Pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”. Pain is classified into nociceptive pain, neuropathic pain and psycogenic pain.
Nociceptive pain is physiological pain caused by a mechanical stimulus, a temperature stimulus or a chemical stimulus, and plays a role as a biosensor to protect a human body from danger.
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).
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. However, the pathophysiology of neuropathic pain, or, especially, molecular mechanisms responsible for its elicitation are not fully clarified yet.
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. 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, digestive trouble, harmful effects on cardiac functions, etc.; and mexiletine may cause dizziness, digestive trouble, etc. Those agents which are not specifically intended for the treatment of neuropathic pain are not satisfactory for many neuropathy cases because their therapeutic effects are not sufficiently separated from their side-effects. Accordingly, there is a need for an agent which show high activity via oral administration and is primarily intended for the treatment of neuropathic pain, presenting with few side-effects.
As 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 morphine which have affinity to the opiate receptors in neurons, and are distinct from the compounds of the present invention in structure. International Publication No. WO 00/61557 discloses 4-hydroxypiperidine derivatives having antiarrhythmic effect and International Publication No. WO 00/61558 discloses 4-hydroxypiperidine derivatives useful as agents for treating neuropathic pain which act on sodium channel and selectively inhibit persistent sodium current in comparison with transient sodium current. However, these products are different from the compounds of the present invention in structure.
As 4-(phenoxymethyl)piperidin-4-ol derivatives, Japanese Patent Application Laid-open No. Sho 60-163861 discloses aryloxymethyl piperidinol derivatives which has antidepressant, antiarrhythimic and hypotensive actions. However, the derivatives of this publication are different from the compounds of the present invention in structure and the publication does not disclose an analgesic activity. International Publication No. WO 93/02052 discloses 2-(4-hydroxypiperidino)-1-alkanol derivatives as an anti-ischemic agent. However, the derivatives of this publication are different from the compounds of the present invention in basic structure and the publication does not disclose an analgesic activity.
Not only desired pharmaceutical activities but also long-term safety are required in the development of medicines. In addition, severe criteria in various tests on absorption, distribution, metabolism and excretion should be satisfied. For example, problems to be examined and solved include drug interation, desentitization and tolerance, absorption at the digestive tract after oral administration, transfer rate into the small intestines, absorption rate and first pass effect, internal organ barrier, binding to proteins, induction of drug metabolizing enzymes, the excretion pathway, clearance in the body and the methods of application (application sites, methods and objects). However, compounds satisfying all these requirements can be seldom found. Therefore, agents having wide safety area and excellent pharmacokinetic property have been desired.
Agents for treating neuropathic pain also involve such general problems as described above in developing as medicine. In addition, with respect to the agents for treating neuropathic pain, agents for having less side-effects mentioned above and having high utility has been sought in comparison with the conventional sodium channel blocking agents which have been now used as the treatment of neuropathic pain.
The problems to be solved by the present invention is to provide analgesics which are applicable orally, have high safety and are excellent in effectiveness and pharmacokinetic property, especially novel compounds which are useful for an agent for treating neuropathic pain.