KR850000696B1 - Process for preparing 1-(acylamino-aryloxy)-2-hydroxy-3-alkinyl-aminopropanes - Google Patents

Abstract

I [R1 = ethyl, isopropyl; R2 = H, halogen, C1-4 alkyl or alkoxy; R3 = H, C1-3 alkyl; R4 = C1-3 alkyl; or R3R4 = (CH2)n n = 4-6 were prepared as, e.g., antiarrhythmics. Thus, 3-(2-methylbutene-3-amine- 2)-5-(2-cyano-4-isobutyroyl-aminophenoxy-methyl)oxazolidine was refluxed for 30 min. with KOH in EtOH to give 1-(2-cyano-4- isobutyroylaminophenoxy)-3-(2-methylbutynyl-3amino-2)-2-propanol.

Description

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

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

In the general formula, R ₁ is an ethyl or isopropyl group, R ₂ is hydrogen, halogen, alkyl having 1 to 4 carbon atoms or alkoxy group having 1 to 4 carbon atoms, or a divalent group having a free atom bond in the 0-position- CH = CH-CH = CH- or (CH ₂ ) _n (n = an integer from 3 to 5), R ₃ is hydrogen or an alkyl group of 1 to 3 carbon atoms, R ₄ is an alkyl group of 1 to 3 carbon atoms or group with R ₃ (CH _{2) p} represents a (p is an integer from 4 to 6).

The novel compounds of formula (I) are prepared by hydrolyzing, for example, oxazolidine derivatives of formula (IV) with sodium hydroxide or potassium hydroxide solution in water or alcohol-water mixtures.

In the general formula, R ₁ , R ₂ , R ₃ and R ₄ are as defined above, X is -CO-, -CH ₂ -or -CH- lower alkyl group.

CH(여기서 R₃및 R₄는 상기에서 정의한 바와 같다)의 아민과 반응시켜 제조 가능함]과 반응시켜 제조할 수 있다.The oxazolidinone of the general formula (IV) (in the case of a compound of which X is CO) is the epoxide of the general formula (II), which is a urethane of the general formula (VII), which is ethyl chloroformate and general NH ₂ -CR ₃ R ₄ -C

Can be prepared by reacting with an amine of CH, wherein R ₃ and R ₄ are as defined above.

또는 -CHOH-CH₂-Hal(Hal=할로겐)이다.In the general formula, R ₁ , R ₂ , R ₃ and R ₄ are as defined above, Z is

Or -CHOH-CH ₂ -Hal (Hal = halogen).

-톨루일)-D-타르타르산 또는 d-3-브로모-캄파-8-설폰산]을 사용하여 분리시키므로써 수득할 수 있다.The compounds according to the invention contain asymmetric carbon atoms on the CHOH group and thus produce racemates and optical colons. Optical colons can be used to treat racemates with conventional auxiliary acids [eg, dibenzoyl (each di-

-Toluyl) -D-tartaric acid or d-3-bromo-campa-8-sulfonic acid].

The 1-phenoxy-2-hydroxy-3-alkynyl aminopropane of general formula (I) according to the present invention can be converted into physiologically acceptable acid addition salts by conventional methods. Examples of suitable acids used at this time 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 addition salts have shown useful therapeutic effects, particularly β-antiadrenergic action, in animal tests using guinea pigs as test animals, for example, in humans It is effective 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 (ace) Compared to butorol), the compounds of the present invention are significantly less toxic and exhibit β-aludrin antagonism and excellent 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, regardless of gender, weighing between 270 and 350 g.

An unlimited supply of standard nutrients and water will not be tested until 16 hours before the start of the test.

anesthesia

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

Ready

Inserting a cannula into the jugular vein for intravenous injection; Connecting cannula and ventilator; A subcutaneous needle electrode (25 mm / sec) whose lead is made of lead (II) for recording an electrocardiogram; Rectal thermometer to control the body temperature, the body temperature is kept constant between 34 ° to 36 ° C using an electronic automatic device.

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 measured 5 times at 2 minute intervals after about 30 minutes and averaged. Subsequently, 1 μg / kg of adrenaline promoter isoprenin 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 was spontaneously constant and the tachycardia response to the first two to three doses of isoprenin became uniform, the first dose of test substance was taken 15 minutes after this time and 15 minutes before the next isoprenaline reaction test. Intravenously. The dose of test substance is increased within the geometric range at 60 minute intervals until the isoprene-induced tachycardia is significantly suppressed.

2. Test Method for Cardiac Selectivity in Guinea Picks

D. Dunlop and Al. G. Inject a histamine aerosol lethal dose to a waking guinea pig according to the method of Cheksk. [See also: 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 6 animals (3 male and female each) were subcutaneously administered with β-antiadrenergic substances in multiple doses of 5 or more, and 15 mg after subcutaneous subcutaneous 0.1 mg / kg of isoprenin 15 minutes later. 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 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. Ritzfield and F. Measure according to the method by Wilcoxon. [See: J. Lichfield and F. Wilcoxon J. Pharmacol. exp. Therap. 96, 99-113, 1949. Selectivity index from the LD ₅₀ obtained in this study and the heart obtained from the isoprenin tachycardia (anesthetic guinea pig) test.

