JPH0142925B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel therapeutic agent for disorders of consciousness and sensory and motor disorders, and more specifically, the present invention provides a novel therapeutic agent for disorders of consciousness and sensory motor disorders. The present invention relates to therapeutic agents containing derivatives.

In recent years, with the increase in the aging population and various accidents such as stroke and car accidents, which are the main causes of death, the number of patients with consciousness disorders and sensory and motor disorders is increasing, and treatments for these are increasing. development has become one of the important issues in the pharmaceutical industry. For such disorders of consciousness and sensorimotor disorders, citicoline (cytidine diphosphate choline), meclofenoxate hydrochloride ((4-chlorophenoxy)-acetic acid 2-(dimethylamino)ethyl ester hydrochloride), or pyrithioxine (3,3′−
(dithiodimethylene)-bis[5-hydroxy-6
-Methyl-4-pyridinemethanol) and other drugs have already been developed and are in actual use.

According to the research of the present inventors, certain phosphatidic acid derivatives have a promoting effect on consciousness and pyramidal tract movements, and have excellent effects on consciousness disorders and sensorimotor disorders. Coupled with its extremely low toxicity, we learned that this compound could be used as a therapeutic agent for disorders of consciousness and sensory and motor disorders that is equivalent to or even better than conventional products.

The purpose of the present invention is to provide a therapeutic agent useful for the treatment of consciousness disorders and sensorimotor disorders,
The aim is to treat consciousness disorders and sensorimotor disorders by administering a new therapeutic agent containing a phosphatidic acid derivative as an essential active ingredient. These and other objects and advantages of the invention will become apparent from the description below.

The therapeutic agent for disorders of consciousness and sensory and motor disorders according to the present invention has the following formula as an essential active ingredient: [wherein one of R ₁ and R ₂ is hydrogen and the other is a fatty acid residue, or both R ₁ and R ₂ are hexanoyl] Phosphatidylcholine of the formula: [In the formula, R ₃ and R ₄ are the same or different and each is hydrogen or a fatty acid residue. however,
At least one of R ₃ and R ₄ is a fatty acid residue] Phosphatidic acid or a salt thereof (for example, an alkali metal such as sodium, potassium, an alkaline earth metal such as magnesium, calcium, ammonium or ethanol) salts of organic bases such as amines, trimethylolaminomethane or choline) and the formula: [In the formula, R ₅ and R ₆ are the same or different and each represents hydrogen or a fatty acid residue. however,
At least one of R ₅ and R ₆ is a fatty acid residue.] Contains a phosphatidic acid derivative selected from the group consisting of phosphatidylethanolamines.

In the above formula, fatty acid residues represented by R ₁ to R ₆ are:
Residues of saturated fatty acids with 6 to 22 carbon atoms such as hexanoic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, myristolenic acid, palmitolenic acid,
It contains residues of unsaturated fatty acids having 14 to 20 carbon atoms such as oleic acid, linoleic acid, linolenic acid, arachidonic acid, and at least one of R ₁ and R ₂ ,
at least one of R ₃ and R ₄ or R ₅ and R ₆
Preferably, at least one of them is a residue of a highly unsaturated fatty acid, such as in particular linoleic acid, linolenic acid and arachidonic acid. Furthermore, the formula [],
In [] and [], 1 of R ₁ and R ₂
, one of R ₃ and R ₄ or one of R ₅ and R ₆ is hydrogen, these compounds are lyso-type compounds, i.e. lysophosphatidylcholines, lysophosphatidic acids and lysophosphatidyl They are called ethanolamines.

Preferred specific examples of phosphatidic acid derivatives are:
1,2-dihexanoylphosphatidylcholine,
1-Palmitoyl-2-linoleoylphosphatidic acid disodium salt, 1-linoleoyl-2-
palmitoylphosphatidic acid disodium salt,
These include dilinoleoylphosphatidic acid disodium salt and diarachidonylphosphatidic acid disodium salt.

These phosphatidic acid derivatives include both natural products and synthetic or semi-synthetic products. Preferred specific examples of such natural or semi-synthetic products include soybean phosphatidic acid disodium salt, soybean phosphatidylethanolamine, and soybean lysate. They are phosphatidylcholine, soybean lysophosphatidic acid disodium salt, soybean lysophosphatidylethanolamine and egg yolk phosphatidic acid disodium salt. Although various known methods can be used to synthesize the phosphatidic acid derivatives, the methods described in JP-A-51-91213 and US Pat. No. 4,130,571 are preferred in that they yield highly pure target products. Other documents describing methods for producing phosphatidic acid derivatives include Biochem. J. 69, p. 458 (1958);
Volume 102, page 205 (1967) and Volume 102, page 221 (1967).

