JPH0710823A - N-3 unsaturated fatty acid derivative and pharmaceutical composition containing the same - Google Patents

Abstract

(57) [Summary] (Modified) [Objective] To provide a novel n-3 unsaturated fatty acid derivative having a memory improving action. [Constitution] The following formula (In the formula, n1 represents an integer of 3 to 6 and n2 represents an integer of 1 to 6.) An n-3 unsaturated fatty acid derivative.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an n-3 unsaturated fatty acid derivative, and a pharmaceutical composition containing it as an active ingredient,
It relates to anti-dementia drugs and anti-psychotic drugs.

[0002]

2. Description of the Related Art In the age of aging, it is urgent to find out the cause and establish a treatment method for senile psychiatric diseases such as dementia of Alzheimer type and Parkinson's disease. Furthermore, the development of treatment methods for various psychiatric disorders such as schizophrenia and manic depression, which have come to the surface due to changes in social structure, is an important issue that must be urgently pursued.

Conventionally, AT has been used as a therapeutic drug for dementia diseases.
P, cytochrome C, CDP-choline, meclofenoxate hydrochloride, pyrithioxine hydrochloride, methicobalamin, idebenone, lisuride maleate, amantadine hydrochloride, α
-Aminobutyric acid, α-aminohydroxybutyric acid, bifemelane hydrochloride, indeloxazine hydrochloride, calcium fopantenate, dihydroergotoxine mesylate, ifenprodil tartrate, pentoxifylline, cinepazide maleate, vinpocetine, brombinamine fumarate, nicergoline, trapidil , Brain metabolism stimulants such as inositol hexanicotinate, and cyclanderate, cinnarizine, nicardipine hydrochloride, calidinogenase, ticlopidine hydrochloride, aspirin, dipyridamole, diraceb hydrochloride,
Cerebral circulation improvers such as flunarizine hydrochloride have been used.
Dementia diseases are broadly divided into cerebrovascular dementia and Alzheimer-type dementia. The former responds well to drug therapy using cerebral circulation improving drugs and has a good prognosis, but the latter causative therapy has been found so far. However, only symptomatic treatments, mainly cerebral metabolism stimulants, are being performed, and the development of true anti-dementia drugs is strongly desired.

Conventionally, as antipsychotic drugs, phenothiazine compounds such as levomepromazine, chlorpromazine and properitazine, butyrophenone compounds such as haloperidol and bromperidol, and benzamide compounds such as sulpiride are mainly treated for schizophrenia. However, these drug effects are not sufficient for the fundamental treatment of schizophrenia.In addition, extrapyramidal symptoms such as parkinsonism and akathisia, dizziness, drowsiness, malaise, apathy, and tardive dyskinesia. Central nervous system symptoms, tachycardia, hypotension,
Dry mouth, nasal congestion, intestinal paralysis, autonomic symptoms such as constipation, hepatitis,
It has become a problem to have various side effects such as allergic symptoms such as dermatitis. In addition, antidepressants such as imipramine, amitriptin, clomipramine, desipramine, noritriptyline, amoxapine, maprotiline, mianserin, and dimeridine have been developed, but they also have anticholinergic properties such as oversedation, dry mouth, constipation, and difficulty in urination. It has many problems such as side effects, cardiotoxicity, slow onset of effect, deferral of disease phase and neurosis of disease state, and the presence of treatment-resistant depression.

On the other hand, it has been reported that eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), which are n-3 unsaturated fatty acids, have a memory-learning function improving action and an intrinsic psychotic symptom improving action ( Lamptey et al., J. Neutr., 106: 86.
-93, 1976; Yamamoto et al., J. Am. Lipi
dRes. , 28, 144-151, 1987; Rud.
in, Biol. Psychiat. , 16,837-
850, 1981). That is, according to Lamptey et al., Rats deficient in α-linolenic acid, which is a precursor of these n-3 unsaturated fatty acids, from the diet had poor Y-maze test results, and further according to Yamamoto et al. On the contrary, it is known that the rats to which α-linolenic acid is administered have an increased learning ability by the light-dark discrimination method. Also, R
According to udin, the administration of linseed oil containing about 50% of α-linolenic acid has been shown to improve symptoms in patients with schizophrenia, manic depression and neurosis.

Among n-unsaturated fatty acids, especially DHA
Is present as a major constituent of phospholipids such as brain gray matter and retina in the living body, and DH in blood.
The higher the amount of A, the more efficiently the amount of DHA in the brain increases, but it is known that α-linolenic acid and EPA do not show such intracerebral transferability (Suzuki, Yuka, 3
7, 781-787, 1988). Also, DHA does not metabolize to prostaglandins by cyclooxygenase like arachidonic acid (AA) and EPA,
It is not converted to leukotrienes, but is metabolized by lipoxygenase into several monohydroxy DHA (HDHE). However, in the studies conducted so far using platelets, neutrophils or vascular endothelial cells, these metabolites have not been found to have the strong physiological activity found in the metabolites of AA and EPA ( Nakamura et al., Inflammation, 1
3, 17-25, 1993).

