JPS5857349A - Dipeptide derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI[R1 is H, lower alkyl, lower halogenoalkyl, halogen, mercapto, hydroxyl, alkoxyl, etc.; (n) is 1-5; R3 is H, lower alkyl, cyano, lower cyanoalkyl, etc.; R4 is H, cyano, lower cyanoalkyl; R5 is H or alkyl]and a salt thereof. EXAMPLE:Methyl ester of N-[2-(2-cyanoethyl)-N-(p-chlorobenzoyl)alanyl]-L- leucine. USE:An immunological activator or carcinostatic agent. PROCESS:An oxazolone derivative of formula II is reacted with an amino acid derivative of formula III in the presence of a base, e.g. triethylamine or pyridine, in an inert solvent, e.g. methanol or acetone, to give the compound of formulaI.

Description

Detailed Description of the Invention The present invention is based on the general formula (wherein R1 is a hydrogen atom, a lower alkyl group, a halogeno-lower alkyl group, a halogen atom, a mercapto group, an alkylmercapto group, a hydroxyl group, an alkoxy group, an acyloxy group, a carboxy group) , an alkoxycarbonyl group, an amino group, an alkyl-substituted amino group, an aryl-substituted amino group, an acylamino group, a halogeno lower alkoxycarbonylamino group, an alkanesulfonyl group, a nitro group, or a cyano group, n is 1 to 5, and n is 2 to S, R1 may be the same or different. R2 and R3 are the same or different and are hydrogen atom, lower alkyl group, cyano group, cyano lower alkyl group, hydroxy lower alkyl group,
It represents a lower alkoxycarbonyl group, a carboxy group, an aryl group, an aralyl group, a mercapto lower alkyl group, an alkylthio lower alkyl group, R4 represents a hydrogen atom or a cyano lower alkyl group, and R5 represents a hydrogen atom or an alkyl group. The present invention relates to a dipeptide 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 (I), R1 is preferably a hydrogen atom; for example, methyl, ethyl, n-propyl.

Straight chain or branched chain carbon number 1 to 4 such as isopropyl, n-butyl, isobutyl, tert-butyl
an alkyl group having 2; e.g. trifluoromethyl, 2
, 2.2-) Logenoalkyl groups having 1 to 2 carbon atoms such as dichloroethyl; halogen atoms such as chlorine, bromine, iodine, and fluorine; mercapto groups; such as methylthio, ethylthio, n-propylthio, and propylthio, 0-butylthio, tert-butylthio,
A linear or branched alkylmercapto group having 1 to 16 carbon atoms such as hexadecylthio; hydroxyl group such as methoxy, ethoxy, n-propoxy, isopropoxy.

