KR850000697B1 - Method for preparing 1- (acylamino-aroxy) -2-hydroxy-3-alkynyl-aminopropane - Google Patents

Abstract

No content.

Description

Method for preparing 1- (acylamino-aroxy) -2-hydroxy-3-alkynyl-aminopropane

The present invention relates to a novel compound of the general formula (I) and acid acid salt thereof having an adrenaline antagonistic effect.

-위치에 자유원자가 결합을 가진 2가 그룹-CH=CH-CH=CH- 또는 (CH₂)_n(n=3 내지 5의 정수)이고, R₃는 수소 또는 탄소수 1 내지 3의 알킬 그룹이고, R₄는 탄소수 1 내지 3의 알킬그룹이거나, R₃와 함께 그룹(CH₂)_p(p는 4 내지 6의 정수)를 나타낸다.In the above general formula, R ₁ is an ethyl or isopropyl group, R ₂ is hydrogen, halogen, alkyl of 1 to 4 carbon atoms or alkoxy group of 1 to 4 carbon atoms,

A divalent group having a free atom bond in the —position is —CH═CH—CH═CH— or (CH ₂ ) _n (an integer of n = 3 to 5), R ₃ is hydrogen or an alkyl group having 1 to 3 carbon atoms , R ₄ is an alkyl group having 1 to 3 carbon atoms, or represents a group (CH ₂ ) _p (p is an integer of 4 to 6) together with R ₃ .

The novel compounds of formula (I) can be prepared by reacting a compound of formula (V) or a salt thereof with an azetidinol derivative of formula (VI) in anhydrous medium.

In the above general formula

R ₁ , R ₂ , R ₃ and R ₄ are as defined above.

The phenols of general formula (V) and azetidinol of general formula (VI) can be prepared according to the methods described in the literature. [See Chem, Pharm, Bull (Japan), Vol 22 (7), 1974, p. 1490].

The compounds according to the invention contain asymmetric carbon atoms on the CHOH group and thus also produce racemates and optically charged objects. The optically-conjugated can be prepared by the use of racemates in conventional auxiliary acids [eg, dibenzoyl (di-p-toluyl-) D-tartaric acid or d-3-bromo-campa-8, even when optically active starting materials are used. -Sulfonic acid] to obtain.

The 1-phenoxy-2-hydroxy-3-alkynylaminopropane of general formula (I) according to the present invention can be converted to physiologically acceptable acid salts by conventional methods. Examples of suitable acids used here include hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, maleic acid, acetic acid, oxalic acid, lactic acid, tartaric acid or 8-chlorotheophylline.

Compounds of formula (I) and their physiologically acceptable acid salts have shown useful therapeutic effects, in particular β-antiadrenergic action, in animal studies using guinea pigs as test animals, for example in humans. It is useful for the treatment and prevention of coronary diseases, cardiac arrhythmias, especially tachycardia. The compounds of the present invention also exhibit therapeutically useful blood pressure lowering action. Known β-receptor blockers, for example 1- (2-acetyl-4-butyroylamino) phenoxy-2-hydroxy-3-isopropyl-aminopropane (commercially available product having a structure similar to this compound) Compared to acebutorol), the compounds of the present invention are significantly low in toxicity and exhibit β-alulid antagonism and good organ selectivity. This property is measured by the following test.

1. Inhibition of tachycardia induced by isoprenin (alludrin antagonistic effect).

Way

Inhibition of tachycardia induced by administration of a standard amount of isoprenin and its effect on base heart rate when increasing the intravenous dose of β-antiadrenergic agent.

Laboratory animals

Guinea pigs, gender 270-350 g. An unlimited supply of standard nutrients and water is required until testing and no impacts are supplied until 16 hours before the start of the test.

anesthesia

Intraperitoneally administer 1.75 g / kg ethyl urethane as a 20% solution and reinject if necessary.

Ready

Injecting cannula into jugular vein for intravenous injection: Connecting cannula and ventilator:

Subcutaneous needle bed (25mm / sec) terminal with lead (II) to record electrocardiogram: Rectal thermometer to control body temperature, body temperature constant between 34˚ and 36˚C using electronic automatic device Maintain.

Examination course

Heart rate is measured by calculating γ-wavelength in ECG (each recording time is 3-4 seconds). Normal heart rate is recorded and averaged by measuring 5 times at 2 minute intervals after approximately 30 minutes. Subsequently, 1 µg / kg of isoprenin, an adrenaline promoter, is injected intravenously and the heart rate is recorded for 3 minutes at 30 seconds each. Isoprenal injections are repeated at 30 minute intervals during the test. When the heart rate is spontaneously constant and the tachycardia response to the first two to three isoprelinin doses is uniform, 15 minutes after this time and 15 minutes prior to the next isoprenaline reaction test, Intravenously. The dose of test substance is increased within the geometric range at 60 minute intervals until the tachycardia induced by isoprenin is significantly suppressed.

