JPH0259522A - Improver for cerebral metabolism and/or mental symptom - Google Patents

Abstract

PURPOSE:To obtain an improver for cerebral metabolism and mental symptom effective against oxygen deficiency state of various nerve cells considered to have participation of improving action on cerebral function disorder, etc., comprising eptazocine or a salt thereof as an active ingredient. CONSTITUTION:The title improver comprises one of eptazocine shown by the formula and salts thereof (e.g., hydrochloride, hydrobromide or sulfate) as an active ingredient. The compound shown by the formula is useful for oral administration, parenteral administration such as intravenous injection, intravenous drip, intramuscular injection or administration to rectum and further for external use. An effective dose is 1-10mg/kg daily and administered dividedly once three times daily, as required.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to an agent for improving brain metabolism and/or psychiatric symptoms. More specifically, the present invention relates to an agent for improving cerebral metabolism and/or mental symptoms that is useful for improving ischemic brain damage, decreased motivation, emotional disorders, and language disorders associated with diseases such as cerebral infarction sequelae, cerebral hemorrhage sequelae, and cerebral arteriosclerosis.

Eptazocine and its pharmaceutically acceptable salts, represented by ), are known compounds that exhibit poor central analgesic action and are already in clinical use as opiate (narcotic) antagonistic analgesics. Regarding the manufacturing method and the usage method, the specification of Patent No. 1245929 and the specification of Patent No. 1245930 filed by the applicant of the present application and Japanese Patent Publication No. 63-20
It is disclosed in Japanese Patent No. 817.

Research has been extensively conducted to develop new therapeutic applications of opiate antagonists in the brain and nervous system areas. The background to this was the discovery in 1973 of opiate binding sites (receptors) in nervous tissues, and subsequently a large number of opiate peptides (receptors) were discovered in the brain and nervous tissues.
The morphine-like effects of these peptides were discovered to be antagonized by naloxone, a typical opiate antagonist.

Oxygen and glucose, which are the energy sources necessary for brain cells to function normally, are hardly stored in the brain and are supplied mostly by the blood. If brain damage occurs and the supply of oxygen and glucose is cut off, energy metabolism disorder progresses and brain cells lose function, causing symptoms based on organic disorders and mental dysfunction in the brain. Here, organic disorders in the brain refer to symptoms derived from cerebral ischemic disorders such as aftereffects of cerebral infarction, aftereffects of cerebral hemorrhage, aftereffects of cerebral arteriosclerosis, as well as senile dementia, presenile dementia, Alzheimer's type dementia, amnesia, and cerebrovascular disease. Mental dysfunction refers to various organic disorders resulting from after-effects of trauma, brain surgery, etc., and mental dysfunction refers to chronic illnesses,
Denotes depression, neurosis, Parkinson's disease, schizophrenia and schizophrenia-like disorder, chorea, and mental function disorders derived from drugs and alcohol.

In recent years, with the increase in the number of patients with the above-mentioned organic disorders in the brain and mental dysfunction, there is a strong demand for drugs for medically treating these diseases, and a large number of drugs have been developed. Conventional compounds developed for this purpose include, for example, idebenone, calcium fobatate, and nidiphenone.

<Problems to be Solved by the Invention> As a result of intensive research to find a compound that is effective in improving and treating symptoms caused by the various disorders in the brain mentioned above, the present inventor has discovered an opiate antagonist analgesic drug. Eptazocine and its salts of the formula (1) have, for example, a brain dysfunction-improving effect,
It is extremely effective against the oxygen-deficient state of various nerve cells (cerebral anoxia), which is thought to be closely related to its pharmacological properties such as protecting against ischemic brain damage and improving the metabolism of neurotransmitters in the brain. This discovery led to the present invention.

Therefore, an object of the present invention is to provide an agent for improving brain metabolism and/or mental symptoms, which contains eptazocine of formula (1) and its salts as an active ingredient.

The above objects and many other objects and advantages of the present invention will become more apparent from the following description.

<Means and effects for solving the problems> The objects and advantages of the present invention are as follows: According to the present invention, a compound selected from eptazocine and its pharmaceutically acceptable salts represented by the following formula (1) This is achieved by an agent for improving brain metabolism and/or mental symptoms, which is characterized by containing at least one of these as an active ingredient.

Eptazocine of the formula (15)-1,4-dimethyl-IO-hydroxy-2,3,4,5,6,7, which is the active ingredient of the agent for improving brain metabolism and/or psychiatric symptoms of the present invention, is
-Hexahydro-1゜6-methano-IH-4-benzazonine, and the method for producing this compound and its salts is disclosed in Patent No. 124599 filed by the same applicant mentioned above.
Specification No. 9, Specification No. 1245930, and Japanese Patent Publication No. 6
It is described in detail in the specification of the prior invention of Publication No. 3-20817, and can be used for producing the active ingredient in the present invention.

