FI60201B - ANALOGIFICATION FOR THE FRAMSTATION OF AV 1-ARYLOXY-4-AMINO-2-BUTANOL WITH MEDICAL ACTIVITIES - Google Patents

Description

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National Board of Patents and Registration .... M. 2b.04.7b ^. _, (44) Date of entry and exit date. - _ n

U.S. Pat. No. 3,834,122 61898¼ Proven-Styrkt (71) AH Robins Company, Incorporated, 1U07 Cummings Drive, Richmond,

Virginia 23220, USA (72) Carl Dalton Lunsford, Richmond, Virginia, Ying-Ho Chen, Richmond,

Virginia, USA (US) (7 * 0 Berggren Oy Ab (5 * 0 Analog method for the preparation of 1-aryloxy-.alpha.-amino-2-butanols for antiarrhythmic disorders) with antiarrhythmic activity

The present invention relates to an analogous process for the preparation of novel 1-aryloxy-β-amino-2-butanols which are antiarrhythmic and have the lowest possible β-adrenergic blocking effect, and their pharmaceutically acceptable acid addition salts.

The compounds prepared by the process of the invention have the formula I.

Ar0-CH2-CHOH-CH2-CH2-NR1R2 (I) wherein

Ar is 1-naphthyl, 2-naphthyl, inden-N- or 5-) yl, 3- (or 5-) chloro-2-pyridyl, biphenyl, phenyl, monosubstituted phenyl, wherein the substituent is chlorine, trifluoromethyl, methoxy, ethoxy or acetylamino or disubstituted phenyl substituted with dimethyl or chloromethyl, R 1 is lower alkyl of 1 to 5 carbon atoms, phenyl, phenylalkyl having 1 to 3 carbon atoms in the alkyl group, 2-hydroxymethyl-2-propyl, hydroxyethyl, adamantyl, dimethylphenyl, cycloalkyl of 5 to 8 carbon atoms or methylcyclopentyl, 2 R is hydrogen or lower alkyl of 1 to 5 carbon atoms, or 1. 2 R and R together with the adjacent nitrogen atom form a heterocyclic residue which is morpholino, 3,5-dimethylmorpholinyl, piperidine, 4-phenylpiperidino, 4-phenylpiperazino, 1,2,3,4-tetrahydroisoquinolyl, 4-phenyl-1, 2,3,6-tetrahydro-1-pyridino, 4- (2-pyridyl) piperazino, 1- (2,6-dimethyl) morpholino, cyclopentylamino, 1-adamantylamino, 1-decahydroquinoline or phthal-2-imido, provided that R is not hydrogen when Ar is 1-naphthyl, phenyl or phenyl substituted by chlorine or nitro and when Ί is isopropyl, phenylpropyl or cyclohexyl.

The compounds of the formula I of the invention are generally characterized by important and significant pharmacological activity, which suggests that they can be used to combat certain physiological abnormalities in the animal body. The compounds are local anesthetics, α-adrenergic blocking agents, β-adrenergic blocking agents and antiarrhythmic agents.

Various 1-aryloxy-3-amino-2-propanols with β-adrenergic blocking, anticonvulsant, anesthetic and sedative activity are previously known. These mentioned 1,3-disubstituted-2-propanols and their US patents on pharmacological activity include e.g. U.S. Patents 3,337,628, 3,415,873, 3,432,545 and 3,520,919. In particular, U.S. Patent 3,337,628 comprises 1-isopropylamino-3- (1-naphthyloxy) -2-propanol, which is an effective β-adrenergic blocking agent. substance.

The pharmacological activity of the novel 1-aryloxy-4-amino-2-butanols of the present invention was tested and found to have antiarrhythmic use in experimentally induced cardiac arrhythmias in dogs. Previously known homologous 1,3-disubstituted-2-propanols also have antiarrhythmic activity. However, in contrast to previously known 2-propanols, the novel 2-butanols of the present invention have very little β-adrenergic blocking activity and can therefore be used to treat moderate and severe arrhythmias without the risk of heart attack and respiratory distress. previously known 1,3-disubstituted-3 60201 2-propanols with a strong β-adrenergic blocking effect.

Preferred compounds due to their antiarrhythmic activity are those compounds of formula I wherein Ar. 1 2 is 1-naphthyl and -NR R is lower alkylamino, lower cycloalkylamino having 5 to 8 carbon atoms in the cycloalkyl, phenylalkylamino, 2-hydroxymethyl-2-propylamino or phenylamino.

Compounds of particular interest due to their antiarrhythmic activity are those compounds of formula I in which Ar is an ortho-lower alkoxyphenoxy radical, in particular a methoxy-12 or ethoxy radical, and -NR R is lower-alkylamino, lower-cycloalkylamino in which lower contains 5-8 carbon atoms, phenylalkylamino, 2-hydroxymethyl-2-propylamino or phenylamino.

The invention thus relates to a process for the preparation of novel 1-aryloxy-4-amino-2-butanols which are pharmacologically useful due to their activity of the type described above, and these novel compounds are prepared by subjecting the formula

ArO-CH2-CHOH-CH2-CH2-Cl (IV)

1-aryloxy-4-chloro-2-butanol according to formula

With an amine of NHR 1 R 2 (V) to give novel 1-aryloxy-4-. . . . 1. 2 amino-2-butanols in which Ar, R and R have the same meanings as above.

