CA2433039C - Agent for therapeutic and prophylactic treatment of neuropathic pain - Google Patents
Agent for therapeutic and prophylactic treatment of neuropathic pain Download PDFInfo
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- CA2433039C CA2433039C CA2433039A CA2433039A CA2433039C CA 2433039 C CA2433039 C CA 2433039C CA 2433039 A CA2433039 A CA 2433039A CA 2433039 A CA2433039 A CA 2433039A CA 2433039 C CA2433039 C CA 2433039C
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- neuropathic pain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Abstract
Medicines for treatment and/or prevention of neurogenic pain, containing as the active ingredient compounds represented by the general formula (|) or pharmaceutically acceptable salts thereof:(|) wherein R1 is hydrogen or hydroxyl; R2 is hydrogen or C1-3 alkyl; R3 is phenyl which may have one to three substituents selected from the group consisting of halogeno, hydroxyl, C1-3 alkyl, and C1-3 alkoxy, or -NH-R4 (wherein R4 is phenyl which may have one to three substituents selected from the group consisting of halogeno, hydroxyl, C1-3 alkyl, and C1-3 alkoxy, or hydrogen); and n is 0 or 1.
Description
AGENT FOR THERAPEUTIC AND PROPHYLACTIC
TREATMENT OF NEUROPATHIC PAIN
Field of the Invention The present invention relates to a medicament for therapeutic and/or prophylactic treatment of neuropathic pain and relates to a supplemental analgesic agent.
Background Art Pains in terminal cancer patients are serious problems, and it is an important object to release cancer patients from their pains to improve quality of life of the patients. Conventionally, narcotic analgesics, morphine as a typical example, have been used for pain treatments of such cancer patients. It is known that, among the types of pains in cancer, there is intractable neuropathic pain (the pain is called as "neuropathic pain" or "neurogenic pain", and will be referred to as "neuropathic pain"
in the specification) for which morphine is hardly effective, besides somatic pain caused by noxious stimulus in peripheries such as mechanical stimulus, chemical stimulus and thermal stimulus, and visceral pain caused by stimulus such as dilatation of membranes due to traction or enlargement of parenchymal organs and elevation of internal pressure of hollow organs.
Normally, pains are generated by damages of tissues at the corresponding tissue portions, and the pains will be dispersed when the tissue damages are cured.
However, although no tissue damage is observed at the site of the pain, pains may sometimes be generated such as burning, constricting, pricking or electrification-like pain. Such pains are called neuropathic pains, and the pains are caused by damages or dysfunctions of peripheral or central nerves.
Although the neuropathic pain may be independently generated, it is considered that, in cancer pain, the pain is combined and mixed with somatic pains in about 30°/ of cases. In drug therapy of neuropathic cancer pain, antidepressants, anticonvulsants, local anesthesia, a a agonists, GABA receptor agonists, NMDA
receptor antagonists and so forth have been used as supplemental analgesic agents for narcotic analgesics and the like. However, they, per se, have severe side effects, and moreover, they may sometimes deteriorate the side effects of morphine which is administered to most of cancer patients, since they have low compatibility with morphine. Therefore, a supplemental analgesic agent has been desired which has high safety and good congeniality with morphine (Kongetsu no Chiryo (Treatment of This Month), Vol.B, No. 3, 2000, Separate Issue).
Furthermore, it is known that neuropathic pains are observed not only in cancer pains but in postherpetic neuralgia, post-thoracotomic pain, diabetic neuropathy, CRPS (complex regional pain syndrome, those in which nervous damages are not apparently observed are referred to as "type-1" (reflux sympathetic dystrophy (RSD) and those in which nervous damages are observed are referred to "type-2"
(causalgia)), multiple sclerosis, AIDS, trigeminal neuralgia, thalamic pain, paraplegic pain caused by myelopathy, anesthesia dolorosa, or phantom limb pain (Igaku no Ayumi (Advance of Medicine), Vol. 195, No.9, 2000.12.2, pp.627-632).
Disclosure of the Invention An object of the present invention is to provide a compound effective for neuropathic pain.
Another object of the present invention is to provide a medicament for therapeutic and/or prophylactic treatment of neuropathic pain.
Still another object of the present invention is to provide a supplementary agent for therapeutic and/or prophylactic treatment of neuropathic pain.
The inventors of the present invention conducted various studies to achieve the foregoing objects. As a result, they found that the compound represented by the general formula (I) and pharmaceutically acceptable salts thereof had excellent suppressing effects on neuropathic pain. The present invention was achieved on the basis of the above finding.
The present invention thus provides a medicament for therapeutic and/or prophylactic treatment of neuropathic pain which comprises as an active ingredient a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:
TREATMENT OF NEUROPATHIC PAIN
Field of the Invention The present invention relates to a medicament for therapeutic and/or prophylactic treatment of neuropathic pain and relates to a supplemental analgesic agent.
Background Art Pains in terminal cancer patients are serious problems, and it is an important object to release cancer patients from their pains to improve quality of life of the patients. Conventionally, narcotic analgesics, morphine as a typical example, have been used for pain treatments of such cancer patients. It is known that, among the types of pains in cancer, there is intractable neuropathic pain (the pain is called as "neuropathic pain" or "neurogenic pain", and will be referred to as "neuropathic pain"
in the specification) for which morphine is hardly effective, besides somatic pain caused by noxious stimulus in peripheries such as mechanical stimulus, chemical stimulus and thermal stimulus, and visceral pain caused by stimulus such as dilatation of membranes due to traction or enlargement of parenchymal organs and elevation of internal pressure of hollow organs.
Normally, pains are generated by damages of tissues at the corresponding tissue portions, and the pains will be dispersed when the tissue damages are cured.
However, although no tissue damage is observed at the site of the pain, pains may sometimes be generated such as burning, constricting, pricking or electrification-like pain. Such pains are called neuropathic pains, and the pains are caused by damages or dysfunctions of peripheral or central nerves.
Although the neuropathic pain may be independently generated, it is considered that, in cancer pain, the pain is combined and mixed with somatic pains in about 30°/ of cases. In drug therapy of neuropathic cancer pain, antidepressants, anticonvulsants, local anesthesia, a a agonists, GABA receptor agonists, NMDA
receptor antagonists and so forth have been used as supplemental analgesic agents for narcotic analgesics and the like. However, they, per se, have severe side effects, and moreover, they may sometimes deteriorate the side effects of morphine which is administered to most of cancer patients, since they have low compatibility with morphine. Therefore, a supplemental analgesic agent has been desired which has high safety and good congeniality with morphine (Kongetsu no Chiryo (Treatment of This Month), Vol.B, No. 3, 2000, Separate Issue).
