JPS5839150B2 - Lysinol derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of the formula (I) (wherein R1 represents a substituted or unsubstituted phenyl group or a benzyloxy group).

) or an acid addition salt thereof.

The object compound of the present invention exhibits excellent anti-peptic ulcer activity,
It is a compound useful as a medicine.

Compounds of formula (I) are, for example, compounds of formula (II) (In the formula, R1 is the same as above.

R2 means a lower alkyl group.

) or an acid addition salt thereof as a raw material compound, and can be produced by appropriately selecting and applying a general reduction method to the compound.

In that case, for example, a method is used in which the starting compound of formula (II) or its acid addition salt is brought into contact with a suitable reducing agent in a suitable solvent.

Examples of reducing agents include metal hydride complex compounds such as sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium dihydro bis-(2
Examples include hydrogenated organometallic complex compounds such as -methoxyethoxy)aluminate, diborane, etc., but are not particularly limited to these.

In some cases, additives such as calcium chloride, aluminum chloride, or halogen compounds such as boron trifluoride may be used together with these reducing agents.

In particular, the addition of calcium chloride may give good results.

As the solvent for reduction, solvents that do not participate in the reaction, such as ethers such as ethyl ether, dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, or aromatics such as benzene, are often used.

For sodium borohydride. It is possible to react in a solvent such as an alcohol or a hydrous alcohol, and is particularly suitable as a reducing agent.

Optionally, along with these solvents, additives such as hahiridine, aniline, N-methylaniline.

It is also possible to advance the reaction advantageously by using γ-collidine or amines such as diethylamine in combination.

The reaction of the present invention generally proceeds at room temperature, but if desired, the reaction may be appropriately heated or cooled to advantageously proceed.

The target compound represented by formula (I) produced in this way can be obtained by known separation procedures such as extraction with various commonly used solvents,
It can be isolated from the reaction solution by washing, concentration, etc.

If desired, it is also possible to further purify by purification means such as recrystallization and chromatography.

In addition, since all of the target compounds of the present invention have an asymmetric carbon atom, they can also be separated as optically active substances.

To the object compound (I) of the present invention thus produced,
Representative examples of the substituted phenyl group or benzyloxy group include phenyl groups or benzyloxy groups substituted with one or more lower alkyl groups, lower alkoxy groups, halogen atoms, amino groups, etc.

The object compound of the present invention exhibits an excellent anti-peptic ulcer effect and is a useful compound as a medicine.The excellent anti-peptic ulcer effect is described in the acetic acid ulcer method of Takagi, Manbe et al. (Japanese Journal on Pharma). Korojii, vol. 19, p. 418 (
1969): Pharmacy, Vol. 25, p. 1453 (1974)).

That is, a group of 10 rats (condition, male, weight 230 ~
After fasting for 24 hours, the abdomen was opened under ether anesthesia, and 0.05 ml of 10% acetic acid was injected into the subcapsular membrane of the stomach to create experimental gastric ulcers.The target compound of the present invention was orally administered for 13 consecutive days. administered.

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.

Based on the ulcer index, the healing effect was calculated relative to the control group (no drug treatment group).

As a control, the well-known anti-ulcer drug glutamine (1000
The comparative healing effect was determined by setting the healing effect when using the drug (orally administered at 1 kg/kg/day) as 1o.

Furthermore, as a result of an acute toxicity test (oral administration) using mice for the target compound of the present invention, the LD5o was 297 kg.
That was it.

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

The results are shown in Table 1, and it is clear that the target compound of the present invention has an extremely excellent anti-ulcer effect.

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
It is sufficiently effective at a dosage of 1,200 μ/day.

In addition, in order to produce the raw material compound represented by formula (I[) used in the present invention, for example, the method of Bezas et al. (Journal of the American Chemical Society, Vol. 83, p. 719, See entry in 1961.

), first, R1C was added to Nε-benzylidene-lysine.
0OH (R1 is the same as above.

), such as acid chloride (R1C0Cl), to produce the lysine derivative shown below.

Next, by esterifying this compound of formula (III), the starting compound of formula (I[) or its acid addition salt can be easily produced.

Reference Example Methanol 240M is cooled to -10 to -12°C, and thionyl chloride 14.3P is added dropwise thereto.

Next, 16.8 f of Nα-benzyloxycarbonyl-lysine (the compound described in the above-mentioned literature by Bezas et al.) is added, and the mixture is stirred overnight at room temperature.

The reaction solution is concentrated under reduced pressure, the concentrate is dissolved in 100 liters of cold water, 240 liters of a cooled 5% aqueous sodium carbonate solution is added, and the mixture is extracted with ethyl acetate.

Wash the extract with brine, dry, and concentrate.

The obtained Nα-benzyloxycarbonyl-lysine methyl ester is treated with methanol/hydrochloric acid to obtain Nα-benzyloxycarbonyl-lysine methyl ester/hydrochloride as an oil.

Elemental analysis Calculated value as C15H2□N2O4・HCl-H20 C51,65, H7,23, N8.03 Actual value C51,52, H7,05, N8.06 Example 1 Sodium borohydride 152η was cooled on ice for 50☆ ☆Dissolved in 3rIll of methanol and added 331 Nα-benzyloxycarbonyl-lysine methyl ester hydrochloride.
Add dropwise 3 ml of 50% methanol solution (2).

After stirring in a water bath for 1 hour, the mixture was stirred at room temperature for 3 hours. The precipitated crystalline substance is filtered, and methanol is distilled off from the filtrate under reduced pressure to precipitate a solid substance.

This was recrystallized from ethyl acetate to obtain 140 m9 of Nα-penzyloxyluponyluridinol.

Colorless needle crystals, melting point 122.5-144.5°C.

Elemental analysis Calculated value as C14H22N203 C63,13, H8,33, N10.52 Actual value C63,04, H8,44, N10.45 Example 2 Nα-benzoyl-lysine methyl ester/hydrochloric acid in the same manner as Example 1 Nα-benzoyl+)cinol is obtained from the salt.

Recrystallized from benzene, melting point 157-158°C.

This is dissolved in methanol/hydrochloric acid, methanol is distilled off, and crystallized from benzene to obtain Nα-benzoyl-ricinol hydrochloride.

Melting point: 150-153.5°C.

Elemental analysis C1s H20N202 Calculated value as HCl C57,24, H7,76, N10.27 Actual value C57,24, H7,67, N10.05 Examples 3 to 5 The following was carried out in the same manner as in Examples 1 and 2. A compound was prepared.

Claims (1)

[Scope of Claims] Ricinol derivatives represented by the general formula 1 (wherein R1 represents a substituted or unsubstituted phenyl group or benzyloxy group) and acid addition salts thereof.