JPS5855461A - Amino acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI[R1 is 5-6-membered heterocyclic group containing 1-4 hetero atoms (O, S or N); R2-R4 are H or lower alkyl; R4 may be CN, lower alkyl having substituent group (e.g. CN, OH, etc.), lower alkoxycarbonyl, etc.; A is OH, alkoxy, amino which may have substituent group (e.g. alkyl which may be substituted with halogen, etc., OH, etc.), or hydrazino which may have lower alkyl, etc.], and its salt. EXAMPLE:2-(2-Cyanoethyl)-N-nicotinoylalanine methyl ester. USE:An immunoactivating agent and host-interstitial carcinostatic agent. PROCESS:The reaction of the compound of formula II (M1 is alkyl) with the compound of formula III (X is halogen) or its hydrohalogenic acid salt in the presence of a base gives the compound of formula IV, which is hydrolyzed to obtain the objective compound of formulaI(A is OH).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of the general formula (wherein R represents a five-membered or six-membered ring containing 1 to 4 heteroatoms selected from oxygen, sulfur, or nitrogen atoms. It represents a heterocyclic group, R2 and R3 are the same or different hydrogen atoms or lower alkyl groups, and R4 is a hydrogen atom, a lower alkyl group, a cyano group, or a cyano lower alkyl group.

Hydroxy lower alkyl group, lower alkoxycar? A is a guisulfide group having a symmetrical structure corresponding to a nyl group, a carmexyl group, an aryl group, an aralkyl group, a mercapto lower alkyl group, an alkylthio lower alkyl group, or a mercazoto lower alkyl group, and A is a hydroxyl group, an alkoxy group, or an amino group. , an alkyl-substituted amino group which may have a halogen atom or a carbamoyl group, a hydrazino group, a lower alkyl- or aryl-substituted hydrazino group, and a hydroxyamino group.

Indicates a lower alkoxyamino group or an aralkyloxyamino group. The present invention relates to an amino acid derivative represented by () and a pharmacologically acceptable salt thereof, a method for producing the same, and an immunostimulant or anticancer agent containing the present compound as an active ingredient.

In the general formula (1), R1 is, for example, a pyrrole ring.

imidazole ring, pyrazole ring, oxazole ring, isoxazole ring, isothiazole ring.

Thiazole term, furan It, thiophene ring, 1.2°5-oxadiazole ring, 1.2.5-thiadiazole ring, 1.2.4-oxadiazole ring, 1.2.
4-thiadiazole ring, 1,3.4-triazole 3
J.

1.2.3-triazole ring or 1,2,3.4-
5-membered 3jI such as a tetrazole ring or for example pyrino/ring, pyridanone ring, biradi/ring, pyrimino/ring, 1.
Indicates a heterocyclic group consisting of a six-membered ring such as a 4-oxazine ring or a 1,4-thiacin ring, and these heterocyclic groups may be unsubstituted or have a substituent. Examples of the substituent include Methyl.

Ethyl, -, elovir, isozolovir, n-butyl,
Straight-chain or branched alkyl group having 1 to 4 carbon atoms such as isobutyl and tart-butyl; 1 to 2 carbon atoms such as trifluoromethyl and 2.2.2-trichloroethyl for example chlorine.

Rhodane atoms such as bromine, iodine, fluorine; mercapto groups; eg methylthio, ethylthio.

Linear or branched alkylmercapto groups having 1 to 16 carbon atoms such as H-propylthio, isozolobylthio, n-butylthio, t@rt-butylthio, and hexadecylthio; hydroxyl groups such as methoxy, ethoxy, n- ! ropoxy, isozolo Ixy, n-! )−?
Linear or branched alkoxy groups having 1 to 16 carbon atoms such as tert-butoxy and hexadecyloxy; e.g. acetoxy, propanoyloxy, n-butyryloxy, isobutyryloxy, piparoyloxy, palmitoyloxy Methyl, ethyl,
Lower alkyl groups such as n-propyl, inpropyl,
Methoxy, ethoxy, n-propoxy.

Lower alkoxy groups such as impropoxy, nitrogen atoms such as chlorine, bromine, iodine, and fluorine, nitro groups, trifluoromethyl groups, and cyano groups.