Straight chain or branched chain carbon number 1 to 16 such as n-butoxy% tart-butoxy, hexadecyloxy
a straight-chain or branched alkanoyloxy group having 2 to 16 carbon atoms, such as acetoxy, propanoyloxy, n-butyryloxy, imbutyryloxy, pivaloyloxy, palmitoyloxy; or methyl as a substituent on the aromatic ring,
Lower alkyl groups such as ethyl, rhopropyl, isopropyl, oromethyl groups such as methoxy, ethoxy, n-propoxy, impropoxy, acyloxy such as benzoyloxy with or without cyano, hydroxyl, amino or carboxy groups. Group; Carboxy group; For example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, impropoxycarbonyl, n-
butoxycarbonyl, isobutoxycarbonyl, tar
Straight chain or branched chain carbon number 2 to 11 such as t-butoxycarbonyl and hexadecyloxycarbonyl
alkoxycarbonyl group; amino group; lower alkyl-substituted amino group such as methylamino, ethylamino, n-propylamino, inbutylamino, dimethylamino, diethylamino, diisopropylamino; aromatic P
JK substituents include lower alkyl groups such as methyl, ethyl, lopropyl, and impropyl; lower alkoxy groups such as methoxy, ethoxy, n-propoxy, and isopropoxy; halogen atoms such as chlorine, bromine, iodine, and fluorine; Aryl-substituted amino groups such as phenylamino with or without nitro, trifluoromethyl, hydroxyl, amino or carboxy groups; for example acetylamino, propionylamino, n-butylamino, imbutyrylamino, pino(roylamino) , straight chain or branched chain having 2 to 16 carbon atoms such as valmitoylamino
Lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, lower alkoxy groups such as methoxy, ethoxy, rhopropoxy, isopropoxy, chlorine, bromine, iodine as substituents on the aromatic ring or alkanoylamino group having , a halogen atom such as fluorine, an acylamino group such as a benzoylamino group with or without a nitro group, a trifluoromethyl group, a hydroxyl group, an amine group or a carboxy group: for example 12.2-)lichloroethoxycarbonylamino, 2 .2.2-) Halogeno lower alkoxycarbonylamino group such as IJ dibromotoxycarbonylamino; for example, an alkanesulfonyl group having 1 to 4 carbon atoms such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl; nitro group or represents a cyano group, n represents 1, and R
2 and R5 are the same or different and are hydrogen atoms or, for example, methyl, ethyl, n-propyl, isopropyl, n-
Butyl, isobutyl% tert-Butyl, a linear or branched alkyl group having 1 to 4 carbon atoms, diano group; cyanomethyl, 2-cyanoethyl,
Cyano lower alkyl groups such as 3-cyanopropyl and 4-cyanobutyl; hydroxy lower alkyl groups such as hydroxymethyl, 2-hydroxyethyl and 4-hydroxybutyl; methoxycarbonyl, ethoxycarbonyl,
Lower alkoxycarbonyl groups such as propoxycarbonyl, n-butoxycarbonyl, and inptoxycarbonyl; carboxyl group; lower alkyl groups such as methyl, ethyl, n-propyl, and isopropyl as substituents on the aromatic ring; methoxy, ethoxy, n - lower alkoxy groups such as propoxy, isopropoxy, 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, bromine; ; Lower alkyl groups such as methyl, ethyl, lopropyl, and isopropyl, and methoxy as substituents on the aromatic ring.

Lower alkoxy groups such as ethoxy, low propoxy,
trifluoromethyl group, cyano group, hydroxyl group, nitro group,
aralkyl groups such as benzyl, phenethyl, phenylpropyl with or without amino groups or halogen atoms such as fluorine, chlorine, bromine: mercaptomethyl;
mercapto lower alkyl group such as mercaptoethyl, mercaptopropyl, mercaptobutyl; lower alkylthio lower alkyl group such as methylthiomethyl, methylthioethyl, methylthiobutyl, propylthioethyl; R4 is a hydrogen atom; for example, cyanomethyl, cyanoethyl, cyano represents a cyano-lower alkyl group such as propyl; R5 is a hydrogen atom; Indicates an alkyl group having 1 to 16 carbon atoms.

The carboxylic acid compound in which R5 is a hydrogen atom in the general formula (IN) can be made into a pharmacologically acceptable salt form if necessary.Such salts include lithium, sodium, potassium, calcium, magnesium,
Examples include salts of inorganic metals such as aluminum or ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium, triethylammonium, preferably sodium salts, potassium salts and calcium salts.

In addition, in the compound having the general formula (I), optical isomers based on asymmetric carbon atoms may exist, and all of these isomers are shown by a single formula, but this does not mean that the main The scope of the description of the invention is not limited. Therefore, if necessary, optical isomers can be obtained by conventional methods, such as optical resolution of the target compound (I) or stereospecific synthesis using an optically active compound as a reaction raw material.

It is a compound that is useful as a medicine and exhibits immunostimulatory and antitumor effects.

The present inventors have repeatedly studied the synthesis and pharmacological activity of dipeptide derivatives with the aim of developing host-mediated anticancer agents. As a result, a novel dipeptide derivative represented by the above general formula (R) exhibits immunostimulatory and antitumor effects. The present invention was completed by discovering that the compound is useful as a medicine.