The phosphatidic acid derivatives of the present invention can be administered to patients by parenteral routes such as oral or intramuscular injection, intravenous drip injection, or intravenous injection, with intravenous drip injection and intravenous injection being particularly preferred. The injection form is usually used in the form of an aqueous solution, in which case deoxycholic acid,
Solubilizing agents for bile acid substances such as apocholic acid, chenodeoxycholic acid, taurocholic acid, cholic acid, isotonic agents such as glucose, sodium chloride, potassium chloride, calcium chloride, ethanol, α
- Stabilizers such as tocopherol and nicotinamide, preservatives such as benzyl alcohol and phenol, and PH regulators such as sodium hydroxide, potassium hydroxide, and calcium hydroxide are added.
For oral administration, the active substance is usually mixed with organic or inorganic pharmacological carriers suitable for enteral application to form tablets, capsules, powders or solutions (suspensions,
It can be used in conventional dosage forms such as solutions, emulsions or syrups. To produce aqueous formulations, the active substance can be mechanically dissolved, suspended or emulsified in an aqueous medium, for example by ultrasound means.

Orally administered formulations of the invention may contain 5 to 50 mg per dosage unit.
It contains 5000 mg, preferably 10 to 2000 mg of the phosphatidic acid derivative, and can usually be administered to adults 1 to 3 times per day. For injectable preparations, 0.5 per dosage unit
~500 mg, preferably 1-100 mg of phosphatidic acid derivative. Injections are usually administered once a day for adults, and the dosage may be increased up to 2 to 3 times a day if necessary. Therefore, for adults, for oral administration, the active substance is administered in doses of 10 mg to 15 g, preferably 50 mg to 10 g, and for parenteral administration, doses of 1 to 1500 g.
mg, preferably 10-500 mg may be administered. For children, a smaller amount is required than for adults, but the same dose can be used since toxicity is extremely low.

The pharmacological activity of the phosphatidic acid derivatives of the present invention is confirmed experimentally. This will be explained below with reference to the attached drawings.

As a method for evaluating the effectiveness of therapeutic agents for consciousness disorders and sensorimotor disorders, methods have been adopted to test the arousal response and evoked muscle discharges in the front and rear limbs by stimulation of the brainstem reticular formation, and the evoked muscle discharges in the front and rear limbs by stimulation of the cerebral cortex and hippocampus. (Seiichi Fujimoto, Journal of Kansai Medical University, Vol. 21, 3)
No., pp. 26-52 (September 1969), Yasuhara et al., Basic and Clinical Studies, Vol. 9, No. 2, pp. 7-14 (January 1975), No. 9
(See Vol. 11, pp. 151-158 (October 1975)). The effects of the compounds of the invention are similarly confirmed.

Experiment Using normal rabbits, the following experiment was conducted on the arousal response caused by stimulation of the brainstem reticular formation. The effects of the test compound on brain function regarding consciousness and movement are evaluated based on the results regarding the arousal response caused by stimulation of the brainstem reticular formation. That is, when the brainstem reticular formation is stimulated and brain waves in the cerebral cortex and hippocampus are recorded, an arousal response appears. In this case, if a drug that has an arousal effect on consciousness is administered, an arousal response can be obtained in the brain waves in the cerebral cortex and hippocampus even if the intensity of electrical stimulation is reduced, and the electrical stimulation necessary to produce an arousal response can be obtained. The strength of the drug's effect on conscious arousal can be determined from the relationship between the degree of stimulation attenuation and the drug dose.

Experimental method: Yasuhara et al. method (Yasuhara et al. Current
Therapeutic Research, Volume 16, Issue 4, 346~
374 (April 1974), especially the method described in the same book, p. 347), electrical stimulation was applied to a group of 5 normal rabbits without anesthesia, and the following test compounds (0.3, 0.5, 1 , 3 and 5 mg/Kg intravenous injection).

