JPH0322869B2 - - Google Patents

Description

[Detailed description of the invention]

TECHNICAL FIELD The present invention relates to ω-amino acid derivatives and salts of these derivatives. Specific explanation of the title, structure, and effects of the invention The present invention is based on the general formula and pharmaceutically and veterinarily acceptable salts. In the general formula, R is C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ ,
C ₈ , C ₉ , C ₁₀ , C ₁₁ or C ₁₂ straight-chain or branched alkyl group; 1 or 2 C ₁ , C ₂ , C ₃ or C ₄ straight-chain or branched alkyl group or by one or two C ₁ , C ₂ , C ₃ or C ₄ straight-chain or branched alkoxy groups, or by 1 halogen atom such as fluorine, chlorine or bromine C ₂ , C ₃ or C ₄ straight-chain or branched alkyl radicals substituted by phenyl or phenoxy groups optionally substituted by 1 or 2; or 1 or 2 C ₁ , C ₂ , C ₃
or by a C ₄ straight-chain or branched alkyl group,
or by one or two C ₁ , C ₂ , C ₃ or C ₄ straight-chain or branched alkoxy groups, or by fluorine,
Straight or branched C ₂ , C ₃ , C ₄ , C ₅ or C ₆ substituted by a phenyl group optionally substituted by one or two halogen atoms such as chlorine or bromine represents an acyl group, R ₁ is hydrogen; C ₂ , C ₃ ,
C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ or C ₁₁ linear or branched acyl group; or 1 or 2 C ₁ ,
by C ₂ , C ₃ or C ₄ straight-chain or branched alkyl groups, or by one or two C ₁ , C ₂ , C ₃ or C ₄
by a straight-chain or branched alkyl group, or 1
by one or two C ₁ , C ₂ , C ₃ or C ₄ straight-chain or branched alkoxy groups, or by one or two halogen atoms such as fluorine, chlorine or bromine. Represents a C ₂ , C ₃ , C ₄ , C ₅ or C ₆ linear or branched acyl group substituted with an optionally substituted phenyl group, and R ₂ is an amino group (-NH ₂ ) , where n has a value of 3, 4 or 5. According to another preferred embodiment of the invention, in the formula R is a _C2 - _C10 straight-chain or branched alkyl group; or by a methyl or methoxy group; or by one chlorine atom; represents a C ₂ to _{C 4} linear or branched alkyl group optionally substituted with a phenyl nucleus or a phenoxy nucleus, _{R 1} is _hydrogen ; a chain or branched acyl group; or a _C2 to _C6 straight or branched acyl group optionally substituted by a methyl or methoxy group or by one chlorine atom; , R ₂ represent an amino group, and n has a value of 3, 4 or 5. According to another preferred embodiment of the invention, in the derivatives of the formula R is substituted by a methyl or methoxy group or by a phenyl group optionally substituted by one chlorine atom. was done
Represents a C ₂ to C ₆ linear or branched acyl group, R ₁
represents hydrogen, R ₂ represents an amino group,
n has a value of 3, 4 or 5. A preferred group of products of the formula wherein R represents a C ₂ to _{C 10} straight-chain or branched alkyl group, R ₁ represents hydrogen and R ₂ represents an amino group where n has a value of 3, 4 or 5. Another preferred group of products of the formula are substituted by a _C2 - _C10 straight-chain or branched alkyl group; or a phenyl group;
Represents a C ₂ to C ₆ linear or branched acyl group, R ₁
represents hydrogen, and R ₂ is an amino group (-NH ₂ )
, and n has a value of 3. Examples of compounds according to the invention are 4-n-pentylaminobutanamide, 5-n-pentylaminopentanamide, 6-n-pentylaminohexanamide, 5-(p-tolylacetylamino)pentamineamide, 6 -n-decylaminohexanamide, 6-[2-n-chlorophenoxyethyl)
Amino]hexanamide, 4-[(N-n-hexyl-N-4-chlorophenylacetyl)amino]
Butanamide. When the derivatives of the formula are in the form of acid addition salts, they can be converted into the free base or addition salts with other acids by conventional methods. The most commonly used salts are addition salts of acids that are non-toxic and have pharmaceutical and veterinary uses.
These are formed, for example, from suitable inorganic acids such as hydrochloric, sulfuric or phosphoric acid, or from fatty acids,
Suitable organic acids such as cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic or sulfonic acids (e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, Lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glycuronic acid, maleic acid, fumaric acid, pyruvic acid,
Aspartic acid, glutamic acid, benzoic acid, anthranilic acid, hydrobenzoic acid
acid), salicylic acid, phenylacetic acid, mandelic acid,
embonic acid, methanesulfonic acid, ethanesulfonic acid, pantothenic acid, toluenesulfonic acid, sulfenyl acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β
- oxybutyric acid, oxalic acid, malonic acid, mucic acid or galacturonic acid). Since the compounds of formula have one or more asymmetric carbon atoms, these compounds may exist in the form of optical isomers or racemates or diastereomers, but these forms are not part of the present invention. It is. The derivatives according to the invention can thus be used in the form of a mixture containing several diastereomers (whatever their relative proportions) or in the form of pairs of enantiomers in equal proportions. (racemic mixtures) or in the form of pairs of enantiomers in different ratios or again in the form of optically single compounds. The products according to the invention may be used for neurological, psychiatric or cardiovascular disorders (e.g. epilepsy, depression, movement disorders such as Parkinson's disease, muscle spasms of neurological origin, hypertension, hypotension, sleep disorders or memory disorders). ) and as an anthelmintic and analgesic. The invention furthermore relates to pharmaceutical compositions containing as active ingredient at least one compound or salt of the general formula together with pharmaceutically used additives and/or excipients. These compositions are prepared in such a way that they are administered orally, rectally or parenterally.
They can be solids, liquids or gels and, depending on the method of administration, can be powders, tablets, lozenges, coated tablets, capsules, granules, syrups, suspensions, etc.
It may be provided in the form of an emulsion, solution, suppository or gel. Additionally, these compositions may contain other therapeutic agents that have similar or different activity to the products of the invention. The compounds according to the invention form part of the invention and are prepared according to the methods as defined below. Method A Following this procedure, the product is transformed into a derivative of formula. R, R ₁ , R ₂ and n are the same as defined above,
Z represents a group which can be converted into a mido function, a carboxylic acid or a ster by the action of suitable reagents. Examples of these functional groups include, inter alia, amide functional groups, carboxylic acid functional groups, nitrile functional groups, ester functional groups (-COOR', where R' is R ₃ above or related to attack by a nucleophile). (represents an alkyl group or phenyl group substituted to activate the ester), an amide function (