Suitable substituted and disubstituted phenyl radicals are those having, as substituent or substituents, radicals which do not react or otherwise act under the reaction conditions to prepare the desired compound, such as methyl, lower alkoxy, trifluoromethyl, acetyl, acetylamino, chlorine and phenyl. Substituted phenyl radicals preferably have one or two of the above substituents, and the substituents may be in different positions on the phenyl ring.

The compounds of the invention are preferably used as pharmaceutically acceptable acid addition salts. The water solubility of these salts is better than that of the free bases. Suitable acid addition salts include those derived from mineral acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acid, and organic acids such as acetic, citric, lactic, maleic, oxalic, fumaric and tartaric acids. The preferred acid addition salt is the hydrochloride. The acid addition salts are prepared in a conventional manner by reacting a basic compound with a selected acid, both of which may then be in the form of an ether, alcohol or acetone solution.

The process of the present invention uses novel 1-aryloxy-4-chloro-2-butanols as starting materials and can be prepared as shown in Reaction Scheme I, in which all symbols have the meanings given above.

Scheme I - Preparation of 1-aryloxy-4-chloro-2-butanols (IV) used as starting materials_

ArOH + C1CH2-CHOH-CH2-CH2Cl2H2-

II III

5 60201

ArO-CH2-CHOH-CH2-CH2

IV

1-Aryloxy-4-chloro-2-butanols are usually prepared by treating a basic aqueous solution of an phenol, a substituted phenol or an aryl compound of formula II having an acidic hydroxyl group or an aqueous alcoholic solution with 1,4-dichloro-2-butanol of formula III. The addition is performed at temperatures below 70 ° C, preferably about 30 to about 65 ° C, for about 3 to about 8 hours. After the addition, the reaction mixture is heated at about 50 to about 75 ° C, preferably at 60 to 70 ° C for about 6 to about 48 h, preferably 12 to 18 h. 1-Aryloxy-4-chloro-2-butanol is isolated from the reaction mixture. extracting as a suitable organic solvent such as ether, isopropyl ether or chloroform, drying the extract and evaporating to dryness to give 2-butanol, which is isolated in a suitable manner, such as by distillation or crystallization. Alternatively, 1-aryloxy-4-chloro-2-butanol can be prepared by adding an aqueous base to a mixture of phenol or an acidic hydroxyl group compound and 1,4-dichloro-2-butanol at a rate such that the pH of the reaction mixture remains about 9.0 to about 10. , 5, preferably at pH 9.5 to 10.0. The product is isolated as described above.

The following preparation examples are presented to illustrate the invention. Preparation 1 4-Chloro-1-phenoxy-2-butanol

To a mixture of 282 g (3 moles) of phenol, 1 liter of water and 300 ml of 50% sodium hydroxide was slowly added with stirring at 60 ° C 443.36 g (3.1 moles) of 1,4-dichlorobutanol. Stirring was continued at 60 ° C for 16 h. The resulting mixture was extracted twice with 1 liter of ether, and the combined ether extracts were washed with water until neutral and dried overnight over sodium sulfate. The dried ether mixture was evaporated to dryness under reduced pressure. The residue was distilled to give 435 g of product, which distilled at 135-138 ° C / 0.05 mm. The product solidified and was recrystallized from petroleum ether (60-110 ° C) to give a white crystalline solid, m.p. 52-54 ° C.

Analysis: Calculated for C 10 H 13 ClO 2: C 59.86, H 6.53 Found: C 59.72, H 6.37 6

Prepare 2 60201 4-chloro-1- (2-chlorophenoxy) -2-butanol

To a stirred mixture of 129 g (1 mole) of 2-chlorophenol, 60 g of potassium hydroxide, 100 ml of water and 400 ml of isopropanol was added 1.3 moles (185.9 g) of 1,4-dichloro at 50 ° C. -2-butanol. The resulting mixture was heated on a steam bath overnight at 65 ° C and then extracted with 300 mL of isopropyl ether. The ether extract was washed successively with 1N sodium hydroxide, water and dried over sodium sulfate. The dried ether solution was concentrated and the oily residue was distilled under reduced pressure to give 152 g of an oily substance (b.p. 130-131 ° C / 0.01 mm).

Analysis: Calculated for C 11 H 19 Cl 2 O 3: C 51.08, H 5.15 Found: C 51.13, H 5.14

Preparation 3-Chloro-1- (3,5-dimethylphenoxy) -2-butanol

To a mixture of 245 g (2 moles) of 3,5-dimethylphenol and 2 liters of 2N sodium hydroxide was added, with stirring at 60 ° C overnight, 2.5 moles of 1,4-dichlorobutanol. On cooling, the separated solid precipitate was filtered and washed with water until neutral. Recrystallization from isopropyl ether gave 375 g of a white crystalline solid, m.p. 74-76 ° C.

Analysis: Calculated for C 12 H 17 ClO 2: C 62.02, H 7.49 Found: C 63.96, H 7.66

Preparation 4 4-Chloro-1- (4-chloro-3-methylphenoxy) -2-butanol

To a mixture of 286 g (2 moles) of 3-methyl-4-chlorophenol, 700 ml of tert-butanol, 700 ml of water and 3.0 moles of 1,4-dichloro-2-butanol were added with stirring at 40 ° C. sodium hydroxide (2.9 mol, 230 g in 700 ml of water) so that the pH remained at 9.5-10.0 as the reaction progressed. The addition took 10 h, then the reaction mixture was stirred at 40 ° C for 48 h. The resulting reaction mixture was extracted with chloroform and sodium hydroxide at 25 ° C. The chloroform extract was dried over sodium sulfate. The dried chloroform solution was evaporated to dryness, and the residue was distilled under reduced pressure at 135-143 ° C / 0.007 mm distillate. 110.9 g of product with a melting point of recrystallized from isopropanol and petroleum ether (30-60 ° C) 87-89 ° C.