Acyloxy groups such as benzoyloxy with or without hydroxyl, amino or cardoxy groups; calgoxy groups; e.g. methoxycardenyl, ethoxycardenyl, 1+-zolo-xicallnyl, iso! Straight-chain or branched alkoxycargenyl groups having 2 to 16 carbon atoms such as lopoxycargenyl, H-butoxycarbonyl, isobutoxycargenyl, tart-butoxycargenyl, and hexadecyloxycargenyl. Amino group; Lower alkyl-substituted amino group such as methylamino, ethylamino, n-propylamino, isobutylamino, dimethylamine, diethylamino, diisozolobylamino; Substituent on aromatic ring such as methyl, ethyl, n- Lower alkyl groups such as propyl and isozorobyl, lower alkoxy groups such as methoxy, ethoxy, n-propoxy, and isopropoxy, halogen atoms such as chlorine, iodine, bromine, and fluorine, nitro groups, trifluoromethyl groups, hydroxyl groups, Aryl-substituted amino groups such as phenylamino with or without amine or carboxy groups; e.g. acetylamino, propionylamino, B-
As a substituent on a straight chain or branched chain alkanoylamino group having 2 to 16 carbon atoms or an aromatic ring such as butyrylamino, isobutyrylamino, piparoylamino, orylumitoylamino, for example, methyl, ethyl,
Lower alkyl groups such as n-propyl and isopropyl,
Methoxy, ethoxy, n-propoxy.

lower alkoxy groups such as isopropoxy, halogen atoms such as chlorine, bromine, iodine, fluorine, nido-Ω groups, trifluoromethyl groups, benzoylamino groups with or without hydroxyl groups, amino groups or carboxy groups; acylamino groups; for example, 2,2.2-)lichloroethoxyrutylamino groups; halogeno-lower alkoxylsanylamino groups such as 2.2.2-tribromoethoxycarbonylamino; for example, methanesulfonyl, ethanesulfonyl, solonylamino groups; An alkanesulfonyl group having 1 to 4 carbon atoms such as sulfonyl and f-tanesulfonyl: may contain a nitro group or a cyano substituent. R2 and R5 are the same or different and represent a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-zorobyl, isopropyl, and R4 is a hydrogen atom. ;For example, methyl, ethyl,
n-Zorovir, Isopropyl.

A linear or branched alkyl group having 1 to 4 carbon atoms such as n-butyl, isobutyl, and tart-butyl; cyanomethyl.

Cyano lower alkyl groups such as 2-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl; hydroxy lower alkyl groups such as hydroxymethyl, 2-hydroxyethyl, 4-hydroxyethyl: methoxycargenyl, ethoxycargenyl,! Ropoxycarinyl, n-p)-
? Lower alkoxycarzanyl groups such as cardanyl, isobutoxycardanyl; carzoxy groups; substituents on aromatic rings such as methyl and ethyl;

Lower alkyl groups such as n-propyl and isopropyl,
Methoxy, ethoxy, n-propoxy.

Lower alkoxy groups such as isopro4xy, trifluoromethyl groups, cyano groups, hydroxyl groups, nitro groups, amino groups, or aryl groups such as phenyl with or without halogen atoms such as fluorine, chlorine, and bromine. ; As a substituent on the aromatic ring, for example, a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, or methoxy.

Has or has a fk@-class alkoxy group such as ethoxy, n-propoxy, trifluoromethyl group, cyano group, hydroxyl group, nitro group, amino group or halogen atom such as fluorine, chlorine, bromine, nichairyl, phenethyl, phenylpropyl aralkyl groups such as mercaptomethyl, mercazotoethyl, mercaptozorovir.

Mercapto lower alkyl groups such as mercaptomethyl:
A lower alkylthio lower alkyl group such as, for example, methylthiomethyl, methylthioethyl, methylthiobutyl, propylthioethyl or, for example, a compound (I) of the formula (wherein R1, R2, R and A are as defined above) ) represents a disulfide group having a symmetrical structure corresponding to the mercapto lower alkyl group, A is a hydroxyl group; for example, methoxy, ethoxy, n-
! Ropoxy, iso! I-oxy, n-butoxy, isobutoxy.

A linear or branched alkoxy group having 1 to 16 carbon atoms such as hexyloxy, decyloxy, hexadecyloxy, niamino group: for example, methylamino,
Dimethylamino, ethylamino, noethylamino! 1
-Glopylamino, iso! Lopylamino, n-butylamino.

lower alkyl substituted amino groups such as inodithylamino;
For example, a halogeno lower alkylamino group such as 2-chloroethylamino, 2-bromoethylamino, 3-chloropropylamino; for example, a carbamoyl lower alkylamino group such as 2-carbamoylethylamine, 3-carbamoylpropylamino; Hydrazo group; for example, methylhydrazino, N,N-trimethylhydrazino.

Lower alkyl-substituted hydrazino groups such as ethylhydrazino, N,N-trimethylhydrazino; lower alkyl groups such as methyl, ethyl, 11-zorobyl, isopropyl, methoxy, ethoxy, n as substituents on the aromatic ring;
-! Ropoxy, in! Aryl-substituted hydrazino groups such as phenylhydrazino with or without a lower alkoxy group such as ropoxy or a rhodane atom such as fluorine, chlorine, bromine; hydroxyamino group; e.g. methoxyamino, ethoxyamino .