2. Testing for Cardiac Selectivity in Guinea Pigs

Way

Inject a histamine aerosol lethal dose to a waking guinea pig according to the D. Dunlop and R. G. Shanks methods [see: D. Dunlop and RG Shanks, Brit, J. Pharmacol. 32, 201 (1968). The animal is pretreated with isoprenaline to protect it from lethality by histamine. β-antiadrenergic action neutralizes with isoprenal so that protection from bronchospasm by histamine is lost, in which case cardiac selective agents are not involved. If the β-antiadrenergic substance in the heart does not show any antagonism against isoprenulin, it may be assumed that a cardiac selective substance (called β ₁ -receptor) is present.

Laboratory animals

Unlimited feeding of standard nutrients and water in one group of male and female guinea pigs weighing 350-400 g (6 animals per dose) is stopped 16 hours before the start of the test.

Examination course

Several groups of animals (6 males and 3 females) in one group were subcutaneously administered with 5 or more doses of β-antiadrenergic substance, and after 15 minutes, subcutaneously subcutaneously with 0.1 mg / kg of isoprenin. Inject. After another 15 minutes, the test animal is placed in a 2 L cylindrical box, sprayed with a water-soluble histamine aerosol (1.25%) for 45 minutes and then evaluated for mortality.

Assessment Methods

가 수득된다. 상기 지수가 1보다 큰 물질은 심장 선택성을 갖는 것으로 간주된다.Lethality was assessed as log dose and LD ₅₀ was Jay. It is measured according to the method by Ritzfield and F. Wilcoxon (J. Litchfield and F. Wilcoxon J. Pharmacol, exp, Therap 96, 99-113, 1949). Selectivity index from LD ₅₀ obtained in this study and cardiac ED ₅₀ obtained from isoprenin tachycardia (anesthetic guinea pick)

Is obtained. Substances with an index greater than 1 are considered to have cardiac selectivity.

Compounds of formula (I) wherein R ₃ and R ₄ are each methyl group [substituted 2-acyl-amino-1-phenoxy-3- (2-methylbutynyl-3-amino-2) -2-propanol ] Are particularly preferred, 1- (2-cyano-4-n-hexanoylamino) phenoxy-3- (2-methylbutynyl-3-amino-2) -2-propanol and salts thereof. . This compound exhibits about 20-fold strong alludrin antagonism compared to acebutorol.

The single dose of the compound according to the present invention is about 1 to 300 mg, preferably about 5 to 100 mg for oral administration, and about 1 to 20 mg for parenteral administration.

The active substances according to the invention can be formulated in conventional herbal forms, for example in dosage forms such as tablets, tablets, solutions, emulsions, powders, capsules or sustained release preparations, in the preparation of which conventional pharmaceutical excipients and conventional Phosphorus manufacturing method can be used. Tablets may contain the active ingredient in known excipients, for example inert diluents (e.g. calcium carbonate, calcium phosphate or lactose), disintegrants (e.g. corn starch or alginic acid), binders (e.g. starch or gelatin), lubricants (e.g. Magnesium stearate or talc) and / or a sustained release solvent such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinylacetate.

Tablets can also be made of multiple layers. The degree of coating can be prepared accordingly, ie the nuclei prepared in analogy to tablets are formulated with a coating of coating, for example polyvinylpyrrolidone, shellac, gum arabic, talc, titanium dioxide or sugar. In order to allow slow release or to avoid incombination, the nucleus is made up of several layers. To allow sustained release, the tablet coating may be in several layers, and the above-mentioned excipients may be used in tablet formulation. Solutions containing the active substances or mixtures of the active substances according to the invention may also contain substances which enhance taste, such as sweeteners such as saccharin, glycerin or sugar and flavoring agents such as vanillin or orange extract, in addition to suspending agents. , Thickening agents (eg sodium carboxymethyl-cellulose), wetting agents (eg condensation products of fatty alcohols with ethylene oxide) or preservatives (eg p-hydroxy benzoate). Injectable solutions are conventionally used, for example, by mixing the active ingredient with a preservative (such as p-hydroxybenzoate) or a stabilizer (such as complexes), and then filling into a vial or ampoule.

Capsules containing the active ingredient or a mixture of active ingredients can be prepared by mixing the active ingredient with an inert carrier (eg lactose or sorbitol) and then filling the gelatin capsule.

Suitable suppositories can be prepared by mixing the active ingredient or active ingredient mixture with conventional carriers, such as natural fats or polyethylene glycols or derivatives thereof.

The compounds according to the invention can also be used in admixture with other pharmaceutically active ingredients, such as coronary vasodilators, sympathetic stimulants, cardiac glycosides, or neurostabilizers.

The following examples illustrate the invention in detail without limiting its scope.