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

That is, an oxacilone derivative having the formula (1) (wherein R1e, R2 and n have the same meanings as defined above) is prepared by formula (wherein, Ra, R4 and R5 indicate the same meanings as defined above). ) in the presence of a base in an inert solvent to produce a target compound having the formula (wherein R1v R2* R1* R4v R5 and Ω have the same meanings as defined 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,
Tertiary amines or inorganic bases such as diethylaniline, pyridine, alkali metal hydroxides such as potassium hydroxide,
Alkali metal bicarbonates such as potassium bicarbonate and sodium bicarbonate, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, etc. can be used, but the reaction system in an organic solvent is the above-mentioned tertiary amine. In a reaction system using a mixed solvent with water, it is preferable to use an alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate.

In addition, the solvent used is not particularly limited, but
alcohols such as alcohol, ethanol, n-propanol, isopropyl alcohol, and n-butanol, aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, and dichlorobenzene, acetone, methyl butyl ketone, and methyl amyl ketone. More ketones.

Chloroform% 1.2-dichloroethane, te) Halogenated hydrocarbons such as dichloroethane, nitriles such as benzonitrile, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, etc. Amides, dimethyl sulfoxide, mixed solvents of these solvents, and mixed solvents of these solvents and water are used. There is no particular limitation on the reaction temperature, but in the range of -20°C to 100°C,
Preferably it is 0°C to 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 reaction is completed, the target compound (1) is collected from the reaction mixture according to a conventional method. For example, if the target compound precipitates from the reaction system, it can be obtained as a residue by removing P, or if it does not precipitate, it can be obtained as a residue by distilling off the solvent. Further, if necessary, it can be further purified by a recrystallization method, a vacuum distillation method, a black thorn 2 fee, or the like.

The oxacylone derivative (1), which is the raw material used to carry out the reaction, is published in the journal Zhuia Brakreitssch Hemi-vol. 82, p. 322 (1910) (J, PrCkt.
(3hem, (2) * 82 e 322 (19
10) ), and the reaction for obtaining the dipeptide derivative (I) is described in Tetrahedron Vol. 11, p. 39 (Tsso year)
It was carried out according to the method of 39 (11160).

The dipeptide derivative having the general formula (I) of the present invention exhibits excellent immunostimulatory and antitumor effects, but
Next, representative examples will be described regarding their pharmacological activities.

ll! 1 tumor effect engineer CjR/Jct mouse (female, T withdrawal K Sarc
2 x 10' oma-31 cancer cells were subcutaneously transplanted into the axillary region, and 1 to 4 days and 7 to 10 days later, the specimen was intraperitoneally administered once a day. Tumor diameter was measured 21 days later. The test results are shown in the table.

Table (Control drug) Levamisole 3゜Tyrolone 30 -5 As is clear from the above pharmacological test examples, the dipeptide derivative of the present invention is
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,
Examples include parenteral administration methods such as intravenous injection, intramuscular injection, and suppositories, and oral administration methods such as tablets, capsules, powders, and granules.

The dosage for adults varies depending on the target disease, route of administration, number of administrations, etc., but is usually 5 to 300 mg per day.
■ Administer in one or several doses.

The dipeptide derivative of the present invention can be prepared for administration by any conventional method by analogy with other immunostimulants and anticancer agents. Therefore, the present invention also includes pharmaceutical compositions containing dipeptide 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 5 SO active ingredients.

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

Example 1 A solution of 2-(p-phenyl)-4-(2-cyanoethyl)-4-methyl-5-oxacylone in dichloromethane (30 mg) with 3.62N of KL-leucine methyl ester hydrochloride and 2JOwt of triethylamine. After stirring at room temperature for 24 hours, the reaction solution was washed with water and the organic layer was dried over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was recrystallized from diethyl ether to give a melting point of 1.
The desired product 121 Ii was obtained as a colorless powder of 18-180c.

Elemental analysis value Calculated value as 020H26NBO40z;
C, 58,89; H, if, 43; N, 1
0jO; at, ass actual value; O, 5aJ5; H, 6,47; N,
1(L35; Oj, 8J1) Dipeptide derivatives exemplified below can be obtained by a similar method.