[Formula]), acid halide functional body (

[Formula] where X represents chlorine, bromine or iodine), anhydride functional body, imidate functional body (

[Formula]) or an N-carbonylimidazolyl group. Z furthermore represents a carboxylic acid precursor group, such as, for example, a trihalomethyl group (-CX ₃ , in which X represents a chlorine, bromine or iodine atom), an oxazoline group, a hydroxymethylene group (- CH ₂ OH), formyl group (-
CHO), α,β-dihydroxyalkyl group or alkenyl group (-CHOH-CHOH-R ₄ or -CH
=CH- _R4 , where _R4 represents a _C1 - _C20 straight-chain alkyl group), acetyl group (-CO- _CH3 ), 1-
Hydroxyethyl group (-CHOH- _CH3 ), 2-hydroxypropyl-1 group (-CH2 _- CHOH-
CH ₃ ), or a halogen atom such as chlorine, bromine or iodine. -CH ₂ -Z groups are equally

[Formula] In this formula, B ₁ and B ₂ may be the same or different and represent a functional entity selected from the following. That is, nitrile group, carboxyl group, carbamoyl group or alkoxycarbonyl group (-
COOR ₃ and R ₃ are selected from (same as specified above). The product-to-product path, i.e. Z
The conversion from a group or a -CH2 _- Z group to a _-COR2 group is as follows:
This is achieved by conventional methods that are very well proven chemically. For example, a conversion of a carboxylic acid to an amide. Several methods make it possible to accomplish this chemical conversion. For example, a carboxylic acid can be placed in the presence of ammonia, and thermal decomposition of the salt thus formed yields an amide, which likewise finds use in dehydrating agents such as phosphorous pentoxide. . Another method of conversion is to convert the carboxylic acid to the acid halide and then to the amide by the action of ammonia. Yet another method of conversion is to convert carboxylic acids and ammonia into peptides such as dicyclohexylanamide, N-thyl-N'-3-dimethylaminopropyl cyanamide, phosphine, phosphite, silicon or titanium tetrachloride. reaction in the presence of a coupling agent such as that used in b Conversion of Nitriles to Amides or Acids Nitriles can be hydrolyzed to amides or acids in acidic or basic media. If this hydrolysis is carried out under acidic conditions, it is possible to use concentrated sulfuric acid, concentrated hydrochloric acid, hydrobromic acid, nitric acid, formic acid without solvent, or acetic acid with boron trifluoride. Another method for converting nitrile to amide in residual medium
One method is to treat the nitrile with hydrochloric acid in an alcohol such as ethanol. In this way, an intermediate iminoether is formed, which is thermally converted to an amide. If this hydrolysis is effected under basic conditions, for example potassium hydroxide in tert-butanol or in aqueous alkaline solution or alkaline earth metal hydroxides can be used. The presence of oxygenated water promotes hydrolysis. The nature of the amide group or carboxyl group formed here essentially depends on the reaction conditions used. c Conversion of nitrile to ester This conversion is accomplished by competing the nitrile against the alcohol in an acidic medium. Alcohol or other inert solvents may be used as this solvent. An intermediate iminoether is thus formed, which is converted into an ester by hydrolysis. d Conversion of Esters to Amides Aminolysis of esters is conventionally carried out by competing the ester with ammonia in water or an inert organic solvent. e Conversion of amidine to amide This reaction is carried out mainly by acid hydrolysis in water or alcoholic medium. The acid may be inorganic, such as hydrochloric acid or sulfuric acid, or organic, such as acetic acid. f Conversion of an acid halide, anhydride or N-carbonylimidazolyl group into a carboxylic acid or alkoxycarbonyl group ( _-COOR3 ) This conversion is carried out either on water to form a carboxyl group (hydrolysis reaction) or Alcohol R ₃ OH (wherein R _{3 is} C ₁
~ _C3 straight-chain or branched alkyl groups) by antagonizing the product. These reactions are carried out using stoichiometric amounts of these reagents in the presence of excess water or alcohol, or in the presence of an inert solvent. This alcoholysis is advantageously carried out in the presence of a catalyst, such as an organic or inorganic acid or base. If the Z group of formula g represents a trihalomethyl group or a carboxylic acid precursor such as oxazoline, the conversion to the carboxylic acid is carried out in water or in an inert solvent in the presence of an acid. As acids, generally used are inorganic acids such as hydrohalic acid, concentrated or dilute sulfuric acid, concentrated or dilute nitric acid or phosphoric acid, or organic acids such as acetic acid. h _-CH2 -Z group, typically