Furthermore, it is known that neuropathic pains are observed not only in cancer pains but in postherpetic neuralgia, post-thoracotomic pain, diabetic neuropathy, CRPS (complex regional pain syndrome, those in which nervous damages are not apparently observed are referred to as "type-1" (reflux sympathetic dystrophy (RSD) and those in which nervous damages are observed are referred to "type-2"
(causalgia)), multiple sclerosis, AIDS, trigeminal neuralgia, thalamic pain, paraplegic pain caused by myelopathy, anesthesia dolorosa, or phantom limb pain (Igaku no Ayumi (Advance of Medicine), Vol. 195, No.9, 2000.12.2, pp.627-632).
Disclosure of the Invention An object of the present invention is to provide a compound effective for neuropathic pain.
Another object of the present invention is to provide a medicament for therapeutic and/or prophylactic treatment of neuropathic pain.
Still another object of the present invention is to provide a supplementary agent for therapeutic and/or prophylactic treatment of neuropathic pain.
The inventors of the present invention conducted various studies to achieve the foregoing objects. As a result, they found that the compound represented by the general formula (I) and pharmaceutically acceptable salts thereof had excellent suppressing effects on neuropathic pain. The present invention was achieved on the basis of the above finding.
The present invention thus provides a medicament for therapeutic and/or prophylactic treatment of neuropathic pain which comprises as an active ingredient a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:
' CA 02433039 2003-06-25 O
\N-~-C--~CO-R3 (I) R~ R2 n wherein R1 represents a hydrogen atom or a hydroxyl group, R2 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R3 represents a phenyl group which may have 1 to 3 atoms or substituents selected from the group consisting of a halogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms, and an alkoxyl group having 1 to 3 carbon atoms, or represents -NH-R4 (R4 represents a phenyl group which may have 1 to 3 atoms or substituents selected from the group consisting of a halogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms, and an alkoxyl group having 1 to 3 carbon atoms or a hydrogen atom), and n represents 0 or 1.
The present invention also provides a medicament for suppressing neuropathic pain which comprises the compound represented by the aforementioned general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient; and a medicament as supplemental analgesic treatment which comprises the compound represented by the aforementioned general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient (hereinafter in the specification, the medicament is occasionally referred to as a "supplemental analgesic agent").
According to the aforementioned inventions, examples of the neuropathic pain include, for example, cancer pains, postherpetic neuralgia, post-thoracotomic pain, diabetic neuropathy, CRPS, multiple sclerosis, AIDS, trigeminal neuralgia, thalamic pain, paraplegic pain caused by myelopathy, anesthesia dolorosa, phantom limb pain and the like.
In the aforementioned medicaments, the compound represented by the general formula (I) may preferably be 2-oxo-1-pyrrolidineacetamide (piracetam), 4-hydroxy-2-oxo-1-pyrrolidineacetamide (oxiracetam), 1-(4-methoxybenzoyl)-2-pyrrolidinone (aniracetam), (S)- a -ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam), or N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide (nefiracetam), and among them, 4-hydroxy-2-oxo-1-pyrrolidineacetamide or N-(2,fi-dimethylphenyl)-2-(2-ozo-1-pyrrolidinyl)acetamide is more preferred, and N-(2,fi-dimethylphenyl)-2-(2-ogo-1-pyrrolidinyl)acetamide is most preferred.
From further aspect, provided are a method for therapeutic and/or prophylactic treatment of neuropathic pain which comprises the step of administering to a mammal including human a therapeutically and/or prophylactically effective amount of the compound represented by the above general formula (I) or a salt thereof;
a method for suppressing neuropathic pain which comprises the step of administering to a mammal including human an effective amount of the compound represented by the above general formula (I) or a salt thereof; a method for supplemental treatment of therapeutic and/or prophylactic treatment of neuropathic pain .which comprises the step of administering to a mammal including human an effective amount of the compound represented by the above general formula (I) or a salt thereof; and a method for therapeutic and/or prophylactic treatment of neuropathic pain which comprises the step of administering to a mammal including human a therapeutically and/or prophylactically effective amount of the compound represented by the above general formula (I) or a salt thereof together with at least one analgesic agent. Further provided is a use of the compound represented by the above general formula (I) or a salt thereof for the manufacture of the aforementioned medicaments.
BRIEF EXPLANATION OF THE DRAWINGS
Fig. 1 is a graph showing suppressing effect on neuropathic pain observed in the peripheral nociception test.
Fig. 2 is a graph showing suppressing effect on neuropathic pain observed in the von Frey test.
Fig. 3 is a graph showing suppressing effect of osiracetam on neuropathic pain observed in the von Frey test.
Fig. 4 is a graph showing suppressing effect of nefiracetam on neuropathic pain by oral administration observed in the von Frey test.
Fig. 5 is a graph showing suppressing effect on diabetic neuropathic pain observed in the Hargreaves test.
Best Mode for Carrying out the Invention The compounds represented by the aforementioned general formula (I) are known compounds disclosed in, for example, Japanese Patent Publication (Kokoku) No.
42-19093, Japanese Patent Unexamined Publication (Kokai) Nos. 52-23072, 54-117468, 60-252461, 56-2960, 61-280470, 4-160496, Japanese Patent Publication No. 3-and so forth. Known pharmacological effects thereof include an effect of improving cerebral functions (Japanese Patent Publication No. 62-5404), an effect of improving Alzheimer type senile dementia (Japanese Patent Unexamined Publication No.
\N-~-C--~CO-R3 (I) R~ R2 n wherein R1 represents a hydrogen atom or a hydroxyl group, R2 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R3 represents a phenyl group which may have 1 to 3 atoms or substituents selected from the group consisting of a halogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms, and an alkoxyl group having 1 to 3 carbon atoms, or represents -NH-R4 (R4 represents a phenyl group which may have 1 to 3 atoms or substituents selected from the group consisting of a halogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms, and an alkoxyl group having 1 to 3 carbon atoms or a hydrogen atom), and n represents 0 or 1.
The present invention also provides a medicament for suppressing neuropathic pain which comprises the compound represented by the aforementioned general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient; and a medicament as supplemental analgesic treatment which comprises the compound represented by the aforementioned general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient (hereinafter in the specification, the medicament is occasionally referred to as a "supplemental analgesic agent").
According to the aforementioned inventions, examples of the neuropathic pain include, for example, cancer pains, postherpetic neuralgia, post-thoracotomic pain, diabetic neuropathy, CRPS, multiple sclerosis, AIDS, trigeminal neuralgia, thalamic pain, paraplegic pain caused by myelopathy, anesthesia dolorosa, phantom limb pain and the like.