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

-아실-아미노-1-페녹시-3-(2-메틸부티닐-3-아미노-2)-2-프로판올]이 유용하며, 특히 1-(2-시아노-4-n-헥사노일아미노)페녹시-3-(2-메틸부티닐-3-아미노-2)-2-프로판올 및 이의 염이 바람직하다. 이 화합물은 아세토부토롤과 비교하여 볼 때 약 20배의 강한 알루드린 길항작용을 나타낸다.A compound of formula (I) wherein R ₃ and R ₄ are each methyl group [substituted

-Acyl-amino-1-phenoxy-3- (2-methylbutynyl-3-amino-2) -2-propanol] are useful, in particular 1- (2-cyano-4-n-hexanoylamino Phenoxy-3- (2-methylbutynyl-3-amino-2) -2-propanol and salts thereof are preferred. This compound exhibits about 20-fold strong alludrin antagonism compared to acetobutorol.

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 It can be used as a manufacturing method. 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, carboxymethylcellulose, cellulose acetate phthalate or polyvinylacetate.

Tablets can also be made in several layers. The degree of coating can be produced accordingly. That is, the nuclei prepared in a similar way to tablets are formulated by coating them with tablet coatings such as polyvinylpyrrolidone, shellac, gum arabic, talc, titanium dioxide or sugar. The nucleus is made up of layers to allow for slow release or to avoid incombination. To allow sustained release, the tablet coating may be composed of several layers, and the above-mentioned excipients may be used in tablet formulation. The solution containing the active substance or mixture of active substances according to the present invention may also contain taste enhancing substances such as sweeteners such as saccharin, glycerin or sugar and flavoring agents such as vanillin or orange extract, in addition to suspensions. Agent, a thickening agent such as sodium carboxymethyl-cellulose, a wetting agent such as a condensation product of a fatty alcohol with ethylene oxide, or a preservative such as P-hydroxy benzoate. Injectable solutions are usually filled with a vial or ampoule, for example by mixing the active ingredient with a preservative (such as P-hydroxy benzoate) or a stabilizer (such as complexes) and the like.

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 may be prepared by mixing the active ingredient or mixture of active ingredients with conventional carriers such as natural fats or polyethylene glycol 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 nerve stabilizers.

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

[A. Production Example]

EXAMPLE

1- (2-cyano-4-isobutyroylaminophenoxy) -3- (2-methylbutynyl-3-amino-2) -2-propanol

4.06 g (0.01 mol) 3- (2-methylbutyn-3-amine-2) -5- (2-cyano-4-isobutyroyl-aminophenoxy-methyl) -oxazoli in 25 ml of ethanol Dinon-2 was added to 25 ml of ethanol to which 2 g of potassium hydroxide in 5 ml of water was added, followed by boiling under reflux for 30 minutes. The solvent was distilled off, the residue was treated with water and shaken with ethyl acetate. The organic phase is extracted with dilute hydrochloric acid, then the aqueous phase is washed with ethyl acetate and made alkaline with sodium hydroxide. The base precipitated in oil form is dissolved in ethyl acetate, washed, dehydrated with sodium sulfate, and the residue obtained by distilling the ester is recrystallized twice under petroleum ether addition.

Yield: 1.6g Melting point: 109-111 ° 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 tablets of 445 mg each containing 40 mg of the active ingredient.

Equivalent amounts of 1- (2-cyano-4-isobutyroylamino-phenoxy) -3- (1-ethynylcyclohexylamino) -2-propanol and 1- in place of the active ingredient mentioned in this example (2-cyano-4-n-propionylaminophenoxy) -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-

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

Corn Starch 175.0mg

Way

After thoroughly mixing the components, 200 mg of this mixture is filled into gelatin capsules of the 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-

Methylbutynyl-3-amino-2) -2-propanol 2.5 parts

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

Until distilled water reaches 100.0 parts

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 sterilized and sealed. Each ampoule contains 25 mg of active ingredient.

4. Slow-release type tablet

Nuclear; (-)-1- (2-cyano-4-isobutyroylphenoxy)-

25.0 g of 3- (2-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 hex and then coated with sugar containing 5% solution made by adding polyvinyl pyrrolidone to water in the usual manner. Each coating contains 25 mg of active ingredient.

5. Refining

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

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

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

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

Lactose 164.0g

Corn starch 194.0g

14.0 g of colloidal silicic acid

6.0 g of polyvinyl pyrrolidone

2.0 g magnesium stearate

Water Soluble Starch 10.0g

Equivalent amount of 1- (2-cyano-4-isobutyroylamino-phenoxy) -3- (2-methylbutynyl-3-amino) in place 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, colloidal silicic acid and polyvinyl pyrrolidone 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 for producing an acid addition salt of a compound of the general formula (I) and an auxiliaries, characterized in that the oxazolidine derivative of the general formula (IV) is hydrolyzed.

In the general 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 together with R ₃ Group-(CH ₂ ) _p- (p is an integer from 4 to 6), and X is -CO-, -CH ₂ -or -CH- lower alkyl group.