The conversion of the group [formula], in which B ₁ and B ₂ have the values given above, into a carboxymethyl group is carried out in a basic or acidic medium under the same conditions as described above for the hydrolysis of nitriles. This is achieved by heating in an acidic medium for a certain period of time in order to hydrolyze and decarboxylate the resulting diacid intermediate. i Conversion of other precursor groups of carboxylic acids to carboxyl groups by oxidation. This transformation is particularly relevant to intermediates, where Z is -CH ₂ OH, -CHO, -CHOH-CH ₃ , -
CO−CH ₃ , −CH ₂ −CHOH−CH ₃ , −CH ₂ +CO−
CH ₃ , -CH=CH-R ₄ or -CHOH-CHOH-
R ₄ , where R ₄ has the specified value. This conversion is conventionally carried out using large amounts of oxidizing agents according to many well known methods. The oxidation proceeds via several intermediate products which may be isolated in some cases and is carried out in water or in an organic inert solvent, depending on the nature of the oxidizing agent. Of course, the choice of the oxidizing agent and the reaction conditions will take into account the nature of the Z group and will be made in such a way as to preserve the other groups in the molecule intact. j Conversion of acids to esters and their back-conversion Esterification of acids is a very common reaction that can be carried out in a variety of ways. Typically, an acid and an alcohol are placed into a reaction in the presence of an acid catalyst. The reaction is advantageously carried out under anhydrous conditions and one of the reactants is used in large excess. This solvent may be one of the reactants or an inert organic solvent. Another way of proceeding with the reaction consists in distilling off the water as soon as the esterification has taken place, using suitable equipment. This reaction condition is 1 of this reactant.
The conditions are the same as those described above, except for the fact that one must not be used in large excess. The hydrolysis of the ester is carried out under conditions of acid or base catalysis, in which case one of the reactants (here water) is used in large excess. k The alkoxycarbonyl group (-COOR ₃ ) of the Z group representing the alkoxycarbonyl group (-COOR'), carboxyl group, its salt, or its anion
Conversion to. Depending on the nature of Z, this transformation is advantageously continuous with the alcohol R′OH formed by the esterification in the presence of an excess of alcohol R ₃ OH and an acid or base catalyst. or by heating the derivative containing the -COOR' group while removing it by distillation, or by removing the reactant by distillation.
WR ₃ (wherein W is a halogen such as chlorine, bromine or iodine, an O-mesyl group or an O-tosyl group, a sulfate group (-O-SO ₂ -OR ₃ ), an acyloxy group (R ₅ -CO- O) or an easily substituted group such as a hydroxyl group). R ₃ represents a C ₁ -C ₃ straight chain or branched alkyl group, and R ₅ represents an R ₃ group or a phenyl group.
Alkylation of carboxyl groups, their salts or their anions usually takes place in an inert organic solvent in the presence of a weak inorganic base or preferably in the presence of an organic base such as pyridine or triethylamine. l Conversion of Z to a carboxylic acid group representing a halogen atom This conversion is typically carried out by converting the halogenated product into an organometallic derivative, which is then treated with carbon dioxide, followed by this intermediate Hydrolysis of the body supplies carboxyl groups.
Metals that can be used here are lithium, magnesium, zinc or manganese. In order to avoid this secondary reaction of conversion, the functional group BR ₁ N- present in the molecule is sufficiently protected. In order to better understand this method, the principle method of arriving at the derivatives is described below. 1 derivatives can be obtained by alkylation or acylation of the product or as outlined below. In the above formula, R, R ₁ , Z, W and n have the values defined above, but in the reactant R ₁ W, the R ₁ group does not represent hydrogen. Furthermore, RW and R ₁ W are expressed as

[Formula] represents acetone, so it can be obtained after acylation of a derivative or

