JPH0651709B2 - Novel phosphinic acid derivative and cerebral circulation metabolism improving agent containing the same as active ingredient - Google Patents

Description

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to a novel substance and its use. More specifically, the present invention relates to a novel phosphinic acid derivative and a cerebral circulation metabolism improving agent containing the same as an active ingredient.

(Problems to be Solved by the Prior Art and the Present Invention) With the advent of an aging society, measures against senile dementia caused by cerebrovascular disorders and intracerebral energy metabolism disorders have become a major social problem. .

Conventionally, it has been developed as various drugs and anti-dementia drugs (JP-A-55-17329, JP-A-54-117468 and JP-A-61-83170), and calcium hopanthenate is known as an example thereof. (Brain metabolism activating agent, pages 11-48, 1984, Pharmaceutical Journal).

However, the effects of these drugs as anti-dementia drugs cannot be said to be perfect. Under such circumstances, the inventors of the present invention have conducted intensive studies on the creation of a safer anti-dementia drug with a stronger effect, focusing on the improvement of calcium hopanthenate.

[Outline of Invention]

SUMMARY OF THE INVENTION The present invention aims to provide a solution to the above point, and provides a novel phosphinic acid derivative, and intends to achieve this object by using the derivative as a cerebral circulation metabolism improving agent.

That is, the present invention relates to a novel compound,
This novel compound is a phosphinic acid derivative represented by the following formula (I).

The present invention also relates to the use of this novel compound, which is a cerebral circulation metabolism-improving agent containing a phosphinic acid derivative represented by the following formula (I) as an active ingredient.

(In the formula, M represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, or an ammonium compound.) Effect Phosphinic acid is considered to be an equivalent of carboxylic acid, and an amino acid derivative (Journal of Chemical Society Parkin Trans I, 1984, p. 2845) and a phosphinic acid derivative of γ-aminobutyric acid (JP-A-61-93189) have been synthesized and reported to have improved biological activity.

Focusing on this point, the present inventor synthesized a phosphine derivative of calcium fopanthenate represented by the formula (I) and investigated its cerebral circulatory metabolism improving action. The inventors have discovered that they have a superior action and completed the present invention.

As mentioned above, it was found in a few compounds that the biological activity is improved by phosphine-oxidizing a compound having biological activity. However, phosphine-oxidizing at a specific site of a specific compound called calcium fopanthenate. It is not surprising that such phosphinic acid derivatives have a better effect than calcium fopanthenate.

[Specific Description of the Invention]

Novel Compounds Definition of Compounds The novel compounds according to the present invention are phosphinic acid derivatives as defined in formula (I) above.

Of the groups represented by M, the alkali metal is sodium, potassium, etc., the alkaline earth metal is magnesium, calcium, etc., and the ammonium compound is ammonia,
Examples thereof include ammonium salts such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzyldiamine, pyridine, morpholine and N-methylmorpholine, and basic amino acid salts such as lysine and arginine.

Further, the compound of the present invention can be D-form, L-form and DL-form, and all are included in the present invention.

Synthesis of Compounds The compounds according to the present invention can be synthesized by any method that is purposeful for the formation or introduction of the skeleton and substituents. The three suitable methods are as follows.

[Method A]

Compound (II) is condensed with allylamine to give compound (II
I), and then hypophosphorous acid or a salt thereof is added to produce (I) as an alkali metal salt, alkaline earth metal salt or ammonium salt, if necessary.

The first step is a step of synthesizing compound (III) by reacting compound (II) with allylamine in water or an organic solvent at a temperature of 50 to 150 ° C. for 30 minutes to 5 hours. The second step is to add compound (III) and, for example, sodium hypophosphite in water or an organic solvent in the presence of a radical initiator at a temperature of 100 to 150 ° C. for 30 minutes to 3 hours.
In this step, compound (I) is synthesized by reacting. As the radical initiator, a compound that decomposes at a given reaction temperature to generate a radical, for example, an azo compound,
Organic or inorganic peroxides, hydroperoxides, and others such as Perhexa 22-50 [produced by NOF CORPORATION, 2,2-bis (t-butylperoxy) butane] and azobisisobutyronitrile can be used. I can.
This step can also be performed in an open system. It is preferably carried out in a sealed tube. After completion of the reaction, IR-120, AG50W
X8, DEAE Sephadex, LH-20 and HP-2
(I) can be obtained as an alkali metal salt, alkaline earth metal salt or ammonium salt, if necessary, by purifying using an ion exchange resin or an adsorption resin such as No. 0. Alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium, ammonium salts such as ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, Pyridine, morpholine, N-
It is clear from the above that salts with amines such as methylmorpholine and salts with basic amino acids such as lysine and arginine can be selected.