In the aforementioned medicaments, the compound represented by the general formula (I) may preferably be 2-oxo-1-pyrrolidineacetamide (piracetam), 4-hydroxy-2-oxo-1-pyrrolidineacetamide (oxiracetam), 1-(4-methoxybenzoyl)-2-pyrrolidinone (aniracetam), (S)- a -ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam), or N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide (nefiracetam), and among them, 4-hydroxy-2-oxo-1-pyrrolidineacetamide or N-(2,fi-dimethylphenyl)-2-(2-ozo-1-pyrrolidinyl)acetamide is more preferred, and N-(2,fi-dimethylphenyl)-2-(2-ogo-1-pyrrolidinyl)acetamide is most preferred.
From further aspect, provided are a method for therapeutic and/or prophylactic treatment of neuropathic pain which comprises the step of administering to a mammal including human a therapeutically and/or prophylactically effective amount of the compound represented by the above general formula (I) or a salt thereof;
a method for suppressing neuropathic pain which comprises the step of administering to a mammal including human an effective amount of the compound represented by the above general formula (I) or a salt thereof; a method for supplemental treatment of therapeutic and/or prophylactic treatment of neuropathic pain .which comprises the step of administering to a mammal including human an effective amount of the compound represented by the above general formula (I) or a salt thereof; and a method for therapeutic and/or prophylactic treatment of neuropathic pain which comprises the step of administering to a mammal including human a therapeutically and/or prophylactically effective amount of the compound represented by the above general formula (I) or a salt thereof together with at least one analgesic agent. Further provided is a use of the compound represented by the above general formula (I) or a salt thereof for the manufacture of the aforementioned medicaments.
BRIEF EXPLANATION OF THE DRAWINGS
Fig. 1 is a graph showing suppressing effect on neuropathic pain observed in the peripheral nociception test.
Fig. 2 is a graph showing suppressing effect on neuropathic pain observed in the von Frey test.
Fig. 3 is a graph showing suppressing effect of osiracetam on neuropathic pain observed in the von Frey test.
Fig. 4 is a graph showing suppressing effect of nefiracetam on neuropathic pain by oral administration observed in the von Frey test.
Fig. 5 is a graph showing suppressing effect on diabetic neuropathic pain observed in the Hargreaves test.
Best Mode for Carrying out the Invention The compounds represented by the aforementioned general formula (I) are known compounds disclosed in, for example, Japanese Patent Publication (Kokoku) No.
42-19093, Japanese Patent Unexamined Publication (Kokai) Nos. 52-23072, 54-117468, 60-252461, 56-2960, 61-280470, 4-160496, Japanese Patent Publication No. 3-and so forth. Known pharmacological effects thereof include an effect of improving cerebral functions (Japanese Patent Publication No. 62-5404), an effect of improving Alzheimer type senile dementia (Japanese Patent Unexamined Publication No.
5-163144), an effect of improving cerebrovascular dementia (Japanese Patent Unexamined Publication No. 5-163145), an effect of suppressing generation of dependency and resistance by a narcotic analgesics (U.S. Patent No.
6,107,330), effect of improving intractable epilepsy (W000/7593), an effect of stabilizing mitochondria membrane (W098/14213), an effect of inhibiting neurocyte death (WQ00/72844) and so forth. However, the pain suppression effect or supplemental analgesic effect of these compounds has not been known.
These compounds can be easily produced by the methods disclosed in, for example, Japanese Patent Publication No. 42-19093, Japanese Patent Unexamined Publication Nos. 52-23072, 54-117468, 60-252461, 56-2960, 61-280470, 4-160496, Japanese Patent Publication No. 3-46466 and so forth.
In the general formula (I), R~ is preferably a phenyl group having an alkoxyl group or -NH-R4. Rø is preferably a phenyl group having two alkyl groups or hydrogen atom.
- Examples of typical compounds among the compounds falling within the scope of the general formula (I) include 2-oxo-1-pyrrolidineacetamide (piracetam), 4-hydroxy-2-oxo-1-pyrrolidineacetamide (oxiracetam), 1-(4-methoxybenzoyl)-2-pyrrolidinone (aniracetam), (S)- a -ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam), and N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide (nefiracetam).
Among them, nefiracetam and oxiracetam are preferred, and nefiracetam is particularly preferred.
As the compounds represented by the general formula (I), compounds either in a free form or in a form of a pharmaceutically acceptable salt may be used.
Further, hydrates thereof or solvates thereof can also be used. Examples of the pharmaceutically acceptable salts include, for example, mineral acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, and phosphates, and organic acid salts such as acetates, maleates, fumarates, citrates, oxalates, succinates, tartrates, malates, mandelates, methanesulfonates, p-toluenesulfonates and 10-camphorsulfonates.
The compounds represented by the general formula (I) and pharmaceutically acceptable salts thereof have analgesic effect on neuropathic pain in experimental models of neuropathic pain as shown in the examples. Therefore, the compounds represented by the general formula (I) and pharmaceutically acceptable salts thereof are useful as medicaments for therapeutic and/or prophylactic treatment of neuropathic gain such as cancer gain, postherpetic neuralgia, post-thoracotomic pain, diabetic neuropathy, CRPS, multiple sclerosis, AIDS, trigeminal neuralgia, thalamic pain, paraplegic pain caused by myelopathy, anesthesia dolorosa, phantom limb pain and the like. Furthermore, they are also useful as supplemental analgesic agents for medicaments used for treatment of pain, for example, narcotic analgesics used for treatment of cancer pain and the like.
Routes of administration of the medicament of the present invention axe not particularly limited, and the medicament can be orally or parenterally administered.
The compounds represented by general formula (I) or pharmaceutically acceptable salts thereof, per se, as the active ingredients may be used as the medicament of the present invention. Generally, the medicament may be provided as pharmaceutical preparations well known to those skilled in the art by adding pharmaceutically acceptable additives.
Examples of pharmaceutical preparations suitable for oral administration include, for example, tablets, capsules, powders, subtilized granules, granules, solutions, syrups and the like, and examples of pharmaceutical preparations suitable for parenteral administration include, for example, injections for subcutaneous, intravenous or intramuscular injections, drip infusions, suppositories, inhalants, transdermal preparations, transmucosal preparations, patches and the like.
As the pharmaceutically acceptable additives, for example, excipients, disintegrating agents or disintegrating aids, binders, lubricants, coating agents, coloring matters, diluents, bases, dissolving agents or dissolving aids, isotonic agents, pH modifiers, stabilizers, propellants, adherents and the like may be used.