The group [formula] corresponds in this case to the R group or the R ₁ group. This alkylation or acylation reaction may be carried out in an inert organic solvent such as a chlorinated hydrocarbon, an alcohol or an aliphatic or aromatic hydrocarbon selected as the reactants are functional. The reaction proceeds at a temperature between 0° C. and the reflux temperature of the solvent. The reaction is carried out in the presence of an organic base such as trimethylamine, pyridine or N-dimethylaniline, or in the presence of an inorganic base such as alkaline or alkaline earth metal carbonates and bicarbonates, or finely ground lime. It can be done. An alternative to this method is shown below. In the above formula, R, R ₁ , W, Z and n have the values defined above. The above reaction is similar to the derivative or alkylation reaction described above, and of course the operating conditions for these three reactions are equivalent. According to another variant of this process, the derivatives may be synthesized by acylation from primary amines with carboxylic acids using phosgene as a coupling agent. This phosgene can be introduced into a solution of the amine and carboxylic acid, or can be antagonized with one of the two reactants, and the intermediate thus formed can then be used as the second reactant. compete with. A variant of the process in which phosgene is placed in a reaction with an amine followed by conversion of the intermediate isocyanate is shown in the figure below. In the above formula, R ₁ represents hydrogen, Z and n have the values specified above, and the R ₈ -CO group represents R as specified above.
Corresponds to the base. According to another alternative, derivatives (wherein R
represents an alkyl group or a substituted alkyl group as defined above) can be obtained by acylation of a derivative or a substituted alkyl group as defined above, followed by reduction of the amide obtained as an intermediate. Although a number of methods are mentioned as reduction-like actions, it is clear that the selection of the reaction conditions must include ensuring preservation of the functionality of the Z group. Another way to arrive at 2 derivatives is characterized by first forming an intermediate iminium salt from an amine and a carbonyl compound. This iminium salt is reduced to lead to a derivative. The condensation between the amine and the carbonyl derivative is conventionally carried out in an inert organic solvent, preferably immiscible with water. This reaction is
It is preferably catalyzed by inorganic or organic acids. This reduction is carried out in the usual manner with hydrogen in the presence of hydrogenation catalysts, or with alkali metal hydrides, or with aluminum and lithium hydrides or at least one other reducing agent, in a suitable solvent. Of course, the method of reduction of this iminium salt will be chosen so as to keep the functionality of the Z group intact. By selecting the reactants differently, the product can be reached via intermediates with similar chemistry as described above. Alternative implementations of the method are possible. R ₁ , Z and n have the content as defined above, while R ₉ and R ₁₀ groups are

[Formula] has a value such that the group is equal to R. The condensation of the carbonyl derivative with the amine and the reduction of the iminium salt X takes place under the conditions described above. Note that when R ₁ represents hydrogen, the above condensation leads to an imine of the formula:

[Formula] or

[Formula] In the above formula, R, R ₉ , R ₁₀ , Z and n have the values specified above. The conditions for the synthesis and reduction of imines XI and XII are exactly the same as those for the synthesis and reduction of iminium salts. 3 Another way to arrive at the derivative of formula is
The formula is converted using reactants, as shown in the diagram below. R, R ₁ , W and n have the contents as defined above,
M represents hydrogen or a metal such as lithium, sodium, potassium or magnesium; Z is the value defined above, consistent with the reaction described above;
That is, it has a group such as a nitrile group, a trihalomethyl group, or a cyclic or acyclic dithioacetal group. Product transformation can be carried out according to other conventional methods selected as W and Z function. Some of these methods are illustrated and summarized here. If aZ represents a nitrile group or a trihalomethyl group, the reaction can be carried out in different solvents, such as, for example, water, lower alcohols or dimethylformamide, or in a mixture of miscible or immiscible solvents. In some cases it is advantageous to carry out in the presence of an organic base or a phase change catalyst. b When Z represents a cyclic or acyclic dithioacetal group, the reaction takes place under anhydrous, low temperature conditions in an inert solvent such as diethyl ether or tetrahydrofuran. The products are then obtained by deprotecting the formyl group by known methods such as hydrolysis in acid media or by the action of mercury salts. 4 In the formula, −CH ₂ Z is

Another way to arrive at derivatives of the formula representing the group is to carry out alkylation of the derivatives with reactants, as shown in the figure below. R, R ₁ , B ₁ , B ₂ , W and n have the values specified above, except in this case W does not represent a hydroxyl group. M represents an alkali metal such as sodium, potassium or lithium. This conventional reaction generally occurs under inert gas and anhydrous conditions using solvents such as alcohols or fatty acids or aromatic hydrocarbons. Step B The method consists in opening the lactam under the action of a base or an acid. The lactams mentioned above are conventionally obtained from lactones according to the formula below. R, R ₂ , M and n have the values specified above.
This conversion of lactones into lactams takes place in an inert organic solvent, preferably at the reflux temperature of the reaction medium. This ring opening of the lactam can occur under the action of ammonia, amides, alcoholates or alkali metal hydroxides, or under the action of inorganic acids such as hydrochloric acid or sulfuric acid. The reaction proceeds in water or in an inert organic solvent such as an ether, alcohol, aliphatic hydrocarbon, aromatic hydrocarbon or chlorinated hydrocarbon. These methods described as syntheses of compounds may be modified if the Z group is already defined above.

