DK154288B - ANALOGY PROCEDURE FOR PREPARING 1-ARYLOXY-4-AMINO-2-BUTANOLS - Google Patents

Description

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DK 154288 B

The present invention relates to an analogous process for the preparation of 1-aryloxy-4-amino-2-butanols of the formula:

ArO-CH2-CHOH-CH2-CH2-NR1R2 (I) 5 wherein Ar, R1 and R2 have the meanings or pharmaceutically acceptable acid addition salts thereof in the preamble of claim.

In the definitions of the symbols of formula I, and where these 10 otherwise appear in the present text, the following terms have the meanings stated.

The term "C 1-4 alkyl" refers to straight and branched groups having a maximum of 4 carbon atoms, and examples of which may be mentioned such as methyl, ethyl, propyl, isopropyl and tertiary butyl.

The term "C 6 -cycloalkyl" refers to cyclic alkyl groups having 5 to 8 carbon atoms and includes such groups as cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "phenyl-C 1-6 alkyl" includes benzyl and phenethyl.

The compounds of this invention are generally characterized by pharmacological activity. The compounds are local anesthetics, α-adrenergic blocking agents, β-adrenergic blocking agents and anti-thymic agents.

Various 1-aryloxy-3-amino-2-propanols with β-30 adrenergic blocking effect, anticonvulsant, sedative and sedative effect are known. Among U.S. Patents which disclose the aforementioned 1,3-disubstituted 2-propanols and their pharmacological effects are U.S. Patents Nos. 3,337,628, 3,415,873, 3,432,545 and 3,520,919.

U.S. Patent No. 3,337,628 specifically relates to 1-isopropylamino-3- (1-naphthyloxy) -2-propanol, which compound is an effective β-adrenergic in so-called blocking agent.

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2

The compounds of this invention were investigated for pharmacological action and were found to have antiarrhythmic utility against experimentally induced cardiac arrhythmias in dogs. The known homologous 1,3-disubstituted 2-propanol also has antiarrhythmic effect. However, in contrast to the known 2-propanols, the compounds of the present invention have minimal β-adrenergic blocking effect, which allows them to be used to influence moderate to severe arrhythmia without the risk of cadiac failure and respiratory difficulties, which hazards arise when the known 1,3-disubstituted 2-propanols with effective / 3-adrenergic blocking effect are used to treat cardiac arrhythmia.

Compounds of formula I wherein Ar is 1-napthyl and -NRIr 2 are alkylamino, cycloal yl amino, wherein the cycloalkyl group has 5, 6 or 7 carbon atoms and phenylalkyl amino are preferred compounds because of their antiarrhythmic effect.

Compounds of formula I wherein Ar is an ortho-alkoxyphenyl group and -NRIr 2 are alkylamino, cycloalkylamino wherein the cycloalkyl group has 5, 6 or 7 carbon atoms, or phenylalkylamino are also of particular interest because of their antiarrhythmic compounds. mical effect.

The compounds are most conveniently used in the form of pharmaceutically acceptable acid addition salts. Such salts have improved water solubility compared to the free bases. Suitable acid addition salts are those derived from mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and inorganic acids such as acetic acid, citric acid, lactic acid, maleic acid, oxalic acid, fumaric acid and tartaric acid. The preferred acid addition salt is the hydrochloride. The acid addition salts may be prepared in the usual manner by reaction of the basic compounds with the selected acid, each or both of which may be in the form of ether, alcohol or acetone solutions.

The compounds can be prepared by the process according to the invention, which is characterized by the characterizing part of the claim.

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3-Aryloxy-4-chloro-2-butanols of Formula IV are useful as intermediates for the preparation of the compounds of Formula I. These intermediates can be prepared by a process schematically illustrated in Scheme I wherein the 5 symbol Ar has the previously stated meaning.