[Method B]

After the lactone ring-opening of compound (IV), the hydroxyl group is protected and esterified to give compound (V), which is hydrolyzed to give compound (VI). Then, the compound (VI) is replaced with the compound (VI
Compound (VIII) is synthesized by condensation with I), and a deprotection reaction is carried out to produce (I) as an alkali metal salt, alkaline earth metal salt or ammonium salt, if necessary.

(In the formula, R and R ¹ represent the same or different protective groups for the hydroxyl group, and R ² and R ³ may be the same or different but represent the protective groups for the carboxyl group and the phosphoric acid group.) The first step Discloses a known compound (IV) (Journal of Organic Chemistry, Vol. 83, pp. 663-667, 1961) with alkali hydroxide and 0 in an aqueous solvent.
The reaction is carried out at a temperature of −100 ° C. for 30 minutes to 2 hours to open the lactone, and then with an alkyl halide in an organic solvent.
In this step, compound (V) is synthesized by further reacting at a temperature of 00 to 180 ° C. for 2 to 24 hours. Water, methanol water, ethanol water, tetrahydrofuran water or the like can be used as the aqueous solvent, and sodium hydroxide, potassium hydroxide or the like can be selected as the alkali hydroxide. Alkyl halides include aralkyl halides, especially benzyl chloride, benzyl bromide, p
-Methoxybenzyl chloride and the like are desirable.

The second step is in an aqueous solvent at a temperature of 50-120 ° C,
It is a step of synthesizing compound (VI) by reacting with alkali hydroxide for 2 to 10 hours. In that case, water, methanol water, ethanol water, tetrahydrofuran water or the like can be used as the aqueous solvent, and sodium hydroxide, potassium hydroxide or the like can be selected as the alkali hydroxide.

The third step is an amidation reaction with compound (VII), and a method used in ordinary peptide synthesis can be used. Compound (VII) can be prepared by
X) (which can be synthesized by the method described in JP-A-61-93189) can be synthesized by deprotecting the amino group of compound (X) obtained by protecting the amino group and phosphoric acid group. Examples of the protecting group R ³ for the phosphoric acid group in the compounds (VII) and (X) include a methyl group, an ethyl group, a t-butyl group, a benzyl group, a benzhydryl group, and a protecting group R ⁴ for an amino group is t. -Butoxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, chloroacetyl group, trifluoroacetyl group,
A phthaloyl group or the like can be selected. As the amidation reaction, thionyl chloride, an acid chloride method using phosphorus oxychloride or phosphorus pentachloride, an active ester method using dicyclohexylcarbodiimide and N-hydroxysuccinimide or 1-hydroxybenztriazole, and diphenylphosphoryl azide are condensed. The method used as an agent can be applied.

(In the formula, R ³ has the above-mentioned meaning and R ⁴ represents a protecting group for an amino group.) The fourth step is a deprotection step, and the reaction test and reaction conditions can be selected depending on the protecting group used. After completion of the reaction, the product is purified using an ion exchange resin or an adsorption resin such as IR-120, AG50WX8, DEAE defadex, LH-20 or HP-20, and if necessary, an alkali metal salt, an alkaline earth metal salt or (I) can be obtained as an ammonium salt.

[Method C] A method of synthesizing the compound of formula (I) by reacting compound (II) with compound (VII) in water, an organic solvent or a water-containing solvent. 30 minutes at a temperature of 50-150 ° C
The reaction proceeds by stirring for 24 hours, and after the reaction is completed, it is purified using an ion exchange resin or an adsorption resin such as IR-120, AG50WX8, DEAE Sephadex, LH-20 or HP-20, and if necessary, (I) can be obtained as an alkali metal salt, an alkaline earth metal salt or an ammonium salt.

Use of compound / Cerebral circulatory metabolism improving agent Physiological activity When the cerebral circulatory metabolism improving action of the compound of the present invention was tested by the protective action against decompressed brain hypoxia, as shown in the examples, the survival time was clearly longer than that of calcium fopanthenate. Prolongation was observed, and the compound of the present invention has an excellent cerebral circulation metabolism improving action.

The compound of the present invention has a low acute toxicity (the LD ₅₀ value for intraperitoneal administration in mice is 1 g / kg or more).

Cerebral Circulation Metabolism Improving Agent The compound of the present invention is useful as a cerebral circulation metabolism improving agent because of the above physiological activities.