60201

Analysis: Calculated for C 13 H 11 Cl 2 O 2: C 53.03, H 5 * 66 Found: C 53 * 11 * H 5.61.

Preparation 5 4-Chloro-1- (4-chloro-2-methylphenoxy) -2-butanol 4-Chloro-1- (4-chloro-2-methylphenoxy) -2-butanol was prepared by the method of Preparation 4 using 105 g (0, 74 moles) of 2-methyl-4-chlorophenol, 171.5 g (1.2 moles) of 1,4-dichloro-2-tutanol, 50.3 g of sodium hydroxide, 300 ml of water and 300 ml of tert-butanol. 84 g (45.5%) of product were obtained, which was distilled at 135 ° C / 0.01 mm.

Analysis: Calculated from the formula O-qH 2 Cl 2 Cl 2: C 53.03, H 5.66 Found: C 53.41, H 5.70

Preparation 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 at 54 ° C was added 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 at 65 ° C for 12 h, then mixed with 500 ml of water and 350 ml of chloroform. The chloroform layer was separated, washed with water, dried over sodium sulfate, evaporated to dryness, and the residual oil was distilled under reduced pressure, whereby 128 g of crystalline material was distilled at 162-165 ° C / 0.01 mm. This was recrystallized from ether and petroleum ether (30-60 ° C) to give the product, m.p. was 75-77 ° C.

Analysis: calculated for C 14 H 15 ° 2 Cl: C 67> ° 7 * H 6.03 found: C 67.19, H 6.19 ·

Preparation 7 4-Chloro- (1-biphenyloxy) -2-butanol

To a solution of 1 mol (158 g) of 4-phenylphenol, 100 g of sodium hydroxide and 500 ml of water was added 1 mol (143.02 g) of 1,4-dichloro-2-butanol with stirring at 40 ° C. The resulting mixture was heated at 68 ° C on a steam bath for 6 h, then cooled and extracted with 300 ml of chloroform. The chloroform extract was washed with water until neutral, dried over sodium sulfate and evaporated to dryness. The residual solid 8 60201 was recrystallized from isopropanol to give 180 g of a white crystalline solid, m.p. 123 ~ 124 ° C.

Analysis: Calculated for C 16 H 17 ClO 2: C 69.44, H 6.19 Found: C 69.79, H 6.22

Preparation 8 4-Chloro-1- (3-trifluoromethyl-phenoxy) -2-butanol

To a mixture of 0.5 moles (75 g) of m-trifluoromethylphenol, 1 mole (56 g) of potassium hydroxide, 100 ml of water and 400 ml of isopropanol were added with stirring at 55 ° C 0.6 moles (84 g) of 1.4- dichloro-2-butanol. The resulting reaction mixture was heated at 65 ° C for 20 h, then stirred in 2 liters of water and extracted with 400 ml of isopropyl ether. The ether extract was washed with 0.5 N sodium hydroxide and then water, dried over sodium sulfate and distilled under reduced pressure. The distillate collected at 120-124 ° C / 0.01 mm became solid at room temperature, m.p. 50 ~ 52 ° C.

Analysis: Calculated for C 11 H 12 ClP 3 O 2: C 49.18, H 4.50 Found: C 49.35, H 4.47

Preparation 9 4-Chloro-1- (4-chlorophenoxy) -2-butanol 4-Chloro-1- (4-chlorophenoxy) -2-butanol was prepared by the method of Preparation 7 from 45 g (0.5 moles) of p-chlorophenol. 72 g (0.5 mol) of 1,4-dichloro-2-butanol, 40 g (1.0 mol) of sodium hydroxide and 400 ml of water gave 85 g (36.1%) the product which, after recrystallization from isopropanol had a m.p. 62-64oc. Analysis: Calculated for C 10 H 15 ClO 2: C 51.09, H 5.14 Found: C 51.76, H 5.12.

Preparation 10 4-Chloro-1- (2-methoxyphenoxy) -2-butanol

To a mixture of 1 mole (248.26 g) of 2-methoxyphenol, 4 moles (160 g) of sodium hydroxide, 250 ml of water and 1 liter of isopropanol were added with stirring 2.2 moles (314.64 g) of 1,4-dichloro- 2-butanol. The mixture was slowly boiled overnight. The reaction mixture was extracted with 1 liter of isopropyl ether, dried over sodium sulfate and distilled under reduced pressure. The distillate (396.8 g) collected at 136-138 ° C / 0.015 mm turned to a white crystalline solid, m.p. 48-50 ° C.

9 60201

Analysis: Calculated for C 11 H 12 O 2 Cl: C 57.52, H 6.14 Found: C 57.49, H 6.54 Using the methods described in Preparations 1-10 and starting from the appropriate phenol II and 1,4-dichloro Several other 1-aryloxy-4-chloro-2-butanols IV were prepared from 2-butanol III.

Preparation 11 4-Chloro-1- (2-methyl-5-chlorophenoxy) -2-butanoyl, b.p. 135-8 ° C / 0.05 mm, was prepared from 2-methyl-5-chlorophenol and 1,4-dichloro-2-butanol.

Preparation 12 4-chloro-1- (2-naphthyloxy) -2-butanol, m.p. 101-102 ° C, prepared from 2-naphthol and 1,4-dichloro-2-butanol.