For example, a substituent on a lower alkoxyamino group or an aromatic ring such as casolo I xyamino, inzolopoxyamino,
Lower alkyl groups such as methyl, ethyl, n-zolobyl, isozorobyl, methoxy, ethoxy, n-! Ropoxy, iso! It refers to a lower alkoxy group such as ropoxy or an aralkyloxyamino group such as pennoroxyamino with or without a halogen atom such as fluorine, chlorine, or bromine.

In the general formula (1), the carboxylic acid or hydroxamic acid compound in which the substituent A is a hydroxyl group or a hydroxyamino group can be converted into a pharmacologically acceptable salt form, if necessary. Such salts include salts of inorganic metals such as lithium, sodium, potassium, calcium, magnesium, aluminum or ammonium.

Mention may be made of ammonium salts such as cyclohexylammonium, diisopropylammonium and triethylammonium, preferably sodium, potassium and calcium salts.

In addition, in the compound having the general formula (I), there are optical isomers based on asymmetric carbon atoms, and all of these isomers are represented by a single formula. The range of is not limited. Therefore, if necessary, the original.

The optical isomer can be obtained by conventional methods, such as optical resolution of the target compound (1) or stereospecific synthesis using an optically active compound as a reaction raw material.

The amino acid derivative having the general formula (1) obtained according to the present invention is a novel compound, and is a compound useful as a medicine that exhibits excellent immunostimulatory and antitumor effects.

The present inventors have repeatedly studied the synthesis and pharmacological activity of amino acid derivatives for the purpose of developing host-mediated anticancer agents. As a result, the novel amino acid derivative represented by the general formula (I) has been found to have immunostimulatory and anti-cancer effects. The present invention was completed by discovering that the compound is a useful compound as a medicine having tumor action.

The novel compound according to the present invention can be produced by the method shown below.

Method l.

(In the formula, R2, R3 and R4 have the same meanings as defined above, and M represents a linear or branched alkyl group having 1 to 16 carbon atoms.) An acid halide or its hydrohalodanic acid addition salt having the formula %() (in the formula, R1 has the same meaning as described above, and X represents a halogen atom such as chlorine or bromine) in the presence of a base. By reacting in an inert solvent, the target compound having the formula (wherein R4, R2, R3, R4 and Ml have the same meanings as described above) can be obtained.

The reaction proceeds equimolar stoichiometrically. This reaction is carried out in the presence of a base, and examples of the base used include organic bases such as triethylamine, dimethylaniline,
Dimethylaniline.

Tertiary amines such as pyridine or inorganic bases such as alkali metal hydroxides such as potassium hydroxide, alkali metal bicarbonates such as potassium bicarbonate, sodium bicarbonate, alkaline earth metal hydroxides such as calcium hydroxide, magnesium hydroxide, etc. However, in the reaction system in an organic solvent, the above-mentioned tertiary amine is used, and in the reaction system using a mixed solvent with water, bicarbonate is used. It is preferred to use

The solvents used are not particularly limited, but include alcohols such as methanol, ethanol, n-f-banol, isozorobyl alcohol, and n-butanol, and aromatic aromas such as benzene, toluene, xylene, chlorobenzene, and dichlorobenzene. group hydrocarbons, ketones such as acetone, methyl butyl ketone, methyl butyl ketone, halogenated hydrocarbons such as chloroform, dichloromethane, tetrachloroethane, nitriles such as benzonitrile, acetonitrile, N, N- Amides such as methylformamide, N,N-trimethylacetamide, hexamethylphosphoric acid triamide, dimethyl sulfoxide, mixed solvents of these solvents, and mixed solvents of these solvents and water are used. The reaction temperature is not particularly limited, but is in the range of -20°C to 100°C, preferably 0°C to
The temperature is 30°C. The reaction time varies depending on the type of raw material compound and the reaction temperature, but is usually 1 to 5 hours.

After the completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.For example, if the target compound precipitates out during the reaction, the residue is collected by diluting the reaction mixture, or if it does not precipitate, the solvent is distilled off. can be obtained as Further, if necessary, FEW can be further carried out by a recrystallization method, a vacuum distillation method, chromatography, or the like.