For example, N-(2-(2-cyanoethyl)-N-(p-
chlorobenzoyl)alanyl)-L-leucine sodium salt, N-(2-(2-cyanoethyl)-N-(p-chlorobenzoyl)alanyl)-L-alanine methyl ester, N-(2-(2-cyanoethyl) -N-(p-chlorobenzoyl)alanyl)-L-alanine sodium salt, N-(2-(2-cyanoethyl)-M-(p-chlorobenzoyl)alanyl)aminomalonic acid dimethyl ester, N-(2- (2-cyanoethyl)-N-(p-chlorobenzoyl)alanyl)glycine methyl ester,
N-(2-(2-cyanoethyl)-1!-(p-chlorobenzoyl)alanyl)-L-valine methyl ester,
N-(2-(2-cyanoethyl)-N-(p-chlorobenzoyl)alanyl)-L-phenylchrysine methyl ester, N-(2-(2-cyanoethyl)-N-(p-
chlorobenzoyl)alanyl)-L-phenylalanine methyl ester, N-(2-(2-cyanethyl)-1
1-(p-chloropency λ)alanyl)-L-serine methyl ester, N-(2-(2-cyanoethyl)-M
-(p-chlorobenzoyl)alanyl)-L-methionine methyl ester, N-(2-(2-cyanoethyl)-
N-(p-chloropensoyl)71nyl)-L-cysteine methyl ester, N-(p-10lopensoyl)alanyl-L-alanine methyl ester, N-(2-(2
-cyanoethyl)-1J-(p-chlorobenzoyl)alanyl)-2-(2-cyanoethyl)-L-alanine methyl ester, N-(2-(2-cyanoethyl)-M-
(p-/lorobenzoyl)crisyl)-I, -alanine methyl ester, N-(2-(2-cyanoethyl)-N
-(p-chloropensoyl)phenylcrisyl)-L-
Alanine methyl ester, N-(2-(2-cyanoethyl)-N-(p-chlorobenzoyl)leucyl)-r,
, -72-nin methyl ester, N-(2-(2-(cyanoethyl)-N-(p-chlorobenzoyl)methionyl)-L-alanine methyl ester, etc., and the compounds that can be synthesized include these exemplified compounds. It is not limited.

Formulation example 1. Injection N-(2-(2-cyanoethyl)-M-(p-chlorobenzoyl)alanyl)-ri-leucyl/methyl ester 1
0■ was dissolved in 5 wtK physiological saline and sterilized by heat according to a conventional method to prepare an injection.

Lactose 100
■Corn starch 141
5119 The powder of the above formulation was mixed and passed through a 30-mesh sieve, and the powder 300Q was placed in a No. 3 gelatin capsule to form a capsule.

■.

Patent applicant Sankyo Co., Ltd. agent Patent attorney Shoji Kashi 2゜:3゜ Procedural amendment (voluntary) July 2'3, 1980 Commissioner of the Japan Patent Office Kazuo Wakasugi Indication of the case 1988 Patent application No. 157231, Name of the invention: dipeptide derivative, relationship with the case of the person making the amendment Patent applicant address: 6 Name, 3-1 Nihonbashihonmachi, Chuo-ku, Tokyo 103 (185) Sankyo Co., Ltd. Representative: President and CEO Yoshinori Kawamura; Agent residence: 140 Sankyo Co., Ltd., 1-2-58 Hiromachi, Partagawa-ku, Tokyo, correction, supplement, correction 1.8A Detailed details lines 239 to 10 rN-(F-1
0 Lopenzoil) 7? Nyl-L-alanine methyl ester," is deleted.

1. Insert the following words between the sentences on the 5th and 6th lines of page 24.

``Further details of the melting points of the specific compounds obtained are shown below.