In view of the above-mentioned conventional techniques, the problems to be solved by the present inventors in the present invention are similar to endogenous substances, and easily pass through the blood-brain barrier and directly to nerve cells in the brain. It is intended to provide a novel n-3 unsaturated fatty acid derivative, an anti-dementia drug and an antipsychotic drug which have very few side effects by acting.

[0008]

Means for Solving the Problems The present inventors have further modified DHA produced by the metabolism of α-linolenic acid before or after passing through the blood-brain barrier into the brain. As a result of an in-depth study, it was found that an ethanolamide derivative of n-3 unsaturated fatty acid has a remarkable memory-improving effect, as it is considered to be an unknown derivative and exhibits an effect of improving memory-learning function or intrinsic psychotic symptoms. The present invention has been completed based on this finding.

That is, the present invention has the following formula

[0010]

[Chemical 2]

(In the formula, n1 represents an integer of 3 to 6, and n2
Represents an integer of 1 to 6. ) N-3 unsaturated fatty acid derivative represented by the following, and a pharmaceutical composition containing the derivative as an active ingredient,
It is an anti-dementia drug and an antipsychotic drug.

In the above formula, n1 is an integer of 3 to 6,
n2 represents an integer of 1 to 6, and as the n-3 unsaturated fatty acid derivative of the present invention, docosahexaenoic acid ethanolamide derivative in which n1 is 6 and n2 is 1, n1 is 5 and n2
The eicosapentaenoic acid ethanolamide derivative in which is 2 can be mentioned as a preferable example.

The n-3 unsaturated fatty acid derivative of the present invention is obtained, for example, by reacting an n-3 unsaturated fatty acid chloride with 10 equivalents of ethanolamine at 0 ° C. under a nitrogen atmosphere and subjecting the product to silica gel column chromatography. It can be obtained by purification.

The present invention further relates to a pharmaceutical composition, an anti-dementia drug and an antipsychotic drug containing the n-3 unsaturated fatty acid derivative as an active ingredient.

The pharmaceutical composition containing the n-3 unsaturated fatty acid derivative of the present invention as an active ingredient means, for example, a therapeutically effective amount of the n-unsaturated fatty acid derivative.
A solid pharmaceutical composition and a liquid pharmaceutical composition can be mentioned from a 3 unsaturated fatty acid derivative and a pharmaceutically acceptable excipient.

The n-3 unsaturated fatty acid derivative of the present invention can be administered orally or parenterally such as intravenously, subcutaneously, intramuscularly, transdermally, and rectally.

Examples of dosage forms for oral administration include tablets, pills, granules, powders, solutions such as syrups, suspensions, capsules and the like.

In the form of tablets, for example, excipients such as lactose, starch and crystalline cellulose; binders such as carboxymethyl cellulose, methyl cellulose and polyvinylpyrrolidone; disintegrants such as sodium alginate, sodium hydrogen carbonate and sodium lauryl sulfate. It can be formed by a usual method using sugar.

Similarly, pills, powders and granules can be formed by a conventional method using the above-mentioned excipients and the like.
Liquids and suspensions are formed by a usual method using, for example, glycerin esters such as tricaprylin and triacetin, alcohols such as ethanol and the like. Capsules are formed by filling granules, powders or liquids into capsules such as gelatin.

The subcutaneous, intramuscular, and intravenous administration forms include injections in the form of aqueous or non-aqueous solutions. As the aqueous solution, for example, physiological saline is used. As the non-aqueous solution, for example, propylene glycol, polyethylene glycol, olive oil, ethyl oleate, etc. are used, and if necessary, a preservative, a stabilizer and the like are added. The injection is sterilized by appropriately performing treatments such as filtration through a bacteria-retaining filter and addition of a germicide.

As the dosage form for transdermal administration, for example, ointment,
Creams and the like can be mentioned. Ointments are oils and fats such as castor oil and olive oil; vaseline and the like are used, creams are fatty oils, and emulsifiers such as diethylene glycol and sorbitan monofatty acid ester are formed by a usual method. It

In these formulations, a colorant, a preservative, a flavoring agent, a flavoring agent and a sweetening agent can be further added, if necessary.

The above-mentioned active ingredient used in the present invention is used in an amount of about 0.05 to about 0.5 per patient for patients in need of such treatment.
0.5 mg over a dose range of 100 mg, generally divided into several doses
It can be administered in a total daily dose of ~ 1000 mg. The dose depends on the degree of symptoms, the weight of the patient, and the person concerned (doctors)
Can be changed by other factors.

[0024]

EXAMPLES The present invention will now be described in more detail by way of examples and test examples.