The raw materials used to carry out the reaction (amino acid analogs) are described in Tetrahedron Letters 417.1455-1458 (1977) (Tetrahedron Lstt.
+srs&17, P, 1455-1458 (1
977)) according to the following. That is, a Schiff base having the formula (wherein R4 and M have the same meanings as described above) is used as a strong base such as evatrimethylbenzylammonium hydroxide [(40 methanol solution) (Triton B)], 1,5-diazabicyclo[4
,3,O]-5-nonene (DBN), 1,8-diazabicyclo(5,4,0)-7-undecene (DBU), etc. A compound having the formula (wherein R2, R,, R4 and M have the same meanings as described above) obtained by reacting with a compound having the same meanings as described above. It can be obtained by hydrolyzing with an acid such as hydrohalodanic acid such as hydrochloric acid, or a mineral acid such as sulfuric acid, and neutralizing with a base. In addition, salts of amino acids having the formula (wherein R2, R3, R4 and M have the same meanings as above, and X represents a halodane atom or a sulfuric acid group) obtained by hydrolysis can be isolated as intermediates. It can also be used directly in the reaction in a mixed solvent with water.

Next, the compound GV) obtained in this way is hydrolyzed with an alkali metal hydroxide in an aqueous solution or a mixed solvent with water to obtain the formula (where M5 represents a metal such as sodium or potassium). , R, , R2, R, and R4 have the same meanings as described above.) A metal salt of carpine is obtained.

Although the reaction proceeds stoichiometrically in equimolar amounts, it is preferable to use 1.0 to 20 moles of caustic alkali. 5. The mixed solvent with water to be used is not particularly limited as long as it is an inert solvent for this reaction. Alcohols such as acetone, ketones such as methyl ethyl ketone, etc. are used. The caustic alkali used is sodium hydroxide,
An alkali hydroxide such as potassium hydroxide is used.

The reaction temperature is preferably 0°C to 50°C.

collected from objects. For example, if the target product precipitates from the reaction solution, it may be removed and washed with an insoluble solvent, or if it does not precipitate, it may be added to the reaction solution using an organic solvent such as alcohols such as methanol or ethanol, acetone, or methyl ethyl ketone. By adding ketones, the target compound (2) can be precipitated.

Next, the compound animation obtained in this way is neutralized with an acid in an aqueous solution or a mixed solvent of water and an organic solvent according to a conventional method. The carboxylic acid having the same meaning as described above is obtained.

After the reaction is completed, the target product (b) is collected from the reaction mixture according to a conventional method. For example, if the target product precipitates from the reaction solution, it can be obtained by distilling the mixed organic solvent off, extracting with an organic solvent that is difficult to mix with water, and distilling off the solvent. I can do it. The extraction organic solvent is not particularly limited as long as it is a solvent that is difficult to mix with water, but examples include ethers such as diethyl ether and diisozolopyl ether, and dichloromethane.

Rodanized hydrocarbons such as chloroform, aromatic hydrocarbons such as benzene, toluene, xylene, and esters such as ethyl acetate are used. Further, if necessary, it can be further purified by recrystallization, chromatography, etc.

Method 2 Amino acid having the formula (% formula %) (wherein R,, R4 and M have the same meanings as described above) and the formula R2-CH=C-CN
By reacting a compound having the formula CIK5 (wherein R2 and R5 have the same meanings as defined above) in the presence of a strong base, ) can be obtained.

Although the reaction proceeds stoichiometrically, it is preferable to use 1.0 to 1.5 mol of compound (1) and 1.0 to 1.5 mol of base per 1 mol of compound GIr). The base used in this reaction is 1,5-diazabicyclo[4,3,
O]-5-no-nene (DBN), 1,8-diazabicyclo[:5,4,0)-7-undecene (DBU) or strong metal hydrides such as sodium hydride, potassium hydride. Use a base. Any solvent may be used as long as it is inert to the reaction, such as chloroform.

halogenated hydrocarbons such as dichloromethane, dichloroethane, diethyl ether, diisopropyl ether,
ethers such as dioxane and tetrahydrofuran,
Examples include amides such as N,N-dimethylformamide, N,N-diethylacetamide, and hexamethylphosphoric triamide. The reaction temperature is in the range of 0°C to 50°C, preferably 20°C to 30°C. The reaction time varies depending on the type of raw material compound and the reaction temperature, but is usually 2 to 20 hours.

After the reaction is completed, the desired product can be obtained by washing with water and distilling off the solvent. If necessary, it can be further purified by recrystallization, vacuum distillation, chromatography, etc.

Method 3゜ (wherein R, , R2, R, and R4 have the same meanings as defined above) is prepared from a compound having the formula %formula% (wherein M2 corresponds to each of the substituents A described above). an amino group, an alkyl-substituted amino group which may have a halogen atom or a carbamoyl group, a hydrazino group, a lower alkyl or haaryl-substituted hydrazino group,
Indicates a hydroxylamino group, lower alkoxyamino group, or aralkyloxyamino group. ) A compound having the formula (wherein R,, R2, R,, R4 and M2 have the same meanings as described above) can be obtained.

Although the reaction proceeds stoichiometrically, it is preferable to use 1.0 to 1.5 moles of amine. There are no particular problems with the solvent used as long as it is inert to the reaction, such as benzene and toluene.

