JPS6042235B2 - 2-Aminocetamido-α-phenylbenzylidene aminoalkanol derivatives and central nervous system depressants containing the derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 2-aminoacetamido α-phenylbenzylidene aminoalkanol derivative having the general formula and a central nervous system depressant containing the same as an active ingredient.

In the above formula, R1 represents a hydrogen atom or a halogen atom;
2 represents a hydrogen atom or a fluorine atom, and A represents an alkylene group having 1 to 4 carbon atoms.

In the general formula (1), the halogen atom represents fluorine, chlorine, or bromine, and the alkylene group represents, for example, methylene, ethylene, trimethylene, 1-methylethylene, 2-methylethylene, tetramethylene, 1,2-butylene, 1, 3-
It represents a linear or branched alkylene group having 1 to 4 carbon atoms, such as butylene or 2,3-butylene.

The compounds having the general formula (1) obtained by the present invention are all novel compounds, and are useful as medicines that have a central nervous system depressant effect and have an excellent minor tranquilizer effect with low toxicity. It is a compound. The pharmacological effects are illustrated below using test methods and ED5O values in mice. [Test method] (1) Anti-bimeglide spasticity effect One hour after oral administration of the sample, 307TLy/
K9 is administered subcutaneously and its inhibitory effect on spasticity is examined over a period of 3 minutes.

(2) Anti-electric shock convulsion effect One hour after oral administration of the sample, electric shock (1000V112.5n
1A10. Test the inhibitory effect on spasticity by administering the drug to both eyes.

(3) Anesthesia-enhancing effect 30Tr1 of thiopental 1 hour after oral administration of the sample,
y/K9 is administered intravenously, and the dose at which the duration of loss of righting reflex is prolonged by twice that of the group administered with thionpetal alone is calculated.

(4) Calculation of ED5O value Litchfield WilcOxOn method [J. Pha
rmacOl. Exp. Tllerap. ，? Volume, 99
Page (194 咋)].

[Pharmacological effect] ED5O value (My/Kg, oral) When administering the compound obtained by the present invention as a central nervous system depressant, it may be administered either orally or parenterally, for example in tablets, Capsules, powders, granules,
Examples include oral administration in the form of syrups, etc., parenteral administration in the form of injections as solutions or suspensions, suppositories, and the like.

The dosage varies depending on symptoms, age, body weight, etc., but is usually about 0.05 to 10 rrI. q/K9 weight/
It can be given in one or several days. The compound of the present invention having the general formula (1) is represented by the general formula (wherein Rl, R2 and A have the same meanings as described above).

) is a 2-amino-α-phenylbenzylidene aminoalkanol compound having the general formula 1
The general formula (in the formula,
Rl, R2, A and Z have the same meanings as described above.

), and in the case of a compound in which Z is a protecting group for an amino group, it can be obtained by hydrolyzing this. The above general formula (■) and (■)
The protecting group for the amino group can be easily removed by hydrolysis, and preferred examples include halogen acetyl groups such as dichloroacetyl, dipromoacetyl, trichloroacetyl, tribromoacetyl, and trifluoroacetyl. be able to.