Schedule I

Preparation of 1-arloxy-4-chloro-2-butanol starting compounds 10

ArOH + C1CH2-CHOH-CH2-CH2C1 OH- (II) (III)

The (O) CH-CH 2 -CH 2 -CH 2 Cl (IV) 1-aryloxy-4-chloro-2-butanol of formula IV can be prepared by treating an aqueous alkaline solution or an aqueous-alcoholic alkaline solution of a phenol, a substituted phenol 20 or another aryl compound having an acidic hydroxy group of formula II having 1,4-dichloro-2-butanol of formula III. The addition is carried out at or below 70 ° C, preferably at a temperature in the range of 30 ° C to 65 ° C, over a period of from 3 hours to approx. 8 hours. After the addition, the reaction mixture is heated to a temperature in the range of ca. 50 ° C to approx. 75 ° C, preferably from 60 ° C to 70 ° C, for a period of about 6 hours to approx. 48 hours, usually for a period of 12 to 18 hours. The 1-aryloxy-4-chloro-2-butanol of formula IV is isolated from the reaction mixture by extraction 30 using a suitable organic solvent, e.g. ether, isopropyl ether or chloroform, and evaporation of the solvent to give l-aryloxy-4-chloro-2-butanol which can be suitably purified, such as by distillation or crystallization. Alternatively, the 1-aryloxy-4-chloro-2-butanol can be prepared by adding an aqueous basic solution to a mixture of the compound ArOH with an acidic hydroxy group and 1,4-dichloro-2-butanol at a rate such that pH is kept in the range of 9.0 to 10.5,

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4 preferably 9.5-10.0. The product is isolated as described above.

The following preparation methods are given to illustrate the processes for preparing the intermediates of formula IV.

Preparation Method 6 4-Chloro-1- (1-naphthyloxy) -2-butanol

To a mixture of 1 mole (147 g) of 1-naphthol, 350 ml of water and 2 moles (112 g) of potassium hydroxide was added at 54 ° C 1 mole (143 g) of 1,4-dichloro-2-butanol. The temperature of the reaction mixture was kept below 60 ° C during the addition of chlorobutanol. The reaction mixture was heated to 65 ° C for 12 hours, then mixed with 500 ml of water and 350 ml of chloroform. The chloroform layer was separated, washed with water, dried over sodium sulfate, concentrated, and the oil residue distilled under reduced pressure to prepare 128 g of a crystalline solid which was distilled at 162-165 ° C / 0.01 mm Hg. The solid was recrystallized with ether and petroleum ether (30-60 ° C) to produce a material which melts at 75-77 ° C.

Analysis: Calculated for 0.15150201: C 67.07%, H 6.03%

Found: C 67.19%, H 6.19%.

Preparation Method 4 4-Chloro-1- (2-methoxyphenoxy) -2-butanol

To a mixture of 2 moles (248.26 g) of 2-methoxypheno 1.4 moles (160 g) of sodium hydroxide, 250 ml of water and 1 liter of isopropanol was added with stirring 2.2 moles (314.64 g) of 1.4 -dichloro-2-butanol. The mixture became uniformly baked overnight. The reaction mixture was extracted with 1 liter of isopropyl ether, dried over sodium sulfate and distilled under reduced pressure. The distillate which was collected at 136-138 ° C / 0.015

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mm Hg (396.8 g), solidified to a white crystalline solid which melted at 48-50 ° C.

Analysis: Calculated for C 11 H 13 OCl: C 57.52%, H 6.14% Found: C 57.49%, H 6.54%.

Using the methods set forth in Preparation Methods 6 and 10, and starting with the appropriate phenol (II) and 1,4-dichloro-2-butanol (III), numerous other 1- aryloxy-4-chloro-2-butanols (IV).

Preparation Method 12 4-Chloro-1- (2-naphthyloxy) 2-butanol, mp 101-102 ° C, 15 was prepared from 2-naphthol and 1,4-dichloro-2-butanol.

Preparation Method 14 4-Chloro-1- (4-methoxyphenoxy) -2-butanol, mp 61-63 ° C, 20 was prepared from 4-methoxyphenol and 1,4-dichloro-2-butanol.

Preparation Method 19 4-Chloro-1- (2-ethoxyphenoxy) -2-butanol, bp 130-132 ° C / 0.01 mm Hg, was prepared from 2-ethoxyphenol and 1,4-dichloro-2 butanol.