Examples include aromatic hydrocarbons such as xylene, ethers such as dioxane, tetrahydrofuran, and diisopropyl ether, and halodanized hydrocarbons such as dichloroethane and chloroform. The reaction temperature is carried out in the range of 0°C to 100°C, usually 20°C to 50°C, and the time required for the reaction is 2 to 12 hours.

After the reaction is completed, the residue can be obtained as the desired product by washing with water and distilling off the solvent.

If necessary, it can be purified by recrystallization, chromatography, etc.

The oxacylones having the general formula (g), which are the raw material compounds of this method, are described in the journal Tsuya Zorakteitshu Hemi-vol. 182, p. 60 (1910) (J, Pra.
kt, Chsrn, [2], 82.60 (191
Method: An amino acid having the formula 4゜kir CH-CH-CN10OH (wherein R1, R2 and R3 have the same meanings as described above) is dissolved in a solvent. A compound having the formula (in the formula, R4, R2 and R3 have the same meanings as described above) can be obtained by heating the compound. Any solvent can be used as long as it does not affect the reaction, such as ethers such as noisozorobyl ether, tetrahydrofuran, nooxane, and benzene.

Aromatic hydrocarbons such as toluene and xylene are used. To facilitate the reaction, organic bases such as triethylamine, trimethylaniline, and pyridine can be used, and furthermore, by dissolving the compound alone in a tertiary organic base such as pyridine and diethylaniline and heating. The target product (X[Il) can be obtained. The reaction temperature ranges from 30°C to 150°C, but usually 50°C to 150°C.
The temperature is 0°C to 120°C, and the reaction time is 1 hour to 8 hours.

After the reaction is completed, the target product (X By doing this, the target object (Xrll) can be obtained. If necessary, it can also be purified by recrystallization, vacuum distillation, chromatography, etc. Further, the compound (1) is esterified to obtain a compound having the formula (wherein R11, R21R5 and M1 have the same meanings as described above). Esterification may be carried out according to a conventional method, but preferably N,N-dimethylformamide,
N,N-diethylacetamide.

When amides such as hexamethylphosphoric triamide are used and a halodanated hydrocarbon is used as the alkylating agent, an alkali carbonate such as potassium carbonate or sodium carbonate is preferably used as the base.

Examples of the amino acid derivative having the general formula (1) according to the present invention include the compounds described below.

(1) 2-(2-cyanoethyl) -N-(2-t/i,l)alanine methyl ester (2) 2-(2-cyanoethyl)-N-(2-(5-chlorotenoyl))alanine methyl ester (3) 2-(2-cyanoethyl)-N-nicotinoylalanine methyl ester (4) 2-(2-cyanoethyl)-N-(6-chloronicotinoyl)alanine methyl ester (5) N-nicotinoyl-2- (2-cyanoethyl)glycine methyl ester (6) N-nicotinoyl-2-(2-cyanoethyl)methionine methyl ester (7) N-nicotinoyl-2-(2-cyanoethyl)
Alanine (8) N-nicotinoylamino-2-(2-cyanoethyl) malonic acid dimethyl ester (9) N-nicotinoyl-2-(2-cyanoethyl) phenylglycine methyl ester (10N-nicotinoyl-2-(2-cyanoethyl) ) Phenylalanine methyl ester (11) N-nicotinoyl-2-(2-cyanoethyl) leucine methyl ester (b) N-nicotinoyl-2-(2-cyanoethyl)
Serine methyl ester α3 N-(6-hydroxynicotinoyl)-2-(
2-cyanoethyl)alanine methyl ester α4 2-(2-cyanoethyl)-N-(5-n-butyl-ubicolinoyl)alanine methylester α! 19N-(2,6-nochloronicotinoyl)-2-
(2-cyanoethyl)alanine methyl ester CIIN-(2-mercaptonicotinoyl)-2=(2
-cyanoethyl)alanine methyl ester (15N-(5-nitrobicolinoyl)-2-(2-
cyanoethyl) alanine methyl ester QIN-1 sonicotinoyl-2-(2-cyanoethyl)
Alanine methyl ester (112-(2-cyanoethyl)-N-(2,6-
dihydroxyisonicotinoyl)alanine methyl ester (e) 2-(2-cyanoethyl)-N-(3-hydroxyisoxazol-5-ylcarzanyl)alanine methyl ester Cl2-(2-cyanoethyl)-N-(2- 2-(2-cyanoethyl)-N-(5-ethoxyoxazol-2-ylcarnyl)alanine methyl ester) 2-(2-cyanoethyl) )-N-(2-furoyl)alanine methyl ester H2-(2-cyanoethyl)-N-(5-promo 2-
furoyl) alanine methyl ester (c) N-(pyrazin-2-ylcarl-nyl)-2-
(2-cyanoethyl)alanine methyl ester (t)N-(2,4-dihydroxypyrimidine-5
-ylcar is nyl)-2-(2-cyanoethyl)alanine methyl ester @ N-(6-medoxypyridanone-3-ylcardenyl)-2-(2-cyanoethyl)alanine methyl ester (c) N-(2- Nitrothiazol-4-ylcal
N-(4-phenyl-1,2,5-thiadiazol-3-ylcarnyl)-2-(2-cyanoethyl)alanine methyl ester (1) N-(3-phenyl-1,2,4-thiadiazol-5-ylcarnyl)-2-(2-cyanoethyl)alanine methyl ester0 N-(5-amino-2,3-dimethylimidazole-4- ylcar(nyl)-2-(2-cyanoethyl)
Alanine methyl ester 0 2-(2-cyanoethyl)-N-(imidazol-2-ylcarnyl)alanine methyl ester (to) N-(5-10 loimidazol-2-ylcarnyl)-2-(2 -cyanoethyl)alanine methyl ester 042-(2-cyanoethyl)-N-(pyrrole-2-
1-carzanyl)alanine methyl ester (c) 2-(2-cyanoethyl)-N-(pyrazol-3-ylcarbonyl)alanine methyl ester The amino acid derivative of the present invention having the above general formula has an excellent immunostimulatory effect. and antitumor effects, and representative examples will be described below regarding their pharmacological activities.