Doses of the medicament of the present invention is not particularly limited, and can be suitably selected depending on the route of administration, degree of neuropathic pain, therapeutic or prophylactic purpose, the age, symptoms and body weight of a patient and the like. For example, the dose for oral administration may be about 20 to 2000 mg, preferably about 30 to 940 mg per day as the weight of the compound represented by the general formula (I) or the pharmaceutically acceptable salt thereof, and the aforementioned daily dose may be administered as several divided portions. Acute toxicity of nefiracetam, which is a typical example of the compounds represented by the general formula (I), is 2,005 mg/kg (male mouse, p.o.), and therefore the compounds are highly safe (Japanese Patent Unexamined Patent Publication No. 5-163144).
Further, the medicaments of the present invention can generally be used as supplemental analgesic agents concurrent with narcotic analgesic agents which themselves are provided in a form of a solution, a tablet or the like. Methods for the combined use are not particularly limited. Examples of employable methods include a method in which the medicament of the present invention is continuously administered during the same and whole period as the administration period of a narcotic analgesic; a method in which the medicament of the present invention is occasionally administered as required during the administration period of a ~iarcotic analgesic; a method in which administration of the medicament of the present invention is started before administration of a narcotic analgesic, and then administrations of the narcotic analgesic and the medicament of the present invention are continued; a method in which a narcotic analgesic and the medicament of the present invention are continuously administered, then the administration of the narcotic analgesic is stopped and the administration of the medicament of the present invention is further continued and the like. If required, a pharmaceutical composition comprising a narcotic analgesic and the active ingredient of the medicament of the present invention (so-called a combined drug) may be prepared and administered.
EXAMPLES
The present invention will be more specifically explained with reference to the following examples. However, the scope of the present invention is not limited to the following examples.
Example 1: Suppressing effect on neuropathic pain in peripheral nociception test 17 of ddY male mice having a body weight of 13 to 15 g were used. The mice were anesthetized with pentobarbital, and skin of right hind leg of each mouse was dissected so that sciatic nerve was observed. The half of sciatic nerve fibers was bound with a suture for 9 mice among 17 mice, and only the dissection was performed for the remaining 8 animals (a control group). After the dissection site was sutured, the animals were left for 7 days (Xun Ye et al, Jpn. d. Pharmacol. 2000, Malmberg AB
and Basbaum AI, Pain 1998). The mice had a body weight of 20 to 22 g after being left.
The group of mice of which sciatic nerves were bound was divided into two groups, and mice of one group were each administered with 5 a 1 ( 10 nmol) of nefiracetam and mice of the other group were each administered with 5 a 1 of physiological saline into spinal subarachnoid space. After the administration, the mice were each subcutaneously administered at a right hind leg footpad with physiological saline at 10 minutes and 15 minutes, 2 ~c 1 (0.1 fmol) of bradykinin at 20 minutes and 25 minutes, 2 ~c 1 (1 fmol) of bradykinin at 30 minutes and 35 minutes, 2 a 1 (10 fmol) of bradykinin at 40 minutes and 45 minutes, and 2 a 1 (100 fmol) of bradykinin at 50 minutes and 55 minutes after the administration. The group of mice that were subjected only to the dissection was also divided into two groups, and mice of one group were each administered with 5 a 1 (10 nmol) of nefiracetam and mice of the other group were each administered with 5 ~c 1 of physiological saline into spinal subarachnoid space. After the administration, the mice were each subcutaneously administered at a right hind leg footpad with physiological saline at 10 minutes and 15 minutes, 2 ,u 1 (0.01 pmol) of bradykinin at 20 minutes and 25 minutes, 2 ,u 1 (0.1 pmol) of bradykinin at 30 minutes and minutes, 2 ~ 1 (1 pmol) of bradykinin at 40 minutes and 45 minutes, and 2 ~,1 (10 pmol) of bradykinin at 50 minutes and 55 minutes after the administration. The noxious flexion reactions caused by the administrations of bradykinin were indicated as a ratio based on the maximum spontaneous flexion reaction.
Example 2: Suppressing effect on neuropathic pain in von Frey test 42 of ddY male mice having a body weight of 16 to 18 g were used. In the von Frey test, the mice were placed on a mesh, and footpada of the mice were stimulated with a von Frey filament (TRANSDUCER INDICATOR MODEL 1601 (IITC INC., U.S.A.)) every 10 minutes, and the threshold values observed at the beginning of an escape reaction were represented in a unit of gram. The mice were anesthetized with pentobarbital, and skin of right hind leg of each mouse was dissected so that sciatic nerve was observed. The half of sciatic nerve fibers was bound with a suture for 24 mice among 42 mice, and only the dissection was performed for the remaining 18 mice (a control group). After the dissection site was sutured, the animals were left for 7 days (Xun Ye et al, Jpn. J. Pharmacol. 2000, Malmberg AB and Basbaum AI, Pain 1998). The mice had a body weight of 23 to 25 g after being left. The group of mice of which sciatic nerves were bound was divided into 4 groups, and the threshold was measured twice. The average of the values was used as a control value. Then, mice of each group were each administered with 5 ,u 1 (1 nmol) of nefiracetam, 5 a 1 (10 nmol) of nefiracetam, 5 a 1 (10 nmol) of morphine or 5 ,u 1 of physiological saline into spinal subarachnoid apace. After the administration, the threshold was repeatedly measured for 60 minutes with intervals of 10 minutes. The group of mice that were subjected only to the dissection was divided into three groups, and a control value was measured in the same manner as described above. Then, mice of each group were each administered with 5 a 1 (10 nmol) of nefiracetam, 5 a 1 (10 nmol) of morphine or ~ 1 of physiological saline into spinal subarachnoid space, and the threshold was measured in the same manner as described above.
Example 3: Suppressing effect on neuropathic pain in von Frey test In the same manner as in Example 2, 5 a 1 (10 nmol) of oxiracetam was administered and the threshold was measured.
Example 4: Suppressing effect on neuropathic pain by oral administration of nefiracetam in von Frey test 36 of ddY male mice having a body weight of 16 to 18 g were used. In the von Frey test, the mice were placed on a mesh, and hind leg footpads of the mice were stimulated with a von Frey filament (digital type von Frey tester MODEL 1601 (IITC
INC., U.S.A.)) every 15 minutes, and the threshold values observed at the beginning of an escape reaction were represented in a unit of gram. The mice were anesthetized with pentobarbital, and skin of right hind leg of each mouse was dissected so that sciatic nerve was observed. The half of sciatic nerve fibers was bound with a suture for 24 animals among the 36 animals, and only the dissection was performed for the remaining 12 animals (a sham group). After the dissection site was sutured, experiments were performed on the 7th day (Xun Ye et al, Jpn. J. Pharmacol.