A process for preparing the novel 1-aryl-30-oxy-4-amino-2-butanols (I) of the present invention is illustrated by the following reaction scheme:

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6

Scheme II

Preparation of 1-arloxy-4-amino-2-butanols 5 ArO-CH2-CHOH-CH2-CH2Cl + HNR1R2 - (IV) (V)

ArO-CH2-CHOH-CH2-CH2-NR1R2 (I) 10 wherein all the symbols have the meanings previously stated.

In the reaction scheme, 1-aryloxy-4-chloro-2-butanol (IV) is reacted with an amine (V) to prepare the novel 1-aryl-oxy-4-amino-2-butanols (I). The foregoing reaction can be carried out by (A) heating a mixture of the chlorine compound (IV) and the amine (V) with a solvent in a steel bomb, (B) heating a mixture of the chlorine compound and the amine without a solvent in a steel bomb, (C) 10 liters of a mixture of the chlorine compound, amine and a solvent at atmospheric pressure, or (D) heating a mixture of the chlorine compound and amine without a solvent at atmospheric pressure and at a suitable temperature. The methods chosen depend in part on the nature of am in the reactant. Thus, when the amine is a low molecular weight volatile amine, method (A) or (B) is preferred and the bomb content is heated to a temperature of from 100 ° C to approx. 150 ° C for a period of approx. 12 hours to approx. 24 hours. When the amine is a high molecular weight non-volatile amine or amine of low volatility, process (C) or (D) is preferred, and the reaction mixture is not refluxed at the boiling temperature of the solvent used, or the mixture is heated to a temperature of about 100 g. . 100 ° C to about 150 ° C. The reaction time can be varied, the reaction time being somewhat shorter when the chlorine compound and the amine are reacted together without the presence of a solvent and a higher reaction is used at room temperature. In each case, the reaction product is isolated by conventional acid-base extraction methods and, if desired, the free base is converted into a pharmaceutically acceptable acid addition salt which is further purified by

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7 crystallization from a suitable solvent or solvent system. 1-aryloxy-4-amino-2-butanol, which does not form well-defined salts, can be purified by vacuum distillation.

Examples 1 and 3 illustrate the preparation of the novel 1-aryloxy-4-amino-2-butanol compounds of the present invention. Table 1 indicates the physical data for additional compounds of formula I and indicates the process used for the preparation of each compound.

10

Table 2 contains the analytical data for the compounds listed in Table 1.

Example 1 4-i sopropylam in no-1- (1-naphthyloxy) -2-butanol hydrochloride

A mixture of 27.1 g (0.1 mole) of 1- (1-naphthyloxy) -2-hydroxy-butyl chloride and 100 ml of sopropylamine in a steel bomb was heated to 120 ° C for 24 hours. The reaction mixture was mixed with 300 ml of 6N hydrochloric acid and extracted with ether at room temperature. The acidic aqueous solution was basified, extracted with isopropyl ether, dried over sodium sulfate and then concentrated to dryness. The residue was dissolved in isopropanol and mixed with ethereal hydrogen chloride. The white crystalline precipitate was recrystallized from isopropanol and isopropyl ether to prepare the hydrochloride salt, melting at 125-128 ° C.

Analysis: Calculated for C 17 H 24 ClNO 2: C 65.90%, H 7.81%, N 4.52% Found: C 65.67%, H 7.91%, N 4.34%.

Example 3 1- (1-Naphthyloxy) -4-phenethylamino-2-butanol hydrochloride

A mixture of 12.5 g (0.05 mole) of 1- (1-naphthyloxy) -2-hydroxy-butyl chloride and 14.5 g (0.1 mole) of phenethylamine was heated.

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s to 120 ° C for 20 minutes on a hot plate. The resulting mixture was mixed with 250 ml of acetone, heated to boiling and then filtered at room temperature. The filtrate was treated with 50 ml of ethereal hydrogen chloride. The resulting white precipitate was filtered. The white crystalline solid was recrystallized from acetone to give 11.8 g of the hydrochloride salt, which melted at 163-165 ° C.

Analysis: Calculated for C 22 H 26 NO 2 Cl 1: C 71.05%, H 7.05%, N 3.77% Found: C 70.99%, H 6.98%, N 3.61%.