1) Immune recovery effect in tumor-bearing mice Ehrlich, cancer cell transplanted ICR/JcL (female) mice were used as tumor-bearing mice, non-tumor-bearing mice were used as controls, and delayed allergic reactions using BCG as antigens were used as mouse foot and foot reactions. Examined.

That is, 9 days before immunization, Ehrlich cancer cells 2×10′
500 cells were transplanted subcutaneously into mice to make them tumor-bearing.
10 tumor-bearing mice per group were immunized with μ20 BCG subcutaneously, and 14 days after immunization, BCG was re-inoculated into the skin of the hind leg, and the swelling of the hopping 24 hours later was compared to that of non-reinoculated BCG hopping. Measured by difference. A normal animal control was similarly immunized with BCG.

The test results are shown in Table-1.

Table 1 (Note 1) The test compound was intraperitoneally administered twice, 4 days and 2 days before immunization, at a single dose of 1"9,109 tl.

(Note 2) Immune function recovery in tumor-bearing animals was determined by calculating the recovery rate according to the progression.

Recovery rate = 100 - (((constant swelling of normal control animals - constant swelling of tumor-bearing test compound-administered animals) / (foot 1! swelling of normal control animals - foot and heel swelling of tumor-bearing control animals) IXloo) From the table The test compound is found to have the effect of restoring the immune response of tumor-bearing mice with decreased immune response. 〇2) Antitumor effect on mouse transplanted tumor (Sarcom&-37) ICR/Jab? Sarco to a female (female, 7 weeks old)
2 x 10' ma-37 cancer cells were subcutaneously transplanted into the axillary thigh, and the specimen was intraperitoneally administered once a day on days 1 to 4 and days 7 to 1. Tumor diameter was measured 21 days later. The test results are shown in Table-2.

Table-2 Methyl ester 1 42 (
Control drug) Repamisole 3゜telolone
As is clear from the pharmacological test examples of 3o-5 or higher, the amino acid derivative of the present invention
It is clear that it is an excellent immunostimulant and host-mediated anticancer agent for treating tumors, bacterial infections, or autoimmune diseases. Its administration forms include subcutaneous injection,
Parenteral administration methods include intravenous injection, intramuscular injection, suppositories, or tablets, capsules, and powders.

Oral administration methods include granules and the like. The dosage for adults varies depending on the target disease, route of administration, frequency of administration, etc., but is usually 5 to 300 Da per day, administered once or divided into several doses.

The amino acid derivatives of the present invention can be prepared for administration in any conventional manner by analogy with other immunostimulants and anticancer agents. Therefore, the present invention also encompasses pharmaceutical compositions containing amino acid derivatives suitable as human medicines. Such compositions are provided for use in a conventional manner with any required pharmaceutical carrier. When these compositions consist of unit doses, each unit preferably contains from 5 to 50 units of active ingredient.

Next, the present invention will be explained in more detail with reference to Examples and Formulation Examples.

Example 1゜2-(2-cyanoethyl)alanine methyl ester 1
．． Nicotinoyl chloride hydrochloride 1.78) and triethylamine 2.
After adding 80- and further stirring at 5°C for 2 hours, the solvent was distilled off under reduced pressure, the resulting residue was subjected to silica dal chromatography (developing agent: ether), and the resulting solid was recrystallized with isozorobyl ether. Target object melting point 70-71℃
1.61 P of colorless powder is obtained.