It is clear that it can equally be applied to products with a formula having the value of the group [formula] and that this method can thus directly lead to products of the invention corresponding to the general formula. be. Of course, for all steps of the synthesis of compounds of formula _and

For all the methods described above for conversion to [formula] groups, the reactants and reaction conditions are such that the functional groups already present in the molecule and those not included in the reactions involved are retained intact. of,
select. In order to be able to carry out the synthesis of such compounds, it may be necessary to use protecting groups in order to protect the functionality of the groups present in the starting molecules. This choice of experimental conditions will condition the selection of protecting groups, which are clearly described in the literature, as are the methods of introduction and deprotection of the protecting groups. Examples Some detailed examples of the preparation of some derivatives related to this experiment are described below. These examples are primarily intended to further illustrate the significant properties of the method according to the invention. Example 1 Synthesis of 4-n-pentylaminobutanamide 5 g (0.041 mol) of 4-chlorobutanamide was added to 19
ml (0.165 mol) of pentanamine and stirred at room temperature for 48 hours. Addition of ether (400ml) formed a precipitate which was filtered and recrystallized twice in isopropanol. Melting point (℃) 187. Elemental analysis C H N Theoretical value % 51.7 10.1 10.4 Actual value % 52.0 10.2 13.4 Example 2 Synthesis of 5-n-pentylaminopentanamide a 4.5 g of 5-chloropentanenitrile (0.040
), 3.8 g (0.044 mol) of pentanamine and
A mixture of 3.7g sodium bicarbonate in 60ml absolute ethanol was refluxed for 48 hours. The sodium chloride formed was filtered and the filtrate was evaporated to dryness in vacuo to remove excess pentanamine. This residual oil was dissolved in ether and ether/hydrochloric acid was added. A white precipitate formed and was filtered (5-n-pentylamine pentanenitrile hydrochloride). Melting point (℃) 207-209. b 2.78 g (0.013 mol) of 5-n-pentylaminopentanenitrile hydrochloride were suspended in 3.4 ml of concentrated hydrochloric acid and stirred at 5°C for 6 days.
The clear solution obtained here was poured onto 20 ml of isopropanol and the solid crystallized out was filtered and washed with isopropanol. Melting point (°C) 216-217 Elemental analysis C H N Theoretical value % 53.9 10.4 12.5 Actual value % 54.2 10.5 12.6 Example 3 Synthesis of 6-decylaminohexanamide 4.5 g of 6-chlorohexanamide (0.030 mol)
, 5.2 g decaneamine (0.033 mol) and 2.52 g
of sodium bicarbonate (0.033 mol)
Heat under reflux in 100 ml of ethanol.
After two days and nights, the solution was cooled, filtered, evaporated and the remaining solid was recrystallized twice in ethyl acetate. The solid obtained here was dissolved in ethanol, ether/hydrochloric acid was added and the newly obtained solid was recrystallized twice in isopropanol. Melting point (℃) 206. Elemental analysis C H N % theoretical 62.6 11.5 9.1 % actual 63.0 1.7 9.3 Example 4 5-(p-tolylacetylamino)pentanamide 2.9 g (0.017 mol) of p-tolylacetyl chloride and 0.7 g in 4 ml of water At the same time, add 0.7 g of a solution containing sodium hydroxide to 10 ml of water cooled to 0°C.
(0.017 mol) of sodium hydroxide and 2 g (0.017 mol) of 5-aminopentanamide dropwise. The suspension formed here was stirred at room temperature for 1 hour. The solid was filtered and recrystallized twice in isopropanol. Example 5 6-[3-(3,4-dimethoxyphenyl)propanoylamino]-hexanamide In 4.6 g (0.02 mol) of 3-(3,4-dimethoxyphenyl)propanoyl chloride and 20 ml of water At the same time, a solution containing 2.6 g (0.020 mol) of 6-aminohexanamide and 0.8 g of sodium hydroxide in 15 ml of water was added to 0.0 g of sodium hydroxide.
It was added after cooling to ℃. This suspension was stirred at room temperature for 2 hours. The solid was then filtered and recrystallized in isopropanol. Melting point (℃) 137. Elemental analysis C H N Theoretical % 63.3 8.1 8.7 Actual % 63.2 8.2 8.6 Example 6 Synthesis of 6-n-pentylaminohexanamide 5 g (0.033 mol) of 6- in 100 ml of ethanol
A mixture containing chlorohexanamide, 4.25 ml (0.037 mol) pentanamine and 2.8 g (0.034 mol) sodium bicarbonate was heated under reflux for 4 days. After cooling the solution, the salt was then filtered off and the solvent was evaporated to dryness. The solidified product was crystallized twice from ethyl acetate, dissolved in a very small amount of methanol, and ether/hydrochloric acid was added. The solid that formed was filtered and dried. Melting point (℃) 190.5. Elemental analysis C H N Theoretical value % 55.8 10.6 11.8 Actual value % 55.8 10.6 11.8 Example 7 4-n-hexylaminobutanamide a 18.5 ml (0.2 mol) of 4-chlorobutanenitrile, 29.1 ml (0.22 mol) of hexane 500ml of a mixture of amine and 18.5g sodium bicarbonate
of ethanol under reflux for 2 days.