Test compounds: (1) Soybean phosphatidic acid disodium salt (2) Soybean lysophosphatidylcholine (3) Soybean lysophosphatidic acid disodium salt (4) Soybean lysophosphatidylethanolamine (5) Egg yolk phosphatidic acid disodium salt Sodium salt (6) 1,2-dihexanoylphosphatidylcholine (7) 1,2-dialachidonylphosphatidic acid disodium salt (8) 1,2-dilinoleoylphosphatidic acid disodium salt (9) 1-Linoleoyl-2-palmitoylphosphatidic acid disodium salt experimental results: When the brainstem reticular formation was electrically stimulated at a frequency of 100Hz,
The threshold of arousal response changed before and after administration of the test compound. It is expressed as a percentage of the threshold value before drug administration. Figures 1 to 9 show the average change values when the above test compounds (1) to (9) were administered, respectively. In these charts, the horizontal axis is the drug dose, and the vertical axis is the change in threshold expressed as a percentage. If the upper part is an increase (+) in the threshold value and the lower part is a decrease (-), the 0 point is the value before drug administration. means. The solid line is the result of the arousal response in the cerebral cortex, and the dotted line is the result of the arousal response in the hippocampus.

It should be noted that the threshold values in these graphs tend to increase as the drug dose increases, but this was also observed in a control experiment in which physiological saline was injected, and is considered to be a natural increase over time.

Experiments To test the effects of the active compounds of the invention on perception, experiments were performed on afferent summation evoked potentials in response to stimulation of the sciatic nerve.

The sciatic nerve is stimulated and the potentials evoked in the cerebral cortex are summed and recorded. These evoked potentials are initially three small negative responses, followed by a positive response and two large negative responses. These are N ₁ , N ₂ ,
Let N ₃ , P, N ₄ and N ₅ .

The above-mentioned components N ₁ , N ₂ , N ₃ , P, of the compound of the present invention: dilinoleoylphosphatidic acid sodium salt,
To test the effect on N ₄ and N ₅ ,
Stimulate the sciatic nerve once every second, and record the results of 50 stimulations. The results are shown in FIGS. 10 to 15. These charts are N ₁ , N ₂ , N ₃ ,
This corresponds to grades P, N ₄ and N ₅ .
The vertical axis represents the change in the value of each component, and when the upper side is an increase (+) in value and the lower side is a decrease in value, 0 point means before drug administration. The chart shows the average value of change.
The horizontal axis means drug dosage.

As is clear from the results, dilinoleoylphosphatidic acid disodium salt showed a promoting effect on components _N1 and _N2 , which have a close relationship with perception, and particularly on _N1 . Initial components such as N ₁ and N ₂ mainly appear along the afferent path from the periphery to the cerebral cortex, and it is clear from the test results that the compound of the present invention has a promoting effect on the afferent path.

Toxicity: The compounds of the present invention are characterized by extremely low toxicity. For example, dilinoleoylphosphatidic acid disodium salt (dose 100 mg/Kg) was administered via the tail vein route for 30 seconds to male mice (body weight 25 g).
This was observed for 72 hours. As a result, no fatal cases were observed.

Next, prescription examples of the therapeutic agent of the present invention will be specifically shown.

Example 1 Soybean phosphatidic acid disodium salt 25.0 mg Deoxycholic acid sodium salt 39.0 mg Glucose 50.0 mg Benzyl alcohol 4.5 mg Distilled water was added to make a total volume of 1.0 ml The above components were mixed in a conventional manner to prepare a 1 ml ampoule. do.

Example 2 1,2-dilinoleoylphosphatidic acid disodium salt 25.0 mg Deoxycholic acid sodium salt 35.0 mg Glucose 50.0 mg Benzyl alcohol 4.5 mg Distilled water was added to make a total volume of 1.0 ml The above ingredients were prepared in a conventional manner. Mix and prepare 1 ml ampoules.

Example 3 Disodium 1,2-dilinoleoylphosphatidate 25.0 mg Glucose 50.0 mg Benzyl alcohol 4.5 mg Distilled water was added to make a total volume of 1.0 ml The above components were mixed, and the mixture was treated with ultrasound to make a 1 ml ampoule. Adjust.

Example 4 Soybean lysophosphatidylcholine 25.0 mg Glucose 50.0 mg Benzyl alcohol 4.5 mg Distilled water was added to make a total volume of 1.0 ml The above components were mixed, and the mixture was treated with ultrasound to prepare a 1 ml ampoule.

Example 5 Soybean phosphatidic acid disodium salt 25.0 mg Glucose 50.0 mg Benzyl alcohol 4.5 mg Distilled water was added to make a total volume of 1.0 ml The above components were mixed, and the mixture was treated with ultrasound to prepare a 1 ml ampoule.

Example 6 1,2-dihexanoylphosphatidylcholine
25.0 mg Glucose 50.0 mg Benzyl alcohol 4.5 mg Add distilled water to make a total volume of 1.0 ml Mix the above components and treat the mixture with ultrasound to prepare a 1 ml ampoule.