In the present invention, when the compound having the general formula (■) is reacted with the compound having the general formula (■),
This is carried out in the presence of a condensing agent exemplified below. That is, for example, N,N''-dicyclohexylcarbodiimide, 1-
(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide, 1-cyclohexyl-3
N,N″-disubstituted carbodiimides such as -(N-methyl-2-morpholiniumethyl)carbodiimide; N
, N″-carbonyldiimizole, di-α-pyridyl carbonate, S,S-carbonyldi(α-thiopyridine), N,N″-carbonyldi(1,2,4-triazolide), N,N″-carbonyldi(1, Substituted carbonyl di-compounds such as 2,3-triazolido), N,N″-carbonyldi(1,2,3,5-tetrazolide), N,N″-carbonyldi(3,5-dimethylpyrazolide); chlorocarbonmethyl , chlorocarbon ethyl, chlorcarbon isobutyl, etc.; di-substituted thionyl compounds such as N,N''-thionyldiimizole, di-p-nitrophenyl sulfite, dip-p-nitrophenyl sulfite thioester; Phosphate compounds such as tri-p-nitrophenyl phosphate, diimidazole-1-phosphinic acid monoester, diethylchlorophosphite, tetraethylpyrophosphite; wood such as N-ethyl-5-phenylisoxazolium-3″-sulfonate Ward reagent: acetylene compounds such as ethoxyacetylene, methylethynyldiethylamine, ethylethynyldiethylamine, propylethynyldiethylamine, butylethynyldiethylamine; trichloroacetonitrile, N
, N-diethyl cyanamide, N,N-diphenyl cyanamide, N,N-dibenzyl cyanamide, diphenyl ketene-p-tolylimine; trifluoroacetic acid esters such as; arylsulfonyl chlorides such as phenylsulfonyl chloride; unsaturated heterocyclic compounds such as dihydrobyran;
-Carbonyl amino acid ester compounds; ketenes such as diphenylketene; oximes such as 3-nitroacetophenone oxime; N-acyloxazolidinones such as N-benzyloxycarbonyloxazolidinone and N-tosyloxazolidinone; triphenylphosphine; Suitable condensing agents include trivalent phosphorus compounds-disulfide compounds such as 2,2''-dipyridyl disulfide, triphenyl phosphite and 2,2''-dipyridyl disulfide; phosphazo compounds, etc. It is not particularly limited to. Generally known methods for producing acid amides can be applied as the production method of the present invention. Furthermore, depending on the type of condensing agent, for example, when a phosphoric acid compound is used as a condensing agent, for example, pyridine, picoline, lutidine, quinoline, isoquinoline, colicin, N-methylpiperidine,
Heterocyclic compounds such as N-methylmorpholine; barred bases such as tertiary amines such as triethyl-amine and tri-n-butylamine; alkali metals and alkalis such as sodium carbonate, potassium carbonate, and calcium carbonate. Carbonates of earth metals; such as sodium hydroxide, potassium hydroxide, and calcium hydroxide. hydroxides of alkali metals and alkaline earth metals; sodium bicarbonate;
It may be suitably carried out in the presence of a base such as inorganic bases such as alkali metal and alkaline earth metal bicarbonates such as potassium hydrogen carbonate and calcium hydrogen carbonate! Ru.

Further, when the condensing agent is an N,N''-disubstituted carbodiimide such as N,N-dicyclohexylcarbodiimide, the compound having the general formula (■) may be a salt such as a hydrochloride, a sulfate, or a nitrate. It is preferably used in the form of
4 In the method of the present invention, the general formula (
When the compound having the general formula (■) is reacted with the reactive derivative of the compound having the general formula (■), examples of the reactive derivative of the compound having the general formula (■) include acid chloride, acid bromide, etc. Acid halogen compounds such as;
Mixed acid anhydrides with phenylacetic acid etc.; acid azides; alkyl esters such as methyl esters, ethyl esters, p
Examples include esters such as aryl esters such as -nitrophenyl ester; mixed acid imides with acetamide, propionamide, etc., but are not particularly limited to these reactive derivatives. Further, when the reactive derivative of the compound having the general formula (■) is, for example, an acid halide compound or an acid azide as a reaction reagent, the reaction is preferably carried out in the presence of a base according to a conventional method. Examples of bases used include pyridine, picoline,
Heterocyclic compounds such as lutidine, quinoline, isoquinoline, colicin, N-methylpi)peridine, N-methylmorpholine; Organic bases such as tertiary amines such as triethylamine, tri-n-butylamine; sodium carbonate, carbonic acid Alkali metal and alkaline earth metal/carbonates such as potassium, calcium carbonate; alkali metal and alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide; sodium bicarbonate, carbonate Examples include inorganic bases such as bicarbonates of alkali metals and alkaline earth metals such as potassium hydrogen carbonate and calcium hydrogen carbonate, but are not particularly limited to these bases. Among these bases, organic bases can absorb solvents. In carrying out the method of the invention, the reaction is carried out in the presence or absence of a solvent.