Preparation 15 4-chloro-1- (4-acetylaminophenoxy) -2-butanol, m.p. 125-128 ° C, was prepared from 4-acetylaminophenol and 1,4-dichloro-2-butanol.

Preparation 14 4-chloro-1- (4-methoxyphenoxy) -2-butanol, m.p. 61-63 ° C, prepared from 4-retoxyphenol and 1,4-dichloro-2-butanol.

Preparation 15 4-chloro-1- (3-chloro-2-pyridyloxy) -2-butanol, m.p. 56-58 ° C, was prepared from 3-chloro-2-hydroxypyridine and 1,4-dichloro-2-butano.

Preparation 16 4-Chloro-1- (5-chloro-2-pyridyloxy) -2-butanol was prepared from 5-chloro-2-hydroxypyridine and 1,4-dichloro-2-butanol.

Preparation 17 4-Chloro-1- (inden-5-yloxy) -2-butanol, m.p. 56-58 ° C, prepared from 6-hydroxyindene and 1,4-dichloro-2-butanol.

Preparation 18 4-Chloro-1- (3-chlorophenoxy) -2-butanol, 60-62 ° C, was prepared from 3-chlorophenol and 1,4-dichloro-2-butanol.

60201 10

Prepared from 2-chloro-1- (2-ethoxyphenoco) -G-butanol L, b.p. 130-132 ° C / 0.01 mm, was prepared from 1: 1 of '1 -' chloro-2-butanol.

Graduation? 00 * 4-chloro-1-vA-acetyl-pooxy--2-butanol, m.p. 125-128 ° C, was prepared from 4-acetyl-eno'1 i, j α 1, · '· 1-dichloro-2-butanol.

Preparation 21-Chloro-1- (o-Veniphenoxy) -2-butanol. , kp. 106-1.60 ° C / 0.25 mm, was prepared from o-phenylphenol and 1,4 * dichloro-2-butanol.

The preparation of the other 1-nitroxy-4-amino-G-butanol according to formula 1 can be described by the following reaction scheme:

In a diagram. " Preparation of O-1-aryl J-β-amino-2-butanol Ar0-CH.-O-10H-CHo-C1lQ-Ci + -> C. £ (i t \! .1 V v

ArO-CHO-G H OH-GH, -CH o -N RJ R ^ d d. d.

in which all symbols pii la have the meaning defined above.

Reaction of vinasa 1-aryl 1-4-chloro-2-butanol (IV) is reacted with amine (V) to give new 1-aryloxy-4-amino-2-butanol. I). The above reaction can be performed by (A) heating a mixture of chlorine compound and amine with a solvent in a steel bomb, (13) heating a mixture of chlorine compound and amine without solvent in a steel bomb, (0) boiling to restore a mixture of chlorine compound, amine and solvent at normal pressure, or (D) heating a mixture of chlorine compound and amine. without solvent at normal pressure and at a suitable temperature. The choice of method depends somewhat on the nature of the amine reactant, so that when the amine is a low molecular weight volatile amine method A or B is preferred, and the contents of the bomb are heated at about 100 to about 150 ° C for 12-2 * 4 h. When the amine is high molecular weight is an amine or a low volatility amine, method C or D is preferred, and the reaction mixture is boiled at the boiling point of the solvent used or the mixture is heated to about 100 to about 100 ° C. The reaction time may vary and is somewhat shorter when the chlorine compound and the amine are reacted without a solvent and at higher reaction temperatures. In either case, the reaction product is isolated by a conventional acid-base extraction method, and the free base is converted, if desired, to a pharmaceutically acceptable acid addition salt, which is further purified by crystallization from a suitable solvent or solvent system. 1-Aryloxy-4-amino-2-butanols, which do not form clearly defined salts, can be purified by vacuum distillation.

Examples 1-6 illustrate the preparation of the novel 1-aryloxy-4-amino-2-butanols of the present invention by one of four alternative methods. Table I summarizes the physical numbers of other compounds of formula I within the scope of the invention; it also indicates the method by which each compound was prepared.

Table II shows the analytical results of the compounds of Table I.

Example 1 4- (1,2,3,4-Tetrahydroisoquinolin-2-yl) -1- (1-naphthyloxy) -2-butanol hydrochloride

A mixture of 12.5 g (0.05 mol) of 1- (1-naphthyloxy) -2-hydroxybutyl chloride, 9.97 g (0.075 mol) of 1,2,3,4-tetrahydroisoquinoline and 300 ml of isopropanol, refluxed for 15 h. Upon standing at room temperature, a crystalline precipitate separated. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The semi-solid residue crystallized and recrystallized from acetone. 12.2 g of crystalline material were obtained, m.p. l69-171 ° C.

Analysis: Calculated from the formula:?

Example 2 1- (1-Naphthyloxy) -4-phenethylamino-2-butanol hydrochloride A mixture of 12.5 g (0.05 mol) of 1- (1-naphthyloxy) -2-hydroxybutyl chloride and 14.5 g g (0.1 mol) of phenethylamine, was heated on a hot plate at 120 ° C for 20 minutes. The resulting mixture was stirred with acetone (250 mL), heated to reflux and then filtered at room temperature. The filtrate was treated with 50 ml of ethereal hydrogen chloride solution. The resulting white precipitate was filtered. The white crystalline material was recrystallized from acetone to give 11.8 g of the hydrochloride salt, m.p. L63-L65 ° C.

