JPH02131454A - Oxamic acid compound and improver for cerebral function disorder - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula Ia (R<1a> and R<2a> are 1-4C alkyl or 2-4C alkenyl) and a salt thereof. EXAMPLE:N-Ethyl-N-n-propyloxamic acid. USE:An improver for cerebral disorder having safety free from side effects, especially useful as a protecting agent for cerebral anoxia. PREPARATION:An oxamic acid ester compound shown by formula II (R<3> is 1-4C alkyl, aralkyl, etc.) is hydrolyzed to give a compound shown by formula Ia. The reaction is carried out in water or a hydrous organic solvent in the presence of a base at -10 to 50 deg.C. Methanol, ethanol, 1,4 dioxan, THF, etc., are used as the organic solvent. NaOH, KOH, etc., are used as the base.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention has a protective effect against anoxia (blood oxygen deficiency) that occurs in the brains of mammals placed in hypoxic conditions, and This invention relates to a useful new oxamidic acid compound that has medicinal effects to improve various symptoms of brain dysfunction caused by disorders of brain energy metabolism. The present invention also relates to drugs for improving brain dysfunction containing these new oxamic acid compounds and known oxamic acid compounds having the same medicinal effects as active ingredients.Furthermore, the present invention relates to a method for producing novel oxamic acid compounds. .

(Prior Art and Problems to be Solved by the Present Invention) With the advent of an aging society, countermeasures against senile dementia caused by brain dysfunction caused by cerebrovascular disorders and intracerebral energy metabolism disorders are becoming more and more important. It has become a major social issue, and various conventional drugs have been developed as anti-dementia drugs. At present, the mechanisms of senile dementia and memory impairment caused by cerebrovascular disorders and their occurrence are not clear, and methods for finding effective drugs have not yet been fully established. Methods of inducing memory impairment (amnesia) in normal animals include administration of drugs that inhibit nucleic acid and protein synthesis, anticholinergic drugs, or cerebral anoxia (amnesia).
Attempts have been made to develop drugs that improve or prevent memory impairment using animal model animals of amnesia induced by amnesia (amnesia) or ischemic stress.

In addition, we investigated cerebral circulation metabolism and intracerebral energy metabolism using model animals of cerebral anoxia induced under hypoxic loading conditions, such as by administering a lethal dose of potassium cyanide or by placing them under hypoxic conditions under low pressure or normal pressure. Attempts are also being made to develop drugs that improve
~328 pages (1985); Same Magazine 86, 445-45
6 (1986); see Japanese Unexamined Patent Publication No. 117468/1986).

However, the drugs that have been provided so far cannot be said to be completely effective as drugs for improving brain function disorders. Under such circumstances,
There is a demand for the creation of drugs for improving brain dysfunction that are more effective and safer than the drugs that have been provided so far.

On the other hand, JP-A-54-24823 describes a method for producing N,N-disubstituted glycolamides that are used as polymer stabilizers or solvents. It is described that di-substituted oxamic acid is produced, but the compounds specifically confirmed to be produced as by-products are N,N-dimethyloxamic acid, N,N-dimethyloxamic acid,
N-jethyloxamic acid, N,N-di-n-propyloxamic acid, N,N-di-n-butyloxamic acid,
Limited to N,N-diallyloxamic acid, N,N-cyclopentyloxamic acid, N-methyl-N-phenyloxamic acid and N,N-diphenyloxamic acid. Moreover, the above-mentioned publication does not describe the uses or physiological activities of the N,N-disubstituted oxamic acids of these examples. Furthermore, N,N-diisoprobyl oxamic acid is described in the literature “
Journal of Organometallic Chemistry, Vol. 297, pp. 379-390 (1985), but there is no description of the physiological activity of this compound.

(Means for Solving the Problems) The purpose of the present invention is to create and provide a safe new compound that has an excellent pharmacological effect of improving brain dysfunction and has no side effects, and The aim is to provide drugs that improve disorders. In order to achieve the above objective, the present inventors have conducted repeated research. As a result, in experiments using mice that developed cerebral anoxia under hypobaric hypoxic stress conditions as model animals, the anti-anoxia effect was found to significantly prolong the survival time of these cerebral anoxia mice. In other words, it has been found that a compound having a protective effect against cerebral anoxia is useful or promising as a medicinal drug capable of improving brain dysfunction in mammals including humans. Therefore, the inventors of the present invention have proposed
Some N,N-dialkyloxamic acids (also referred to as N,N-dialkyloxamic acids) described in Publication No. 23
We focused on the following and tested the protective effects of these compounds against cerebral anoxia. In addition, novel N,N-disubstituted oxamidic acid compounds not described in conventional literature were newly synthesized, and these novel compounds were also tested for their protective effects against brain anoxia.