As a cerebral circulation metabolism improving agent, the compound of the present invention can be administered orally or parenterally (for example, in the form of suppository or injection solution). In the case of oral administration, for example, tablets, powders, capsules, granules, etc. can be used, and these are conventional excipients such as calcium carbonate, calcium phosphate, corn starch, sugar, lactose, talc, magnesium stearate, etc. May be included. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes,
Examples include oils and fats and polyols. Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerin, vegetable oils and the like.

The appropriate dose is usually about 0.5-3.0 g per day for an adult.

〔Example〕

Example 1 (a) D-(-)-pantoyl lactone (3.7 g)
Was dissolved in ethanol (50 ml) and allylamine (5.
5 ml) and the mixture is heated under reflux for 6 hours. Remove ethanol and excess allylamine under reduced pressure to give D-(+)-
2,4-Dihydroxy-3,3-dimethylbutyric acid allylamide (5.67 g) (compound (III)) was obtained. Yield 1
00%.

PMR (CDCl ₃ ) δ: 0.94 (3H, s), 2.
05 (3H, s), 2.80 (1H, br, s), 3.
35 (1H, br, s), 3.50 (1H, d), 3.
56 (1H, d), 3.9 (2H, m), 4.08 (1
H, s), 5.15 (1H, q), 5.23 (1H,
q), 5.84 (1H, m,), 6.91 (1H, b
r, s).

(B) The compound (III) (3.8 g) was dissolved in methanol (30 ml), sodium hypophosphite monohydrate (2.1 g) and Perhexa 22-50 (0.3 ml) were added, and the mixture was sealed in a sealed tube. Then, it is heated at 130 ° C. for 1.5 hours. After cooling, the mixture was concentrated, and the residue was treated with an ion exchange resin (AG50WX8,
H ⁺ , 80 ml, eluted with H ₂ O). Fractions containing compound (I) were concentrated and the residue was stirred at room temperature for 4
Leave for days. Ion exchange resin (AG50WX8,
50 ml, eluted with H ₂ O). Compound (I)
The fraction containing was concentrated, the residue was adsorbed on DEAE-Sephadex (140 ml, OAc type) and H ₂ O was added.
(300 ml), 0.5M AcOH (500 ml) and 0.
After washing with 1N HCl (500 ml), compound (I) was eluted with 0.2N HCl. The pH of the eluate is adjusted to 2.5 with an ion exchange resin (IR-45, OH ⁻ ), and then adjusted to 7.0 with saturated aqueous sodium hydrogen carbonate. The obtained solution was concentrated and dried to obtain 0.55 g of compound (I) as a sodium salt.

[Α] _D = + 5.62 (C = 0.52, H ₂ O) PMR (D ₂ O) δ: 0.96 (3H, s), 0.99
(3H, s), 1.58 (2H, m), 1.75 (2
H, m), 3.33 (2H, m), 3.45 (1H,
d), 3.57 (1H, d), 4.03 (1H, s),
6.97 (1H, d, J = 505Hz).

Example 2 (a) Compound (IV) (R = benzyl group) is dissolved in ethanol (30 ml), 1N-NaOH (35 ml) is added, and the mixture is heated under reflux for 3 hours. The solvent was distilled off and the residue was removed to 75
Dry under reduced pressure overnight at ° C. Then xylene (50m
l) and benzyl chloride (7.6 ml) are added, and the mixture is heated under reflux for 3 hours. Add 1N-HCl and extract with ethyl acetate. After washing with water, dehydration with magnesium sulfate,
The solvent is distilled off. The residue was subjected to silica gel column chromatography (300 g, n-hexane: AcOEt = 4:
Purified in 1), DL-2,4-dibenzyloxy-
3,3-Dimethylbutyric acid benzyl ester (V) was added to 1.3
9 g were obtained.

PMR (CDCl ₃ ) δ: 0.97 (6H, s), 3.
21 (1H, d), 3.49 (1H, d), 4.06
(1H, s), 4.43 (2H, s), 4.58 (1
H, d), 4.70 (1H, d), 5.21 (2H,
s), 7.4 (15H).

(B) The compound (V) (1.945 g) is dissolved in ethanol (30 ml), 1N-NaOH (10 ml) is added, and the mixture is heated under reflux for 3 hours. After concentrating, dilute with water, wash with ether and adjust the pH to 1.5 with 1N HCl. After extraction with ethyl acetate, dehydration with magnesium sulfate, evaporation of the solvent, and DL-2,4-dibenzyloxy-3,3-
1.42 g of dimethylbutyric acid (VI) was obtained.

PMR (CDCl ₃ ) δ: 1.00 (6H, s), 3.
33 (1H, d), 3.37 (1H, d), 4.00
(1H, s), 4.44 (1H, d), 4.47 (1
H, d), 4.53 (1H, d), 4.64 (1H,
d), 7.3 (10H).

