Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-05
2001-06-19
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06248774
ABSTRACT:
The present invention relates to normalization of a pathologically hyper-excited sensory nerve function in a conscious human subject. In particular, the invention relates to a treatment method for reducing or eliminating hyper-excited sensory symptoms such as neuropathic pain. Some examples of neuropathic pain are diabetic neuropathy, post-herpetic neuralgia (shingles), trigeminal neuralgia, pain associated with AIDS infection and treatment, whip-lash pain, pain due to cancer treatment, phantom limb pain, traumatic injury, complex regional pain syndrome and pain due to peripheral vascular disease.
The development of hyper-excited sensory nerve function has been described by Sollevi 1997 (1). These symptoms are often manifested as neuropathic pain. Neuropathic pain is a persistent, chronic pain usually described as a burning, shooting or lancinating sensation without an obvious cause. These symptoms are often associated with damage to nerves or nerve fibers. Such pain is associated with the transmission of abnormal pain signals from injured peripheral nerves to neurons in the brain and spinal cord. Briefly, the sensory nervous system projects signals to the central nervous system (CNS), mediating information from the periphery to the brain. These comprise signals from sensors in peripheral tissues and other organs, sensitive for qualities like touch, temperature changes, vibration, painful stimuli, pressure, vision, hearing, smell, taste and balance. This sensory nervous system is an important physiological control in the subject's relation to the environment. The sensory nervous system can be damaged by various types of trauma, such as infections and mechanical lesions including whip-lash injury, diseases such as diabetes and HIV infection, cancer or HIV treatments. This can result in disturbance in the signal transmission into the CNS, leading to reduced perception of sensory signals (hypoestesia) as well as hyper-function (more excited signals in the CNS) due to some largely unknown changes in the nerve transmission process (neuropathic damage). The neuropathic condition with hyper-excitation is described as a “wind-up” phenomenon and often involves several of the above mentioned sensory functions. This may therefore be associated with decreased thresholds for touch and temperature (hyperesthesia), discomfort in the perception for touch and temperature (dysesthesia), discomfort or pain with touch, pressure and/or temperature stimulation (allodynia), and hypersensitivity to pain stimuli (hyperalgesia), balance disturbance, disturbance of auditory type (tinnitus) as well as ganglionic dysfunction. These types of hyper-reactive sensory nerves may develop after various types of trauma, and are called chronic when persistent for more than 3-6 months.
Adenosine, administered intravenously or intrathecally, has been proposed as a treatment for this sensory nerve hyper-reactivity (1, 2, 3). The objective of the treatment is to restore a normal perception of pain, as well as other sensory functions, in patients suffering from pathological hyper-excitation due to nerve damage.
Adenosine is an endogenous nucleoside present in all cell types of the body. It is endogenously formed and released into the extracellular space under physiological and pathophysiological conditions characterized by an increased oxygen demand/supply ratio. This means that the formation of adenosine is accelerated in conditions with increased high energy phosphate degradation. The biological actions of adenosine are mediated through specific adenosine receptors located on the cell surface of various cell types, including nerves (4). The hyper-reactive nerves increase adenosine release due to an increase in metabolic activity.
A
1
receptors are widely distributed in most species and mediate diverse biological effects. The following examples are intended to show the diversity of the presence of A
l
receptors rather than a comprehensive listing of all such receptors. A
1
receptors are particularly ubiquitous within the central nervous system (CNS), with high levels being expressed in the cerebral cortex, hippocampus, cerebellum, thalamus, brain stem, and spinal cord. Immuno-histochemical analysis using polyclonal antisera generated against rat and human A
1
adenosine receptors has identified different labeling densities of individual cells and their processes in selected regions of the brain. A
1
receptor mRNA is widely distributed in peripheral tissues such as the vas deferens, testis, white adipose tissue, stomach, spleen, pituitary, adrenal, heart, aorta, liver, eye, and bladder. Only very low levels of A
1
receptors are thought to be present in lung, kidney, and small intestine.
The present invention relates to a class of compounds known as allosteric modulators or allosteric enhancers. At present, allosteric enhancers have only been described for the Al adenosine receptor (5, 6, 7). No allosteric modulators have been proven effective in neuropathic pain models at any concentration. All the currently known enhancers are derivatives of the 2-amino-3-benzoylthiophenes first described by Bruns et al. (5). These benzoylthiophenes are not agonists at the A
1
adenosine receptor (5, 6, 8). Structurally, all known agonists for the A
1
adenosine receptor are derivatives of adenosine. The presence of an unmodified ribose ring is essential for agonist activity at the A
1
adenosine receptor (9). Benzoylthiophenes are not agonists at the A
1
adenosine receptor. Importantly, these compounds are antagonists at the A
1
adenosine receptor (5, 6, 7, 8). At low concentrations, these benzoylthiophenes enhance the effect of agonists. At higher concentrations, these compounds act as antagonists. Therefore, the concentration range where these compounds can enhance the effects of agonists is limited (8).
Mechanistically, benzoylthiophenes appeared to enhance A
1
adenosine receptor function by stabilizing the high affinity state of the receptor-G-protein complex (8, 10). This property is manifested as an increase in high affinity binding in radioligand binding reactions where an agonist radioligand is used to label the A
1
adenosine receptor. An enhancer that increases agonist binding can do so by either accelerating the association of agonist and receptor, or by retarding the dissociation of the “receptor-ligand” complex. Kinetic studies have shown the benzoylthiophenes to retard the dissociation of the “receptor-ligand” complex. In contrast, an agonist, or an antagonist will both compete with the radioligand for the binding site and accelerate the dissociation of the “receptor-ligand” complex (8). Since the benzoylthiophenes only selectively retard the dissociation of the “receptor-ligand” complex when an agonist radioligand is used, the benzoylthiophenes must bind to a site different from the agonist recognition site. This putative site is termed the allosteric site, and presumably, compounds that bind to this site and enhance the agonist effect are termed “allosteric enhancers”.
Another challenge is that that wide distribution of adenosine receptors offers both opportunities and drawbacks for therapeutic intervention. As an example, A1 adenosine receptors are found in the CNS, in heart and adipose tissue. Thus, agonists are capable of reducing free fatty acid levels in the blood through their interaction with adenosine A1 receptors on fat cells. This is a useful feature in non-insulin dependent diabetes mellitus. However, the concomitant bradycardia and drop in mean arterial pressure due to interference with cardiovascular adenosine receptors are to be considered as serious side effects.
SUMMARY
An object of the present invention is to provide a therapeutically useful enhancer with improved potency as an enhancer, and preferably, without antagonist property. The present invention describes the discovery of a compound that meets these criteria.
The present invention relates to a composition and a method for the treatment of hyper-excited sensory nerve functions, e.g., neuropathia in human subjects. The treatment me
Henley III Raymond
King Pharmaceuticals Research & Development, Inc.
Roberts Abokhair & Mardula LLC
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