Claims (1)

[Claims] 1. Formula (wherein R1 is a hydrogen atom, a lower alkyl group, a lower alkyl group, a hapgen atom, a mercapto group, an alkylmercapto group, a hydroxyl group, an alkoxy group, an acyloxy group, a carboxy group, alkoxycarbonyl group, amino group, alkyl-substituted amino group, aryl-substituted amino group, acylamino group, halogeno lower alkoxycarbonylamino group, alkanesulfonyl group, nitro group or cyano group, n represents 1 to S, n When represents 2 to S, R1 may be the same or different. R2 and R1 are the same or different and are hydrogen atom, lower alkyl group, cyano group, cyano lower alkyl group, hydroxy lower alkyl group,
It represents a low M flukoxycarbonyl group, carboxy group, aryl group, aralkyl group, mercapto lower alkyl group, or alkylthio lower alkyl group, R4 represents a hydrogen atom or a cyanogen lower alkyl group, and Rs represents a hydrogen atom or an alkyl group. ) and its pharmacologically acceptable salts. Formula 1 () (wherein, R1 is a hydrogen atom, a lower alkyl group. Halokeno lower alkyl group, halogen atom, mercapto group, alkylmercapto group, hydroxyl group, alkoxy group, acyloxy group, carboxy group, alkoxycarbonyl group,
represents an amino group, an alkyl-substituted amino group, an aryl-substituted amino group, an acylamino group, a halogeno lower alkoxycarbonylamino group, an alkanesulfonyl group, a nitro group, or a cyano group; n represents 1 to 5; n represents 2 to 5; Sometimes R1 may be the same or different. R2 is a hydrogen atom, a lower alkyl group, a cyano group, a cyano lower alkyl group, a hydroxy lower alkyl group, or a lower alkoxycarbonyl group. Indicates a carboxyl group, an aryl group, an aralkyl group, a mercapto lower alkyl group, and an alkylthio lower alkyl group. ) is a compound having the formula (wherein Rli is a hydrogen atom, a lower alkyl group, a cyano group, a cyano lower alkyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group,
Carboxy group, aryl group, aralkyl group, mercapto lower alkyl group, alkylthio lower alkyl group,
R4 represents a hydrogen atom or a cyanogen lower alkyl group,
RIs represents a hydrogen atom or an alkyl group. ) in the presence of a base, wherein R1e R2@R5e R4t R5 and n are the same as defined above. Formula 1 (wherein R1 is a hydrogen atom, a lower alkyl group, a halogeno-lower alkyl group, a halogen atom, a mercapto group, an alkylmercapto group, a hydroxyl group, an alkoxy group, an acyloxy group, a carboxy group, an alkoxycarbonyl group, an amino group, an alkyl-substituted group) represents an amino group, an aryl-substituted amino group, an acylamino group, a halogeno lower alkoxycarbonylamino group, an alkanesulfonyl group, a nitro group, or a cyano group, n represents 1 to 5, and when n represents 2 to S, R1 is the same or R2 and R5 may be the same or different and are a hydrogen atom, a lower alkyl group, a cyano group, a cyano lower alkyl group, a hydroxy lower alkyl group,
Indicates lower alkylcarbonyl group, carboxy group, aryl group, aralkyl group, mercapto lower alkyl group, and alkylthio lower alkyl group. R4 represents a hydrogen atom or a cyano lower alkyl group, and R
, indicates a hydrogen atom or an alkyl group. ) and a pharmacologically acceptable salt thereof as an active ingredient. 4, Formula (wherein R1 is a hydrogen atom, a lower alkyl group, a halogeno-lower alkyl group, a halogen atom, a mercapto group, an alkylmercapto group, a hydroxyl group, an alkoxy group, an acyloxy group, a carboxy group, an alkoxycarbonyl group, an amino group,
It represents an alkyl-substituted amino group, an aryl-substituted amino group, an acylamino group, a halogeno lower alkoxycarbonylamino group, an alkanesulfonyl group, a nitro group, or a cyano group, where n represents 1 to 5, and when n represents 2 to 5, R
1 may be the same or different. R2 and R are the same or different and are a hydrogen atom, a lower alkyl group, a cyano group,
Cyano lower alkyl group, hydroxy lower alkyl group, lower alkoxycarbonyl group, carboxy group. It represents an aryl group, an aralkyl group, a mercapto lower alkyl group, or an alkylthio lower alkyl group, R4 represents a hydrogen atom or a cyanogen lower alkyl group, and Rs represents a hydrogen atom or an alkyl group. ) and a pharmacologically acceptable salt thereof as an active ingredient.