[A. Production Example]

EXAMPLE

1- (2-cyano-4-n-propionylamino phenoxy) -3- (2-methylbutynyl-3-amino-2) -2-propanol

6.3 g (0.045 moles) of 1- (2-methyl-butyn-1-yl-3-)-3-acetidinolol in 30 ml of benzyl alcohol, followed by 9.0 g (0.05 moles) of 2-sia No-4-n-propionylaminophenol and 100 mg potassium hydroxide are added with continuous stirring. The mixture is cooled by heating to 140 ° C. for 5 hours under a stream of nitrogen and then 70 ml of ether is added. After shaking several times with dilute hydrochloric acid, the basic material is extracted. This aqueous phase is washed with water and made alkaline with sodium hydroxide. The basic material precipitated in oil form is treated with ethyl acetate and washed with water and then dehydrated over sodium sulfate. The ester is distilled off and the residue is recrystallized from ethyl acetate by addition of petroleum ether. The crystals thus obtained are purified twice in the same manner.

Yield: 4.1g, Melting point: 137-139 ° C

[B. Formulation Example]

1. Refining

1- (2-cyano-4-isobutyroylamino-phenoxy) -3- (2-

Methylbutynyl-3-amino-2) -2-propanol 40.0 mg

Corn Starch 164.0mg

Secondary Calcium Phosphate 240.0mg

1.0 mg magnesium stearate

Way

The mixture obtained by thoroughly mixing the components is granulated in a conventional manner, and the granules are compressed into 445 mg tablets each containing 40 mg of the active ingredient.

Equivalent amount of 1- (2-cyano-4-isobutyroylamino-phenoxy) -3- (1-ethynyl-cyclohexylamino) -2-propanol and 1 in place of the active ingredient mentioned in this example -(2-cyano-4-n-propionyl amino-phenoxy) -3- (2-methylbutynyl-3-amino-2) -2-propanol can also be used.

2. Gelatin Capsule

The content of capsules is as follows:

1- (2-cyano-4-isobutyroylamino-phenoxy) -3- (2-

Methylbuvinyl-3-amino-2) -2-propanol 250 mg

Corn Starch 175.0mg

Way

After thoroughly mixing each component, 200 mg of this mixture is filled with gelatin capsules of appropriate size. Each capsule contains 25 mg of active ingredient.

3. Injection solution

This solution consists of the following components.

1- (2-cyano-4-n-propionylamino-phenoxy) -3-

2.5 parts of (2-methylbutynyl-3-amino-2) -2-propanol

0.2 parts of sodium salt of EDTA (ethylene diamine tetraacetic acid)

Until 100.0 parts of distilled water

Way

After dissolving the active ingredient and EDTA-salt in a sufficient amount of water, add water to a suitable volume. The solution is filtered to remove suspended particles and filled into 1 cm ampoules under sterile conditions. Finally, the ampoule is sterile sealed. Each ampoule contains 25 mg of active ingredient.

4. Slow-release type tablet

Nuclear:

(-)-1- (2-cyano-4-isobutyroylphenoxy) -3- (2-

25.0 g of methylbutynyl-3-amino-2) -2-propanol

Carboxymethyl Cellulose (CMC) 295.0 g

20.0 g of stearic acid

Cellulose acetate phthalate (CAP) 40.0 g

Way

After thoroughly mixing the active ingredient, CMC and stearic acid, the mixture is granulated in a conventional manner, using a solution of CAP dissolved in 200 ml of ethanol / ethylene acetate mixture. The granules are compressed to 380 mg of nuclei and then coated with sugar containing 5% solution made by adding polyvinyl pyrrolidone to water in the usual manner. Each coated tablet contains 25 mg of active ingredient.

5. Refining

1- (2-cyano-4-isobutyroylaminophenoxy) -3- (3-

35.0 g of ethylpentynyl-4-amino-3) -2-propanol

2,6-bis- (diethanolamino) -4,8-dipiperidino pyrimido-

75.0 g of [5,4-d] -pyrimidine

Lactose 164.0g

Corn starch 194.0g

Clomic Silicic Acid 14.0g

6.0 g of polyvinyl pyrrolidone

2.0 g magnesium stearate

Water Soluble Starch 10.0g

Equivalent amount of 1- (2-cyano-4-isobutyroyl-amino-phenoxy) -3- (2-methylbutynyl-3-amino instead of the β-antiadrenergic active substance described above in this example 2-propanol can also be used.

Way

The active ingredient is thoroughly mixed with lactose, corn starch, claptic silicic acid and polyvinyl phytolidone and granulated in a conventional manner, using an aqueous solution of water soluble starch. The granules are mixed with magnesium stearate and compressed into 1,000 tablets, each weighing 500 mg. Each tablet contains 35 mg of the first active ingredient and 75 mg of the second active ingredient.

Claims (1)

A method of preparing a compound of formula (I) and acid addition salts thereof, characterized by reacting a compound of formula (V) or a salt thereof with an azetidinol derivative of formula (VI):

In the above formula, R ₁ is an ethyl or isopropyl group, R ₂ is hydrogen, R ₃ is hydrogen or an alkyl group having 1 to 3 carbon atoms, R ₄ is an alkyl group having 1 to 3 carbon atoms, or R ₃ together with R _{3 represents} a group- (CH ₂ ) _p (p is an integer of 4 to 6).