They are present in constants for some representative 1-aryloxy-4-α-mino-2-butanols prepared from 1-aryloxy-4-chloro-2-butanols and a selected amine by the methods (A), ( B), 15 (C) and (D) are listed in Table 1 and Table 2.

20 25 30 35 9

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Table 1 - Examples 7 - 72 r1 /

Ar-O-CH2-CHOH-CH2-CH2-N 5 \ R2 r1 /

-N

Ex. \ M.p.

no .__ Ar_ ___Sal t ° C Process

7 1-C10H7 -NHC2H5 HCl 153-5 A

8 1-C10H7 -NHC øHii HCl 158-60 D

11 1-C10H7 -N (CH3) C5H11 - 62-5 D

13 1-C10H7 -NHCH2C6H5 HCl * H2O 83-5 D

28 2-CH30C6H4 -NH (CH2) 2C6H5 - 112-14 D

2-CH3OC6H4 -NHCoHu H2 O 55-7 C

42 2-CH30 CgH4 -N (CH3) C6Hh maleate 109-11 D

45 2-CH3OCgH4 -NHC5H9 in HCl 112-14 D

47 2-C10H7 -NHCH (CH3) 2 - 96-8 B

48 48 4-CH3OC6H4 -NtCH3JC0Hu - 50-2 C

50 4-CH3OC6H4 -NHC0Hh - 93-5 C

58 1-C10H7 -N (CH3) C8H15 HC1 143-5 C

59 4-CH3OC6H4 -NHCH (CH3) 2 HCl 118-20 C

60 4-CH3OC6H4 -NHCgHn HCl 136-8 C

64 1 “CjqH7 -NHCgHg HCl 148-50 D

b O

67 2-C2H5OC6H4 -NHCH2C6H5 HCl 107-9 C

68 2-C2H50C6H4 -NHCgH !! - 83-5 C

69 2-C2H50CgH4 -NCgH3m m) HCl 140-2 C

72 1-C10h7 -NHCøHn _ 96-8 C

I) cyclopentyl amino m) 1-decahydroquinol in.

35

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Table 2.

Analytical data regarding Examples 7 - 72 5 Calculated_ Found_

Ex. empirically

No. formula_ C Η N _C___H_ N

7 C16H23C1N02 64.75 7.81 4.72 63.97 7.52 4.51 8 C20H28C1N02 68.65 8.07 4.00 68.46 8.16 4.03 10 11 C21H2gN02 77.02 8.93 4 , 28 76.89 8.95 4.17 13 C21H26C1N03 67.10 6.97 3.73 67.33 6.89 3.88 28 C ^ gH25N03 72.35 7.79 4.44 72.23 7.99 4.39 30 C17H29N04 65.57 9.38 4.50 65.53 8.86 4.46 42 C22H33N07 62.39 7.85 3.31 62.15 7.68 3.15 15 45 C16H26C1N03 60.85 8 4.43 60.71 8.12 4.34 47 C17H23N02 74.69 8.48 5.12 74.21 8.50 5.02 48 C18H29N03 70.32 9.51 4.56 70.15 9, 41 4.56 50 C17H27N03 70.79 8.91 4.59 70.71 8.91 4.76 58 C23H34C1N02 70.48 8.73 3.57 69.98 8.64 3.45 20 59 C14H24C1N03 58.02 8.35 4.83 57.68 8.27 4.81 60 C17H28C1N03 61.90 8.56 4.25 61.37 3.44 4.01 64 C19H26C1N02 67.94 7.80 4.17 67.76 7 , 78 4.21 67 C19H26C1N03 64.86 7.45 3.98 64.83 7.35 4.23 68 C18H29N03 70.32 9.51 4.56 70.40 9.58 4.59 25 69 C21H34C1N03 65, 69 8.93 3.65 65.78 8.77 3.60 72 C16H24N02C1 64.53 8.12 4.70 64.40 8.17 4.55

The products are preferably prepared as dosage units, each unit being intended to supply a specific dose of active ingredients. Each dosage unit suitable for oral administration may conveniently contain 10-40 mg of active ingredient. Each dosage unit intended for intracardiac or intravenous administration may conveniently contain 1-2 mg of the active ingredient per day. cm3.