Elemental analysis value C13H15N30. Calculated value as: C
,59,76;I(,5,79:N,16.08 Actual value: C,59,89:H,5,82;N, 16.3
3. Amino acid derivatives exemplified below were obtained by a similar method.

Formulation example 1. Injection 10'mg of 2-(2-cyanoethyl)-N-nicotinoylalanine methyl ester was dissolved in 0.3% of N,N-dimethylacetamide, then added to 4.7w7 of physiological saline, and heated according to a conventional method. It was sterilized and made into an injection.

Formulation example 2. Capsules for oral administration 2-(2-cyanoethyl)-N-nicotinoylalanine methyl ester 50 ■Lactose 100
m9 corn starch 148.5 ~ total 30
0 ■ The powder of the above formulation was mixed and passed through a 3o mesh sieve, and the powder 3oorn9 was placed in a No. 3 gelatin capsule to form a capsule.

Patent Applicant Sankyo Co., Ltd. Agent Patent Attorney Shoji Kashide Continued from page 1 0 Inventor Kimi Kitamura - Sankyo Co., Ltd. Biological Laboratory, 1-2-58 Hiromachi, Parts Industry Ward, Tokyo 0 Inventor Kenkichi Shinkai Tokyo No. 1-2-58 Hiromachi, Parts Ward, Sankyo Co., Ltd. Biological Research Institute 0 Inventor: Hiro Yasuda, Tokyo Parts Ward, No. 1-2-58 Hiromachi, Sankyo Co., Ltd. Biological Research Laboratory Amendment (voluntary) 1981 July 2. Mr. Kazuo Wakasugi, Commissioner of the Japan Patent Office (Japanese Patent Office)■, Indication of the case, Patent Application No. 151873, filed in 1982, 2, Name of the invention: Amino acid derivative 3, Person making the amendment Relationship to the case Patent applicant address: 103 Nihonbashi Honmachi, Chuo-ku, Tokyo 6 Name of 3-1 (185) Sankyo Co., Ltd. Representative Director and President Yoshinori Kawamura 4, Agent Residence 6, Sankyo Co., Ltd. 1-2-58 Hiromachi, Honbunagawa-ku, Tokyo 140 Subject of amendment Statement of Column 7 of Detailed Description of the Invention, Contents of Amendment As shown in Attachment 1, Insert the following words and phrases in MK of "Description in Table 1, Line T, Page 4 T, of the Specification."

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Claims (1)