As a result of the above research and tests, it has been found that N,N-disubstituted oxamic acid compounds represented by the below-mentioned formula (I), including a group of new oxamic acid compounds represented by the below-mentioned formula (Ia), have brain anoxia. They discovered that it has a protective effect against ζ and has low toxicity, and also recognized that it can be expected to be useful as a drug for improving brain dysfunction, and especially as a brain anoxia protectant. Furthermore, the present inventors have succeeded in providing a method for producing the novel compound of formula (Ia) industrially and advantageously. Therefore, the first invention is based on the following formula (Ia)n (wherein R1a and R!a are mutually different groups, and each linear group having 1 to 4 carbon atoms is a branched alkyl group or The gist thereof is an oxamidic acid compound represented by (representing an alkenyl group having 2 to 4 carbon atoms).

Furthermore, the second invention provides the following general formula (1) (wherein, Ri
and R2 represents a linear or branched alkyl group having 1 to 4 carbon atoms or an alkenyl group having 2 to 4 carbon atoms, which may be the same or different from each other. The main focus is drugs that improve functional disorders.

Specific examples of the straight or branched alkyl group having 1 to 4 carbon atoms represented by Hla and R2'' of the compound of formula (Ia) and 81 and R2 of the compound of general formula (I) are: , methyl group, ethyl group, n-probyl group, iso
-probyl group, n-butyl group, iso-butyl group, Se
Examples include G-butyl group and tart-butyl group, and specific examples of alkenyl groups having 2 to 4 carbon atoms include allyl group, methallyl group, crotyl group, and the like. Examples of novel compounds of formula (Ia) according to the invention include N-ethyl-N-n-probyloxamic acid and its sodium or potassium salts; N-ethyl-N-isoprobyloxamic acid and its sodium or potassium salts; sodium or potassium salt;
N-ethyl-N-n-butyloxamic acid and its sodium or potassium salt; and N-ethyl-N-imbutyloxamic acid and its sodium or potassium salt. The compounds of general formula (1) according to the second invention include novel compounds of general formula (Ia) according to the first invention, and furthermore, compounds of the general formula (Ia) according to the first invention, Suitable examples include N,N-dimethyloxamic acid, N,N-diethyloxamic acid, N,N-di-n-probyloxamic acid, N,N-diisoprobyloxamic acid. , N,N-di-n-butyloxamic acid, N,N-diallyloxamic acid, and their sodium or potassium salts.

The pharmacologically acceptable salts of the compound represented by formula (Ia) or formula (1) of the present invention generally include salts of the carboxylic acid group of the compound with a pharmaceutically acceptable metal;
In particular, there are customary non-toxic salts, such as alkali metal salts such as sodium salts, potassium salts, alkaline earth metal salts such as calcium salts, magnesium salts, ammonium salts, and addition salts with organic bases, such as lower salts such as triethylamine. Examples include salts with alkylamines, addition salts with organic amines such as pyridine salts, ethanolamine salts, triethanolamine salts, and dicyclohexylamine salts, and addition salts with basic amino acids such as lysine and arginine.

The novel compound of formula (Ia) according to the invention can be prepared by a process consisting of hydrolyzing an oxamic acid ester compound of formula (n) below according to the reaction scheme shown below.

(II) (Ia) In the above reaction formula, Hl& and Ba& are different from each other, and each is a linear or branched almer group having 1 to 4 carbon atoms,
Alternatively, it represents an alkenyl group having 2 to 4 carbon atoms, and R3 represents a linear or branched heptalkyl group having 1 to 4 carbon atoms, an aralkyl group such as a benzyl group, or an aryl group such as a phenyl group.

R1 of the raw material ester compound represented by general formula (II)
Specific examples of linear or branched alkyl groups having 1 to 4 carbon atoms represented by I'' and RIM include methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-propyl group, n-butyl group, iso-propyl group, n-butyl group, -butol group, see-butyl group, tart
-butyl group, and specific examples of alkenyl groups include allyl group, methallyl group, crotyl group, etc.

Specific examples of the linear or branched alkyl group having 1 to 4 carbon atoms represented by R3 include methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso
-butyl group, see-butyl group, tert-butyl group, etc. Examples of aralkyl group include phenyl-(C-C4)monoalkyl group such as benzyl or phenethyl group. Further examples of R3 being an aryl group include unsubstituted or substituted phenyl groups.