35 Each dosage unit intended for intramuscular administration,. may, on the other hand, conveniently contain 5-10 mg of active ingredient per day. cm3.

11 ·

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Biological Compilation Testing

These experiments illustrate the useful and unexpected biological effects of the compounds prepared by the process of the invention compared to the properties of known compounds.

In these comparisons, the antiarrhythmic effect and the β-adrenergic receptor blocking action of the following: 10 compounds I-III prepared by the process of the invention are tested in comparison with the propanol homolog to compound I, which is homologous. also referred to as propranolol. The test conditions and test results of the study are set out in Tables 3, 4 and 5 below.

15

Compound I is:

4-isopropylamino-1- (2-naphthyloxy) -2-butanol and has the structure 20 OH

0-C H 2-CH-CH2-CH2NHCH (CH3) 2 .; 2 and is the compound of Example 1.

Compound II is: 4-ethylamino-1- (1-naphthyloxy) -2-butanol and has the structure:

OH

Q-CH2-CH-CH2-CH2-NHC2H5; and is the compound of Example 7.

35

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12

Compound III is: 4-phenethylamino-1- (i-naphthyloxy) -2-butanol and has the structure: 50H f-

1 / A

O-CH2-CH-CH2-CH2-NHC2H4-C /

hrs

and is the compound prepared according to Example 3.

Propranolol is: 3-isopropylamino-1- (i-naphthyloxy) -2-propanol and has the structure:

OH

20 I

0-CH 2 -CH-CH 2 NHCH (CH 3) 2;

ISLAND ISLAND

25 Sample for ventricular inheritance

Ventricular arrhythmias were induced in phenobarbital-pentobarbi number-anesthetized dogs when administered ouabain 40 µg / kg i.v. followed by 30 minutes of administration of 20pg / kg and 10 µg / kg every 30 minutes until arrhythmia developed. The abnormal rhythm was allowed to continue continuously for at least 15 minutes to ensure spontaneous reversal of the fast ectopic rhythm. The test compound or reference standard was administered by infusion at a rate of 1 mg / kg / minute until a normal sinus rhythm was restored. The following criteria were required to determine the efficacy of the drug against this type of arrhythmia: l) in establishing normal sinus rhythm, the compound must be able to maintain it for 60 minutes or 13 ';

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further; 2) vagal stimulation should not exhibit an automatic extopt ventricular focus, although it may induce cardiac arrest or sparse nodal escape beats (infrequent nodal escape beats); 3) i.v. administration of 80 I.U. insulin should spring-5 reverse the abnormal rhythm. The latter procedure is performed to ensure the presence of ouabain at sufficient concentrations to induce cardiac toxicity.

Table 3 10

Anti-arrhythmic effects against ouabain-induced inheritances Average

Sample correction Number of dogs 15 bundles see dose in (mq / kq i.v.) tested_

Compound I (a) 2 "75 2

Compound II (&) 1 75 75 .2

Compound III (c) 3,, 5 2

Propranolol (d) 2,, 85 2 20 (a) 4-Isopropylamino-1- (1-naphthyloxy) -2-butanol (b) 4- (ethylamino) -1- (1-naphthyloxy) -2- butanol (c) 1- (1-naphthyloxy) -4-phenethylamino-2-butanol (d) 3-isopropylamino- (1--; naphthyloxy) -2-propanol.

25

Test for β-adrenergic receptor blocking effect

The ability to antagonize isoproteronol-induced increase in cardiac rhythm of anesthetized dogs with open chest was used as a measure of β-adrenergic receptor blocking action. Geometrically separated doses of isoproteronol were administered intravenously until maximal heart rate increase was achieved. After administration i.v. of the compound or reference standard under test, the isoproteronol sequences 35 were repeated and the dose was further increased to the point of maximum reaction. Dose-response curves for isoproteronol in the presence of the antagonist were plotted and the maximum dosiS5Q (MD50) for isoproteronol was determined for each control.

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centering of antagonist. The potency of the compounds under test was determined relative to propranolol by comparing the ratio of MD50 to antagonist growth.