Analysis: Calculated for C 12 H 12 NO 2 Cl: C 71.0 ?, H 7.05, N 3.77 Found: C 70.99, H 0.98, N 3.61

Example 5 1- (2-Chloro-phenoxy) -9- (1,2,3,9-tetrahydro-isoquinolyl) -2-butanol hydrochloride hydrate

A mixture of 11.8 g (0.0 mol) of 1- (2-chlorophenoxy) -2-hydroxybutyl chloride, 13.3 g (0.1 mol) of 1,2,3,9-tetrahydroisoquinoline and 100 ml of n-butanol, heated in a steel bomb at 120 ° C for 29 h. The reaction mixture was filtered at room temperature, the filtrate was stirred with 200 ml of 3N hydrochloric acid and extracted twice with 100 ml of sopropyl ether. The acidic aqueous solution was basified and extracted with isopropyl ether and then treated with ethereal hydrogen chloride. Recrystallization from isopropanol gave 6 g of the product hydrochloride hydrate, m.p. ll8-120 ° C.

Analysis: calculated for C ^ F ^ Cl ^ MO ^: C 59.07, H 6.52, N 3.63 Found: C 59.08, H 6.51, N 3.55

Example 1 1- (o-Chloro-1-phenoxy) -9- (9-phenyl-1-piperazinyl) -2-butanol A mixture of 35.1 g (0.15 mol) of 1- (o-chlorophenoxy) - 2-Hydroxy-butyl chloride, 32.6 g (0.2 mol) of N-phenylpiperazine and 400 ml of isopropanol were boiled at reflux for 98 t. The reaction mixture was allowed to stand in the refrigerator overnight, then filtered. The filtrate was treated with ethereal hydrogen chloride, and the salt precipitated upon addition of ether. The hard crystalline substance formed was dissolved in 0.1 molar hydrochloric acid and then neutralized with sodium hydroxide to give a crystalline precipitate. This was recrystallized from isopropanol to give 36 g of the free base, m.p. 100 to 101.5 ° C.

Analysis: Calculated from CooHol-N 'O 0Cl: G 66.56, H 6.98, N 7.76 c. U dj d <- found: C 66.99, H 7.03, N 7.86

The physical constants of some representative 1-aryloxy-9-amino-2-butanols prepared from 1-aryloxy-9-chloro-2-butanols and selected amines by Methods Λ, B, C and D are shown in Tables I and II.

1 3 60201

Table I - Examples 5-63 9H R1

Ar-O-CH 2 - (!: H-CH 2 -CH 2 -N 2 -

R

R1

-NX

For example, Sp.