The hydrolysis reaction of the ester compound of formula (II) is carried out in water or a water-containing organic solvent in the presence of a base at -10°C to 50°C for 0.1 to several hours. As an organic solvent,
Alcohols such as methanol, ethanol, and propanol, or aprotic solvents such as 1,4-dioxane, tetrahydrofuran, and pyridine can be used. Examples of bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, etc. Quaternary ammonium hydroxides such as quaternary ammonium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, trialkylamines such as triethylamine. Examples include tertiary amines such as N-methylpiperidine and 4-(N,N-dimethylami,no)pyridine. The raw material ester compound represented by formula (II) is, for example, (r
It is produced according to the reaction of condensing (chloroformyl)formic acid ester shown in V).

(III) (mV)
(II) (wherein Hla.Ra& and R3 have the same meanings as above) Next, a reference synthesis example showing the preparation of the raw material ester of formula (II) and the production of the present compound of formula (Ia) will be described. The present invention will be explained in more detail with reference to the following examples. Magnesium was added to dehydrate the mixture. Thereafter, the filtered organic layer was concentrated under reduced pressure to obtain 955 mg (5.5 mmol) of methyl N-ethyl-N-n-propyl-oxamate as a colorless oil. "I{-NMR, δI direct (CDCQ,): 0.90
(311, dt, J=8Hz, 311z), 1
．． 19 (3H, dt, J = 7Hz, 3Hz),
1.62 (2H, sext, J=71{z), 3
．． 05-3.53(4H, m)N-ethyl-N-n-
Probylamine Ig (11.5 mmol) was added to 30++ fl of methylene chloride and dried in a dry ice/acetone bath.
Stir while cooling to 78°C. Add 703 mg (5.7 mmol) of methyl (chloroformyl)formate to this solution dropwise. Stir for 2 hours while gradually raising the temperature of the reaction vessel to room temperature. The reaction solution was poured into ice water, extracted with 10 vaQ of methylene chloride, and the organic layer was washed with a 10% aqueous citric acid solution, water, a saturated aqueous sodium bicarbonate solution, water, and saturated brine in that order, and diluted with sulfuric anhydride, ethyl chloride, and sulfuric anhydride. The title compound was obtained in the same manner as in Reference Synthesis Example 1 using n-butylamine as the starting compound. 1H-NMR, δ value (CDCI2,): 0.92 (3
H, t, J=7Hz)* 1.19(3H, dt
, J=7Hz, 311z), 1.15~1.90(
4H, m), 3.50-3.60 (4H, m) 1, N-ethyl-N-n-probyl oxamide u1
4/rrC,H,N-ethyl-N-n-methylpropyloxamate 87
Dissolve 0 mg (5.0 mmol) in methanol 201Ω and stir on a water bath while cooling with water. To this obtained solution, add 594 g (15 mmol) of sodium hydroxide to 1 liter of water.
Drop a solution of water dissolved in O■Ω. After dropping, remove the water bath and stir at room temperature for 1 hour. After adding 10 mfi of IN aqueous hydrochloric acid to the reaction solution, the solvent was distilled off under reduced pressure. Add ethanolome BOvxQ to the residue and filter off the undissolved solids. The organic layer was concentrated to obtain 305 g (1.9 mmol) of N-ethyl-N-n-probyl oxamic acid as a colorless oil. "H-NMR, δ value (D, 0): 0.93 (3H
, t, J=7Hz), 1.22 (3 skin dt, J
:7Hz, 6Hz), 1.40~2.00(2}1,
m), 3.10-3.60 (2H, m) IR absorption (cm-', neat): 1635, 1440,
The title compound was synthesized from methyl 1230, 1200, 1145/rr-C,H,N-ethyl-N-n-butyl-oxamate in the same manner as in Example 1 above. "II-NMR. δ value (D, O,): 0.70 ~ 1.20 (3}1, II), 1.00 ~
1.90 (7H, m), 3.41 (21{, t,
J=71Iz), 3.46(2}1, q, J=7
Hz) IR absorption (am-1, neat): 1710
, 1630, 1460, 1380, 1280,
1250/ n-C3H, N-ethyl-N-n-probyloxamate methyl 47
5 mg (2-75-: rimole), +E tar/- LO
ml: Dissolve and keep the resulting methanol solution cooled in water. Dissolve IQmg (2.75 mmol) of sodium hydroxide in 51 g of water, drop this aqueous solution into the methanol solution, and stir the mixture for 3 hours at room temperature. Methanol is distilled off from the reaction solution under reduced pressure. , wash the remaining aqueous layer with 5mM methylene chloride. Separate the aqueous layer,
Distillation under reduced pressure gave sodium N-ethyl-N-n-propyloxamate 495B (2.7 mmol) as a white solid. 'I-NNR, δ value (ago): 3-75 to 3-20 (411-m)t 2-10 to 1
-35 (2H-ml)? 1.50-1. OO(311
, m), 1.20-0.75 (3H, dt, J
=8Hz, 2Hz) (iso-C, HJr-N-Co
-COOHC4) I of N,N-diisopropylamine
g (9.9 mmol) to methylene chloride 30@Q,
Cool to -78°C in a dry ice/acetone bath and stir. To this, 605 g (4.9 mmol) of chloroformic acid (chlorophonoleminole) was added dropwise. The reaction vessel was stirred for 2 hours while gradually raising the temperature to room temperature.