5 Table 4 β-adrenergic receptor blocking potency relative to propranolol 10 Test compound Relative potency

Propranolol (®) 100.0

Compound 1 (b) 3.3

Compound II (°) 3.3

Compound III (d) 5.0 (a) 3-isopropylamino-1- (1-naphthyloxy) -2-propanol (b) 4-isopropylamino-1- (1-naphthyloxy) -2-butanol (c) 4- (ethylamino) -1- (1-naphthyloxy) -2-butanol (d) 4-phenethylamino-1- (1-naphthyloxy) -2-butanol.

20

It can be seen from Tables 3 and 4 that Compounds I - 111 exhibited antiarrhythmic activity of the same magnitude as propranolol and Compounds I - 111 exhibited only a fraction of the propranolol's β-adrenergic blocking power. It is known that pro-25 pranolol's pronounced β-adrenergic blocking force can "accelerate bronchospasm, 1aryngospasm or other respiratory distress" (Remington's Pharmaceutical Sciences, 15th edition Mack Publ., Easton, Pa., Page 835). The test results in Tables 3 and 4 showed that Compounds I-III exhibited an advantageous combination of antiarrhythmic activity and minimal β-adrenergic-blocking activity compared to propranolol.

The hypotensive effect of compound I (4-isopropylamino-1- (1-naphthyloxy) -2-butanol) was tested in comparison to pro-35anol (3-isopropylamino-1- (1-naphthyloxy) -2-propanol). The test protocol and test results of the comparison study are presented in Table 5.

Test for hypotensive effect.

15 '

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Spontaneously hypertensive rats were used to determine the blood pressure lowering effect of compound I and propranolol.

5 Fixed artery catheters were placed either in the caudal artery or in the abdominal aorta. The placed catheters were used to directly measure the blood pressure of conscious animals using a Statham pressure transducer recorded with a Grass polygraph.

10

The results summarized in Table 5 show that “compound I lowered blood pressure more consistently than propranolol. As summarized in Table 5, propranolol raised blood pressure at the 5 mg / kg dose level for the first two hours and induced fluctuations in blood pressure, while compound I maintained a leaf pressure lowering effect during the same two-hour period. A sustained blood pressure lowering effect is an important and advantageous property of a hypotensive agent. Prior to the table in summarized studies of the hypotensive effect: it was not predictable that compound I would exhibit a sustained blood pressure lowering effect at the same time as propranolol at the same dose level and during the same trial showed a hypertensive effect and induced fluctuations. in the blood.

25 30 35

16 DK 154288 B

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Study of the compound 4- (cyclohexylamino) -1- (ortho-methoxyphenoxy) -2-butanol

In the present study, the antiarrhythmic effect and β-ad-5 renergic receptor blocking effect of the compound IV according to the invention were investigated in comparison with the propanol homologous compound to compound IV, ie. compound V, and with propranolol. The study method and test results are shown below.

10

Compound IV is: 4- (Cyclohexy 1 amine) -1- (neat home thoxyphenoxy) -2-butanol having the following structure: OCH3

/ OH H

/ q \ -O-ch2-ch-ch2-ch2-n- / ~ \ 20 and is the compound of Example 30.

Compound V is: 1- (Cyclohexy1 amine) -3- (ortho-methoxyphenoxy) -2-propanol of the following structure: and 3

/ OH H

30 / “t \ i i / - \ / Q Vo-CH2 -CH-CH2-N - ^ _ 2

Compound IV is a butanol compound and is homologous to Compound V, which is a propanol derivative which differs only from Compound IV with a methylene group.

Propranolol is described above.

Trial of ventricular arrhythmias 18

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Ventricular arrhythmias have been induced in phenobarbital-pentobarbi number-anesthetized dogs by administration of ouabain 40 Mg / kg i.v. after-5 followed for 30 minutes at 20 pg / kg and 10 Mg / kg every 15 minutes until arrhythmia was induced. The abnormal rhythm was allowed to continue continuously for at least 15 minutes to ensure spontaneous reversal of the fast ectopic rhythm. The test compound or reference standard was administered by infusion at a rate of 1 mg / kg / minute until the normal sinus rhythm was restored. The following criteria were met to determine the efficacy of the drug against this type of arrhythmia: 1) after establishing normal sinus rhythm, the compound must be able to maintain it for 60 15 minutes or longer; 2) vagal stimulation must not exhibit an automatic ectopic ventricular focus, although it may induce cardiac arrest or sparse nodal discharge; 3) by i.v. administration of 80 I.U. insulin must return to the abnormal rhythm. The latter measure was taken to ensure the presence of ouabain at sufficient concentrations to induce cardiac toxicity.