[Claims] 1. Formula (wherein R represents a heterocyclic group representing a five- or six-membered ring containing 1 to 4 heteroatoms selected from oxygen, sulfur, or nitrogen atoms) , R2 and R5 are the same or different hydrogen atoms or lower alkyl groups, and R4 is a hydrogen atom, lower alkyl group, cyano group, cyano lower alkyl group. Hydroxy lower alkyl group, lower alkoxycarmenyl group, calgexyl group, aryl group, an aralkyl group, a mercapto lower alkyl group, an alkylthio lower alkyl group, or a disulfide group having a symmetrical structure corresponding to the mercapto lower alkyl group, A is a hydroxyl group, an alkoxy group, an amino group, a) a) f atom or Alkyl-substituted amino group, hydrazino group, lower alkyl- or aryl-substituted hydrazino group, hydroxyamino group which may have a carbamoyl group. A compound represented by ), which represents a lower alkoxyamino group or an aralkyloxyamino group, and a pharmacologically acceptable salt thereof. 2. Formula (wherein R4 is a hydrogen atom, a lower alkyl group, a cyano group,
Cyano lower alkyl group, hydroxy lower alkyl group, lower alkoxycarzanyl group. Car is an xy group, an aryl group, an aralkyl group, or a mercapto lower alkyl group. It represents a glysulfide group having a symmetrical structure corresponding to the alkylthio lower alkyl group or the mercapto lower alkyl group, Ml represents an alkyl group, and R2 and R3 are the same or different and represent a hydrogen atom or a lower alkyl group. ) is a compound having the formula 0% (wherein R4 is a heterocyclic group representing a five-membered or six-membered ring containing 1 to 4 heteroatoms selected from oxygen, sulfur, or nitrogen atoms). (wherein R1s R2,85# R4 and M are (same as the previous definition). 3, Formula % Formula % (wherein B represents a heterocyclic group representing a five-membered or six-membered ring containing 1 to 4 heteroatoms selected from oxygen, sulfur groups or nitrogen atoms, R2 and R6 are the same or different hydrogen atoms or lower alkyl groups, and R4 is a hydrogen atom, lower alkyl group, cyano group, cyano lower alkyl group. Hydroxy lower alkyl group, lower alkoxycarginyl group, carboxy group, aryl Group s7: a compound having a ``alkyl group, a mercapto lower alkyl group, an alkylthio lower alkyl group, or a giusulfide group having a symmetrical structure corresponding to the mercapto lower alkyl group, and M represents an alkyl group. A method for producing a compound represented by the formula % (wherein Rt , R2+ Rs and R4 are the same as defined above) and a metal salt thereof, which is characterized by being decomposed. 4, Formula (wherein, R1 represents a heterocyclic group representing a five- or six-membered ring containing 1 to 4 heteroatoms selected from oxygen, sulfur, or nitrogen atoms, and R4 represents a hydrogen atom) , lower alkyl group, cyano group, cyano lower alkyl group, hydroxy lower alkyl group. Lower alkoxy carmenyl group, cargeoxy group. Aryl group, aralkyl group, mercazoto lower alkyl group, alkylthio lower alkyl group or the above mercapto lower alkyl group represents a guisulfide group having a corresponding symmetrical structure, and M represents an alkyl group) in the presence of a strong base. A compound represented by the formula 0 (wherein R1, R2, town, R4 and M are the same as defined above), characterized in that it is reacted with a compound having a lower alkyl group) manufacturing method. 5, Formula (wherein R1 represents a heterocyclic group representing a five- or six-membered ring containing 1 to 4 heteroatoms selected from oxygen, sulfur, or nitrogen atoms, and R2 and R3 are They represent the same or different hydrogen atoms or lower alkyl groups, and R4 is a hydrogen atom, a lower alkyl group, a cyano group, a cyano lower alkyl group, a hydroxy lower alkyl group, a lower alkoxycarnyl group, a carmex group, an aryl group, an aralkyl group 8
A mercapto lower alkyl group, an alkylthio lower alkyl group, or a guisulfide group having a symmetrical structure corresponding to the mercapto lower alkyl group. ) and a compound having the formula (in the formula, M2 is an amino group), an alkyl-substituted amino group that may have a rhodane atom or a carbamoyl group, a hydrazino group, a lower alkyl- or aryl-substituted hydrazino group, a hydroxyamino group, a lower (representing an alkoxyamino group or an aralkyloxyamino group)
A method for producing a compound represented by the formula % (wherein R1ゎR2, R, , R4 and M2 are the same as defined above), characterized by reacting a compound having the following formula. (Formula %) (wherein, R1 represents a heterocyclic group representing a five-membered or six-membered ring containing 1 to 4 heteroatoms selected from oxygen, sulfur, or nitrogen atoms. 1.. R2 and R3 are the same or different hydrogen atom or lower alkyl group) is heated in the presence of a base. (same as the definition). 7.Formula %Formula %) (wherein, R1 is a 5jk term or a 6j term containing 1 to 4 heteroatoms selected from oxygen, @yellow or nitrogen atoms)
R2 and R3 are the same or different hydrogen atoms or lower alkyl groups, R4
is a hydrogen atom, a lower alkyl group, a cyano group, a cyano lower alkyl group, a hyProxy lower alkyl group, a lower alkoxycardenyl group, a calgexyl group, an aryl group, a 7-furkyl group, a mercapto lower alkyl group, an alkylthio lower alkyl group. represents a guisulfide group having a symmetrical structure corresponding to the mercapto lower alkyl group, and A is an alkyl-substituted amine group which may have a hydroxyl group, an alkoxy group, an amino group, a rhodane atom or a carbamoyl group, or a hydrazino group. , lower alkyl- or aryl-substituted hydrazino group, hydroxyamino group) lower alkoxyamino group or aralkyloxyamino group) and a pharmacologically acceptable salt thereof as an active ingredient. Formula % Formula % (wherein R1 represents a heterocyclic group representing a five-membered or six-membered ring containing 1 to 4 heteroatoms selected from fluorine, sulfur, or nitrogen atom λ; R2 and R3 represent the same or different hydrogen atoms or lower alkyl groups, R4 is a hydrogen atom, a lower alkyl group, a cyano group, a cyano lower alkyl group. A hydroxy lower alkyl group, a lower alkoxycarbunyl group, a carboxy group, an aryl group. Aralkyl group, mercapto lower alkyl group. Indicates an alkylthio lower alkyl group or a guisulfide group having a symmetrical structure corresponding to the mercapto lower alkyl group, where M is a hydroxyl group, an alkoxy group, an amino group, a halogen atom, or a carbamoyl group. (which may have an alkyl-substituted amino group, a hydrazino group, a lower alkyl- or aryl-substituted hydrazino group, a hydroxyamino group, a lower alkoxyamino group, or an aralkyloxyamino group) and their pharmacologically acceptable compounds An anticancer agent containing salt as an active ingredient.