It is preferable to use a solvent to facilitate the reaction.
The solvent to be used is not particularly limited as long as it participates in the reaction; for example, lower alkanols such as methanol, ethanol, and isopropanol; diethyl ether,
Ethers such as tetrahydrofuran and dioxane;
Halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane; Aromatic hydrocarbons such as benzene, toluene, and xylene; Lower carboxylic acid esters such as ethyl acetate and methyl propionate; Nitriles such as acetonitrile: Dialkyl amides such as dimethylformamide; dialkyl sulfoxides such as dimethyl sulfoxide; heterocyclic compounds such as pyridine, picoline, lutidine, quinoline, isoquinoline, colicin, N-methylpiperidine, N-methylmorpholine; triethylamine, Examples include tertiary amines such as n-butylamine. Particularly suitable solvents include benzene, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, dimethylformamide, and the like. The reaction temperature is not particularly limited, but in order to suppress side reactions, it is desirable to carry out the reaction at a relatively low temperature, and it is usually preferable to carry out the reaction under ice cooling at the beginning, and then gradually raise the reaction temperature to room temperature. It is done by twisting.

When the reactive derivative of the compound having the general formula (■) among the reaction reagents is an ester, the reaction does not proceed satisfactorily below room temperature and is usually suitably carried out by heating. The time required for the reaction differs mainly depending on the type of raw material compound, the presence or absence of a solvent, the type, reaction temperature, etc. After the reaction is completed, the target compound having the general formula (■) is collected from the reaction mixture by a conventional method.

For example, after the reaction is complete, add an appropriate amount of water or saline to the reaction mixture, add an appropriate organic solvent for extraction, wash the organic layer with water, dry it, and then distill off the solvent from the organic layer. You can get it. The obtained target compound is further purified by conventional methods such as recrystallization and column chromatography to obtain a pure target compound. Next, among the compounds having the general formula (■), the substituent Z
is a protecting group for an amino group such as a dichloroacetyl group, a trichloroacetyl group, or a trifluoroacetyl group, the reaction of removing these protecting groups by hydrolysis is carried out using a hydrolysis reagent in the presence of water. It can be carried out according to conventional methods.

Hydrolysis reagents used include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; and sodium carbonate and potassium carbonate. alkaline metal carbonates; alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkaline hydrolysis reagents such as ammonium hydroxide; Salt is preferably used. The reaction is usually suitably carried out in the presence of a solvent. Examples of suitable solvents include water; alkanols such as methanol, ethanol, and n-propanol; ethers such as tetrahydrofuran and dioxane; and organic solvents such as dialkylformamides such as dimethylformamide. In particular, mixed solvents of water and organic solvents are used as suitable solvents. The reaction temperature is not particularly limited, but in order to suppress side reactions, it is desirable to carry out the reaction at a relatively low temperature, and it is usually preferably carried out at around room temperature. The time required for the reaction varies mainly depending on the type of raw material compound and solvent, reaction temperature, etc., but is about 8 hours to 2 hours. After the reaction is completed, the target compound having the general formula (1) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the organic solvent from the reaction mixture, then extracting with a suitable organic solvent, washing the extract with water, drying, and then distilling off the solvent from the extract. The obtained target compound can be purified, if necessary, by conventional methods such as recrystallization and column chromatography. Next, a method for producing the compound of the present invention will be described.

Production Example 1 2-([2-aminoacetamide 5-bromo α-(
2-Fluorophenyl)benzylidene]amino)ethanol N,N″-dicyclohexylcarbodiimide 4.5
After dissolving y in 100 ml of dimethylformamide, 2.2 q of glycine hydrochloride was added to 2.2 ml of water while stirring under ice cooling.
Add the solution dissolved in m1 in about 30 seconds.