(C) The compound (VI) (1.393 g) was added to DMF.
(10 ml), dicyclohexylcarbodiimide (982 mg) and N-hydroxybenztriazole (5
85 mg), and the mixture is stirred at room temperature for 1 hour. The insoluble material was removed, and the solution was treated with trifluoroacetic acid salt of compound (VII) (897 mg) and triethylamine (0.99 ml) in DM.
Add to solution F (5 ml) and stir at 60 ° C. overnight. Add water and extract with ethyl acetate. The extract is washed with water, saturated aqueous sodium hydrogen carbonate, and water, dried over magnesium sulfate, and the solvent is evaporated. The residue was purified by silica gel column chromatography (100 g, chloroform: methanol = 50: 1) and methyl 3- (2,4-dibenzyloxy-3,3-dimethylbutyrylamino) -1-propylphosphinate. 525 mg of ester (VIII)
Obtained.

PMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.
02 (3H, s), 1.78 (4H, m), 3.25
(1H, d), 3.29 (2H, m), 3.41 (1
H, d), 3.76 (3H, d), 3.89 (1H,
s), 4.45 (4H, m), 7.04 (1H, d, J
= 534 Hz), 7.3 (10H).

(D) Compound (VIII) (525 mg) was added to ethanol (5
ml), 1N-NaOH (2 ml) is added, and the mixture is stirred at room temperature for 1 hour. After concentration, water is added, the mixture is washed with ether, and the pH is adjusted to 1 with 1N-HCl. After extraction with ethyl acetate, dehydration with magnesium sulfate, evaporation of the solvent,
441 mg of (2,4-dibenzyloxy-3,3-dimethylbutyrylamino) -1-propylphosphinic acid are obtained. The compound obtained is dissolved in about 20 ml of liquid ammonia, sodium metal (about 100 mg) is added, and the mixture is stirred for 30 minutes. Let stand overnight at room temperature and distill off the ammonia.
After adding water and washing with ether, the pH is adjusted to 1.2 with 1N HCl and the mixture is concentrated to dryness. Ethanol is added, insoluble matter is removed, and the solution is concentrated. Chloroform and ethanol are added to the residue, and the insoluble matter is removed. The solution is concentrated, dissolved in water and washed with chloroform. Concentrate the aqueous layer to LH
Purification by -20 (2 L, eluted with 50% aqueous methanol) gave 131 mg of compound (I).

PMR (D ₂ O) δ: 0.92 (3H, s), 0.95
(3H, s), 1.56 (2H, m), 1.71 (2
H, m), 3.29 (2H, m), 3.41 (1H,
d), 3.53 (1H, d), 4.00 (1H, s),
6.96 (1H, d, J = 512Hz).

Example 3 The cerebral circulatory metabolism-improving effect of the compound of the present invention was examined for the survival time of mice under hypoxia.

Using a male ddy mouse, an aqueous solution of the test substance was intraperitoneally administered, and 30 minutes later, the mouse was exposed to a low-pressure environment of 200 mmHg, and the time until the absorption was stopped was measured and used as the survival time. The results are as shown in Table 1.

Example 4 Regarding the anticonvulsant action, the cerebral circulation metabolism improving action of the compound of the present invention was examined.

30 days after intraperitoneal administration of test substance using male ddy mouse
N-methyl-DL-aspartic acid was intraperitoneally administered at a dose of 500 mg, and the onset time of clonic convulsion and the time until death were measured. The result was as shown in display 2.

Example 5 An example of the formulation of the compound of the present invention is a tablet having the following composition.

Compound of the present invention 500 mg Corn starch 250 mg Lactose 90 mg Microcrystalline cellulose 80 mg Polyvinylpyrrolidone 90 mg Magnesium stearate 5 mg

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Shinsuke Kato, 760, Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Confectionery Co., Ltd., Pharmaceutical Research Laboratory (72) Hiroko Takahashi 760, Shimo-oka, Kohoku-ku, Yokohama, Kanagawa Haruka Seika Co., Ltd., Pharmaceutical Research Laboratory (72) Inventor Takashi Tsuruoka 760, Shimooka-cho, Kohoku-ku, Yokohama, Kanagawa Meiji Seika Chemicals Laboratory, (72) Inventor Shinichi Kondo, 760, Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Seika Co., Ltd. Pharmaceutical Research Center

Claims (2)

[Claims] 1. A phosphinic acid derivative represented by the following formula (I). (In the formula, M represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom or an ammonium compound) 2. A cerebral circulation metabolism-improving agent comprising a phosphinic acid derivative represented by the following formula (I) as an active ingredient. (In the formula, M represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom or an ammonium compound)