ki No. Ar K2 Salt ° C Method

5 I-C10H7 -NHC2 »5 HCl 153-5 A

6 I-C10H7 -NOCi + Ha h - 54-6 D

7 I-C10H7 -NOCl2H (CH3) 2 0 HCl * H2O 118-20 D

8 I-C10H7 -N (CH3) CrHi1-62-5 D

9 1-CxoH7 -NC5H10 ° HCl 135-7 D

10 I-C10H7 -NHCH2C6H5 HCl * H2O 83-5 D

11 4-C6H5-C6H1, -NHCH (CH3) 2 HCl 190-2 B

12 3-CH3-4-ClC6H3 -NHCH (CH3) 2 - 74-6 A

13 3-CF3CgHit -NHCH (CH3) 2 HCl 92-4 B

14 2-CH3-5-ClC6H3 -N (CH3) CH2C6H5 HCl 169-71 C

15 3-CH3-4-ClC6H3 -NH (CH2) 2C6H5 HCl 163-5 A

16 2-CH3-4-ClC6H3 -NH (CH2) 2C6H5 HCl 128-30 A

17 2-ClCeHi * -NHC (CH3) 2CH2OH HCl 117-119 ° C

18 C6H5 -NH (CH2) 2C6H5, HCl 143-4 D

19 2-CH3-4-ClC6H3 -NC5H9-4-C6H5 HCl 148-50 D

20 2-CH3-4-ClC6H3 -NCi, H8N-C6H5 di-HCl 186-8 C

21 2-ClCeHi, -NC5H1 o HCl 1 59-60 C

22 3-CF 3 C 6 H ·, -NH (CH 2) 2 C 6 H 5 HCl 131-3 D

23 2-CH3-5-ClC6H * -NH (CH2) 2C6H5 HCl 141-3 D

24 3-ClCeHi * -NH (CH2) 2C6H5 HCl 154-6 D

25 2-CH3OC6H- -NH (CH2) 2C6H5 - 112-14 D

26 C6H5 -NHCH2C6H5 HCl · 1 / 2H2O 108-10 D

27 3-ClCl 6 Hi * -NHCH 2 CSH 5 HCl 139-41 D

28 2-CH3-4-ClC6H3 -NC9H10 f HCl 149-51 D

29 3,5- (CH3) 2C6H3 -1NH (CH2) 2C8H5 HCl-1 / 2H2O 1 17-20 D

30 3,5- (CH3) 2C6H3 -NCi, H8N-C6H5 - 88-90 D

31 3,5- (CH3) 2C6H3 -NC9H10 HCl · 1 / 2H2O 141-3 D

32 3,5- (CH3) 2C6H3 -NC5H7-4-C6H5 9 HCl 162-4 D

33 3,5- (CH3) 2C6H3 -N (CH3) C6Hh HCl 158-60 D

34 2-ClC6H9 -NH (CH2) 2C6H5 h - 92-4 D

35 C6H5 -NCi, H8N-2-C5H., N-maleate 123-5 D

36 C6H5 -N (CH3) C6Hh - 50-2 D

37 C6H5 -N (CH3) CH2C6H5 maleate 118-20 D

38 2-CH3OC6 Hi, -N (CH3) C6Hix. maleate 109-11 D

39 2-CH3OC6Hi, -NOCi * H6 (CH3) 2 D, n - - D

40 2-CH3OC6Hi, -NCi, H8N-2-CsHi, N3 HCl * 1 / 2H2O 95-7 D

41 2-CH 3 OC 6 Hi, -NHC 5 H 9 1 HCl 112-14 D

42 2-C10H7 -NC5H7-4-C6H5 9 HCl 168-70 ° C

43 2-C x O 7 -NHCH (CH 3) 2 - 96-98 B

44 4-CH3OC6H1, -N (CH3) C6Hix - 50-2 C

(cont'd) 14 60201

Table I (cont. <) R1

Example \ p2 Sp.

ki No. Ar _1_ Salt ° C Method

45 4-CH3CO0HCeH4 -NHCeHlx - ΐ4θ-2 C

46 1-CxoHt NHC (CH3) g.Ci20H - 98-100 ° C

47 3,5-CH3CeH3 -NHCxoHxs3 HCl 229-31 C

48 5-c9h7 * -NHCeHn - 95-7 c

49 5-C8H7 -NHCH (CH3) 2 HCl-HaO 103-5 C

50 2-CH3-5-ClCeH3 -NHCeHn. HCl 189-92 C

51 4-CH3OCeH4 -NHClO15H-78-80 ° C

52 1-C 10 H 7 -NHClO 15 H HCl 195-7 ° C

53 i-c10h7 -n (ch3) cbh15 HCl 143-5 c 54 5-C9H7K, -NHC (O¾) 2 CH3 OH - 93-5 c

55 5-ClCsH3N -NHCeHxx HCl-IfeO - C

56 1-C 10 H 7 -N (CH 3) CH 2 CH 2 OH HCl 115-17 ° C

57 1-CxoH7. -NHC5H9 HCl 148-50 D

58 5-C1CsH3N -nhch (ch3) 2 2HCl-HaO 174-77 c

59 4-CeH5-CeH4 -nhc (ch3) 2ch2oh HCl 155 ~ 57 C

60 2-C2H50CeH4 -NHCH2CgH5 HCl 107-7 C

61 2-C2H5OCeH4 -NCgHigra HCl ΐ4θ-2 C

62 2-C2H50C6H4 -NOC4He (CH3) 2n HCl 115-17 D

63 1-C10II7 -NHC5H8-2-CH3 HCl 176-8 c a. Morpholino b. 3,5-dimethylmorpholinyl c. piperidino c. 4-phenylpiperidino e. 4-phenylpiperazino f. 1,2,3,4-tetrahydroisoquinolyl g. 4-phenyl-1,2,3,6-tetrahydro-1-pyridino h. 4- (2-pyridyl) piperazino i. Cyclopentylamino j. 1-adamantyl dissolution k. Inden-5-yl 1. 5-chloro-2-pyridyl m. 1-decahydroquinoline n. 1- (2,6-dimethyl) morpholino.

15 60201

TABLE II

Analysis results of the compounds of Examples 5-63

Example- Empire- —competition- -Found_

ki n nth formula C H N C H N

5 CieHa3ClN02 64.75 7-8l 4.72 63-97 7-52 4.51 6 C18Ha3NO3 71-73 7-69 4.65 71-59 7-70 4.58 7 CaoHaoClNO * 62.57 7-88 3.65 62.51 7-68 3-73 8 c2iHa9N02 77-02 8.93 4.28 76.89 8.95 4.17 9 C18HaeClNO2 67-95 7.8o '4.17 67.73 7-79 4.06 10 CilylfeeClNOa 67-10 6.97 3-73 67.33 6.89 3-88 11 c19Ha6clNO2 67.94 7.80 4.17 67.90 7-78 3-72 12 C14H22ClNO5 61.87 8.16 5.15 61.13 8.05 4.99 13 Ci4h21NO2p3c1 51.30 6.46 4.27 51.24 6.42 4.4l 14 CiOHssCl2NO2 61.62 6.80 3.78 61.42 6.77 3.88 15 Ci9H; »9ci2no2 61.62 6.80 3-78 61.72 6.89 3-88 16 C IgHj; 5Cl2NO2 61.62 6.80 3.78 61.56 6.68 3.83 17 c i4Ha 3NO3Cl2; 51.86 7.15 4.32 51.85 7.17 4.4o 18 c1BHa4N02cl 67.17 7.52 4.35 67-22 7.56 4.31 19. c22Ha 9cl2NO2 64.39 7.12 3-41 64.10 7.28 3-57 20 CgiHssCl3N2O2 56.32 6.53 6.25 56.07 6.47 6.24 21 Ci5Ife3ClaNO2 56.26 7.24 4.37 56.00 7.23 4.30 22 c19H;> 3clF3NO2 58.54 5.95 3-59 58.35 6.00 3-75 23 ci9H5 61.51 6.85 3-64 24 C 3Cl2NO2 60.68 6.51 3.93 60.75 6.58 3.96 25 CisHasNiOa 72.35 7-79 4.44 72.23 7-99 4.39 26 c34h40o5c12n2 64.45 7.32 4.42 64.75 7-19 4.66 27 CirHaiClgNOg 59-67 6.13 4.09 59-62 6.23 4.09 59-62 6.23 62.83 6.59 3-66 62.52 6.60 3-31 29 C4OHseCl2Na0s 66.93 8.14 3.90 67.19 8.03 3.76 30 C22H30N2O2 74.54 8.53 7-90 74.36 8.61 8.03 31 c44h58ci2n2os 69.00 7.63 3.66 68.59 7.72 3-70 32 C23H30N02C1 71.21 7.79 4.10 66.72 9.46 3-98 34 CiaHssNiOaCli 67.6Ο 6.93 4.38 67.28 6.96 4.37 35 C27H33N30lo 57.96 5.94 7.5I 57.7I 5.82 7.3Ο 36 c17H27no2 73-61 9.8I 5.05 73.32 9.64 4.94 37 c22H27N0e 65.82 6.78 3.49 65.82 6.78 3.49 65.8 -39 7.85 3.31 62.15 7.68 3.15 39 c17Hs7no4 65.99 8.80 4.53 65.15 8.77 4.33 40 c2oH3 5cl3N304 49-24 7.23 8.61 49.18 6.99 8.85 41 CeifeeCiNOa 60.85 8.30 4.43 60.71 8.12 4.34 42 C25H20OClNO2 73.25 6.88 3.42 72.59 6.99 3.43 43 CiT-HaaNOa 74-69 8.48 5.12 74.21 8.50 5-02 44 C18H39K03 CieffeeNsOa 67.47 8.8l 8.74 67.35 8.75 8.65 46 CieifesNOa 71-26 8.30 4.62 71.34 8.23 4.46 / Ϊ j · · ΐ6; 60201