The suspension was then cooled, the salts were filtered off and the filtrate was evaporated. The residue was separated into water and dichloromethane phases. The dichloromethane phase was washed with water, dried over potassium carbonate and evaporated at room temperature. The excess hexaneamine was evaporated under high vacuum and the remaining oil was dissolved in anhydrous ether and ether/hydrochloric acid was added. Filter the solid matter that appears here,
Dissolved in a very small amount of methanol and added anhydrous ether. The product obtained in this way is
It was used as it was in the next step. b 4.2 g (0.02 mol) of 4-hexylaminobutanenitrile were stirred in 5 ml of concentrated hydrochloric acid at 5° C. for 4 days. This solution was then poured into 50ml of chilled acetone. The white solid that formed was recrystallized in isopropanol. Melting point (℃) 194. Elemental analysis C H N Theoretical % 53.9 10.4 12.6 Actual % 54.1 10.4 12.6 Example 8 4-[(N-n-hexyl-N-4-chlorophenylacetyl)amino]butanamide 650 mg (0.003 mol) of 4-hexyl Aminobutanamide hydrochloride was dissolved in 0.4 ml of 1N potassium hydroxide at 10°C. 0.65 for this solution
ml of 4-chlorophenyl acetate chloride was added dropwise. Oil appeared immediately and solidified. Two hours after the reaction, the oil was extracted with ether, the ether phase was washed with water and 1N hydrochloric acid, and it was dried and evaporated over potassium carbonate. The solid matter remaining here was recrystallized from ethyl acetate. Melting point (℃) 105-106. Elemental analysis C H N Theoretical value % * 63.1 8.0 8.2 Actual value % 63.0 7.9 8.1 * Theoretical value when containing 1.03% water Example 9 Synthesis of 5-n-dodecylaminopentanamide 7.4 g of dodecaneamine ( 0.04 mol), 4.23g of 5
-chloropentanenitrile (0.036 mol) and
3.4 g of sodium bicarbonate was heated under reflux in 100 ml of ethanol for 2 days. The solution was then cooled, filtered and the filtrate was evaporated. The oil remaining here was distilled under a pressure of 0.25 mmHg. The fractions distilled at 170°C were collected. This was dissolved in ethanol and ether/hydrochloric acid was added.
The solid precipitated here was filtered and used in the next step without further purification. b 2 g (0.007 mol) of 5-dodecylaminopentanenitrile hydrochloride were dissolved in 50 ml of acetic acid. This solution was saturated with dry hydrochloric acid and stirred at room temperature for 2 days. The acetic acid was then evaporated, the solid taken up in ether was filtered and the solid was recrystallized twice in isopropanol. Melting point (℃) 212. Elemental analysis C H N Theoretical value % 63.6 11.6 8.7 Actual value % 63.9 11.6 8.8 Example 10 Synthesis of 4-n-pentylaminobutanamide a 18.5 ml of 4-chlorobutanenitrile (0.2 mol), 19.1 g of pentanamine ( A mixture of 0.22 mol) and 18.5 g of sodium bicarbonate (0.22 mol) was heated at reflux in 500 ml of ethanol for 2 days, then the suspension was cooled, the salts were filtered and the filtrate was evaporated. The residue was partitioned between water and dichloromethane. The dichloromethane phase was washed with water, dried over potassium carbonate and evaporated at room temperature. The residual pentanamine was evaporated in high vacuum, the remaining oil was dissolved in anhydrous ether and ether/hydrochloric acid was added. The resulting solid was filtered, dissolved in a small amount of methanol, and anhydrous ether was added until a large amount of precipitate was obtained. This precipitate was filtered and used as it was in the subsequent steps. b 3.1 g of 4-pentylaminobutanenitrile (0.02 mol) were dissolved in 30 ml of glacial acetic acid and saturated with hydrochloric acid at room temperature. After stirring for 24 hours the acetic acid was evaporated and the remaining solid was recrystallized in isopropanol. Melting point (℃) 187.5. Elemental analysis C H N Theoretical % 51.7 10.1 13.4 Actual % 51.8 10.2 13.4 Example 11 Synthesis of 4-n-pentylaminobutanamide 2.76 g of 4-aminobutanamide hydrochloride (0.02 mol), 1.9 g of pentanal (0.022 mol), 100 mg of 10% palladium on carbon and 50 ml of ethanol were added. The bottle was stirred under hydrogen gas at room temperature overnight. Then the catalyst was filtered, the solvent was evaporated and the residue was solidified in ether. The resulting solid was recrystallized three times in isopropanol. Melting point (℃) 186.5. Elemental analysis C H N % theoretical 51.7 10.1 13.4 % observed 52.0 10.3 13.5 Example 12 Synthesis of 4-n-pentylaminobutanamide Contains 3.9 g of sodium amide (0.1 mol) suspended in 50 ml of toluene In a 200ml flask,
3.1 g of N-pentylpyrrolidone (0.02 mol) was added. After the suspension was refluxed for 3 days, 10 ml of water and enough 1N hydrochloric acid to make an acidic solution (PH2) were added. The aqueous phase was decanted and lyophilized in vacuo. The residue was extracted with boiling isopropanol, the crystalline solid was filtered and recrystallized twice in isopropanol. Melting point (℃) 186. Elemental analysis C H N % theoretical 51.7 10.1 13.4 % found 51.4 10.0 13.7 Table 1 below lists derivatives of the above sample and other derivatives of the invention prepared according to the above method. All compounds listed in Table 1 provide accurate elemental analysis values for carbon, hydrogen, and nitrogen.

