JPS5833222B2 - New dipeptides - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula (I) (wherein R1 represents a hydrogen atom or a lower alkoxy group, and 2 represents a hydrogen atom, an alkali, an alkaline earth metal, an aluminum atom, or a lower alkyl group).

) relates to novel dipeptides represented by

The dipeptides according to the present invention exhibit excellent anti-peptic ulcer activity and are useful compounds as pharmaceuticals.

The target compound of the present invention can be produced, for example, by the method shown in the following reaction formula.

(In the formula, -COX is a carboxyl group or an acid halide,
Refers to reactive derivatives of carboxyl groups such as acid anhydrides.

) That is, the benzoyl compound represented by formula (n) and the phenylalanyl-tyrosine represented by formula (m) are reacted (method ■), or the substituted phenylalanine represented by formula (IV) and the formula (V ) The target compound of the present invention can be produced by reacting with the tyrosines shown in ().

To explain in more detail, it is possible to directly react both raw materials according to the method (■) or the law (■), but when the substituent -COX in the compound of formula (n) or (■) is a carboxyl group, dicyclohexyl It is preferable to react with the other raw material represented by formula (■) or (V) using a condensing agent such as carbodiimide or 1-ethyl-3-(3-methylaminopropyl)carbodiimide.

Alternatively, the acid halide of formula (II) or (IV) may be converted into a compound of formula (III) or (V) in a suitable solvent in the presence of a suitable deoxidizing agent.
It can also be produced by reacting with a compound of

The reaction generally proceeds at room temperature, but if desired, the reaction may proceed advantageously with an appropriate amount of cooling or heating.

Examples of the condensing agent include inorganic compounds such as caustic alkali and alkali carbonate, and organic tertiary amines such as pyridine and triethylamine. In order to promote the reaction advantageously, these deoxidizing agents should be selected as appropriate. It is used as

As a reaction solvent, a solvent that does not participate in the reaction, such as chloroform, dimethylformamide, tetrahydrofuran,
Examples include ethyl acetate.

The object compound of formula (I) thus prepared is isolated from the reaction solution by known separation operations, such as extraction with various commonly used solvents, washing, concentration, etc., and if desired, further subjected to recrystallization, chromatography, etc. It is also possible to purify by the following purification means.

The target compound is usually obtained as a free acid, but if desired, it can also be obtained in the form of an alkali metal salt such as sodium, potassium, or lithium, an alkaline earth metal salt such as calcium or magnesium, or an aluminum salt.

In addition, since all of the target compounds of the present invention have an asymmetric carbon atom, it is also possible to separate them as optically active substances.

The objective compound dipeptides of the present invention exhibit excellent anti-peptic ulcer activity and are useful compounds as pharmaceuticals. Confirmed through tests, etc. (Japanese Journal Pharmacology, Vol. 19, p. 418 (1)
969); see Pharmacy, Vol. 25, p. 1453 (1974))
.

That is, 1 group of 10 rats (donryu type, male, weight 230 ~
270? ) were fasted for 24 hours, the abdomen was opened under ether anesthesia, and 0 and 05 ml of 10% acetic acid were injected into the subcapsular membrane of the stomach to create experimental gastric ulcers.Then, the target compound of the present invention was administered for 13 consecutive days. Administered orally.

On the 15th day after the ulcer was created, the abdomen was opened, the stomach was removed, and the major and minor axes of the ulcer formed in the glandular stomach were measured, and the product was used as the ulcer coefficient.

Comparative groups based on ulcer index (no drug treatment group)
The healing effect was calculated.

As a control, the well-known anti-ulcer drug glutamine (1000
The comparative healing effect was determined by setting the healing effect when using m97 kg (1 day, oral administration) as 1.00.

Furthermore, as a result of an acute toxicity test (oral administration) using mice for the target compound of the present invention, the LD, o was 4? /k
It was more than g.

For comparison, in addition to glutamine, the healing effects of tyrosine and the well-known commercially available anti-ulcer drug gefarnate were also investigated.

The results are shown below, and it is clear that the target compound of the present invention has extremely excellent anti-ulcer activity.

For the main administration, various dosage forms, such as capsules,
It can be processed into any form such as tablets, powders, injections, suppositories, etc. using known formulation techniques.

Furthermore, depending on the symptoms of the ulcer, the present invention may be used in combination with other anti-ulcer agents, such as antacids, anti-pepsin agents, or anti-cholinergic agents, and a synergistic effect can be expected when used in combination with these agents.

The basic dosage varies depending on the administration method, but it is 200 to
A dose of x2 oomy/day is sufficiently effective.

Example 1 Phenylalanyl-tyrosine methyl ester hydrochloride 3.
799 and 0.53 P of sodium carbonate were suspended in 10 parts of water and 50 ml of chloroform, cooled with water, stirred, and then mixed with 1.75 f of 4-methoxybenzoyl chloride and 0.0 ml of sodium carbonate.
．． 75f aqueous solution 107711 was added dropwise at the same time and stirred for 2 hours.

The chloroform layer was separated, washed with 5% hydrochloric acid and water, dried, and the solvent was distilled off.

The residue is recrystallized from ethyl acetate to obtain 3.91 N-(4methoxybenzoyl)-phenylalanyl-tyrosine-methyl ester.

Yield 82%. Melting point: 195-197°C.

