JPS584026B2 - Pyrazine Yudoutai Oyobi Seihou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to racemic mixtures, optically active forms thereof,
In particular, it relates to 2-(3-substituted amino-2-hydroxyglopoxy)-3-substituted pyracine compounds in the form of the levorotatory (S)-configured isomer, which have beta-adrenergic blocking activity.

The new pyrazine compounds of the present invention have the structural formula: and also have pharmaceutically effective salts thereof.

In the formula, R is phenyl and R1 is represented by straight or branched C3-6 alkyl.

Suitable pharmaceutically active salts of product (i) include, for example, acid addition salts prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid, or oxalic, lactic, malic, or maleic acids. , acid addition salts prepared from organic acids such as formic acid, acetic acid, succinic acid, tartaric acid, salicylic acid, citric acid, phenyl acetic acid, benzoic acid, p-toluenesulfonic acid, 1-1'-methylene-bis(2-hydroxy -3-naphthoate) which slowly dissociates to a relatively insoluble product, etc.

The new compound (1), which has one asymmetric carbon atom in the propylene chain, as well as its intermediates, are obtained as racemic mixtures and can be separated into optically active isomers by known methods.

Alternatively, levorotatory (S) isomers can be obtained directly using optically active oxazolidines with levorotatory (S) configuration.

Suitable separation methods for racemic mixtures include a number of optically active acids well known to those skilled in the art, such as optically active tartaric acid, mantelic acid, cholic acid, 0.0-
These include di-p-toluoyltartaric acid, O.O-di-benzoyltartaric acid, or other acids conventionally used for this purpose, and those to form salts.

Natural resolution is also conceivable as a method for separating optically active isomers.

The potential of the products as β-adrenergic blockers is conventionally evaluated in the test records used to investigate the β-blocking properties of the new compounds of the invention.

The characteristics of this protocol used include administering a selected compound to rats intravenously in a gradient dose followed by a standard dose of isoproterenol, a substance known to be a beta-agonist.

The clinical applications of beta-adrenergic blockers are well known to physicians.

The use of the new compounds of the invention may include the treatment of angina pectoris, use in hypertension in combination with or without other hypertension agents,
This includes controlling tachycardia or treating cardiac arrhythmias with excess catecholamines.

In view of the extensive literature that has accumulated regarding beta-adrenergic blocking agents, physicians are encouraged to use the present invention to treat many well-known conditions in which beta-blockade is necessary, such as the treatment of angina pectoris. will use things.

The product can be prepared by known methods, excipients, diluents, lubricants, etc. into pharmaceutical forms suitable for oral or parenteral administration, such as tablets, solutions, suspensions, emulsions, etc. It can be done using etc.

The physician may use unit dosages ranging from 1 milligram to 40 milligrams to adjust the dosage for symptoms, depending on the age of the patient and the condition.

The new pyrazine product (1) of the present invention can be produced by the synthetic steps exemplified below.

Pyrazine compound (1) is reacted with oxazolidine (2) to give oxazolidine adduct (2) which is treated with a mineral acid to give the desired final product (2).

When R2 of pyrazine ■ is chloro, this compound is
3 is reacted with hydrogen oxazolidine (■).

The reaction is carried out in the presence of a strong base and the reaction mixture can be heated to reflux or cooled to 0°C, preferably at room temperature.

A solvent for the reactants is desirable, and many conventional solvents can be used for this purpose.

Good ones are polar, aprotic solvents such as lower alkanols, dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), hexamethylphosphoramide (HMP) and the like.

It has been discovered that tert-butanol, which is easy, effective, and relatively inexpensive, is quite good as a common solvent for these intermediates.

Strong bases recommended for use in the reaction are alkali metal alkoxides and alkali metal hydroxides, and preferred ones include sodium or potassium alkoxides or hydroxides or sodium hydride.

When the S-isomer of oxazolidine is used in the reaction, the levorotatory (S) configuration of the product (1) is obtained.

If the oxazolidine used is not optically active, the final product is obtained as a racemic mixture and can be separated by many methods conventionally used for this purpose.

These reagents are advantageously combined with the reactants in the presence of a solvent as described above to produce intermediate (1), which is treated with a mineral acid to provide the desired product (2).

Heating the reaction mixture to reflux temperature is used if necessary.

Common organic solvents selected from those listed above can be used.

If the oxazolidine reagent is an optically active compound with a levorotatory configuration, the final product I is also obtained in a levorotatory configuration.