Table II (cont'd) „. , „.... Calculated Found

Eslmerk- Empixrxndn —---- J - * -

ki n: o formula_ C H N C H M

47 c22h34c1no2 69-54 9-02 3.69 69.26 8.95 5-73 48 CialfesNO; » 75-21 9.63 4.62 75-04 9-55 4.60 49 Cx6Ha8CiNO3 60.46 8.88 4.41 59 * 81 8.05 4.47 50 Cx7H2eClNO2 58.79 7-55 4.03 58.54 7.70 3.93 51 CsxH32N04 69.58 8.90 3 * 86 69.29 8.89 4.20 52 C24H35ClN04 65.96 7.85 3.25 53 C23H34ClN02 70.48 8.75 3-57 69.98 8.64 3-45 54 CxtHssNOs 69.59 9.27 4.77 69.66 9-24 4.65 55 CxsHaoClaNOa 51-00 7-42 7-93 51-19 7-32 8.02 56 CX7H24ClN03 62.67 7.42 4.30 62.58 7.40 4.20 57 CieffeeClNOa 67.94 7.80 4.17 67.76 7.78 4.21 58 C χ2 Ha 3C 13n2 03 41.22 6.63 8.01 42.27 6.27 8.09 59 CzoHaeCiNOa 65.65 7 * 71 3 * 83 65.37 7.67 3.75 60 Cx9Ha6ciN03 64.86 7.45 3.98 64.83 7.35 3.98 64.83 7.35 62 C18h30C1NO4 60.07 8.40 3.89 60.04 8.28 3.81 63 C2 0¾ eNO2Cl 68.65 8.06 4.00 68.28 8.06 3.85

Example 54 1- (2-Methoxyphenoxy) -4-phthalimido-2-butanol

A mixture of 24.6 g (0.1 mol) of 1- (2-methoxyphenoxy) -4-chloro-2-butanol, 18.5 g (0.1 mol) of potassium phthalimide, 150 ml of dimethylformamide and 150 ml of toluene, boiled under reflux for 8 h. The cooled filtered solution was diluted with 500 ml of water, the toluene layer was separated and washed with water until the washings were neutral.

The product separated from the washed toluene solution as a crystalline substance which was recrystallized from acetone. The recrystallized product m.p. was 1C8-110 ° C.

Analysis: 1 calculated for C 19 H 19 NO 5: C 66.85, H 5.61, N 4.10 found: C 66.94, H 5.74, n 4.15

Example 65 1- (2-Ethoxyphenoxy) -4-phthalimido-2-butanol.

A mixture of 30 g (0.12 mol) of 1- (2-ethoxyphenoxy) -4-chloro-2-1760201 butanol and 18.5 g (0.10 mol) of potassium phthalimide was slowly heated to 130 ° C: within 10 minutes and then at 160 ° C for one hour with stirring. The reaction mixture was extracted with 250 ml of hot toluene. As the toluene extract cooled, a crystalline solid separated. This was recrystallized from toluene, m.p. 93 ~ 95 ° C ·

Analysis: Calculated from the formula ^ 2οΗ2ΐΝ <^ 5: C 67.59, H 5.96, N 3.94 Found: C 67.78, H 6.03, N 4.06

The invention also provides pharmaceutical compositions for administration to live animals which contain as active ingredient at least one compound of the invention in association with a pharmaceutical carrier or diluent. The compounds are thus formulated for oral, rectal, parenteral or intracardiac administration. Thus, for example, compositions for oral administration are preferably solid and may be in the form of capsules, tablets or coated tablets containing conventional pharmaceutical carriers. Suitable diluents include, for example, lactose, potato, and corn starch, talc, gelatin and stearic and silicic acid, magnesium stearate, and polyvinylpyrrolidone.

For parenteral administration, the carrier or diluent may be a sterile, parenterally-acceptable liquid, e.g., water, or a parenterally-acceptable oil, e.g., peanut oil, filled into ampoules.