A solution of 3.4y of 2-([2-amino-5-bromo α-(2-fluorophenyl)benzylidene]amino)ethanol dissolved in 10ml of tetrahydrofuran was immediately added dropwise to the reaction mixture, and the reaction was further stirred for 3 hours at room temperature. After that, 1' of water was added to the reaction mixture, and 100% of benzene was added.
Extract once with m1 and then four times with 50 mL. After washing the organic layer with water and drying over anhydrous sodium sulfate, the solvent is distilled off from the organic layer to obtain a yellow oily residue. The obtained oil was purified by column chromatography using alumina, and then recrystallized from benzene-n-hexane to obtain the target compound 2.3 having a melting point of 167-168°C.
y is obtained. Production Example 2 2-[(2-aminoacetamido-5-bromo-α-phenylbenzylidene)amino]ethanol 2-(2-
After dissolving 3.2 y of amino-5-bromo α-phenylbenzylidene amino) ethanol and 2.6 y of trichloroacetylglycine in 50 ml of dichloromethane,
N,N''-dicyclohexylcarbodiimide 2.5 at °C
Add y, gradually warm to room temperature, and stir for 3 hours.

After completion of the reaction, the precipitate precipitated from the reaction mixture is removed, and the solvent is distilled off from the solution to obtain crystal 4.3y having a melting point of 175-176°C. Knead the crystals in methanol 80m
1 and 80 ml of tetrahydrofuran, a solution of 4.0 y of sodium carbonate dissolved in 80 ml of water was added, and the mixture was further stirred at room temperature overnight. After the reaction, the solvent is distilled off from the reaction mixture, the residue is extracted with dichloromentane, the extract is washed with water and dried over anhydrous sodium sulfate, and the solvent is distilled off from the extract to obtain crystals of the target compound. .
When this is recrystallized from ethyl acetate, the melting point is 153-154.
A crystal of the target compound having a temperature of 0.96y is obtained. Production Example 3 2-([2-aminoacetamide 5-chloro α-(
2-Fluorophenyl)benzylidene]amino)ethanol N,N″-dicyclohexylcarbodiimide 4.5
After dissolving ~y in 100 ml of dimethylformamide,
While stirring under ice-cooling, 2.2 g of glycine hydrochloride was added to 2 g of water.
Add 2 ml of the solution in about 30 seconds.

Immediately a solution of 3.2 y of 2-([2-amino-5-chloroα-(2-fluorophenyl)benzylidene]amino)ethanol dissolved in 10 ml of tetrahydrofuran is added dropwise to the reaction mixture, and the mixture is further stirred at room temperature for 3 hours.
After completion of the reaction, the reaction mixture is treated and purified in the same manner as in Production Example 1 to obtain the target compound 1.7y having a melting point of 128 to 137C.Production Example 42-[(2-aminoacetamide 5-chloro α -phenylbenzylidene)
4.5f of amino]propanol N,N''-dicyclohexylcarbodiimide and 100ml of dimethylformamide
1, a solution of 2.2 y of glycine hydrochloride dissolved in 2.2 ml of water was added in about 30 seconds while stirring under ice-cooling.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 represents a hydrogen atom or a halogen atom, and R
^2 represents a hydrogen atom or a fluorine atom, and A represents an alkylene group having 1 to 4 carbon atoms. ) 2-Aminoacetamido-α-phenylbenzylidene aminoalkanol derivative. 2 2-{[2-
The compound according to claim 1, which is represented by aminoacetamido-5-bromo-α-(2-fluorophenyl)benzylidene]amino}ethanol. 3 2-[(2-aminoacetamide-5-bromo-α
-phenylbenzylidene)amino]ethanol according to claim 1. 4 2-{[2-aminoacetamido-5-chloro-α
-(2-fluorophenyl)benzylidene]amino}ethanol The compound according to claim 1, which is represented by ethanol. 5 2-[(2-aminoacetamide-5-chloro-α
-phenylbenzylidene)amino]propanol according to claim 1. 6 General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents a hydrogen atom or a halogen atom,
R^2 represents a hydrogen atom or a fluorine atom, and A has 1 carbon number.
represents an alkylene group having 4 to 4 atoms. ) A central nervous system depressant containing a 2-aminoacetamido-α-phenylbenzylidene aminoalkanol derivative. 7. Claim 6, wherein the 2-aminoacetamido-α-phenylbenzylidene aminoalkanol derivative is 2-{[2-aminoacetamido-5-bromo-α-(2-fluorophenyl)benzylidene]amino}ethanol central nervous system depressant.