[Brief explanation of drawings]

FIGS. 1 to 9 show the average changes in the threshold of arousal response when test compounds (1) to (9) were administered, with the horizontal axis representing the dose and the vertical axis representing the percentage change in the threshold. Figures 10 to 15 show the average change values of the afferent additive evoked potential components N ₁ , N ₂ , N ₃ , P, N ₄ , and N ₅ when dilinoleoylphosphatidic acid disodium salt was administered. The horizontal axis represents the dose, and the vertical axis represents the change in each component value.

Claims (1)

[Claims] 1. General formula [wherein one of R ₁ and R ₂ is hydrogen and the other is a saturated fatty acid residue having 6 to 22 carbon atoms or an unsaturated fatty acid residue having 14 to 20 carbon atoms, or R ₁ and R ₂ are both hexanoyl] A phosphatidylcholine of the formula: [In the formula, R ₃ and R ₄ are the same or different,
hydrogen, a saturated fatty acid residue with 6 to 22 carbon atoms or an unsaturated fatty acid residue with 14 to 20 carbon atoms, respectively. However, at least one of R ₃ and R ₄ is the above saturated or unsaturated fatty acid residue. ) Phosphatidic acid or its salt and the formula: [In the formula, R ₅ and R ₆ are the same or different,
Hydrogen, a saturated fatty acid residue with 6 to 22 carbon atoms or an unsaturated fatty acid residue with 14 to 20 carbon atoms, respectively. However, R ₅ and R ₆
at least one of which is the above saturated or unsaturated fatty acid residue.] A therapeutic agent for disorders of consciousness and sensory and motor disorders, which comprises as an essential active ingredient a phosphatidic acid derivative selected from the group consisting of phosphatidylethanolamine and phosphatidylethanolamine. 2 The phosphatidic acid derivative is phosphatidylcholine [] (one of R ₁ and R ₂ is hydrogen,
2. The therapeutic agent according to claim 1, wherein the other is an unsaturated fatty acid residue having 14 to 20 carbon atoms, or _R1 and _R2 are both hexanoyl. 3 The phosphatidic acid derivative is phosphatidic acid [ ] (at least one of R ₃ and R ₄ is 14 to 20
is an unsaturated fatty acid residue with carbon atoms)
The therapeutic agent according to item 1. 4. The therapeutic agent according to claim 3, wherein both _R3 and _R4 are unsaturated fatty acid residues having 14 to 20 carbon atoms. 5. The therapeutic agent according to item 3 or 4, wherein the unsaturated fatty acid residue is a residue of an unsaturated fatty acid selected from linoleic acid, linolenic acid, and arachidonic acid. 6. The therapeutic agent according to item 1, wherein the phosphatidic acid derivative is phosphatidylethanolamine [] (at least one of _R5 and _R6 is an unsaturated fatty acid residue having 14 to 20 carbon atoms) . 7. The therapeutic agent according to item 6, wherein the unsaturated fatty acid residue is a residue of an unsaturated fatty acid selected from linoleic acid, linolenic acid, and arachidonic acid. 8 The phosphatidic acid derivative is soybean phosphatidic acid disodium salt, soybean phosphatidylethanolamine, egg yolk phosphatidic acid disodium salt, soybean lysophosphatidylcholine, soybean lysophosphatidic acid disodium salt, soybean lysophosphatidylethanol Amine, 1,2-dihexanoylphosphatidylcholine, 1-palmitoyl-2-linoleoylphosphatidic acid disodium salt, 1-linoleoyl-2-palmitoylphosphatidic acid disodium salt, 1,2- Dilinoleoylphosphatidic acid disodium salt, 1,2
- The therapeutic agent according to item 1 selected from the group consisting of diarachidonylphosphatidic acid disodium salt. 9. The phosphatidic acid derivative is selected from soybean lysophosphatidic acid disodium salt, soybean lysophosphatidylcholine, 1,2-dihexanoylphosphatidylcholine and 1,2-dilinoleoylphosphatidylcholine and 1,2-dilinoleoylphosphatidic acid disodium salt. The therapeutic agent according to item 1 selected from the group consisting of: 10 per dosage unit of the phosphatidic acid derivative
The therapeutic agent according to item 1, which is suitable for intravenous injection and contains 0.5 to 500 mg. 11 The phosphatidic acid derivative per dosage unit
The therapeutic agent according to item 1, which is suitable for oral administration and contains 10-5000 mg.