【table】

【table】

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TABLE The products according to the invention were subjected to a series of pharmaceutical tests according to the method described below. These LD _50s were converted into Lichtfield (Licht−
Field) and Wilcoxon (J. Pharmacol. Exp. Ther, 96 , 99, 1949) and expressed in mg/Kg. This product was administered orally to mice. In general, the products of the invention exhibited low toxicity. The influence on behavior was determined using S. Irwin's method (Gordon Res. Conf.
on Medicinal Chem. 133 , 1959). These substances suspended in 1% tragacanth mucus were fasted for 18 hours.
One group of male mice was administered orally via intragastric probe. The dose tested as a function of the observed activity was 3000-3 mg/Kg. This behavior was investigated at 2, 4, 6 and 24 hours after treatment. If symptoms persisted during observation, observation was extended. After processing mortality
Recorded over the course of 14 days. None of the products tested induced any abnormal behavior in mice. The numbers correspond to the numbers given to the products in column 2 of Table 1. Generally, certain products of the invention have anticonvulsant properties. This anticonvulsant effect is caused by bicuculline (bicuculline).
-culline) induced tonic convulsions. Compounds according to the invention, 0.7
Bicuculline was administered orally to 20 mice at a dose of 10 mg/Kg 3 hours before intravenous injection at a dose of mg/Kg. The number of mice that showed suppression of tonic convulsions and the number of mice that died were recorded. In this test, compound numbers 1, 5, 8, 10
and 13 were particularly active, with a percentage inhibition of 55% or more. Compound 2081 (compound number 1 in Table 1) was subjected to a more in-depth evaluation. In a study of bicuculline-induced convulsion suppression, its ED ₅₀
was 3 mg/Kg. At a dose of 300 mg/Kg, the percentage inhibition against bicuculline-induced convulsions was 75%. Compound 2081 also has anticonvulsant activity induced by leptazol and electric shock. Biochemical tests revealed that certain compounds of the invention have gamma-aminobutyric acid (GABA)-mimetic effects. This effect can be controlled by C.Braestrup and M.
M.Neilsen's method (Brain
Research Bulletin, Vol.5, supp1.2, p.681～
684 (1980), in vitro. A homogenate of rat brain (but not the cerebellum), which has been washed with the purpose of removing the presence of γ-aminobutyric acid (GABA), when increasing the concentration of the product or control substance to be tested (in this case GABA) ³ H-flunitrazepam was used to measure the degree of binding to the receptor in the case of no increase and in the case of no increase. This non-specific binding was determined in the presence of Diazepam. The 200-fold diluted homogenate was incubated at 0°C for 60 minutes. After keeping warm, this sample was
Filtration and washing were performed on CFB filter paper. After drying the filter paper at 60° C. for 20 minutes, the remaining radioactivity was measured by the method of liquid scintillation in a suitable medium. Under these circumstances, the product compound 2818 (compound number 16 in Table 1) exhibits GABA-like behavior;
Regarding ED ₅₀ (50% effective dose), GABA is 8.2
×10 ^-7 M compared to 4.7 × 10 ^-5 M, and even the efficacy
Characterized by being identical to GABA. Compound 2818 has been shown to be effective against the connective membrane of the rat brain.
Further evaluation was performed in vitro for ^3H -musimol binding. This test is anti-GABA
(GABA-ergic) receptor specific;
It can be shown whether or not it acts on GABA receptors.
These bind directly to benzodiazepine receptors. Preparation of connected membranes and testing of ³ H-musimol binding to connected membranes are described in Brain Research 100 , 81-97.
(1978) Enna, S.
J.) and Snyder S.H.
Same as H.). The specific binding value of ³ H-muscimol to this membrane is the same as that of ³ H-muscimol alone and 10 μM GABA.
is obtained by forming a difference with this bond in the presence of . This membrane was coated with different concentrations of compound 2818.
The product concentration required for 50% inhibition ( _IC50 ) of ^3H -muscimol binding was determined. A value of 2.5×10 ⁻⁵ M was obtained as IC ₅₀ for compound 2818. The IC ₅₀ of GABA in this system is 2×10 ⁻⁷ M. The effects of bicuculline, leptazol, and anticonvulsions caused by electric shock, as well as GABA-like effects, indicate the following. Thus, the compounds according to the invention have particularly effective pharmaceutical properties for the treatment of various forms of epilepsy and movement disorders such as Parkinson's disease. Furthermore, the activity of these products at the level of the central nervous system makes this compound useful for the treatment of certain cardiovascular diseases such as hypertension and hypotension, psychosis such as depression, and memory disorders. It is of potential interest for the treatment of sleep disorders and sleep disorders, and as an analgesic. Certain compounds according to the invention additionally have anti-thermintic activity. This activity is associated with the hookworm brasiliensis
(stage L3). The product to be tested is administered in mucus form via an esophageal probe 8 days after entry. On the 12th day, the rats were sacrificed and a list of infestations in the intestines was made. The results obtained here were expressed as a percentage of effectiveness in comparison with the control group. In this test, the product compound 2081 (compound number 1 in Table 1) has an efficacy of 91% at a dose of 50 mg/Kg. In humans, the compound according to the invention can be administered in doses of 50 to 4000 mg.
will be administered orally at a dosage of . This amount would be a dose of 5 to 1000 mg intravenously. The products according to the invention can be used in the form of various formulations. The examples below are non-limiting and relate to the formulation of preparations containing the active products indicated by the letter A. This active product can be formed by one of the compounds listed below. That is, the compounds are: 4-n-pentylaminobutanamide 5-n-pentylaminopentanamide 6-n-pentylaminohexanamide 5-(p-tolylacetylamino)pentanamide 6-n-decylaminohexanamide 6-[ (2-p-chlorophenoxyethyl)amino]hexanamide 4-[(N-n-hexyl-N-4-chlorophenylacetyl)amino]butanamide. Tablets A 600mg Star Etsukus (STA -RX) 1500 starch 80mg Hydroxy Pripil Methyl Cell Loose 20mg Aerosil (Aerosil) 5 mg Magnesium stearate 15mg ) 5mg tark 5mg Magnesium stearate 10mg zerang couled circle Agent A 50mg Lactose 110mg Corn starch 20mg Gelatin 8mg Calcium stearate 12mg A 200mg Polyvinylpyrrolidone 10mg Corn starch 100mg Cutina HR 10mg Intramuscular or intravenous injection A 20mg Sodium chloride 40mg Distilled for injection with sodium acetate to pH 7 Intramuscular injection A made up to 5 ml with water 200 mg Benzylrubenzoate 1 g Syrup A made up to 5 ml with injection oil 5 g Tartaric acid 0.5 g Nipacept 0.1 g Satucarose 70 g Flavor 0.1 g Lotion A made up to 100 ml with water 2 g Sorbitol 50 g Glycerin 10 g Mint essence 0.1g propylene glycol 10g Suppository A made up to 100ml with deionized water 500mg Butylated hydroxyanisole 10mg Rectal gel A made up to 3g with semi-synthetic glyceride 100mg Carbomer 15mg made up to 5g with purified water to pH 5.4 with triethanolamine