The reaction solution was poured into ice water and extracted with 10 mm of methylene chloride. The organic layer was washed successively with 1O% citric acid aqueous solution, water, saturated sodium hydrogen carbonate aqueous solution, water, and saturated brine, and dehydrated by adding anhydrous magnesium sulfate. The filtered organic layer was concentrated under reduced pressure to obtain 800 mg (4.3 mmol) of methyl N,N-diisoprobyl oxamate as a colorless oil.

(a) Dissolve 500 mg of methyl N,N-diisoprobyl oxamate in 20 mfl of methanol and stir under water cooling. IN aqueous sodium hydroxide solution 15- is added dropwise to this methanol solution. After addition, stir at room temperature for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, 20mM of IN-HCQ was added to the residue, and the insoluble white precipitate was collected by filtration, washed with cold water and n-hexane, dried, and the title N
, N-diisopropyloxamic acid (180 mg) was obtained as a white solid.

″H-NMR, δ value (Cfl, 00): 1-23 (
61{ed= J==71Iz), 1-40(6H
, d- J==71lz), 3.40~4.00(2H
, m) IR absorption (cn+7', KBr): 1720, 1
565, 1370, 1230, 1190? Example 4
Starting from N,N-di-n-probylamine, N,N-di-n-probyl oxamic acid was obtained in the same manner as described above.

'! {-NMR, δ value CCDCQ■): 0.92 (61
1, t, J=7Hz), 1.30"1.90 (4
H, m) 3.35 (2}1, t, J=71{z)
, 3.66 (2H, t, J==7Hz), 5.9
4 (Ill, broad) IR absorption (cm-', Nujol): 1730, 1
600, 1265, 1125 (CH2=CH-CH
2), -N-CO-COOH (a) Add 1 g of N,N-diallylamine to methylene chloride 301, and stir while cooling to -78°C in a dry ice/acetone bath. Add 630 mg of methyl (chloroformyl)formate dropwise to this. 2 while gradually raising the temperature of the reaction vessel to room temperature.
I stirred for hours. The reaction solution was poured into ice water and extracted with 10 mQ of methylene chloride. The organic layer was washed successively with 10% citric acid aqueous solution, water, saturated sodium bicarbonate aqueous solution, water, and saturated brine, and dehydrated by adding anhydrous magnesium sulfate. The filtered organic layer was concentrated under reduced pressure to obtain 875 mg of methyl N,N-diallyloxamate as a colorless oil. 'H-NMR, δ value (CDCI,): 3.85 (31
{, s) 4.07-4.36 (4H, m), 4
．． 98-5.33 (4H, m), 5.49-6.00
(2H, m) (a) Methyl N, N-diallyloxamide 6ΩO
Dissolve mg in 20+oQ methanol and keep it cooled in water. Add 15n+Q of IN sodium hydroxide aqueous solution dropwise to this methanol solution. After addition, stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure at room temperature to about 10 mQ,
Add IN aqueous hydrochloric acid to bring the pH of the solution to 4. Extract with ethyl acetate 50+++Q, wash with saturated brine, and dehydrate by adding anhydrous magnesium sulfate. The filtered organic layer was concentrated under reduced pressure to obtain 460 mg of N,N-diallyloxamic acid as a white solid. '11-NMR, δ value (CD
CI, ): 4.03 (21L d, J = 7Hz)
, 4.18 (2N, d, J = 711z), 5.
10-5.40 (4H, m), 5.65-5.95
(2H, m) IR absorption (cm-1, sujoor): 1735, 1640, 1500, 1420, 1
300, 1288, 1210 The toxicity of the compound of general formula (1) used in the present invention was evaluated for N,N-diisopropyrokizamic acid, as an example. Specifically, when the test compound was intravenously administered to a group of three ddY mice (male, 5 weeks old, body weight 25 g) at a dose of 1000 B/kg, all mice survived, indicating that the compound used in the present invention has a low It has been shown to be toxic and useful as an agent for improving brain dysfunction.