For example, 7-medoxy3,4-dihydro-2(IH)-
Obtained from naphthalenone through 8 steps (±)-1,4
-dimethyl-1O-hydroxy-2,3,4,5,6
, 7-hexahydro-1,6-methano-1) (-4-benzazonine) can be optically resolved using d-mandelic acid to produce eptazocine.

The pharmaceutically acceptable salt of eptazocine may be either an inorganic acid salt or an organic acid salt. Examples include salts of maleic acid, citric acid, lactic acid, methanesulfonic acid, and the like.

As detailed later in the Examples, eptazocine and its salts significantly prolonged survival time in various experimental animal models of cerebral hypoxia, such as KCN loading, vacuum loading, and head contusion, and exhibited cerebral protective effects. . This effect was observed with morphine, pentazocine, butorphanol, and buprenorphine, which are analgesics with chemical structures similar to eptazocine, but morphine and pentazocine conversely shorten survival time and exacerbate cerebral hypoxia injury in some models. I got the result. The brain protective effect of eptazocine and its salts was completely suppressed by atropine, a muscarinic acetylcholine (m-Ach) receptor antagonist, and naloxone, an opiate receptor antagonist.
It is thought that the acetylcholine nervous system and the opiate nervous system in the brain are closely related to the brain protective effect of eptazocine and its salts, and from this point of view, eptazocine and its salts of the formula (1) have no effect on the conventional It was confirmed that this compound is a significant compound as a new field of brain-protective substance, which has a completely different mechanism of action from other compounds that exhibit brain-protective effects.

Furthermore, eptazocine of formula (1) and its salts protect against a decrease in brain ATP content in a KCN loading model using rats, and also prevent the occurrence of ischemic stroke, mortality, cerebral edema, etc. in a bilateral common carotid artery ligation model. significantly improved,
Results showed activation of brain energy metabolism.

Furthermore, since eptazosine and its salts were also observed to have the effect of increasing Ach content in rats, it was also found that effects related to learning and memory promotion via the Ach nervous system can be expected.

Thus, eptazocine and its salts of formula (1) can be used as agents for improving brain metabolism and/or mental symptoms, for example, aftereffects of cerebral infarction, aftereffects of cerebral hemorrhage, ischemic brain damage associated with diseases such as cerebral arteriosclerosis, loss of motivation, It has been revealed that this compound has extremely important medical value and is useful for improving and treating emotional disorders, language disorders, etc.

Eptazocine and its salts represented by the formula (1), which are the active ingredients of the present invention, can be used to treat, for example, cerebral infarction sequelae, cerebral hemorrhage sequelae, ischemic brain damage associated with cerebral arteriosclerosis, decreased motivation,
It can be administered by any method that is recognized as being appropriate for improving or treating emotional disorders, language disorders, etc.

Examples of such administration methods include oral administration, parenteral administration such as intravenous injection, infusion, intramuscular injection, and rectal administration, as well as external administration. The amount of eptazocine of formula (1) and its salts to be administered varies depending on the patient's age, symptoms, physical condition, etc., and can be selected as appropriate, but in general, the effective dose is 1 to
The dose is 10 mg/kg, and it can be administered in 1 to 3 divided doses a day if necessary.

Eptazocine and its salts of the formula (1) can be used alone or in appropriate combinations with other medicines, or in any dosage form mixed with a pharmaceutical carrier, diluent, or other pharmaceutical aids, and used as a medicine. Examples of such dosage forms include tablets, granules, capsules, oral liquid preparations, injections, halves, and transdermal absorption preparations.

To prepare a solid dosage form for oral use, the active ingredient of the present invention may be used as is or with suitable excipients, such as conventional bases such as lactose, mannitol, corn starch, barley/iostarch, etc., such as crystalline cellulose, Tablets are prepared by combining a cellulose derivative, a binder such as gum arahia, corn starch, gelatin, etc., a disintegrant such as potato starch, corn starch, sodium carboxyl methyl cellulose, and a lubricant such as talc, magunium stearate. , granules, capsules, etc.

Further, when the preparation is used as a liquid preparation such as a suspension or syrup, water, physiological saline, simple syrup, aqueous dextrose solution, glycerin, ethanol, etc. can be used as a carrier.

The injection may be a solution or suspension in an aqueous solvent such as distilled water for injection, physiological saline, or an aqueous glucose solution, or a non-aqueous solvent such as vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, or propylene glycol. .

Furthermore, for sentencing purposes, conventional plasticizers and carriers such as polyalkylene glycols and fatty acid triglycerides can be used.

In addition, these dosage forms may contain coloring agents, flavoring agents,
Preservatives, pH adjusters, buffers, solubilizing agents, tonicity agents, etc. may also be added.

<Example> The present invention will be described in detail below with reference to Examples. However, before that, the method for producing eptazocine, an active ingredient used in the present invention, and its acute toxicity value will be shown as Reference Example 1 and Reference Example 2, respectively.

