Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-22
2002-06-25
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...
C514S314000, C546S159000, C546S162000, C546S178000, C546S171000
Reexamination Certificate
active
06410561
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a nociceptin antagonist containing a novel amide derivative or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to an analgesic containing, as an active ingredient, a novel amide derivative or a pharmaceutically acceptable salt thereof, which show analgesic effect as nociceptin antagonist by selectively acting on an opioid receptor like-1 receptor and which are useful for the treatment of pain, particularly sharp pain or pain caused by sensory nerve abnormality, such as hyperalgesia and allodynia. The present invention moreover relates to a novel use of a certain kind of amide derivative as a nociceptin antagonist and analgesic.
BACKGROUND ART
Pain is a sensation felt by anybody and is an important vital signal or alarm signal.
Pain caused by injury, surgery, inflammation and the like, as well as chronic pain stemming from injury, dysfunction and the like of nerves after recovery from an injury is one of the major clinical problems. Chronic pain sometimes causes autonomic disorder, dyskinesia or mental disorder, wherein the pain itself is the cause of a different disease.
There is also known to exist pain due to sensory nerve abnormality, such as hyperalgesia associated with promotion of reaction in response to an ordinary pain stimulus, allodynia wherein pain is felt in response to a stimulus that normally causes no pain, and the like.
Analgesics are divided into central analgesic and peripheral analgesic according to the main action site thereof. Inasmuch as the cause of pain is a complicated entanglement of autonomic nerve reactions, feeling and the like, sedative, antianxiety, antidepressant, hypnotic, antispasmodic, vasodilator and the like are used as analgesic auxiliary agents.
Central analgesics are roughly divided into narcotic analgesic, anarcotic analgesic and antipyretic analgesic.
Narcotic and anarcotic opioids have been used for the treatment of sharp pain such as postoperative pain and myocardial infarction, burn and the like. These analgesics show noticeable effects resulting from a strong analgesic action combined with an action to remove fear of pain. On the other hand, narcotic analgesics accompany physical dependence and mental dependence and express withdrawal syndrome by drug dependence. Other side effects of respiratory suppresion, nausea, emesis, constipation, dysuria and the like restrict their use.
Antipyretic analgesic is effective for superficial pain, such as toothache, myalgia and the like, but is considered to be ineffective for visceralgia. Its antipyretic action is considered to focus on hypothalamus thermoregulation center, and analgesic action is mainly exerted via peripheral nerves. However, there are many unknown parts in the central action mechanism thereof. Its analgesic effect is generally weaker than that offered by narcotic and anarcotic opioids. Consequently, sharp pain is cautiously treated with narcotic and anarcotic opioids in clinical situations to the extent that causes less side effects.
Although more than 20 years have passed since the analgesic effect of morphine by intrathecal administration to human was confirmed and morphine was first applied to clinical situations, a pharmaceutical agent exceeding morphine in terms of various side effects, histotoxicity to spinal cord and the like, that accompany analgesic effect of morphine, has not been found.
Certain pain caused by injury and functional disorder of nerves and the like is resistant to analgesics currently in clinical use, such as antipyretic analgesic and narcotic analgesic, and shows no significant analgesic effect.
Thus, there reaims a demand for a safe and effective analgesic, particularly a strong analgesic free from addiction and an analgesic to treat pain caused by sensory nerve abnormality such as hyperalgesia, allodynia and the like.
Pain is caused when an algesic substance, which is released upon occurrence of tissue disorder due to nociceptive stimulus (chemical stimulus, mechanical stimulus, thermal stimulus), excites nociceptor (free nerve terminal) at the sensory nerve terminal, and the information of the pain sensation reaches the cerebral cortex and is recognized as pain. In addition, visceralgia is considered to be caused by the contraction of visceral smooth muscle, that mechanically extends and excites the sensory nerve.
Pain sensation is mostly transmitted by two kinds of thin nerve fiber A&dgr; and C fibers, wherein sharp mechanical stimulus conducts myelinated A&dgr; fiber and dull pain conducts unmyelinated C fiber. Typical algesic substance includes bradykinin, serotonin, histamine and the like, that act on nociceptor at the nerve terminal. There is a substance that encourages action of an algesic substance, like prostaglandin synthesized at the inflammation site in the peripheral tissue. Such pain afferent fiber (primary afferent fiber) forms synapse on the surface layer of dorsicornu. The primary afferent fiber excites nociceptive neuron via neurotransmitters, such as excitatory amino acid, substance P and the like, and the information is transmitted from dorsicornu to medulla oblongata, thalamus and to cerebral cortex.
Pressure and tactile sensation is mainly transmitted by thicker A&bgr; fiber which transmits the information from sensory nerve terminal to dorsicornu, medulla oblongata, thalamus and to cerebral cortex, like pain afferent fiber.
Opioid receptors involved in algesia exist in various parts of these spinothalamic tracts. The respiratory suppressive action, nauseant action and the like result from the action on the opioid receptor in the medulla oblongata. While opioid acts on spinal cord, medulla oblongata, thalamus and cerebral cortex to show strong analgesic effect, suppression of thalamus and cerebral cortex is not its main action. Direct suppression of opioid receptor in the dorsicornu neuron and suppression of dorsicornu neuron by descending depression via midbrain and medulla oblongata are considered to be the main action.
Tactile sensation tends to be dull upon sustained application of stimuli of the same intensity. This adaptation is unfeasible in case of pain, but sustained release of neurotransmitter by long-term stimulation of sensory nerve is considered to induce chronic pain by changing the excitatory or information transmission efficiency of the nerve cell. In addition, inhibitory neurotransmitters, such as &ggr;-aminobutyric acid (GABA), glycine and the like, suppress excitement of nerves upon activation of each receptor. While allodynia is considered to be partly induced by dull suppression of neurotransmission due to the stimuli repeatedly applied to the sensory nerve, the mechanism of the onset of chronic pain, hyperalgesia and allodynia has been known only to a limited degree.
As described, the sensory nerve transmission is controlled by excitatory nerve fiber and inhibitory nerve fiber in complicated relationship with each other, and many neurotransmitters involved therein have been found to exist. Hence, there are many targets used to find a pharmaceutical agent exhibiting effective analgesic action.
Following the discovery of cerebral morphine receptor in 1973, enkephalin, which is an endogenous pentapeptide having analgesic effect, was first found and isolated in 1975. There are known more than 20 kinds of morphinomimetic peptides under the category of opioid peptide, that inhibit the transmission of algesia information.
These opioids inclusive of morphine act on opioid receptor. The opioid receptor is known to include several subtypes, wherein morphine shows high affinity for &mgr; receptor, enkephalin shows high affinity for &dgr; receptor and dynorphin shows high affinity for &kgr; receptor, these consisting the base thereof.
It is a long-known fact that involvement of &mgr; receptor from among these is important for the analgesic effect and the mechanism thereof has been most elucidated. The study of withdrawal syndrome induction capability and the like of each subtype by the use of opioid antagonist has revealed
Ito Takao
Shinkai Hisashi
Yamada Hideki
Foley & Lardner
Japan Tobacco Inc.
Robinson Binta
Rotman Alan L.
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