2000, Malmberg AB and Basbaum AI, Pain 1998). The mice had a body weight of 23 to 25 g after the 7 days. The group of mice of which sciatic nerves were bound was divided into 4 groups, and the threshold was measured twice. The average of the values was used as a control value. Then, mice of each group were each orally administered with 3 mg/kg, 10 mg/kg or 30 mg/kg of nefiracetam or physiological saline (10 ml/kg), and the threshold was repeatedly measured for 90 minutes with intervals of 15 minutes.
The mice of the control group (the sham group) that were subjected only to the dissection were divided into two groups, and a control value was measured in the same manner as described above. Then, mice of each group were each orally administered with 30 mg/kg of nefiracetam or physiological saline (10 ml/kg), and the threshold was measured in the same manner as described above.
Example 5: Analgesic effect on diabetic neuropathic pain in Hargreaves test 36 of ddY male mice having a body weight of 28 to 30 g were used. In the Hargreaves test, the mice were placed on a glass plate, and hind leg footpads of the mice were stimulated with radiant heat (combination type analgesia meter MODEL
336 (IITC INC., U.S.A.)) every 10 minutes. And the latent time until the beginning of an escape reaction was measured. The mice with diabetes mellitus were prepared by administering streptozotocin (200 mg/kg) dissolved in 0.1 N citrate buffer (pH
4.5) to caudal arteries, and the experiment was performed on the 7th day. The mice having a blood glucose level of 300 mg/dl or higher under a starved condition (after starvation for 3 hours) were used as mice with diabetes mellitus. 24 animals among the 36 animals were determined as mice with diabetes mellitus according to the method described above, and the remaining 12 mice were administered with 0.1 N
citrate buffer at caudal arteries and used as a comparative control group (control group).
The mice with diabetes mellitus were divided into 4 groups, and the threshold was measured twice. The average of the values was used as a control value. Then, mice of each group were each orally administered with 3 mg/kg, 10 mg/kg or 30 mglkg of nefiracetam or physiological saline (10 ml/kg), and the latent time was repeatedly measured for 60 minutes with intervals of 10 minutes. The control group was divided into two groups, and a control value was measured as described above. Then, mice of each group were each orally administered with 10 mg/kg of nefiracetam or physiological saline (10 ml/kg), and the latent time was measured in the same manner as described above.
In the mouse peripheral nociception test, nociceptive flexion reactions caused by chemical pain stimulus using bradykinin were evaluated. In the control group subjected only to the dissection and without nervous disturbance, the effect of nefiracetam, administered into.the spinal subarachnoid space at a dose of 0.01 to 10 pmols, on the reaction caused by bradykinin administered to footpad was found to be not significant as compared to that obtained by physiological saline. Whilst in the neuropathic pain model in which the nervous disturbance was generated, an equivalent bradykinin response was caused with a dose in the range of 0.1 to 100 fmol, which was lower by 100 times. The administration of nefiracetam into the spinal subarachnoid space gave strong analgesic effects to an extent that the bradykinin sensitive response was completely suppressed.
In the von Frey teat, the escape reactions caused by mechanical noxious stimulus, which was given fox a time period of 60 minutes with intervals of 10 minutes, were evaluated as a threshold (g). In the control group subjected only to the dissection and without nervous disturbance, both of the administrations of nefiracetam and morphine into the spinal subarachnoid spaces did not give significant effect as compared to the administration of physiological saline. Whilst in the neuropathic -- pain model in which the nervous disturbance was generated, the noxious response threshold fell down to an about half level compared with the control group, which indicated sensitivity reaction. The administration of morphine into the spinal subarachnoid apace (10 nmol) gave no significant effect on the reaction.
However, nefiracetam gave analgesic effect in a dose-dependent manner at doses of 1 and nmol, which were lower than that of morphine, and its degree reached the threshold observed in the control.
Further, oxiracetam gave analgesic effect substantially equivalent to that of nefiracetam in the von Frey test. Nefiracetam also gave suppressing effect on neuropathic pain even by oral administration, and nefiracetam also gave suppression effect also on diabetic neuropathic pain.
As described above, it was demonstrated that the compounds of the present invention represented by the general formula (I) and salts thereof have superior analgesic effects on morphine-resistant neuropathic pain.
Industrial Applicability The compounds of the present invention represented by the general formula (I) and salts thereof have superior analgesic effects on morphine-resistant neuropathic pain, and therefore, are useful as medicament for therapeutic and/or prophylactic treatment of cancer pain and the like, or as supplemental analgesic agents..
These compounds can be easily produced by the methods disclosed in, for example, Japanese Patent Publication No. 42-19093, Japanese Patent Unexamined Publication Nos. 52-23072, 54-117468, 60-252461, 56-2960, 61-280470, 4-160496, Japanese Patent Publication No. 3-46466 and so forth.
In the general formula (I), R~ is preferably a phenyl group having an alkoxyl group or -NH-R4. Rø is preferably a phenyl group having two alkyl groups or hydrogen atom.
- Examples of typical compounds among the compounds falling within the scope of the general formula (I) include 2-oxo-1-pyrrolidineacetamide (piracetam), 4-hydroxy-2-oxo-1-pyrrolidineacetamide (oxiracetam), 1-(4-methoxybenzoyl)-2-pyrrolidinone (aniracetam), (S)- a -ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam), and N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide (nefiracetam).
Among them, nefiracetam and oxiracetam are preferred, and nefiracetam is particularly preferred.
As the compounds represented by the general formula (I), compounds either in a free form or in a form of a pharmaceutically acceptable salt may be used.
Further, hydrates thereof or solvates thereof can also be used. Examples of the pharmaceutically acceptable salts include, for example, mineral acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, and phosphates, and organic acid salts such as acetates, maleates, fumarates, citrates, oxalates, succinates, tartrates, malates, mandelates, methanesulfonates, p-toluenesulfonates and 10-camphorsulfonates.
The compounds represented by the general formula (I) and pharmaceutically acceptable salts thereof have analgesic effect on neuropathic pain in experimental models of neuropathic pain as shown in the examples. Therefore, the compounds represented by the general formula (I) and pharmaceutically acceptable salts thereof are useful as medicaments for therapeutic and/or prophylactic treatment of neuropathic gain such as cancer gain, postherpetic neuralgia, post-thoracotomic pain, diabetic neuropathy, CRPS, multiple sclerosis, AIDS, trigeminal neuralgia, thalamic pain, paraplegic pain caused by myelopathy, anesthesia dolorosa, phantom limb pain and the like. Furthermore, they are also useful as supplemental analgesic agents for medicaments used for treatment of pain, for example, narcotic analgesics used for treatment of cancer pain and the like.