Reference example 1 d-mandelic acid (15.2g) in methanol (50mC
) solution contains (±)-1,4-dimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-
Methano-IH-4-benzazonine (23,19) was added and the mixture was heated to dissolve. Next, 40 mQ of methanol was distilled off at normal pressure, and then diluted with acetone (40 mQ) and left at 0°C for 2 days. The solid was separated and recrystallized from methanol-acetone (1:9) to obtain 11.59 eptazocine mandelate. mp177-18000 This salt was dissolved in water, made alkaline with aqueous ammonia, and the precipitated crystals were washed several times with water and dried to obtain 6.7 g of eptazocine. mp249-252°C [#] -21,8° (c 2.0, IN-HCI
) Reference Example 2 Acute Toxicity Test Example - Mice and rats were tested in groups of 10 each male and female.
Oral and intravenous administration routes using animals were investigated.

The L Dso value is calculated from the number of deaths 72 hours after administration.
It was calculated by the tcbf 1eld-Wi 1 coxon method. The results obtained are shown in the table below.

Example 1 (Protective effect on cerebral hypoxia injury) Lethality due to vacuum loading -ddY mouse (male, 25-3
0g) in a desiccator and use a vacuum pump to
The pressure was reduced to 190 mmHg within seconds. The time from the start of decompression to the end of breathing was measured and used as an index of the life-prolonging effect of the drug. The test drug was administered intraperitoneally 30 minutes before the start of decompression. The results obtained are shown in Table-1.

Example 2 (Anti-cerebral edema effect) Cerebral ischemia model by bilateral common artery ligation - Wistar rats (male, 80~loOg) were fixed in a dorsal position without anesthesia, and bilateral common carotid arteries were ligated in two stages with sutures. Thereafter, the test drug was administered intraperitoneally. Thereafter, the animals were immediately returned to their cages and observed for up to 3 hours for the onset of ischemic attack (jumping, rolling behavior, and jerking) and for death. Surviving cases were decapitated, their brains removed, their wet weights measured, and then left in an oven at 110°C for 24 hours, their dry weights were measured, and their brain water content was calculated using the following formula.

Furthermore, the brain was homogenized with IN-nitrate 5IIIQ,
The Na content of the filtered supernatant was measured using a flame photometer (Hitachi, 7
50 type) to determine the Na/K ratio. The results obtained are shown in Table-2.

Example 3 (Brain Acetylcholine (Ach) Nervous System Activation Effect) Antagonism of excessive exercise by scopolamine (anti-Ach agent) - Method of Toyama et al. (El Pharmacology, Vol. 89, 103-1)
10, 1987). That is, scopolamine (
1 m9/kg) was administered subcutaneously, and Animex (
The subsequent amount of exercise was measured at 5-minute intervals for 30 minutes using a Muromachi Machine (SE model). Antagonism was evaluated by comparing the amount of exercise with the scopolamine alone administration group. The results obtained are shown in Table 3.

Example 4 (Intracerebral Ach Nervous System Activation Effect) Antagonism of Intracerebral Ach Depletion by Scopolamine - The test drug was administered intraperitoneally to mice, and 10 minutes later, scopolamine (2 mg dose, kg) was administered subcutaneously. 20 minutes later, microwave (5kw).

The mice were sacrificed by irradiation (1.3 seconds), and the cerebral cortex and striatum were separated. 0 for each. Extracted with IN perchloric acid,
The Ach concentration of the extract was measured using an electrochemical detector (Acom, EC
The content of Ach in the brain was calculated using a high-performance liquid chromatograph connected to D-100), and the antagonistic effect of scopolamine on Ach thirst was evaluated. The results obtained are shown in Table 4.

Example 5 (tablet) mg amount in 1 tablet eptazocine 150 lactose
113 Corn starch 20 Crystalline cellulose 15 Magnesium stearate 2 The above ingredients are mixed and pressed to make one tablet.

Example 6 (capsules) mg amount in 1 capsule eptazocine 1OO lactose
110 Corn starch 48 Magnesium stearate 2 Mix the above ingredients and fill into a No. 2 capsule.

Example 7 (injection) An injection with the following composition adjusted to pH 7 was prepared.
.

Eptazocin 15 mg Sodium chloride Appropriate amount IN Hydrochloric acid Appropriate amount IN Potassium hydroxide Appropriate amount Potassium dihydrogen phosphate Appropriate amount Injection m Distilled water Total amount 1 m Q Example 8 (skewered) Eptazocin 1 g Fatty acid glycerin ester 9 hours The above ingredients were heated to a uniform temperature and poured into a metal mold. After cooling and solidifying, remove the skewers from the mold.

Patent applicant: Japan Pharmaceutical Industry Co., Ltd.

Claims (1)

[Claims] (1) The active ingredient is at least one compound selected from eptazocine and its pharmaceutically acceptable salts represented by the following formula (I) ▲Mathematical formula, chemical formula, table, etc.▼-----(I) An agent for improving brain metabolism and/or mental symptoms, characterized by containing: