JPS639491B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention utilizes 2-
The present invention relates to a pharmaceutical composition containing at least one aminoacetamide derivative as an active ingredient. Glycinamides conventionally known in chemical reactions include the following compounds: CH ₃ NHCH ₂ CONH ₂ , C ₂ H ₅ NHCH ₂ CONH ₂ , i-C ₃ H ₇ NHCH ₂ CONH ₂ ,
C ₄ H ₉ NHCH ₂ CONH ₂ , C ₆ H ₁₁ NHCH ₂ CONH ₂ ,
C ₇ H ₁₅ NHCH ₂ CONH ₂ , C ₆ H ₅ NHCH ₂ CONH ₂ ,
C ₆ H ₅ CH ₂ NHCH ₂ CONH ₂ , PClC ₆ H ₄ CH ₂ NHCH ₂ CONH ₂ . Other glycinamides are known as fungicides (DOS 2 511 311). Still other glycinamides have the formula C ₂ H ₅ O
Compounds -CO( _CH2 ) _3NH - _CH2 - _CONH2 and those described in Belgian Patent No. 636245 are known to have medicinal properties. One of the important objects of the invention is to provide 2-amino-acetamide derivatives which have particular advantages as pharmaceuticals. The derivative of the present invention has the following general formula: (R in the formula is a linear or branched alkyl group C ₅
~ _C18 , straight-chain or branched alkenyl group _C5 ~
_C18 , straight-chain or branched alkynyl group _C4 - _C10 ,
Straight-chain or branched acyl group _C4 - _C18 , or phenoxy group, hydroxyl group, carboxyl group, straight-chain or branched alkoxycarbonyl group C1 _{- C4} , acetal group, one or more phenyl groups basis,
straight-chain or branched alkyl group C ₁ -C ₁₀ substituted by one or more phenyl groups substituted by halogen atoms such as fluorine, chlorine or bromine, R ₁ is hydrogen Atomic, straight-chain or branched acyl group
C ₁ - C ₆ , benzoyl group, straight chain or branched chain alkoxycarbonyl group C ₁ - C ₈ , or carboxamidomethyl group, R ₂ is hydrogen atom, straight chain or branched chain alkyl group C ₁ - C ₃ , phenyl group, R ₃ is a hydrogen atom, R ₄ is a hydrogen atom). In a preferred embodiment, the invention provides that R is a straight-chain or branched alkyl group _C5 , _C6 , _C7 , _C8 , _C9 , _C10 ,
C ₁₁ or C ₁₂ , straight or branched alkenyl group
_C5 - _C18 , straight-chain or branched alkynyl group _C4-
C6 , a straight-chain or branched acyl group _C4 to _C12 , or one or more phenyl groups substituted by one or more phenyl, fluorine, chlorine or bromine atoms, Phenoxy group, hydroxyl group,
straight-chain or branched alkyl groups _C1 , _{C2 ,} C3, _C4 , _C5, substituted by carboxyl groups, straight-chain or branched alkoxycarbonyl groups C1 _{- C4} ,
C ₆ , C ₇ , C ₈ , R ₁ is hydrogen atom, straight chain or branched acyl group
C ₁ - _{C 4} , benzoyl group, straight chain or branched chain alkoxycarbonyl group C ₁ - _{C 8} or carboxamidomethyl group, R ₂ is hydrogen atom, straight chain or branched chain alkyl group C ₁ - _{C 3} , or a phenyl group, R ₃ is a hydrogen atom, and R ₄ is a hydrogen atom. A preferred group of products of the invention is a general formula in which R is a straight-chain or branched alkyl group C ₅ , C ₆ ,
C ₇ , C ₈ , C ₉ , straight or branched alkenyl group
_C5 to _C10 , straight chain or branched alkynyl group _C4 to
C ₆ , straight-chain or branched acyl groups C ₄ -C ₈ , or one or more phenyl groups, one or more substituted by halogen atoms such as fluorine, chlorine or bromine a straight-chain or branched alkyl group C 1 , C ₂ , C _{3 ,} C ₄ , R substituted by a phenyl group, a carboxyl group, a straight-chain or branched alkoxycarbonyl group C ₁ to C _{4 1} is a hydrogen atom, a straight or branched acyl group
_C1 to _C4 , a carboxamidomethyl group, or an alkoxycarbonyl group, _C1 to _C8 , _R2 represents a hydrogen atom, a methyl group or a phenyl group, _R3 represents a hydrogen atom, and _R4 represents a hydrogen atom. A special group of products of the invention are those of the general formula in which R is a straight-chain or branched alkyl group.
C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , straight-chain or branched alkenyl group C ₅ -C ₆ , straight-chain or branched acyl group
C ₄ to C ₆ or a straight or branched alkyl group C ₁ , C 2 , _{C 3} substituted by a phenyl group, carboxyl group, alkoxycarbonyl group C ₁ to _{C 2 ,}
C ₄ , R ₁ are hydrogen atoms, linear or branched acyl groups
C ₁ - _{C 4} , alkoxycarbonyl group C ₁ - C ₈ , or carboxyamidomethyl group R ₂ is a hydrogen atom, alkyl group C ₁ - _{C 2} , or phenyl group, R ₃ is a hydrogen atom, R ₄ is a hydrogen atom represent. Other preferred products of the invention are of the general formula: R is a straight-chain or branched alkyl group C ₅ ;
C ₆ , C ₇ , C ₈ , straight or branched alkenyl group
C ₅ , C ₆ , C ₇ , C ₈ , straight chain or branched alkynyl group C ₅ , C ₆ , C ₇ , C ₈ , or phenyl group, carboxyl group, alkoxycarbonyl group C ₁ to _{C 2} straight-chain or branched-chain alkyl groups substituted with
C ₁ , C ₂ , C ₃ , C ₄ , R ₁ are hydrogen atoms, beyzoyl groups or carboxyamidomethyl groups, R ₂ is hydrogen atoms, alkyl groups C ₁ to C ₂ or phenyl groups, R ₃ is hydrogen atoms, R ₄ represents a hydrogen atom. In the present invention, R is a carboxyl group, a linear or branched alkoxycarbonyl group C ₁ , C ₂ ,
A linear or branched alkyl group substituted by C ₃ or C ₄ C ₅ , C ₆ , C ₇ , R ₁ is a hydrogen atom or a carboxyamidomethyl group, R ₂ is a hydrogen atom, a methyl group or a phenyl group Preference is given to compounds of the general formula in which the radicals R ₃ and R ₄ represent hydrogen atoms. Derivatives of particular interest are those having the general formula C 2 , C 3 , C , where R is an alkyl group substituted by a phenyl group optionally substituted by a halogen atom such as fluorine, _chlorine or _bromine . ₄ , R ₁ represents a hydrogen atom, R ₂ represents a hydrogen atom, a methyl group or a phenyl group, and R ₃ and R ₄ represent a hydrogen atom. Products of further particular interest are those of the general formula in which R is a straight-chain or branched alkyl group C ₅ ,
C ₆ , C ₈ , C ₉ , R ₁ are hydrogen atoms, carboxyamidomethyl group or alkoxycarbonyl group C ₁ - C ₈ , R ₂ are hydrogen atoms, methyl group or phenyl group, R ₃ and R ₄ are hydrogen atoms represent. Preferred secondary products have the general formula:
R is a straight chain or branched alkyl group C ₅ , C ₆ , C ₈ ,
C ₉ , R ₁ , R ₂ , R ₃ and R ₄ represent hydrogen atoms. When the derivative of the general formula is an acid addition salt, it can be converted into the free salt or a salt with other acids by conventional methods. The most commonly used salts are acid addition salts,
More particularly, they are non-toxic and pharmaceutically useful addition salts with suitable inorganic or organic acids. Such inorganic acids are, for example, hydrochloric acid, sulfuric acid or phosphoric acid, organic acids, e.g.
Aliphatic, cycloaliphatic, aromatic, aromatic substituted aliphatic or heterocyclic acids, carboxylic acids or sulfonic acids, such as formic acid, acetic acid, dialkyl acetic acids, such as dipropylacetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid , lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid,
Maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, hydroxybenzoic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, pantothenic acid, toluenesulfonic acid, Sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β
-Hydroxypropionic acid, β-hydroxybutyric acid, oxalic acid, malonic acid, galactaric acid, and galacteuronic acid. In addition, these salts are lysine, glycine, arginine, ornithine, asparagine,
glutamine, alanine, vanillin, threonine,
It can be derived from serine, leucine, cysteine and other natural or synthetic amino acids. Examples of derivatives of the invention are described below. 2-n-pentylaminoacetamide, 2-n-octylaminoacetamide, methyl-6-[bis(carboxyamidomethyl)]aminohexanoate, 2-n-decylaminoacetamide, methyl-8-[bis(carboxylaminoacetamide)] methyl)] aminooctanoate, 2-n-hexylaminoacetamide, 2-(2-phenylethyl)aminoacetamide, 2-n-octadecen-9-ylaminoacetamide, 2-(N-carboxyamidomethyl-N-n −
hexyl)-aminoacetamide, 2-(1,1-dimethylpropyn-2-yl)
Aminoacetamide, Ethyl N-n-hexyl-N-carboxyamidomethyl carbamate, 2-n-pentylaminobutyramide, 2-(3-phenylpropyl)aminoacetamide, 2-octen-7-ylaminoacetamide, 8- Carboxamidomethylaminooctanoic acid, 2-(4-phenylbutyl)aminoacetamide. The products of the invention may contain one or more asymmetric centers. Products with asymmetric centers may be optical antipodes or racemic or immiscible. Separation of bilateral symmetry can be achieved by formation of diastereomeric salts. As products of the invention with two asymmetric centers, two racemates corresponding to the erythro and threo configurations can be obtained. These two racemates can be prepared using conventional methods such as optically active acids such as tartaric acid,
Formation of diastereomeric salts by the action of diacetyltartaric acid, tartranic acid, dibenzoyltartaric acid, ditolyltartaric acid and dispersion of the diastereomers by recrystallization, distillation, chromatography and then resolution from these salts by isolation of optically active bases. Can be done. The derivatives of the invention can therefore be used as mixtures containing several diastereomers whatever their relative relationship, or as enantiomeric pairs in equal (racemic) or different proportions, or as optically pure compounds. It can be used as The products of the invention can be used in the treatment of movement disorders such as Parkinson's syndrome, in the treatment of memory disorders and in the treatment of various forms of epilepsy. Some products of the invention can be used in the treatment of mental disorders, such as depression. The invention also encompasses pharmaceutical compositions containing as active ingredient at least one compound of general formula () and/or a salt thereof together with pharmaceutical excipients. These compositions are prepared and administered orally, rectally or parenterally. Thus, for example, compositions for oral administration can be liquid or solid and can be administered as tablets, dragees, capsules, capsules, granules, powders, syrups or suspensions. Dry oral preparations contain additives and adjuvants commonly used in herbal preparations, inert diluents, disintegrating agents, binders and lubricants, such as lactose, starch, talc, gelatin, stearic acid, cellulose and its derivatives, silicic acid,
Magnesium stearate, polyvinylpyrrolidine, calcium phosphate, calcium carbonate, etc. are used. Such preparations are carried out in order to postpone decomposition and prolong the activity of the active ingredients. In preparing aqueous suspensions, emulsions and oily solutions, sweetening agents such as dexterose or glycerol, flavoring agents such as vanillin and thickening agents, wetting agents and preservatives are used. Oily emulsions and solutions are prepared with vegetable or animal oils and can contain emulsifying agents, flavoring agents, dispersing agents, sweetening agents and antioxidants. For parenteral administration, sterile water, polyvinylpyrrolidone aqueous solution, peanut oil, ethyl oilate, etc. are used as excipients. Aqueous or oil solutions for injection may contain thickening agents, wetting agents, dispersing agents and gelling agents. The products of the invention can be prepared by various methods such as the experimental examples described below. Method A According to this procedure, an amine is converted to a glycinamide of formula. (wherein R, R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above, and Z is a functional group which can be converted into an amide functional group by the action of a suitable reagent, such as a carboxylic acid Functional group (-COOH), nitrile functional group (-
CN), an ester functional group ( _-COOR5 , _R5 is a lower alkyl group _C1 - _C3 or a substituted phenyl group,
activates the ester with respect to nucleophilic attack), amidine functional group: Acid halide functional group: (wherein X represents a halogen atom, such as chlorine or bromine), or even an anhydride function.
Z is, for example, a trichloromethyl group or oxazoline: can represent a carboxylic acid precursor such as The step of product to product, ie the conversion of the amide precursor to the amide, is carried out by conventional methods known in chemistry, such as the examples given below. (a) Conversion of carboxylic acid to amide. Chemical transformations can be carried out in several ways. For example, a carboxylic acid can be led in the presence of an amine to an amide by thermal decomposition of the salt thus formed and the action of a dehydrating agent such as P ₂ O ₅ . Another method is to convert the carboxylic acid to an acid halide and then to an amide by the action of an amine. Conversion of acids to acid halides is often carried out without solvents using thionyl chloride, phosphorus pentachloride or phosphorus oxychloride. Also, the corresponding bromides can be used. For complete reaction, it is advantageous to heat the reaction mixture to a temperature of 50 to 150°C. When a solvent is used to develop the reaction, it is an inert organic solvent, for example a hydrocarbon such as benzene, toluene or an ether such as petroleum ether, diethyl ether. The reaction between acid halide and amine reduces the mixture to 0
This is carried out by cooling to a temperature of between 0.degree. C. and -50.degree. C. and an excess of amine is added (at least 2 equivalents or at least 1 equivalent of amine and at least 1 equivalent of a tertiary organic base such as triethylamine). Conventionally, the acid chloride is added to the amine as a solution in an inert organic solvent as described above, or as an aqueous solution. Yet another method consists of carrying out the reaction of a carboxylic acid with an amine in the presence of a coupling agent, such as those used in peptide synthesis. Currently, the majority of coupling agents, such as dicyclohexylcarbodiimide, N-ethyl-N',3-
Dimethylaminopropylcarbodiimide, phosphine, phosphite, silicon tetrachloride or titanium tetrachloride. (b) Conversion of Nitriles to Amides Nitriles can be hydrolyzed to amides in an acidic or basic medium. When hydrolysis is carried out under acidic conditions, concentrated sulfuric acid,
Concentrated aqueous hydrochloric acid, formic acid in the absence of a medium, acetic acid in the presence of boron trifluoride can be used. In most cases it is advantageous to heat the reaction mixture to a temperature of up to 200°C. Another method of converting nitriles to amides in an acid medium consists of treating said nitriles with hydrochloric acid in an alcohol such as ethanol. An intermediate iminoether is thus formed which is thermally converted to an amide. When hydrolysis is carried out under basic conditions, an aqueous alkali or alkaline earth metal hydroxide solution is used. Advantageously, the presence of hydrogen peroxide improves the hydrolysis reaction. The inventors
Adding 1 equivalent of cupric chloride to 1 equivalent of nitrile,
Forming a first method for the hydrolysis of nitriles, consisting of carrying out the reaction preferably at room temperature with an aqueous alkali metal hydroxide solution with pH = 10,
Furthermore, it is often advantageous to carry out the hydrolysis reaction at a temperature between room temperature and the reflux temperature of the reaction mixture. Other conventional methods for basic hydrolysis of nitriles include the use of an alkali metal hydroxide, preferably potassium hydroxide, dissolved in t-butanol. (c) Conversion of esters to amides Aminolysis of esters is carried out conventionally in water or inert organic solvents. As solvents used, mention may be made, for example, of aromatic hydrocarbons such as benzene or toluene, aliphatic hydrocarbons such as hexane or petroleum ether, halogenated hydrocarbons such as dichloromethane or chloroform. The presence of a strong base is necessary when reacting with amines that are not strongly basic or are sterically hindered. The above reaction can be carried out at a temperature between room temperature and the reflux temperature of the solvent. (d) Conversion of amidine to amine This reaction is mainly carried out by acid hydrolysis in an aqueous or alcoholic medium. As the acid, an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid can be used. The reaction is carried out at a temperature between room temperature and the reflux temperature of the reaction mixture. When the Z group in the general formula is a carboxylic acid precursor,
Conversion to the carboxylic acid is carried out in the presence of an acid in water or in an inert organic solvent. Inert organic solvents mean chlorinated or non-chlorinated aromatic or aliphatic hydrocarbons, such as solvents such as benzene, toluene, chloroform, ethers such as dichloromethane or diethyl ether, tetrahydrofuran or dioxane. Mineral acids are generally used as acids, for example organic acids such as hydrohalic acid, concentrated or dilute sulfuric acid, concentrated or dilute nitric acid, phosphoric acid or acetic acid. The reaction temperature is 0°C to 150°C, preferably 50°C to 100°C. In some cases, Z is amido: Although it is advantageous not to directly convert Z into another group before forming the amide function, it may be advantageous to convert Z into another group before forming the amide function. Methods for making these transitions are well known in the industry and readily available. - Conversion of esters of acids and conversion of esters to acids. Esterification of acids is a very common reaction that is carried out in a variety of ways. Traditionally, acids and alcohols are reacted in the presence of an acid catalyst such as hydrochloric or sulfuric acid or p-toluenesulfonic acid.
The reaction is advantageously carried out under anhydrous conditions and one of these reactants is used in large excess. The solvent can be one of the reactants or an inert organic solvent such as a chlorinated hydrocarbon, for example chloroform or carbon tetrachloride or an aromatic or aliphatic hydrocarbon such as benzene, toluene or petroleum ether. The temperature is between ambient temperature and the reflux temperature of the reaction mixture. Other methods use suitable equipment to distill off water as soon as it is produced. The reaction conditions are similar to those described above except that one of the reactants is not used in large excess. Hydrolysis of the ester is carried out under similar conditions to the esterification reaction, but one of the reactants, in this case water, is used in large excess. Catalyst and temperature conditions are similar to esterification. - Conversion of Nitriles to Esters Conversion of nitriles to esters is carried out by reacting the nitrile with an alcohol dissolved in an acidic medium. Most of the catalysts are hydrochloric acid as mentioned above,
These are hydrobromic acid, hydroiodic acid, sulfuric acid, p-toluenesulfonic acid and naphthalenesulfonic acid. Alcohols can be used as solvents or other inert organic solvents such as chlorinated hydrocarbons or aliphatic or aromatic hydrocarbons. The reaction is carried out at a temperature between room temperature and the reflux temperature of the solvent. An intermediate iminoether is thus formed which is converted into an ester by hydrolysis. - Conversion of Nitriles to Acids The hydrolysis of nitriles to carboxylic acids is carried out in acidic or basic media. As acids generally used are hydrohalic acids, for example hydrochloric acid, hydrobromic acid or oxyacids such as sulfuric acid or nitric acid. As base, an alkali hydroxide such as sodium hydroxide or potassium hydroxide is used. This hydrolysis is carried out in water under reflux for several hours. - Conversion of Nitriles to Amidines Conversion of nitriles to amidines is carried out by reacting the nitriles with amines. It is often advantageous to activate one of the reagents to obtain a good yield of amidine. Activated forms of nitriles include iminoethers or iminohalides. Amines can be activated as salts with alkali or alkaline earth metals. Amidine can be obtained in good yield under these conditions. In order to further understand the method of the invention, the method for obtaining the derivatives is described below. Synthesis of Compounds 1 Derivatives can be obtained from the products by alkylation or acylation. R, R ₁ and R ₂ are as defined above, but in this case R ₁ does not represent hydrogen. X represents a good nuclear repellent, for example a halogen such as chlorine, bromine or iodine, a tosyl or mesyl group or an acyloxy group. The reaction is carried out in an organic solvent such as chloroform, dichloromethane, an alcohol such as methanol or ethanol, a saturated or aromatic hydrocarbon such as petroleum ether, benzene, toluene. The reaction is carried out at room temperature or between 0°C and the reflux temperature of the solvent.
The reaction can be carried out in the presence of organic bases such as triethylamine, pyridine or N-dimethylaniline, or inorganic bases such as alkali or alkaline earth metal hydroxides, carbonates and bicarbonates or pulverized coal. A variation of this method is shown below. The above reactions and the reactions described above are two types of reactions that alkylate or acylate secondary amines to tertiary amines. Clearly the reaction conditions for these two reactions are quite comparable. In preferred products of the invention, R and R ₁
If represents an alkyl group and the substituent R ₁ results from acylation of an amine, it is necessary to reduce the amide thus formed to the amine. There are many ways to make this type of reduction.
Hydrogenation is carried out in the presence of Raney nickel or cupric chromite in lower alcohols such as methanol or ethanol or in inert solvents such as acetic acid, and also in lithium hydride in an ether such as diethyl ether, tetrahydrofuran or dioxane. Can be reduced with aluminum. When choosing the conditions for reduction, consideration must be given to the need to preserve the functionality of the Z group. 2 The following is a modification that is valid only when Z represents nitrile (-CN). R, R ₁ and R ₂ are as defined above, Y represents a cation and is more particularly defined below. The cyanohydrins used as test agents are synthesized or produced directly from aldehydes (R ₂ CHO) or inorganic or organic cyanides, such as sodium or potassium cyanide or trimethylsilyl cyanide or alkyl aluminum cyanides or alkylammonium cyanides. The condensation of the amine and cyanohydrin is carried out in an inert organic solvent, for example a chlorinated hydrocarbon such as chloroform or dichloromethane, or benzene,
It is carried out in aromatic or aliphatic hydrocarbons such as toluene or petroleum ether or in ethers such as diethyl ether or dioxane. In some cases, 20°C to obtain good yields.
It is advantageous to carry out the reaction at a temperature of ~120°C. Acid-catalyzed reactions: e.g. hydrohalogen acids such as hydrochloric acid, or oxyacids such as sulfuric acid, or p-
Choose an organic acid such as toluenesulfonic acid. The reaction between iminium salts and cyanide compounds occurs in a similar manner. R, R ₁ , R ₂ and Z are as defined above. The addition of cyanide to iminium salts is
It is carried out in an inert organic solvent, for example a chlorinated hydrocarbon such as chloroform or dichloromethane, or an aromatic or aliphatic hydrocarbon such as benzene, toluene or petroleum ether. It is advantageous to operate at temperatures between 0° C. and the reflux temperature of the solvent. Depending on the hydrolysis conditions, Z
is a carboxylic acid, amide, ester or amidine. 3 The third modification to obtain the derivative is shown in the following equation. R, R ₁ , R ₂ and Z are the same as defined above, but AIK represents a lower alkyl group C ₁ to _{C 4} . The derivative is anionically substituted with a strong base in an inert organic solvent. The bases used include potassium, alkoxides such as t-butoxide, or amides such as sodium or lithium amides, or double salts, which are mixtures of amides and alkoxides, referred to as "Caubere bases." Organic solvents are aromatic or aliphatic such as benzene, toluene or petroleum ether. The reaction temperature is between -20 DEG C. and the reflux temperature of the solvent, depending on the reactivity of the substrate. The anion of the derivative is then reacted with the o-alkylated derivative of hydroxylamine to form the product. The displacement reaction is carried out in an inert organic solvent at a temperature between -20°C and the reflux temperature of the solvent. According to this method, which is valid only when Z represents a nitrile group (-CN), derivatives are obtained from enamines by addition of hydrocyanic acid. R, R ₁ and R ₂ are the same as above, represents a substituent R ₂ . Hydrocyanic acid can likewise be added or produced neat. The addition reaction is carried out in an inert organic solvent, preferably a slightly polar solution such as a chlorinated hydrocarbon such as chloroform or dichloromethane or acetonitrile, at a temperature between room temperature and the reflux temperature of the solvent. 5 This method consists of reduction of the carbon-carbon double bond of α-cyanoenamine XI. R, R ₁ and R ₂ are the same as those in the above general formula, The substituent R ₂ is shown. Reduction of carbon-carbon double bonds is traditionally carried out by hydrogenation of transition metals, their oxides or their sulfides on an inert support in the presence of a catalyst. As a catalyst, a catalyst in which Raney nickel, platinum, platinum oxide or palladium is supported on carbon can be used. The presence of a solvent is preferably selected from the group comprising lower alcohols such as methanol or ethanol or from the group comprising glacial acetic acid and its simple salts. Further, the reduction is carried out at normal pressure or high pressure. The reduction is also advantageously carried out with a hydride such as sodium hydroxide in the presence of a Lewis acid, or with diborane in a solvent such as methanol, ethanol, diglyme, tetrahydrofuran or dioxane.
Reduction conditions must be selected appropriately to retain the nitrile group. Furthermore, according to the recent prior art, some very general methods of obtaining α-cyanoenamines XI have been noted. Synthesis of Compounds The reagents that are the starting materials in the first synthetic method of glycinamide of the present invention can be obtained by various methods. 1 The first synthesis method and its variations are described above. 1
Compare this with the alkylation or acylation of secondary amines to tertiary amines as described in . or R, R ₂ and Z are the same as above, but
The property of X is a method. It is summarized in 1. The alkylation or acylation of a primary amine to a secondary amine is carried out in a similar manner under much the same conditions as the alkylation or acylation of a secondary amine to a tertiary amine. Above. 1
The experimental conditions described above can be easily applied to the present reaction to a satisfactory extent. 2 The following reaction formula shows a modification that is effective only when Z represents a nitrile group (CN). R and R ₂ are the same as above,
Y is as above. represents a group similar to that in 2. This method is described above. 2, the only difference being that the amine involved is in this case a primary amine instead of a secondary amine. This only difference is not decisive for limiting the reaction conditions;
Above. The conditions mentioned in 2 can be satisfactorily applied to carry out the method. 3 Above. A third method for obtaining similar derivatives mentioned in 3 is shown below. R, R ₂ and Z are the same as above, and AIK is the same as above. 3, the lower alkyl group is _C1 - _C4 . The requirements for solvent as well as temperature and base for this reaction are as described above. 3. 4 Other methods for producing derivatives include intermediate imines obtained from amines and carbonyl compounds.
It is characterized by forming XII. The condensation between the amine and the carbonyl derivative is preferably carried out in a conventional manner in an inert organic solvent immiscible with water, such as benzene or toluene. The reaction is catalyzed by organic or inorganic acids. p-Toluenesulfonic acid is very commonly used to carry out this catalysis. The imine thus obtained is reduced to the amine in a conventional manner. The reduction is carried out in the presence of hydrogen and a hydrogenation catalyst, such as platinum, platinum oxide or palladium on carbon, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, but also under high pressure. Advantageously, it is alternatively carried out with alkali metal hydrides such as hydrogen or sodium borohydride in a solvent such as methanol, or with aluminum and lithium borohydrides in a solvent such as ether or tetrahydrofuran. It is clear that the method of reduction of the imine is chosen in such a way as to keep the functionality of the Z group intact.
By choosing different reagents, it is possible to illustrate variant methods in which products can be produced via intermediates with similar chemical functionality to those described above. In the above formula, R ₂ and Z are the same as above, but R ₆ and R ₇ are

[Formula] represents a group such that R is equal to R. The condensation of the carbonyl derivative and the amine and the reduction of the imine are carried out under the conditions described above. 5 In a synthetic method that is only acceptable if Z represents a carboxyl group (-COOH), a derivative of creatinine is reacted in the presence of an aldehyde, and the product obtained is then reduced and hydrolyzed to give the derivative. In the above reaction formula, R, R ₂ and Z mean the same as above, or the substituent R ₈ CH ₂ is R ₂
Shows the same thing as the group. Condensation with aldehydes can be carried out using inert organic solvents, such as chlorinated hydrocarbons such as chloroform or dichloromethane, lower alcohols such as methanol or ethanol, benzene,
It is carried out in aromatic or aliphatic hydrocarbons such as toluene or petroleum ether, aliphatic or cyclic ethers or dimethylformamide. Although the reaction temperature can be selected from a wide range of temperatures, the reaction is usually carried out at a temperature between room temperature and 100°C. The presence of a base is essential for carrying out the reaction. The base is an inorganic base such as an alkali metal or alkaline earth metal hydroxide, or an organic chlorine such as pyridine, triethylamine, or a salt of a carboxylic acid such as sodium acetate. The reduction of the carbon-carbon double bond of a compound is
Hydrogenation is carried out in the conventional manner by hydrogenation in the presence of a catalyst comprising a transition metal, its oxide or sulfide supported on an inert support. Examples of the catalyst include catalysts in which Raney nickel, platinum, platinum oxide, or palladium is supported on carbon. The presence of a solvent is recommended, chosen from methanol or ethanol or from glacial acetic acid and its esters. This reduction is carried out under normal pressure or high pressure. Reduction can also be carried out using a hydride such as sodium borohydride, preferably in the presence of a Lewis acid, or using diborane in a solvent such as methanol, ethanol, diglyne, tetrahydrofuran or dioxane. Hydrolysis of the derivative is carried out in aqueous solution or in an inert organic solvent. The presence of acid is essential to this reaction. The acid can be an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid or p-toluenesulfonic acid. The starting heterocycle can be modified to obtain derivatives while preserving the reaction sequence and experimental conditions. It is thus possible to start from hydantoin XI, thiohydantoin XII, dioxopiperazine or 2-thiono-5-oxathiazolidine.

【formula】

【formula】

【formula】

##STR6## A method for preparing the product, which is valid only if Z also represents a carboxyl group (-COOH), uses an amine and an α-carbonylaldehyde according to the following reaction scheme. Redox amination of glyoxal compounds in aqueous solution or with chlorinated hydrocarbons such as chloroform or dichloromethane, or lower alcohols such as methanol or ethanol, or aromatic or aliphatic hydrocarbons such as benzene, toluene or petroleum ether. in an inert organic solvent selected from Furthermore, it is advantageous to add thiols (R'SH) to the reaction mixture as catalysts (R' represents a lower alkyl group C ₁ -C ₄ or a phenyl ring). Method B This method consists of the hydrogenolysis of sydnonimine according to the following reaction scheme: In the formula, R is the same as above, and W is an anion such as hydride, sulfate, nitrate, phosphate, or an anion derived from an organic residue such as acetate. Cydnonimine is synthesized by methods well known in the prior art literature; its hydrogenolysis gives 2-aminoacetamide. The catalyst used was palladium supported on activated carbon, nickel,
It can be platinum oxide. Usually the catalyst is selected from the group consisting of transition metals, their oxides or sulfides. Advantageously, the reaction solvent is methanol, ethanol, petroleum ether or any organic solvent that is inert under the reaction conditions. The reaction usually develops at room temperature, but the temperature can be raised or lowered to match the reactivity of the molecules. Method C According to this method, isonitriles are obtained from aldehydes or amines in the presence of carboxylic acids. R, R ₁ , R ₂ and R ₃ are as defined above. The condensation of amine and aldehyde is carried out under the same general conditions as for imine synthesis. These conditions are. 4
Described in . The isonitrile addition is carried out in an inert organic solvent, such as an aromatic or aliphatic hydrocarbon such as benzene, toluene or petroleum ether, or a chlorinated hydrocarbon such as chloroform or dichloromethane.
Alternatively, it is carried out in a cyclic or acyclic ether. The reaction temperature is determined by using the reaction temperature of the reagent.
If the reaction is exothermic, the reaction mixture can be cooled using an ice bath or a cooling bath, for example with dry ice; conversely, if the reaction is very slow, it is necessary to raise the temperature to the reflux temperature. A variation of this method is to first react the aldehyde with the isonitrile and then ring-open the intermediate iminooxirane with an amine. The reaction between aldehyde and isonitrile is preferably carried out at cryogenic temperatures (-30<0>C to -100<0>C) and is advantageously catalyzed by a Lewis acid, such as _BF3 -ether. Ethers such as diethyl ether are suitable for the reaction. The reaction is carried out in a nitrogen or argon atmosphere to avoid moisture. Ring opening of the imino-oxirane is carried out by adding the amine to the reaction mixture at low temperature and then gradually raising the temperature to room temperature. When optically active amines are used to open the imino-oxiranes, one glycinamide enantiomer can be obtained in non-negligible optical yields. Imino-oxiranes can be synthesized by oxidation of cetenimine. A commonly used oxidizing agent is m-chlorobenzoic acid (m-
CPBA). Method D According to this method, a secondary amine RR ₁ NH is reacted with glyoxal to form glycinamide. R and R ₁ in the formula are the same as defined above, and R ₃ and R ₄ are the same as R and R ₁ . This reaction is carried out in two stages. When the reagents first come into contact, an exothermic reaction develops. It is then necessary to raise the temperature of the reaction mixture or product solid to about 150° C., preferably to reflux temperature, in order to obtain the desired glycinamide. The reaction is carried out without the use of inert organic solvents, such as aromatic or aliphatic hydrocarbons, such as benzene, toluene, or petroleum ether, or chlorinated solvents, such as chloroform or carbon tetrachloride. If it is necessary to use a base, preferably inorganic salts are used, such as hydroxides or oxides of alkali or alkaline earth metals, quicklime or sodium hydroxide, or carbonates such as potassium carbonate. Hereinafter, experimental examples for preparing some glycinamide derivatives according to the present invention will be explained in detail. Example 1 2-n-octadecylaminoacetamide 500 with refrigerator and magnetic stirrer installed
ml Erlenmeyer flask, 21.6 g (0.08
mol) of octadecylamine, 7.48 g (0.08 mol) of chloroacetamide, and 7.4 g of sodium bicarbonate were mixed in 350 ml of methanol at room temperature. This mixture was refluxed for 16 hours.
After cooling the solution, the solids were filtered and the solution was evaporated. The evaporation residue and the solid matter previously filtered off were combined and recrystallized from cyclohexane. 5
Sublimation at 120-140℃ under pressure of ×10 ^-3 mmHg,
An analytically pure product could then be obtained by fresh recrystallization from cyclohexane. MP (°C): 102.5-103.5 Analysis result C H N Calculated value % 73.56 12.96 8.57 Actual value % 73.4 12.7 8.55 Example 2 Synthesis of 2-n-hexylaminoacetamide 500 with refrigerator and magnetic stirrer installed
ml Erlenmeyer flask, 11 g (0.11 mol) hexylamine, 10 g (0.107 mol) chloroacetamide, and 9.9 g (0.118 mol) sodium bicarbonate were mixed in 200 ml ethanol at room temperature. . This mixture was refluxed for 24 hours. After cooling, the sodium chloride was filtered and the product was washed with 50 ml of ethanol. The filtrates were combined, this was evaporated and the resulting white solid was dissolved once with 120 ml of 140 ml of cyclohexane.
of acetone and finally from a minimum amount of ethyl acetate. The product thus obtained was
Sublimated at 120°C under a pressure of 10 ^-3 mmHg and again at 110°C.
ml of cyclohexane. MP (°C): 62-63 Analysis result C H N Calculated value % 60.72 11.46 17.71 Actual value % 60.60 11.2 17.4 Example 3 Synthesis of methyl-6-(carboxamidomethyl)amino-hexanoate 250 with refrigerator and magnetic stirrer installed
ml Erlenmeyer flask, 22 g (0.121
6-aminocaproic acid methyl ester (mol) and
21 g (0.250 mol) of sodium bicarbonate and 200
ml of isopropanol. This mixture was refluxed for 1 hour, then 11.22 g (0.120 mol)
of chloroacetamide was added at room temperature.
The suspension was stirred at room temperature for 4 minutes, the resulting precipitate was filtered, washed with 50 ml of boiling ethanol, and the combined filtrates were evaporated. The residue was chromatographed on 1000 g of silica, eluting with a methanol-ether mixture (4/6). 25th 50ml fraction and 58th 50
The product was collected between ml fractions. Finally, it was purified by dissolving in isopropanol and saturating the solution thus obtained with HCl. MP (°C): 160 Analysis result C H N Calculated value % 45.28 8.02 11.73 Actual value % 45.00 8.05 11.73 Example 4 (a) Synthesis of dodecylaminoacetonitrile C ₁₂ H ₂₅ NH ₂ +HO−CH ₂ −CN→C ₁₂ H ₂₅ NH- _CH2 -CN In a 500 ml flask equipped with a magnetic stirrer, 4.56 g (0.08 mol) of hydroxyacetonitrile and 16.3 g (0.088 mol) of dodecylamine were mixed in 250 ml of methanol at room temperature. This mixture was allowed to stand at room temperature for 16 hours to evaporate methanol. the obtained liquid
Distilled at 10 ^-2 mmHg. The fraction distilled at 106-116°C was crystallized after cooling. MP (°C): 28-29 (b) Synthesis of 2-n-dodecylaminoacetamide A solution of 15.2 g (0.068 mol) dodecylaminoacetonitrile in 20 ml ethanol was added dropwise to 2.5 ml sulfuric acid in 25 ml ice-cold ethanol. The white precipitate formed was filtered off and dried (19 g of hydrogen sulfate dodecylaminoacetonitrile). This product was slowly added to 60 c.c. of sulfuric acid in a 250 ml flask. This solution in 1.30 hours
The temperature was set to 100℃. After cooling, this solution was added dropwise to 400 ml of ice-cold ethanol. The white precipitate produced was filtered off and recrystallized from ethanol. MP (°C): 190 (decomposition) Analysis result C H N Calculated value % 49.38 9.47 8.22 Actual value % 49.30 9.55 8.15 Example 5 (a) Synthesis of hexylaminoacetonitrile C ₆ H ₁₃ NH ₂ +HO-CH ₂ -CN→ _C6H13NH - _CH2 -CN+ _H2O In a 100 ml flask, 5.7 g (0.1 mol) of hydroxyacetonitrile and a solution of 11 g (0.11 mol ₎ hexylamine dissolved in 10 ml of methanol were mixed. The temperature rose rapidly during mixing. This solution was allowed to stand for 24 hours. The methanol was evaporated and the resulting solution was distilled at 72° C. at 0.8 mm Hg. (b) Synthesis of 2-n-hexylaminoacetamide 11.2 g (0.081 mol) of hexylaminoacetonitrile were added dropwise to 31 ml of H ₂ SO ₄ diluted in 30 ml of ice-cold ethanol. After the addition was complete, the ethanol was evaporated and 40 ml of H ₂ SO ₄ was added to the resulting white solid. This solution was heated at 100° C. for 1 hour and added dropwise to 200 ml of ice-cold ethanol. The white precipitate formed was separated by filtration, and
Washed with ml of ethanol. MP (℃): 151-152 Analysis result C H N Calculated value % 37.49 7.87 10.93 Actual value % 37.80 7.80 10.90 Example 6 (a) Synthesis of 2-(n-pentylamino)butyronitrile In a 250 ml flask fitted with a magnetic stirrer, 35 g of Na ₂ S ₂ O ₅ was dissolved in 95 ml of water. The solution was cooled on ice, 14.9 g (0.2 mol) of propionaldehyde was added, and the new solution was stirred at 0° C. for 2 hours. Very little precipitate formed. Return this solution to room temperature, then
23.9g (0.2 mole) of aluminum amine was added.
After 2 hours of reaction, 13 g (0.2 mol) of KCN was added to 1
Added twice. After reacting at room temperature for 24 hours, the solution was saturated with NaCl and extracted with ether. The ether phase was dried over MgSO ₄ and a solution of HCl in ether was added. The formed precipitate was filtered off and dried. MP (°C): 104-105 (b) Synthesis of 2-(n-pentylamino)-butyramide In an ice-cooled 50 ml flask equipped with a magnetic stirrer, 1.9 g (0.01 mol) of 2-(n-pentylamino)butyronitrile was added to 17 ml of concentrated HCl. When the solids were completely dissolved, the solution was stored in the refrigerator for 24 hours. The hydrochloric acid was then evaporated by rotary evaporation and the solution was reduced to 1N
Neutralized with NaOH solution and at PH=6, the solution was washed several times with benzene. The solution was ether extracted at PH=11-12, the ether extracts were combined, dried over MgSO ₄ and evaporated. The resulting residue was sublimed at 70° C. and 2×10 ⁻² mmHg. MP (°C): 58-59 Analysis result C H N Calculated value % 62.75 11.7 16.26 Actual value % 62.7 11.65 16.05 Example 7 Synthesis of 2-(N-benzyl-N-hexyl)aminoacetamide In a 258 ml three-necked flask equipped with a magnetic stirrer, thermometer, addition funnel, and calcium chloride scraps on top, 100 ml of chloroform, 6.23 g (0.04 mol) of 2-(n-hexylamide)acetamide, and 8 ml (0.055 mol) of 2-(n-hexylamide)acetamide were added. ) was mixed with triethylamine (Et ₃ N). This solution was cooled to 10° C., and a solution of 5.1 ml (0.044 mol) of benzoyl chloride dissolved in 10 ml of chloroform was added dropwise to this solution. The reaction mixture was refluxed for 20 hours, cooled, and washed three times with 1N HCl, once with water, and twice with 1N NaOH.
and twice with water. chloroform solution
Dry over _MgSO4 , evaporate and the residue is crystallized from an ether-pentane mixture and then from cyclohexane. MP (°C): 97-98 Analysis result C H N Calculated value % 68.67 8.45 10.67 Actual value % 68.7 8.25 10.60 Example 8 Synthesis of 2-(n-hexylamino)acetamide 1g in a 250ml Erlenmeyer flask
(0.072 mol) of n-hexylaminoacetonitrile, 1.22 g (0.072 mol) of dehydrated cupric chloride and 100 ml of _H2O were added. Ethanol was then added until a homogeneous phase was obtained. PH of this solution
Adjusted to 10 with 1N NaOH, the reaction mixture was stirred at room temperature for 4 hours. A purple solid is formed,
This is filtered off, resuspended in ammonia solution,
Extracted with dichloromethane. The organic phase was washed three times with water, dried over K ₂ CO ₃ and evaporated. The residue was recrystallized from cyclohexane. MP (°C): 62-63 The melting points and recrystallization solvents of the derivatives of the present invention are shown in Table 1 below.

【table】

【table】

【table】

TABLE The pharmacological and genetic results of the compounds of the invention are shown in Table 2 below. In this table, the numbers in the first column correspond to the numbers in the first column of Table 1. The results shown in this table will be explained below. The antispasmodic effects of the compounds of the invention were investigated on tonic convulsions induced by bicuculline. The compound of the invention was administered to 10 mice at a dose of 30 mg/Kg.
or to two groups of 5 mice or to 5 mice each at doses of 10 and 100 mg/Kg and 3 hours later 0.6
Bicuculline was injected intravenously at a dose of mg/Kg.
The number of mice protected from tonic convulsions and the number of dead mice were recorded. The result is 30 or 10 and 100
The evaluation was expressed as the total number of animals protected at a dose of mg/Kg of compound. The LD ₅₀ value was calculated using the Lichtfield and Wilcoxon method (J.Pharmacol.Exp.Ther. 96 , 99, 1949).
This is the dose (mg/Kg) that causes death in 50% of the animals tested. The product was orally administered to mice. The influence on behavior is S. Irwin (Gordon Res. Conf. on Medicinal Chem., 133 ,
(1959) using a method derived from the method of (1959). The substance suspended in 1% tragacanth gum mucus was administered orally via intragastric tube to groups of 5 male mice (CDI, Charles River strain, fasted for 18 hours). Doses were 3000, 1000 and 300 mg/Kg, if possible with the available quantities of the drug.
If the latter dose was effective, the effect of the drug was investigated at 100, 30 and 10 mg/Kg, and if possible also at 3 mg/Kg. Behavior is 2, 4, 6 after treatment
and examined in 24 hours. If symptoms persisted at this point, the observation period was extended. After treatment 14
The number of deaths was recorded over a period of days. None of the products tested induced abnormal behavior in mice. It is particularly noteworthy that the products tested did not exhibit sedative effects.

【table】

【table】

Table: The substance of the invention has the property of suppressing bicuculline-induced convulsions in mice. This effect indicates that the substance of the present invention has antiepileptic properties, probably by acting on the GABA (γ-aminobutyric acid) system. In fact, bicuculline is a special antagonist of GABA. Furthermore, the effects of the products of the present invention on the activities of GABA synthase and carboxyl group degrading enzyme glutamate (GAD) were investigated. The activity of GAD is L. Parker's Methods in Enzymolgy, Ed.
The measurements were carried out in a homogenized rat brain according to S. Fleischer. 1974, Vol. 32, Part 5, p. 779). The products tested were added to a final concentration of 10 ⁻⁴ M. Generally, the products of the invention were found to be active in this test. Typically, the products of the invention are GABA transaminase (GABA-T),
GABA in Nieuron increases the activity of GAD without changing the activity of the enzymes of GABA catabolism, thus liberating GABA as a neurotransmitter.
(γ-aminobutyric acid) concentration increases. Among the substances of the invention, 2-n-pentylaminoacetamide and its hydrochloride were particularly investigated. Some of these results are shown in Table 3. LD ₅₀ refers to the same as above, and ED ₅₀ refers to the 50% effective dose (mg/dose) that protects 50% of the animals tested.
Kg). These products inhibit bicuculline-induced convulsions in mice and
_ED50 values are 11.2 and 11.2 when administered orally, respectively.
It is 5.74mg/Kg. Hydrochloride was administered intravenously. In this case, the ED ₅₀ value was 2.19 mg/Kg. This value is not much lower than when administered orally, indicating excellent absorption from the intestinal tract. Table 3 also shows the therapeutic index (LD ₅₀ /ED ₅₀ ). The compounds of the invention have a greater therapeutic index than valproate, diphenylhydantoin and phenobarbital.

Table: Like valproate, 2-n-pentylaminoacetamide is inactive against strychnine-induced convulsions. Its anticonvulsant action appears to be central rather than spinal. Furthermore, 2-n-pentylaminoacetamide and its hydrochloride salt appear to act specifically at the level of the GABA receptor. This is shown by the following results. (1) Its antagonistic effect on bicuculline-induced convulsions may be overcome by increasing the bicuculline dose. (2) 2-n-pentylaminoacetamide only slightly suppresses leptazol-induced convulsions in mice. (3) 2-n-pentylaminoacetamide hydrochloride has no effect on convulsions caused by picrotoxin. In fact, repetasol does not act at the level of GABA receptors, and picrotoxin acts adjacent to, but not directly at, GABA receptors. Furthermore, 2-n-pentylaminoacetamide is bicuculline, i.e.
Comparable to specific antagonist of GABA. 2-n-pentylaminoacetamide hydrochloride and GABA
When administered orally to rats at 200 mg/Kg, the product increased GAD activity by 26% without altering GABA-T activity; substantia nigra GABA levels increased by 2 after treatment. , confirmed by the fact that after 3 and 4 hours there is an increase of 28, 33 and 38%, respectively. 2-n-pentylaminoacetamide is KCN
It has the property of protecting mice from mortality caused by This activity is explained by its effect on active brain metabolism during anoxia. The effect on active brain metabolism was confirmed for 2-n-pentylaminoacetamide hydrochloride in a series of experiments on cerebral anoxia induced by decapitation of rats. It has thus been found that the products of the invention prevent the accumulation of lactate in the brain during the first seconds of anoxia. Furthermore, 2-n-pentylaminoacetamide potentiates the action of 1-tryptophan, indicating stimulation of the central serotonergic system in mice, and thus psychotropic, especially antidepressant properties. Double-blind administration of 400 mg of 2-n-pentylaminoacetamide hydrogen chloride to men and women over 60 years of age.
The results of a placebo-controlled electroencephalogram recording test are shown in FIGS. 1 and 2. In Figures 1 and 2, the horizontal axis shows EEG (electroencephalogram) of spectrum analysis controlled by a computer.
The main frequency is expressed in (Hz). 2-
The difference between the change induced by n-pentylaminoacetamide hydrogen chloride salt and the change induced by the placebo is shown in l-value on the vertical axis. The zero line shows the change after induction with a placebo. In addition, Figure 2 shows the condition under arousal control.
Figure 1 shows EEG changes under resting conditions.
The EEG changes are shown, and in FIGS. 1 and 2, the top row shows the EEG changes 2, 4, 6, and 8 hours after administration of 2-n-pentylaminoacetamide hydrogen chloride, respectively. In FIG. 1, administration of 400 mg of miracemide increased β activity and promoted the centroid frequency of β activity, indicating improvement in wakefulness. On the other hand, in FIG. 2, there was a dissociative vigilance shift that occurred after administration of antidepressants of the amitriptyline and imipramine type (which increase delta/theta and beta activity and reduce alpha activity). Therefore,
It was confirmed that 2-n-pentylaminoacetamide has an antidepressant effect. In other respects, when 2-n-pectylaminoacetamide (50 mg/Kg ip) was tested in passive prevention experiments in mice, this compound delayed extinction of behavior. Therefore, this product, and perhaps other compounds of the invention, may be useful for memory retention (mnesic).
improve retention). The memory retention effect was tested using male rats. Approximately 270g of Sprague
-Dawley) rats were placed in a light room connected to a small dark room. When the rats entered the small dark room, they were given a shock to their legs, so after 24 hours, the rats were able to stay still in the light room (learning). If you attach electrodes to the temples of trained rats and apply an electroconvulsive shock through the electrodes, the rats will forget what they have learned and enter a small dark room (induced memory loss). However, when 2-n-pentylaminoacetamide hydrogen chloride was administered one hour before learning, the rats remained in the light room to a greater extent than when a placebo was administered, ie, showed a memory retention effect. Some of the compounds of the invention inhibit platelet aggregation in human plasma. Suppression of platelet aggregation reaction is performed by G.V.R.Bone and M.B.
J.Cross turbidity measurement method (J.Physiol.
168, 178, 1973). The platelet-rich plasma is preheated for 3 minutes and then the inducible thrombofax is introduced. The maximum magnitude of inhibition of the agglutination reaction was determined using an Upchurch agglutination monitor. Compounds 1, 11, 14 and 18 were found to be active in this test. Therefore, 2-n-pentylaminoacetamide and its hydrochloride act on the GABA-ergic system by promoting GABA transmission, as indicated by antagonism of bicuculline action.
This effect occurs as a result of activation of GAD. These products are therefore particularly desirable for the treatment of movement disorders such as epilepsy and Parkinsonism. This syndrome is the result of a deficiency in the GABA system. Due to the active metabolism of the brain and its activity against anoxia, this product can be used in ischemic diseases of the brain. Moreover, the effects of 2-n-octylaminoacetamide in memory tests and the effects of 2-n-pentylaminoacetamide on the serotonin ergic system further suggest that the compounds of the present invention may be useful for memory disorders and certain psychotic disorders such as depression. It can be applied to When administering the novel compounds of the invention, the daily dose is 10 mg to 2 g, and the unit dose is 10 to 300 mg.
shall be. Since the products of the invention have very low toxicity, such amounts can be increased without risk. The products of the invention can be used in various herbal forms. The following examples relate to galenic compositions containing the active product designated A, to which the invention is not limited. The active product is one of the following compounds: 2-n-pentylaminoacetamide, 2-n
-octylaminoacetamide, methyl-6-
[Bis(carboxamidomethyl)]aminohexanoate, 2-n-decylaminoacetamide,
Methyl-8-[bis(carboxamidomethyl)]
Aminooctanoate, 2-n-hexylaminoacetamide, 2-(2-phenylethyl)aminoacetamide, 2-n-octadecen-9-ylaminoacetamide, 2-(N-carboxyamidomethyl-Nn-hexyl) Aminoacetamide, 2-(1,1-dimethylpropyn-2-yl)aminoacetamide, Ethyl-N-n-hexyl-N-carboxyamidomethyl carbamate, 2-n-pentylaminobutyramide, 2-
(3-phenylpropyl)aminoacetamide,
2-octen-7-ylamine acetamide, 8
-carboxamidomethylaminooctanoic acid, 2
-(4-Phenylbutyl)aminoacetamide tablets Formulation A 300mg Starch Starx (trade name, Sta-Rx) 1500 180mg Calcium phosphate 100mg Aerosil 5mg Magnesium stearate 15mg A 100mg Corn starch 100mg Lactose 80mg Aerosil 5mg Talc 5mg Magnesium stearate 10mg Capsule A 50mg Lactose 110mg Corn Starch 20mg Gelatin 8mg Magnesium Stearate 12mg A 200mg Polyvinylpyrrolidone 10mg Corn Starch 100mg Cutina HR 10mg Intramuscular or Intravenous Injection A 100mg Sodium Chloride 20mg Sodium Acetate 6mg Distilled Water for Injection 5mg intramuscular injection A 200mg benzyl benzoate 200mg oil for injection 1mg syrup 5mg A 5g ammonium glycyrrhizinate 0.5g citric acid 0.5g Nipacept 0.1g sutucarose 70g flavoring agent 0.1g water 100ml solute A 2g sorbitol 50g glycerin phosphorus 10g anise Essence 0.1g Propylene glycol 10g Deionized water 100ml Suppository A 250mg Butylhydroxyanisole 10mg Semi-synthetic glyceride 3g

[Brief explanation of the drawing]

Fig. 1 is a curve diagram showing the electroencephalogram changes induced by the compound of the present invention or a placebo under resting conditions. Fig. 2 is a curve diagram showing the electroencephalogram changes induced by the compound of the present invention or a placebo under arousal-controlled conditions. A curve diagram representing brain wave changes in each case is shown. REL...Relative output of main frequency, ABS...Absolute output of main frequency, T...Total output, C...Centroids, DT...Combination of δ and θ, D...
...DT deviation, A...α band, B...β band, t...
Total activity of α and β bands.

Claims (1)

[Claims] 1. The following general formula; (R in the formula is a linear or branched alkyl group C ₅
~ _C18 , straight-chain or branched alkenyl group _C5 ,
C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ , C ₁₃ , C ₁₄ ,
_C15 , _C16 , _C17 or _C18 , straight chain or branched alkynyl group _C4 to _C10 , straight chain or branched acyl group _C4 to _C18 , or phenoxy group, hydroxyl group, carboxyl group , straight-chain or branched alkoxycarbonyl groups C ₁ -C ₄ , acetal groups, one or more phenyl groups, one or more substituted by halogen atoms such as fluorine, chlorine or bromine A linear or branched alkyl group C ₁ to _{C 10} substituted with the above phenyl group, R ₁ is a hydrogen atom, a linear or branched acyl group
_C1 to _C6 , benzoyl group, straight chain or branched alkoxycarbonyl group _C1 , _C2 , _C3 , _C4 , _C5 , _C6 ,
C ₇ or C ₈ or carboxamidomethyl group, R ₂ is a hydrogen atom, linear or branched alkyl group C ₁ , C ₂ , C ₃ , phenyl group, R ₃ is a hydrogen atom, R ₄ is a hydrogen atom A therapeutic agent for epilepsy, comprising at least one glycinamide derivative represented by the following as an active ingredient. Quadratic equation 1. A therapeutic agent for depression, comprising 2-n-pentylaminoacetamide as an active ingredient. cubic formula 1. A therapeutic agent for memory disorders, comprising 2-n-pentylaminoacetamide as an active ingredient.