Routes of administration of the medicament of the present invention axe not particularly limited, and the medicament can be orally or parenterally administered.
The compounds represented by general formula (I) or pharmaceutically acceptable salts thereof, per se, as the active ingredients may be used as the medicament of the present invention. Generally, the medicament may be provided as pharmaceutical preparations well known to those skilled in the art by adding pharmaceutically acceptable additives.
Examples of pharmaceutical preparations suitable for oral administration include, for example, tablets, capsules, powders, subtilized granules, granules, solutions, syrups and the like, and examples of pharmaceutical preparations suitable for parenteral administration include, for example, injections for subcutaneous, intravenous or intramuscular injections, drip infusions, suppositories, inhalants, transdermal preparations, transmucosal preparations, patches and the like.
As the pharmaceutically acceptable additives, for example, excipients, disintegrating agents or disintegrating aids, binders, lubricants, coating agents, coloring matters, diluents, bases, dissolving agents or dissolving aids, isotonic agents, pH modifiers, stabilizers, propellants, adherents and the like may be used.
Doses of the medicament of the present invention is not particularly limited, and can be suitably selected depending on the route of administration, degree of neuropathic pain, therapeutic or prophylactic purpose, the age, symptoms and body weight of a patient and the like. For example, the dose for oral administration may be about 20 to 2000 mg, preferably about 30 to 940 mg per day as the weight of the compound represented by the general formula (I) or the pharmaceutically acceptable salt thereof, and the aforementioned daily dose may be administered as several divided portions. Acute toxicity of nefiracetam, which is a typical example of the compounds represented by the general formula (I), is 2,005 mg/kg (male mouse, p.o.), and therefore the compounds are highly safe (Japanese Patent Unexamined Patent Publication No. 5-163144).
Further, the medicaments of the present invention can generally be used as supplemental analgesic agents concurrent with narcotic analgesic agents which themselves are provided in a form of a solution, a tablet or the like. Methods for the combined use are not particularly limited. Examples of employable methods include a method in which the medicament of the present invention is continuously administered during the same and whole period as the administration period of a narcotic analgesic; a method in which the medicament of the present invention is occasionally administered as required during the administration period of a ~iarcotic analgesic; a method in which administration of the medicament of the present invention is started before administration of a narcotic analgesic, and then administrations of the narcotic analgesic and the medicament of the present invention are continued; a method in which a narcotic analgesic and the medicament of the present invention are continuously administered, then the administration of the narcotic analgesic is stopped and the administration of the medicament of the present invention is further continued and the like. If required, a pharmaceutical composition comprising a narcotic analgesic and the active ingredient of the medicament of the present invention (so-called a combined drug) may be prepared and administered.
EXAMPLES
The present invention will be more specifically explained with reference to the following examples. However, the scope of the present invention is not limited to the following examples.
Example 1: Suppressing effect on neuropathic pain in peripheral nociception test 17 of ddY male mice having a body weight of 13 to 15 g were used. The mice were anesthetized with pentobarbital, and skin of right hind leg of each mouse was dissected so that sciatic nerve was observed. The half of sciatic nerve fibers was bound with a suture for 9 mice among 17 mice, and only the dissection was performed for the remaining 8 animals (a control group). After the dissection site was sutured, the animals were left for 7 days (Xun Ye et al, Jpn. d. Pharmacol. 2000, Malmberg AB
and Basbaum AI, Pain 1998). The mice had a body weight of 20 to 22 g after being left.
The group of mice of which sciatic nerves were bound was divided into two groups, and mice of one group were each administered with 5 a 1 ( 10 nmol) of nefiracetam and mice of the other group were each administered with 5 a 1 of physiological saline into spinal subarachnoid space. After the administration, the mice were each subcutaneously administered at a right hind leg footpad with physiological saline at 10 minutes and 15 minutes, 2 ~c 1 (0.1 fmol) of bradykinin at 20 minutes and 25 minutes, 2 ~c 1 (1 fmol) of bradykinin at 30 minutes and 35 minutes, 2 a 1 (10 fmol) of bradykinin at 40 minutes and 45 minutes, and 2 a 1 (100 fmol) of bradykinin at 50 minutes and 55 minutes after the administration. The group of mice that were subjected only to the dissection was also divided into two groups, and mice of one group were each administered with 5 a 1 (10 nmol) of nefiracetam and mice of the other group were each administered with 5 ~c 1 of physiological saline into spinal subarachnoid space. After the administration, the mice were each subcutaneously administered at a right hind leg footpad with physiological saline at 10 minutes and 15 minutes, 2 ,u 1 (0.01 pmol) of bradykinin at 20 minutes and 25 minutes, 2 ,u 1 (0.1 pmol) of bradykinin at 30 minutes and minutes, 2 ~ 1 (1 pmol) of bradykinin at 40 minutes and 45 minutes, and 2 ~,1 (10 pmol) of bradykinin at 50 minutes and 55 minutes after the administration. The noxious flexion reactions caused by the administrations of bradykinin were indicated as a ratio based on the maximum spontaneous flexion reaction.
Example 2: Suppressing effect on neuropathic pain in von Frey test 42 of ddY male mice having a body weight of 16 to 18 g were used. In the von Frey test, the mice were placed on a mesh, and footpada of the mice were stimulated with a von Frey filament (TRANSDUCER INDICATOR MODEL 1601 (IITC INC., U.S.A.)) every 10 minutes, and the threshold values observed at the beginning of an escape reaction were represented in a unit of gram. The mice were anesthetized with pentobarbital, and skin of right hind leg of each mouse was dissected so that sciatic nerve was observed. The half of sciatic nerve fibers was bound with a suture for 24 mice among 42 mice, and only the dissection was performed for the remaining 18 mice (a control group). After the dissection site was sutured, the animals were left for 7 days (Xun Ye et al, Jpn. J. Pharmacol. 2000, Malmberg AB and Basbaum AI, Pain 1998). The mice had a body weight of 23 to 25 g after being left. The group of mice of which sciatic nerves were bound was divided into 4 groups, and the threshold was measured twice. The average of the values was used as a control value. Then, mice of each group were each administered with 5 ,u 1 (1 nmol) of nefiracetam, 5 a 1 (10 nmol) of nefiracetam, 5 a 1 (10 nmol) of morphine or 5 ,u 1 of physiological saline into spinal subarachnoid apace. After the administration, the threshold was repeatedly measured for 60 minutes with intervals of 10 minutes. The group of mice that were subjected only to the dissection was divided into three groups, and a control value was measured in the same manner as described above. Then, mice of each group were each administered with 5 a 1 (10 nmol) of nefiracetam, 5 a 1 (10 nmol) of morphine or ~ 1 of physiological saline into spinal subarachnoid space, and the threshold was measured in the same manner as described above.
