino-4-phenylcyclohexane ketal compounds having analgesic activity.
U.S. Pat. No. 4,212,878 discloses phenylacetamide derivatives having analgesic properties and reduced physical dependence liability properties, relative to morphine and methadone.
U.S. Pat. No. 4,145,435 discloses N-(2-amino-cycloaliphatic)-phenylacetamide compounds having analgesic activity and narcotic antagonist activity.
U.S. Pat. No. 4,098,904 discloses N-(2-amino-cycloaliphatic)-benzoamides and naphthamides useful for relieving pain.
U.S. Pat. No. 4,359,476 discloses substituted cycloalkane-amides useful as analgesics and having low abuse liability.
U.S. Pat. No. 4,438,130 discloses 1-oxa-, aza- and thia-spirocyclic compounds having analgesic activity, low physical dependence and abuse liability properties and little dysphoric inducing properties.
U.S. Pat. No. 4,663,343 discloses substituted naphthalenyloxy-1,2-diaminocyclohexyl amides as analgesics.
U.S. Pat. No. 4,906,655 discloses 1,2-cyclohexylaminoaryl amides having high kappa-opioid affinity, selectivity and potency and useful as analgesics, diuretics, anti-inflammatory and psychotherapeutic agents.
B) Kappa (&kgr;)-receptor Agonists as Anti-Pruritic Agents
The prior art has investigated the physiology and treatment of pruritus as illustrated hereunder.
Itch is a well known sensory state associated with the desire to scratch As with pain, itch can be produced by a variety of chemical mechanical, thermal or electrical stimuli. In addition to the difference in the sensory quality of itch and pain, they also differ in that (1) itch, unlike pain, can only be evoked from the superficial layers of skin, mucosa, and conjunctiva, and (2) itch and pain usually do not occur simultaneously from the same skin region; in fact, mildly painful stimuli, such as scratching, are effective in eliminating itch. In addition, the application of histamine to skin produces itch but not pain. Itch and pain are further dissociated pharmacologically: itch appears to be insensitive to opiate and non-steroidal anti-inflammatory drug (NSAID) treatment, both of which are effective in treating pain.
Although itch and pain are of a class in that both are modalities of nociception transmitted by small unmyelinated C fibers, evidence that itch is not just a variety of low-threshold pain is overwhelming. Itch leads to the reflex or urge to scratch; pain leads to withdrawal. Itch occurs only in the skin; pain arises from deeper structures as well. Heat may stop pain but usually increases pain. Removal of the epidermis eliminates itch but causes pain. Analgesics, particularly opioids, relieve pain but often cause itch (see, for example
J. Am. Acad. Derm
. 24: 309-310, 1991). There can be no doubt that itching is of eminent clinical importance; many systemic and skin diseases are accompanied by persistent or recurrent itch attacks. Current knowledge suggests that itch has several features in common with pain but exhibits intriguing differences as well (see, for example, W. Magerl,
IASP Newsletter
, pp. 4-7, Sept/Oct 1996).
McMahon et al. (
TINS
, Vol. 15, No. 12, pp. 497-501, 1992) provides a description of stimuli (Table a) and a comparison of the established features of itch and pain (Table b):
TABLE a
Stimuli that can elicit or augment itch
Physical
Mechanical.
Light touch, pressure, suction.
Thermal.
Warming.
Electrical.
Focal transcutaneous repetitive stimulation,
transcutaneous constant current
stimulation, intraneural microstimulation.
Chemical
Non-specific irritants.
Acids, alkalis.
Inflammatory mediators.
Histamine, kallikrein, bradykinin,
prostaglandins.
Histamine-releasing
Compound 48/80, protamine, C3a.
substances.
Peptidases.
Mucunain, papain, trypsin, mast cell chymase.
Neuropeptides.
Substance P, vasoactive intestinal polypeptide,
neurotensin, secretin.
Opioids.
Morphine, &bgr;-endorphin, enkephalin analogues.
TABLE b
Comparison of the established features of itch and pain
ITCH
PAIN
Psychophysiology
Tissue
Skin. Mucous
Most tissues
membranes
Stimulus
See Table a
Many stimuli
Intraneural microstimulation
Occasionally
Yes
Secondary sensations
Alloknesis (itchy
Hyperalgesia
skin)
Psychogenic modification
Pronounced
Present
Counterstimuli
Scratching, pain,
Tactile stimuli, cooling
cooling
Neurophysiology
Primary afferent neurones
C- and A&dgr;-fibres
C- and A&dgr;-fibres
Flare size
Large
Small
Spinal pathway
Anterolateral
Anterolateral funiculus
funiculus
Protective reflexes
Scratching,
Flexion, guarding
sneezing
Autonomic reflexes
Yes
Yes
Pharmacology
Capsaicin sensitivity
Yes
Chemogenic pain; yes
NSAID sensitivity
Probably not
Yes
Morphine sensitivity
No
Yes
Abbreviation:
NSAID, non-steroidal anti-inflammatory drugs.
Experimental focal itch stimuli are surrounded by a halo of seemingly unaffected tissue where light tactile stimuli are capable of eliciting itch-like sensations. The term itchy skin or alloknesis has been coined for these secondary sensations that are reminiscent of the features of secondary
Gaul Forrest
Guo Deqi
Kumar Virendra
Marella Michael Anthony
Maycock Alan L.
Adolor Corporation
McKane Joseph K.
Sackey Ebenezer
Woodcock & Washburn LLP
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