[0025]

Example 1 Docosahexaenylethanolamide From oxalyl chloride and docosahexaenoic acid, a known method (Corey et al., J. Am. Chem. Soc. 19) was used.
84, 106, 1503-1504), 100 mg of docosahexaenoic acid chloride was dissolved in 1 ml of methylene chloride. This solution was reacted with 10 equivalents of ethanolamine also dissolved in 1 ml of methylene chloride at 0 ° C. under a nitrogen atmosphere for about 15 minutes. The reaction mixture was washed with water, dried and the solvent was distilled off. The product was applied to a silica gel column and eluted with chloroform containing 2% methanol to obtain 76.5 mg of docosahexaenylethanolamide. When the purity of the final preparation was measured by GC-MS, it was 97%.

[0026]

EXAMPLE 2 From the eicosapentaenoic enyl ethanolamide oxalyl chloride and eicosapentaenoic acid, a known method (Corey et al., J.Am.Chem.Soc.1
984, 106, 1503-1504) and 100 mg of doeicosapentaenoic acid chloride prepared in 1 m
It was dissolved in 1 methylene chloride. This solution is still 1m
10 equivalents of ethanolamine dissolved in 1 methylene chloride were reacted at 0 ° C. under a nitrogen atmosphere for about 15 minutes.
The reaction mixture was washed with water, dried and the solvent was distilled off. The product was applied to a silica gel column and eluted with chloroform containing 2% methanol to obtain 69.2 mg of eicosapentaenylethanolamide. The purity of the final preparation is GC-
It was 96% as measured by MS.

[0027]

Test Example 1 Using the compound obtained in Example 1 as a test compound using a CO ₂ -induced amnesia model, its learning and memory function improving action was measured.

The CO ₂ -induced amnesia model was prepared as follows using 30 mice per group. As an acquisition trial, the animals were placed in a light box and 0.25 mA immediately after entering the dark box.
It was learned by giving a shock for 2 seconds. Immediately after the acquisition trial, pure CO ₂ is immediately aerated (51 / min)
The glass container was left for 8 seconds. After recovery from the loss of the righting reflex caused by CO ₂ exposure, the animal was returned to its home cage and a test trial was carried out 24 hours later. As a test trial, the animal was put in the light box again, and the time (reaction latency) until it entered the dark box was measured up to 600 seconds. CO in this model
₂ The response latency of the exposed control group was significantly shorter than that of the control group,
Amnesia was evoked.

The test compound was suspended in 0.5% methylcellulose (MC) solution to give 0.5 and 1 mg / kg.
(Ip) immediately after exposure to CO ₂ or 0.5 mg
/ Kg (ip) was administered 30 minutes before the acquisition trial.
The results are shown in Table 1. From Table 1, in the case of the test compound, C
It can be seen that the shortening of the response latency observed in the O ₂ exposure control group was significantly antagonized.

[0030]

[Table 1]

[0031]

Test Example 2 Using the compound obtained in Example 2 as a test compound using a CO ² -induced amnesia model, its learning and memory function improving action was measured.

The test method was the same as in Test Example 1.

The test compound was suspended in a 0.5% methylcellulose (MC) solution and added to 5 and 100 mg / kg.
(Ip) immediately after exposure to CO ₂ or 50 mg /
kg (ip) was administered 30 minutes before the acquisition trial. The results are shown in Table 2. From Table 2, in the case of the test compound, CO
₂ It can be seen that the shortening of the response latency observed in the ₂ exposure control group was significantly antagonized.

[0034]

[Table 2]

[0035]

Example 3 Production of Tablet A tablet containing 30 mg of the compound of Example 1 was produced according to the following formulation. Example 1 Compound 30 mg Lactose 87 mg Starch 30 mg Magnesium stearate 3 mg

[0036]

Example 4 Preparation of Injection A solution for injection containing 0.3 mg of the compound of Example 1 in 1 ml was prepared according to the following formulation. Example 1 Compound 30 mg Salt 900 mg Injectable distilled water 100 mg

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Noriaki Endo 4-3-2 Asahigaoka, Hino City, Tokyo Teijin Limited Tokyo Research Center

Claims (6)

[Claims] 1. The following formula: (In the formula, n1 represents an integer of 3 to 6 and n2 represents an integer of 1 to 6.) An n-3 unsaturated fatty acid derivative. 2. The n-3 unsaturated fatty acid derivative according to claim 1, wherein n1 is 6 and n2 is 1 in the above formula. 3. The n-3 unsaturated fatty acid derivative according to claim 1, wherein n1 is 5 and n2 is 2. 4. A pharmaceutical composition comprising the n-3 unsaturated fatty acid derivative according to claim 1 as an active ingredient. 5. An anti-dementia drug comprising the n-3 unsaturated fatty acid derivative according to claim 1 as an active ingredient. 6. An antipsychotic drug comprising the n-3 unsaturated fatty acid derivative according to claim 1 as an active ingredient.