Example 3: Suppressing effect on neuropathic pain in von Frey test In the same manner as in Example 2, 5 a 1 (10 nmol) of oxiracetam was administered and the threshold was measured.
Example 4: Suppressing effect on neuropathic pain by oral administration of nefiracetam in von Frey test 36 of ddY male mice having a body weight of 16 to 18 g were used. In the von Frey test, the mice were placed on a mesh, and hind leg footpads of the mice were stimulated with a von Frey filament (digital type von Frey tester MODEL 1601 (IITC
INC., U.S.A.)) every 15 minutes, and the threshold values observed at the beginning of an escape reaction were represented in a unit of gram. The mice were anesthetized with pentobarbital, and skin of right hind leg of each mouse was dissected so that sciatic nerve was observed. The half of sciatic nerve fibers was bound with a suture for 24 animals among the 36 animals, and only the dissection was performed for the remaining 12 animals (a sham group). After the dissection site was sutured, experiments were performed on the 7th day (Xun Ye et al, Jpn. J. Pharmacol.
2000, Malmberg AB and Basbaum AI, Pain 1998). The mice had a body weight of 23 to 25 g after the 7 days. The group of mice of which sciatic nerves were bound was divided into 4 groups, and the threshold was measured twice. The average of the values was used as a control value. Then, mice of each group were each orally administered with 3 mg/kg, 10 mg/kg or 30 mg/kg of nefiracetam or physiological saline (10 ml/kg), and the threshold was repeatedly measured for 90 minutes with intervals of 15 minutes.
The mice of the control group (the sham group) that were subjected only to the dissection were divided into two groups, and a control value was measured in the same manner as described above. Then, mice of each group were each orally administered with 30 mg/kg of nefiracetam or physiological saline (10 ml/kg), and the threshold was measured in the same manner as described above.
Example 5: Analgesic effect on diabetic neuropathic pain in Hargreaves test 36 of ddY male mice having a body weight of 28 to 30 g were used. In the Hargreaves test, the mice were placed on a glass plate, and hind leg footpads of the mice were stimulated with radiant heat (combination type analgesia meter MODEL
336 (IITC INC., U.S.A.)) every 10 minutes. And the latent time until the beginning of an escape reaction was measured. The mice with diabetes mellitus were prepared by administering streptozotocin (200 mg/kg) dissolved in 0.1 N citrate buffer (pH
4.5) to caudal arteries, and the experiment was performed on the 7th day. The mice having a blood glucose level of 300 mg/dl or higher under a starved condition (after starvation for 3 hours) were used as mice with diabetes mellitus. 24 animals among the 36 animals were determined as mice with diabetes mellitus according to the method described above, and the remaining 12 mice were administered with 0.1 N
citrate buffer at caudal arteries and used as a comparative control group (control group).
The mice with diabetes mellitus were divided into 4 groups, and the threshold was measured twice. The average of the values was used as a control value. Then, mice of each group were each orally administered with 3 mg/kg, 10 mg/kg or 30 mglkg of nefiracetam or physiological saline (10 ml/kg), and the latent time was repeatedly measured for 60 minutes with intervals of 10 minutes. The control group was divided into two groups, and a control value was measured as described above. Then, mice of each group were each orally administered with 10 mg/kg of nefiracetam or physiological saline (10 ml/kg), and the latent time was measured in the same manner as described above.
In the mouse peripheral nociception test, nociceptive flexion reactions caused by chemical pain stimulus using bradykinin were evaluated. In the control group subjected only to the dissection and without nervous disturbance, the effect of nefiracetam, administered into.the spinal subarachnoid space at a dose of 0.01 to 10 pmols, on the reaction caused by bradykinin administered to footpad was found to be not significant as compared to that obtained by physiological saline. Whilst in the neuropathic pain model in which the nervous disturbance was generated, an equivalent bradykinin response was caused with a dose in the range of 0.1 to 100 fmol, which was lower by 100 times. The administration of nefiracetam into the spinal subarachnoid space gave strong analgesic effects to an extent that the bradykinin sensitive response was completely suppressed.
In the von Frey teat, the escape reactions caused by mechanical noxious stimulus, which was given fox a time period of 60 minutes with intervals of 10 minutes, were evaluated as a threshold (g). In the control group subjected only to the dissection and without nervous disturbance, both of the administrations of nefiracetam and morphine into the spinal subarachnoid spaces did not give significant effect as compared to the administration of physiological saline. Whilst in the neuropathic -- pain model in which the nervous disturbance was generated, the noxious response threshold fell down to an about half level compared with the control group, which indicated sensitivity reaction. The administration of morphine into the spinal subarachnoid apace (10 nmol) gave no significant effect on the reaction.
However, nefiracetam gave analgesic effect in a dose-dependent manner at doses of 1 and nmol, which were lower than that of morphine, and its degree reached the threshold observed in the control.
Further, oxiracetam gave analgesic effect substantially equivalent to that of nefiracetam in the von Frey test. Nefiracetam also gave suppressing effect on neuropathic pain even by oral administration, and nefiracetam also gave suppression effect also on diabetic neuropathic pain.
As described above, it was demonstrated that the compounds of the present invention represented by the general formula (I) and salts thereof have superior analgesic effects on morphine-resistant neuropathic pain.
Industrial Applicability The compounds of the present invention represented by the general formula (I) and salts thereof have superior analgesic effects on morphine-resistant neuropathic pain, and therefore, are useful as medicament for therapeutic and/or prophylactic treatment of cancer pain and the like, or as supplemental analgesic agents..
Claims (12)
1. A medicament for therapeutic and/or prophylactic treatment of neuropathic pain, which comprises a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient:
wherein R1 represents a hydrogen atom or a hydroxyl group;
R2 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
R3 represents a phenyl group which may have 1 to 3 atoms or substituents selected from the group consisting of a halogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms, and an alkoxyl group having 1 to 3 carbon atoms, or represents -NH-R4 wherein R4 represents a phenyl group which may have 1 to 3 atoms or substituents selected from the group consisting of a halogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms, and an alkoxyl group having 1 to 3 carbon atoms or a hydrogen atom, and n represents 0 or 1.
wherein R1 represents a hydrogen atom or a hydroxyl group;
R2 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
R3 represents a phenyl group which may have 1 to 3 atoms or substituents selected from the group consisting of a halogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms, and an alkoxyl group having 1 to 3 carbon atoms, or represents -NH-R4 wherein R4 represents a phenyl group which may have 1 to 3 atoms or substituents selected from the group consisting of a halogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms, and an alkoxyl group having 1 to 3 carbon atoms or a hydrogen atom, and n represents 0 or 1.