In the case of racemic form (1), the final product I is obtained in racemic form.

If the final product (1) is obtained in the form of the free base as an oil, the crystalline material can be prepared by forming its salt by known methods.

Suitable salts are prepared with mineral or organic acids, such as hydrochlorides, sulfates, hydrogen malates, or other mineral or organic acid salts.

The oxazolidine reagent (■) as a racemic mixture and S-isomer is reacted with 1,2-dihydroxy-3-substituted aminopropane or 1-sulfonyloxy-2-hydroxy-3-substituted aminopropane and an altehyde, R'CHO. It can be prepared by established methods to give the oxazolidine.

When the S-isomer of amino-alkanol is used to prepare oxazolidine, one with its levorotatory configuration is obtained,
If the starting material is racemic, it is possible to provide the racemic oxazolidine and resolve it into the optically active compounds.

The aldehyde used in the production of oxazolidine is not particularly limited, as many altehydes can be used to remove the group formed by the altehyde and to create a cyclic structure that can be decomposed by acid hydrolysis. .

For practical purposes, many commercially available and inexpensive aldehydes can be used, including aliphatic, cyclic, aromatic, or heterocyclic altehydes, such as formaldehyde, lower Alkyl aldehyde, penzaltehyde, phenyl-lower aldehyde (phenyl residue hahalogen, lower alkyl, haloalkyl, amine, acylamino, mono- or dialkylamine, nitro, alkoxy, phenoalkoxy, haloalkoxy,
A heterocyclic aldehyde optionally having one or more of the same or different substituents selected from hydroxy, etc., is a halogen,
It has substituents such as lower alkyl and phenoalkyl.

) etc. can be mentioned.

Among the many altehydes that can be used, mention may be made of formaldehyde, acetaltehyde, propionaltehyde, butylaltehyde, phenylacetaltehyde, anisaltehyde, benzaldehyde, mesitaltehyde, tolualtehyde, furfural, etc.

As mentioned above, R3 is hydrogen.

The following examples illustrate representative products of the invention made by the method described above.

However, the following examples should not be construed as limiting the preparation of many specialty compounds to the methods described in the examples, which are merely those previously known to the inventors for making the many specialty compounds of the present invention. This is just an example of the best way to do it.

Example l S-(-)-2-(3-tert-butylamino-2
-hydroxypropoxy)-3-phenylupyrazine hydrodiene maleate S-2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine (540 mg, 2 mmol +
15% excess), 2-chloro-3-phenylpyrazine (3
A mixture of potassium tert-butoxide (224 mg, 2 mmol) in tert-butanol (3 ml) is allowed to stand at room temperature for 6 days.

The solution is then evaporated and the residue treated with N-hydrochloric acid (4 ml) and stirred at 55-65°C for 75 minutes.

The mixture is cooled and extracted with diethyl ether.

Treat the aqueous layer with potassium carbonate until it becomes a strong base.

The mixture was extracted with diethyl ether and the ether extract was evaporated to give 557 mg of a pale yellow oil.

Thin layer chromatography (TLC) shows the presence of a single substance that gives a different Rf value than the starting material.

The oil was dissolved in ethyl acetate (10 ml) and maleic acid (2 l 5 mg) in ethyl acetate (9 ml).
) to give 570 mg of S-(-)-2-(
3-tert-butylamino-2-hydroxypropoxy)-3-phenylpyrazine-hydrodiene maleate is obtained.

Melting point 136.0-138.5°C. Recrystallize from a methanol ethyl acetate mixture and dry in vacuo to give 485 mg of product.

Melting point 137.5-139.0℃ (α)■-5.205(
C=3 percent, CH30H).

In the above method, racemic 2-phenyl-3-tert-butyl-5-hydroxy-methyloxazolidine was used instead of S-2-phenyl-3-tert-butyl-5-hydroxymethyl-oxazolidine to produce the final product. A substance is obtained as a racemate.

In place of the above oxazolidine, S-3-tert-butyl-5-hydroxymethyloxazolidine or S-2-ingrovir-3-tert-butyl-5-hydroxymethyloxazolidine may be used in an equivalent amount to the pyrazine starting material. The target compound can be obtained in a similar manner.

Claims (1)

[Claims] 1. It has the formula (■) and the formula (■). A method for preparing a pyrazine product having the formula: wherein R is phenyl; R1 is a straight or branched C3-
6 alkyl; R2 is chloro; R3 is hydrogen; R4 is hydrogen,
(lower alkyl, phenyl).