Brain dysfunction improving agents containing the compound represented by general formula (1) or a salt thereof as an active ingredient are mainly used for injections such as intravenous injection, oral or rectal preparations such as capsules, tablets, and powders, and oil-based preparations. It is used in various dosage forms such as suppositories and water-soluble suppositories. These various preparations contain commonly used excipients, fillers, binders, wetting agents, disintegrants, surfactants,
B5 can be produced by a conventional method using a lubricant, a dispersant, a buffer, a preservative, a solubilizing agent, a preservative, a flavoring agent, a soothing agent, and the like. Specific examples of the formulation method are given in Examples 7 to 9 below.
This will be explained in more detail.

The dosage of the compound of formula (r) is appropriately determined depending on the individual case, taking into account the symptoms, age, gender, etc., but it is usually 250 to 3000 mg per day for adults, and this is administered once per day. Administer in ~4 doses.

The following Examples describe methods for preparing various formulations, but the present invention is not limited thereto.

Mix 1 part by weight of N, N-diisopropyroxamic acid, 2.7 parts by weight of lactose, 0.8 parts by weight of cornstarch, and 0.05 parts by weight of polyvinylpyrrolidone, and moisten with ethanol. Pelletize by conventional method, dry and sieve, and add 0.

After adding 5% magnesium stearate and mixing, each tablet is made into 100 mg tablets using a conventional method.

For JLL, 5 g of N,N-diisoprobyl oxamidic acid and 5 g of mannitol were dissolved in distilled water to make 1000 mn, and after sterilization by the usual method, 2 mQ each was dispensed into vials and freeze-dried. Before use, this drug is dissolved in distilled water for injection to form an injection solution.

1 part by weight of N,N-diisoprobyl oxamic acid and 4 parts by weight of lactose are thoroughly mixed, and the mixture is sieved through a 50 mesh sieve to obtain a powder.

The effect of improving brain dysfunction of the compound of the present invention according to general formula (1) was investigated using as an indicator the effect of prolonging the survival time of mice that had developed cerebral anoxia due to a vacuum-induced hypoxic load.

6 mice per group (7) ddY mice (6 weeks old, weight 25-3
0 g), and the compound of the present invention (administered solution volume was 0.1 m
Q/10g (dissolved in double-distilled water) was administered intraperitoneally. After 30 minutes, each animal was placed in a transparent sealed container and the pressure was rapidly reduced to 190 mmlg using a vacuum pump.

The time from the start of decompression until the mouse died due to respiratory arrest was measured and defined as survival time (seconds).

The ratio of the survival time of the test compound administration group of the present invention to the survival time of the control group to which no drug was administered was determined, and the ratio was determined in the following Table-1.
Described in.

Table 1 (Effects of the Invention) As is clear from the above test examples, the compound of formula (1) according to the present invention prolongs the survival time of animals with cerebral anoxia induced under hypobaric hypoxic loading conditions. , has a protective effect against cerebral anoxia, promotes the supply of oxygen to the brain, reduces wasted oxygen and ATP consumption in the brain, and increases ATP production in the brain, thereby improving brain energy metabolism. It is thought that it improves circulation.

Particularly in clinical practice, it is thought to be useful for improving motivation and emotional disorders caused by cerebral infarction and cerebral hemorrhage sequelae. Furthermore, since the compound of formula (I) according to the present invention is thought to improve motivation loss, it is thought to be effective as a therapeutic agent for senile dementia.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I a) (In the formula, R^1^a and R^2^a are mutually different groups, and each has a carbon number A novel oxamic acid compound represented by a linear or branched alkyl group having 1 to 4 carbon atoms or an alkenyl group having 2 to 4 carbon atoms, or a pharmacologically acceptable salt thereof. 2. General formulas ▲ Numerical formulas, chemical formulas, tables, etc. An oxamidic acid compound represented by (representing an alkyl group or an alkenyl group having 2 to 4 carbon atoms) or a pharmacologically acceptable salt thereof as an active ingredient. 3. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, R^1^a and R^2^a are mutually different groups, and are straight chain or branched groups with 1 to 4 carbon atoms. Oxamide acid represented by a chain alkyl group or an alkenyl group having 2 to 4 carbon atoms, and R^3 represents a linear or branched alkyl group having 1 to 4 carbon atoms, an aralkyl group, or an aryl group. Claim 1 characterized in that the ester compound is hydrolyzed.
A method for producing an oxamic acid compound of formula (Ia) as described in .