Elemental analysis Calculated value as C27H2806N2 C68,05, H5,92, N 5.88 Actual value C68,42, H6,08, N 5.74 Example 2 Dissolve 3.28P of phenylalanyl-tyrosine in 20ml of N-caustic soda. The mixture was cooled with ice, and 1.72 g of 4-methoxybenzoyl chloride and 10 ml of N-caustic soda were added dropwise, followed by stirring for 2 hours.

Neutralize with hydrochloric acid, extract with ethyl acetate, and wash the ethyl acetate layer with water, dry, and concentrate.

The residue was recrystallized from ethyl acetate to obtain 2.61 N-(4-methoxybenzoyl)-phenylalanyl-tyrosine.

Yield 56%. Melting point: 198-200°C.

Elemental analysis C26N2606 Calculated value as N2 C6
7,52, H5,67, N 6.06 Actual value C67
, 17, H5, 69, N 5.95 Example 3 Phenylalanyl-tyrosine 3.2 s Pwon-4
Dissolve the solution in 20 r/Ll of sodium chloride, cool with water, add 1.42 ml of benzoyl chloride and 10 ml of N-caustic soda dropwise, and stir for 2 hours.

Thereafter, in the same manner as in Example 2, 2.29 ft of N-pensoylphenylalanyl-tyrosine was obtained.

Yield 51%. Example 4 N-(4-methoxybenzoyl)-phenylalanyl-
Dissolve 0.9f of tyrosine in 10ml of ethanol and 10ml of water.
Add TLl.

Adjust the pH to 8 by adding N-caustic soda.

Concentrate and dry to obtain sodium N-(4-methoxybenzoyl)-phenylalanyl-tyrosine in powder form.

Example 5 N-benzoyl-phenylalanyl-tyrosine 202 was dissolved in 400 M of water-isopropanol (1:1) to give 4
Heat to 0', stir, and add 200 ml of an impropatol solution of 18.8 P of aluminum isopropoxide.

After stirring at 40° for 1 hour, the mixture was left overnight, centrifuged, and the supernatant was concentrated. Dissolved in isopropanol, centrifuged, and concentrated.

The residue is dissolved in an inproper tool and water is added to obtain aluminum N-penzoyl-phenylalanyl terocinate 101 as a powder.

Melting point: 287°C (decomposition point). Example 6 N-Pen''/El phenylalanine 5.39f, tyrosine methyl ester hydrochloride 4.64f, triethylamine 2.029, N-hydroxysacmineimide 2.3
09 to chloroform-tetrahydrofuran (221) 1
00 mA, cooled on ice, added 4.129 g of N.N'-dicyclohexylcarbodiimide, and stirred for 3 hours.

After standing overnight at room temperature, the precipitate was filtered off, the filtrate was concentrated and extracted with ethyl acetate.

The ethyl acetate layer was washed with 2% hydrochloric acid, 4% sodium bicarbonate, water, dried and the solvent was evaporated.

The residue was recrystallized from ethyl acetate-petroleum ether to give N-benzoyl phenylalanyl-tyrosine methyl ester 6.
．． Get 6f.

Yield 74%. Melting point: 188-190°C.

4.49 ml of N-benzoyl phenylalanyl tyrosine methyl ester was dissolved in 50 ml of methanol, 23 ml of N-caustic soda was added, and the mixture was stirred for 1 hour.

Neutralize with hydrochloric acid, concentrate, and extract with ethyl acetate. The ethyl acetate layer is washed with water, dried, and concentrated.

The residue is recrystallized from ethyl acetate to obtain 3.81 N-benzoyl-phenylalanyl tyrosine.

Yield 87%. Melting point: 191-192°C.

Example 7 N-(4-methoxybenzoyl)-phenylalanine 2
9.9? , tyrosine methyl ester hydrochloride 23.2f,
10.1 fI of triethylamine and 11.1' of N-hydroxysuccinimide were dissolved in 500 ml of chloroform-tetrahydrofuran (2:1), cooled on ice, and N-N'-
Add 20.69 g of dicyclohexylcarbodiimide and stir for 2 hours.

After standing overnight at room temperature, the precipitate was filtered off, the filtrate was concentrated and extracted with ethyl acetate.

The ethyl acetate layer was washed with 2% hydrochloric acid, 4% sodium bicarbonate, water, dried and the solvent was evaporated.

Recrystallize with ethyl acetate to obtain N-(4methoxybenzoyl)
- Phenylalanyltyrosine methyl ester point 195-197°C.

N-(4-methoxybenzoyl)-phenylalanyl-
Tyrosine methyl ester 302 in methanol 15Qml
Add N-caustic soda 1451111 to 50
Warm to °C and stir for 2 hours.

Neutralize with hydrochloric acid, concentrate, and extract with ethyl acetate. The ethyl acetate layer is washed with water, dried, and concentrated.

The residue was recrystallized from ethyl acetate to obtain 23.9P of N-(4-methoxybenzoyl)-phenylalanyl-tyrosine.

Yield 82%.

Claims (1)

[Scope of Claims] Dipeptides represented by the general formula 1 (wherein R1 represents a hydrogen atom or a lower alkoxy group, and Z represents a hydrogen atom, a metal atom or a lower alkyl group). The dipeptide according to claim 1, which is 2N-(4-methoxybenzoyl)-phenylalanyl-tyrosine.