Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-04
2003-11-04
Vollano, Jean F. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S216000
Reexamination Certificate
active
06642257
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel 4-hydroxypiperidine derivatives, a method for their manufacture, and pharmaceutical compositions containing, as its active ingredient, at least one of the derivatives, particularly an orally applicable agent for treating neuropathic pain. The present invention further relates to an agent for treating neuropathic pain, characterized by its containing, as its active ingredient, a substance which selectively inhibits the persistent sodium current.
2. Description of Related Art
Neuropathic pain is caused by a primary damage or by a functional disorder of some part of the neuro transmission system connecting the periphery to the central nervous system (New Illustrated Anesthetic Science Series, No. 4, “Clinics of Pain Control,” 1st Chapter, Written by Kenjiro Dan, 1998, Medical View). In contrast with the physiological pain (nociceptive pain) caused by a mechanical stimulus or a thermal stimulus, the neuropathic pain might be called as a pain felt even by a feeble stimulus which would cause no pain in the normal person, or a pain which is felt without stimulus.
The damage to nerves which becomes a cause to induce the neuropathic pain typically includes traumas and injuries inflicted to the peripheral nervous system, nerve plexus, and soft tissues surrounding the nerves, as well as injuries to the somatesthesia paths in the central nervous system (such as ascending somatesthesia paths found at the levels of spinal cord, brain stem, thalamus and cerebral cortex). For example, neuropathic pain may occur in association with nerve degenerative diseases, bone degenerative diseases, metabolic diseases, cancer, infection, inflammation, post-surgery state, trauma, radiation therapy and anti-cancer chemotherapy, etc. The pathophysiology of neuropathic pain, especially molecular mechanisms responsible for its elicitation are not fully clarified yet. However, it has been thought that over-excitation or abnormal spontaneous excitation prevails in a injured nerve, which is the cause for the neuropathic pain.
The abnormal reaction against sensation, which is characteristic with neuropathic pain, includes, e.g., allodynia. Allodynia refers to a state in which one feels a pain in the presence of a feeble stimulus which would cause no pain in a normal person. In allodynia, even a gentle tactile stimulus can elicit a pain. Basically this is thought to be accounted for by two factors, namely, a qualitative change in sensory responses and the abnormally lowered sensory threshold. Of the patients with neuralgia subsequent to herpes zoster (postherpetic neuralgia), which is a representative neuropathic disorder, 87% was confirmed to have been affected with allodynia. In addition, it has been said that the severity of pain felt in postherpetic neuralgia is proportional to the severity of allodynia. Allodynia, a pathologic state severely restricting the activity of the patient attracts attention as a target for the treatment of postherpetic neuralgia.
If a patient complains of chronic pain as a result of neuropathy, and is disturbed in his/her everyday activity on account of that pain, relieving him/her of that pain through medication will directly lead to the improvement of his/her quality of life. However, it has been shown that the centrally affecting analgesics represented by morphine, non-steroidal anti-inflammatory agents, or steroids are ineffective for the treatment of neuropathic pain. In the current drug therapy, antidepressants such as amitriptyline, sodium channel blockers such as carbamazepine, anti-epileptic agents such as phenytoin, anti-arrhythmic agents such as mexiletine, etc. are diverted from their respective proper fields to the prescription for the treatment of neuropathic pain. Among them, the sodium channel blockers are used to inhibit the hyper-excitability or abnormal spontaneous activity of injured nerves which is regarded as one of the causes for neuropathic pain, because the sodium channel blockers are known to inhibit the excitation and conduction in nerves. The above therapeutic agents, however, are known to bring about a number of side-effects: amitriptyline may cause thirst, drowsiness, sedation, constipation, dysuria, etc.; carbamazepine and phenytoin may cause gait disorder (staggering), eruption, dyspepsia, harmful effects on cardiac functions, etc.; and mexiletine may cause dizziness, dyspepsia, etc. Those agents which are not originally intended for the treatment of neuropathic pain are not satisfactory for many neuropathy cases because their therapeutic effects are inseparably linked with their side-effects. Accordingly, there is a need for an agent which is primarily intended for the treatment of neuropathic pain, presenting with few side-effects.
About the pain-relieving activity of the sodium channel blocker such as phenytoin, what follows is known.
A sodium current ordinarily observed in an excitable cell is a transient inward current (transient sodium current) which is activated rapidly in the presence of a stimulus (depolarization), and then inactivated. In certain states, however, the inactivation process is greatly retarded or hardly occurs, and the sodium current observed then is called a persistent sodium current. It is known, the occurrence of such a persistent sodium current may increase when the cell falls to certain pathological conditions.
Recently, it was reported that phenytoin inhibits the persistent sodium current in neurons, and that this is responsible for the anti-epileptic activity of that agent (Segal and Douglas, J. Neurophysiol., 77:3021, 1997). Recent studies indicate the persistent sodium current may be involved in the pathologic state of myocardium (for example, the development of arrythmia), in addition to epilepsy (Yue-Kun et al., Br. J. Pharmacol., 107:311-316, 1992). It has been also suggested, because phenytoin and carbamazepine inhibit the transient sodium current which plays an important role in the excitation and conduction in neurons, as well as the persistent sodium current (Willow et al., Mol. Pharmacol., 27:549, 1985), they will be able to inhibit not only the abnormal excitation responsible for neuropathic pain, but also the normal nerve activity, and the latter effect may be responsible for their adverse side-effects mentioned above.
With regard to 4-hydroxypiperidine derivatives, Huegi et al. (J. Med. Chem., 26:42, 1983) reported there are some among them that have a pain-relieving activity. However, the compounds cited by them are centrally affecting pain-relieving agents like morphines which have affinity to the opiate receptors in neurons, and are distinct from the compounds of the present invention which are primarily intended for the treatment of neuropathic pain.
The problem to be solved by this invention is to provide an agent for treating neuropathic pain which will exert its therapeutic effects by selectively inhibiting the persistent sodium current in comparison with the transient sodium current, and thus presenting with less side-effects but more therapeutic effects than do the conventional sodium channel blockers which have been diverted from other fields for the treatment of neuropathic pain, particularly to provide such an agent orally applicable.
SUMMARY OF THE INVENTION
The present inventors had intensively studied to solve the above problem, or to obtain a pain-relieving agent highly active and safe, and found that substances capable of selectively inhibiting the persistent sodium current in comparison with the transient sodium current, for example, 4-hydroxypiperidine derivatives as represented by Formula (I) and their salts are highly effective for the treatment of neuropathic pain, and particularly that those substances are effective for the treatment of neuropathic pain by selectively acting on injured sites. These findings led to this invention.
DETAILED DESCRIPTION OF THE INVENTION
Specifically, the inventors found that the compound as represented by Formula (I) has at least one of the following properties: (1
Akada Yasushige
Itoh Manabu
Miyazaki Yutaka
Ogawa Shin-ichi
Yamamoto Ichiro
Mochida Pharmaceutical Co. Ltd.
Vollano Jean F.
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