Table 6 25 Antiarrhythmic effects against ouabain-induced arrhythmias

Through- Number

Ouabain-induced arrhythmia test 30 Sample Forms, correction dose corrected dose see for each sample_ dose_ dogs

Compound IV 1.0; 10.0; 3.25; 4.0 4.6 4

Compound V 8.0; 12.0 10.0 2

Propranolol 4.0; 3.5; 1.0; 1.0; 8.25 5.2 10.5 5.5; 4.25; 8.0; 10.0; 7.0

DK 154288B

Test for g-adrenergic receptor blocking effect 19

The ability to antagonize isoproterenol-induced increase in cardiac rhythm in barbariat anesthetized dogs was used as a target of island receptor blocking action. Geometrically separated doses of isoproterenol ranging from 0.5 to 20 pg / kg were administered intravenously to induce a dose-dependent increase in heart rate. Following intravenous administration of the test compounds or reference standard, the isoproterenol rows 10 were repeated and dose-response curves for isoproterenol in the presence of the antagonist were plotted. Cardiac arrhythmias induced by the 2.5 µg / kg intermediate isoproterenol dose were submaximal and appropriate for subsequent determination of the relative β-adrenergic blocking activity, β-15 adrenergic blocking activity of the test compounds was determined relative to propranolol at each of the three dose levels (0.3, 1.0 and 3.0 mg / kg) and relative activity was calculated.

20 Table 7 β-adrenergic receptor-blocking effect relative to propranolol 25 Relative island-blocking effect at test compound dose (mg / kg)

Sample test (a) 0.3_1.0_3.0 X ± -s E._

Compound IV 12 24 16 16 ± 3 (b) / (c) Compound V 70 59 55 61 ± 4 (b)

Propranolol 10o ('d) ioo (d) ioo (d) 100 ± 0 (a) Each compound was tested on a separate dog. Three geometrically separated doses of the same test compound were administered, - 35 to an animal.

(b) Significantly (p <0.05) less than propranolol.

(c) Significantly (p <0.05) less than compound V.

(d) Assigned value for comparison.

Claims (1)

It is apparent from Tables 6 and 7 that Compound IV exhibits antiarrhythmic activity of the same order of magnitude as propranolol and Compound V. It is apparent from Table 7 that Compound IV exhibits only a fraction of the β-adrenergic blocking potency that Thus, compound IV exhibits a beneficial combination of antiarrhythmic activity combined with a minimal β-adrenergic blocking effect. 10 Patent Claims. Analogous process for the preparation of 1-aryloxy-4-amino-2-butanols of the formula: ArO-CH2-CHOH-CH2-CH2-NR1R2 wherein Ar represents a 1-naphthyl group, an orthomethoxyphenyl group, a paramethoxyphenyl group or an orthoethoxyphenyl group represents R 1 represents a C 1-4 alkyl group, a phenyl C 2 -C 2 alkyl group or a C 5 -C 8 cycloalkyl group, and R 2 represents hydrogen or methyl or wherein the group NR 1 R 2 represents decahydro-q ui η o 1 in, 25 or pharmaceutically acceptable acid addition salts thereof, characterized by success carrying out the steps: (1) reacting 1,4-dichloro-2-butanol with a compound of the formula ArOH, wherein Ar has the meaning defined above to form a 1-aryloxy-4-chloro-2-butanol of the formula : 30 ArO-CH2-CHOH-CH2-CH2-Cl, where Ar has the meaning defined above, and (2) reacting the latter compound with a compound 35 of the formula HNR1R2, wherein R1 and R2 have the meanings defined above, and ( 3) possible turnover of the product from step (2) with a suitable acid to form a pharmaceutically acceptable acid addition salt.