2. A medicament for suppressing neuropathic pain, which comprises a compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
3. A medicament for supplemental treatment of neuropathic pain, which comprises a compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
4. The medicament according to any one of claims 1 to 3, wherein the neuropathic pain is neuropathic pain of cancer pain, postherpetic neuralgia, post-thoracotomic pain, diabetic neuropathy, CRPS, multiple sclerosis, AIDS, trigeminal neuralgia, thalamic pain, paraplegic pain caused by myelopathy, anesthesia dolorosa, or phantom limb pain.
5. The medicament according to any one of claims 1 to 4, wherein the active ingredient is 2-oxo-1-pyrrolidineacetamide, 4-hydroxy-2-oxo-1-pyrrolidineacetamide, 1-(4-methoxybenzoyl)-2-pyrrolidinone, (S)-.alpha.-ethyl-2-oxo-1-pyrrolidineacetamide, or N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide.
6. The medicament according to any one of claims 1 to 4, wherein the active ingredient is 4-hydroxy-2-oxo-1-pyrrolidineacetamide or N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide.
7. The medicament according to any one of claims 1 to 4, wherein the active ingredient is N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide.
8. A method for therapeutic and/or prophylactic treatment of neuropathic pain, which comprises the step of administering to a mammal including human a therapeutically and/or prophylactically effective amount of the compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
9. A method for suppressing neuropathic pain, which comprises the step of administering to a mammal including human an effective amount of the compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
10. A method for supplemental treatment for a therapeutic and/or prophylactic treatment of neuropathic pain, which comprises the step of administering to a mammal including human an effective amount of the compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
11. A method for therapeutic and/or prophylactic treatment of neuropathic pain, which comprises the step of administering to a mammal including human a therapeutically and/or prophylactically effective amount of the compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof together with at least one analgesic.
12. A use of the compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for manufacture of the medicament according to any one of claims 1 to 7.
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| CZ281170B6 (en) | 1991-05-02 | 1996-07-17 | Daiichi Pharmaceutical Co., Ltd | The use of n-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide for preparing a pharmaceutical preparation |
| ZA923134B (en) | 1991-05-02 | 1993-01-27 | Daiichi Seiyaku Co | Agent for improving dementia |
| CA2098663A1 (en) | 1992-06-19 | 1993-12-20 | Shinji Kamihara | Process for preparing pyrrolidinylacetamide derivative |
| GB9505692D0 (en) * | 1995-03-21 | 1995-05-10 | Glaxo Group Ltd | Chemical compounds |
| US5885976A (en) * | 1995-05-08 | 1999-03-23 | Sandyk; Reuven | Methods useful for the treatment of neurological and mental disorders related to deficient serotonin neurotransmission and impaired pineal melatonin functions |
| US6116270A (en) * | 1995-08-04 | 2000-09-12 | Hydro-Flo Holdings Pty Ltd. | Piston valve |
| US6107330A (en) | 1995-08-07 | 2000-08-22 | Daiichi Pharmaceutical Co., Ltd. | Inhibitor for narcotic analgesic dependence/resistance acquisition |
| US5551846A (en) | 1995-12-01 | 1996-09-03 | Ford Motor Company | Scroll compressor capacity control valve |
| CA2267375A1 (en) | 1996-10-01 | 1998-04-09 | Mitsunobu Yoshii | Mitochondrial membrane stabilizer |
| DE69823851D1 (en) | 1997-07-15 | 2004-06-17 | Daiichi Seiyaku Co | NEFIRACETAM FOR PROPHYLAXIS AND TREATMENT OF PROPOFOL CAUSED MEMORY LOSS |
| TW544311B (en) | 1998-08-06 | 2003-08-01 | Daiichi Seiyaku Co | Therapeutic or preventive agent for intractable epilepsies |
| US20040077709A1 (en) * | 1999-05-31 | 2004-04-22 | Daiichi Pharmaceutical Co., Ltd. | Neuronal death inhibitors |
| KR20020015321A (en) | 1999-05-31 | 2002-02-27 | 스즈키 다다시 | Neuronal death inhibitors |
| US6349442B1 (en) * | 1999-06-23 | 2002-02-26 | Advanced Prosthetic Technologies, Inc. | Brush tip for a motorized toothbrush |
| NZ518901A (en) | 1999-12-01 | 2004-08-27 | Ucb S | A levetiracetam alone or in combination with a compound inducing neural inhibition mediated by the GABA receptors for treatment of chronic pain, bipolar disorder, mania and migraine |
| US6423739B1 (en) * | 2000-02-23 | 2002-07-23 | Daiichi Pharmaceutical Co., Ltd. | Method for aiding cerebral recovery following neurodegeneration |
-
2001
- 2001-12-25 US US10/450,524 patent/US7608636B2/en not_active Expired - Fee Related
- 2001-12-25 EP EP01272527A patent/EP1356812B1/en not_active Expired - Lifetime
- 2001-12-25 WO PCT/JP2001/011356 patent/WO2002053153A1/en active Application Filing
- 2001-12-25 JP JP2002554103A patent/JPWO2002053153A1/en active Pending
- 2001-12-25 CA CA2433039A patent/CA2433039C/en not_active Expired - Fee Related
- 2001-12-25 KR KR1020037008668A patent/KR100823668B1/en not_active IP Right Cessation
- 2001-12-25 AT AT01272527T patent/ATE431142T1/en not_active IP Right Cessation
- 2001-12-25 CN CNA018216242A patent/CN1484527A/en active Pending
- 2001-12-25 MX MXPA03005889A patent/MXPA03005889A/en not_active Application Discontinuation
- 2001-12-25 DE DE60138733T patent/DE60138733D1/en not_active Expired - Lifetime
- 2001-12-27 AR ARP010106055A patent/AR032066A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP1356812B1 (en) | 2009-05-13 |
| US20040063776A1 (en) | 2004-04-01 |
| DE60138733D1 (en) | 2009-06-25 |
| MXPA03005889A (en) | 2005-02-14 |
| JPWO2002053153A1 (en) | 2004-04-30 |
| US7608636B2 (en) | 2009-10-27 |
| CN1484527A (en) | 2004-03-24 |
| WO2002053153A1 (en) | 2002-07-11 |
| AR032066A1 (en) | 2003-10-22 |
| KR100823668B1 (en) | 2008-04-21 |
| EP1356812A4 (en) | 2006-04-12 |
| EP1356812A1 (en) | 2003-10-29 |
| KR20040025882A (en) | 2004-03-26 |
| CA2433039A1 (en) | 2002-07-11 |
| ATE431142T1 (en) | 2009-05-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20141229 |