Claims (1)

[Claims] 1. General formula A derivative of the ω-amino acid represented by, or a pharmaceutically or veterinarily acceptable salt of this derivative. In the above formula, R is a C ₂ to C ₁₂ straight chain or branched alkyl group; 1
by one or two _C1 - _C4 straight-chain or branched alkyl groups, or by one or two C1-C4 straight-chain or branched alkoxy groups, or by one or two C1 _{- C4} straight-chain or branched alkoxy groups; , a _C2 - _C4 straight-chain or branched alkyl group substituted by a phenyl or phenoxy group optionally substituted by one or two halogen atoms; or,
by one or two _C1 - _C4 straight-chain or branched alkyl groups, or by one or two C1 _{- C4} straight-chain or branched alkoxy groups, Or 1
C ₂ to C ₆ substituted by a phenyl group optionally substituted by one or two halogen atoms
represents a straight-chain or branched acyl group; R ₁ is hydrogen; a _C2 - _C11 straight-chain or branched acyl group; or one or two _C1 - _C4 straight-chain or by branched alkyl groups or by one or two
By a C ₁ to C ₄ straight chain or branched alkoxy group,
or substituted by a phenyl group optionally substituted by 1 or 2 halogen atoms
It represents a _C2 - _C6 straight-chain or branched acyl group, _R2 represents an amino group, and n has a value of 3, 4 or 5. 2. The derivative according to claim 1, wherein R represents a _C2 - _C10 alkyl group. 3. The derivative according to claim 1, wherein R represents a _C2 - _C5 alkyl group. 4. The derivative according to claim 1, wherein R represents a _C6 to _C12 alkyl group. 5. The derivative according to claim 1, wherein R is a _C5 - _C7 alkyl group. 6 R represents a _C2 to _C4 alkyl group substituted by a methyl group or a methoxy group, or a phenyl or phenoxy group optionally substituted by a chlorine atom or a bromine atom, A derivative according to claim 1. 7 C 2 - R is substituted by a phenyl group optionally substituted by one or two methyl or methoxy groups, or by one or _two chlorine or bromine atoms represents a C ₄ acyl group,
A derivative according to claim 1. 8. The derivative according to any one of claims 1 to 7, wherein _R1 represents a _C2 to _C5 acyl group. 9. The derivative according to any one of claims 1 to 7, wherein _R1 represents a _C6 to _C11 acyl group. 10 C 2 ~ in which R ₁ is substituted by one or two methyl or methoxy groups, or by a phenyl group optionally substituted by one or two chlorine or _bromine atoms represents a C ₄ acyl group,
A derivative according to any one of claims 1 to 7. 11. The derivative according to any one of claims 1 to 7, wherein R ₁ represents hydrogen and R ₂ represents an amino group. 12. The derivative according to claim 1, which is selected from the group consisting of the following compounds. 4-n-pentylaminobutanamide 5-n-pentylaminopentanamide 6-n-pentylaminohexanamide 5-(p-tolylacetylamino)pentanamide 6-n-decylaminohexanamide 6-[(2-p -chlorophenoxyethyl)amino]hexanamide 4-[(N-n-hexyl-N-4-chlorophenylacetyl)amino]butanamide