For rectal administration, the carrier may be a suppository base, e.g. cocoa butter or glyceride.

The compositions are preferably in dosage form, each unit being suitable for administration of a specified dose of active ingredient. Examples of preferred dosage unit forms according to the invention are tablets, coated tablets, capsules, ampoules and suppositories. A dosage unit suitable for oral administration preferably contains 10 to 40 mg of active ingredient; for intracardiac or intravenous administration, the dosage unit suitably contains 1-2 mg of active ingredient per cm 2, whereas for intramuscular administration, each dosage unit suitably contains 5-10 mg of active ingredient per cm 2.

Below are examples of compositions with active ingredient amounts in the preferred range: 18 60201

Pharmacological test

In anesthetized dogs, the ability of test compounds to resist isoproteronol-induced increased cardiac output was measured to give the β-adrenergic blocking effect of the compound. Dogs were given a periodic dose of isoproteronol until a maximum increase in heart rate was reached. A compound of the invention or a reference compound was added intravenously, followed by a series of isoproteronol administration until the maximum increase in stroke rate was reached. A reaction corresponding to each dose of isoproterol was prepared in the presence of the test compound and the maximum dose of isoproteronol (MD 2 Q) corresponding to each concentration of test compound was determined. The potency of test compounds with respect to propanalol was determined by comparing the ratio of MD ™ to the dose increase of 50 test compounds.

Table 111

Example Cardiac arrhythmias β-adrenergic blocking effect and relative potency 46 12.5 47 7.0 14 19.0 15 3.5 17 5.0 7 1.75 3.3 19 9.3 6 5.5 23 9.3 3 3.5 28 3.0 37 8.0 42 2.25 51 1.5

Propanol 2.85

Lidocaine 2.25 A 2.75 3.3 B 2 and 0.67

The antiarrhythmic activity of the compounds in Table 1 for which the S-adrenergic blocking effect was measured is similar.

Claims (6)

An analogue process for the preparation of novel 1-aryloxy-β-amino-2-butanols of formula I which are antiarrhythmic and have a low β-adrenergic blocking effect and which are of the formula Ar -naphthyl, 2-naphthyl, inden-4- (or 5'-yl) -3- (or 5-) chloro-β-pyridyl, biphenyl, phenyl, monosubstituted phenyl substituted with chloro, trifluoromethyl, methoxy, ethoxy or acetylamino or disubstituted phenyl substituted with dimethyl or chloromethyl, R 1 is lower alkyl of 1 to 5 carbon atoms, phenyl, phenylalkyl having 1 to 3 carbon atoms in the alkyl group, 2-hydroxymethyl-2-propyl, hydroxyethyl, adamantyl , dimethylphenyl, cycloalkyl of 5 to 3 carbon atoms or methylcyclopentyl, O 1 is hydrogen or lower alkyl of 1 to 5 carbon atoms, or 1 2. K "and R together with the adjacent nitrogen atom form a heterocyclic residue which is morpholino, 3,5-dimethylmorpholinyl, piperidino, N-phenylpiperidino, 4-phenylpiperazino, 1,2,3'-tetrahydroisoquinolyl, 4-phenyl-1, 2,3,6-Tetrahydro-1-pyridino, N- (2-pyridyl) piperazino, 1- (2,6-dimethyl) morpholino, cyclopentylamino, 1-adamantylamino, 1-decahydroquinoline or phthalol-2-imido provided that R is not hydrogen when Ar is 1-naphthyl, phenyl or phenyl substituted by chlorine or nitroxy and when R 1 is isopropyl, phenylpropyl or cyclohexyl, and for the preparation of these pharmaceutically acceptable acid addition salts, characterized in that ArO-CH 2 -CHOH-CH 2 of formula IV 1-Aryloxy-A-chloro-2-butanol of -CH2-Cl (IV) is reacted with an amine of formula V 60 60201 NHR1R2 (V) to give new 1-aryloxy-4-amino-. 2-butanols in which Ar, R and R have the same meanings as above. 2. A patent according to claim 1, comprising 1-naphthyl. Process according to Claim 1, characterized in that Ar is 1-naphthyl. 3. A compound according to claim 1, which comprises a monosubstituted phenyl. Process according to Claim 1, characterized in that Ar is monosubstituted phenyl. H. A process according to claim 3, characterized in that the monosubstituted phenyl is 2-methoxyphenyl. 4. A preferred embodiment of claim 3 is the conversion of monosubstituted phenyl to 2-methoxyphenyl. 5. The first patent claim 2, which is incorporated in Figure 1, is cyclopentyl and R is used. Method according to claim 2, characterized by 1. . 2 that R is cyclopentyl and R is hydrogen. Process according to Claim 3, characterized in that the monosubstituted phenyl is 2-ethoxyphenyl and R 1 and 2 R together with the adjacent nitrogen atom form a phthalimido residue. A method according to claim 1, characterized in. . . i.2 that Ar is 5-chloro-2-pyridylx, R is isopropyl and R is hydrogen. I. An analogous compound for the preparation of 1-aryloxy-4-amino-2-butanoler with antiarrhythmic and inert e-adrenergic activity, which is a compound of formula I ArO-CH2-CHOH-CH2-NR1R2 (I) with 1-naphthyl , 2-naphthyl, inden-4 (or 5-) yl, 3- (or 5-) chloro-2-pyridyl, biphenyl, phenyl, monosubstituted phenyl, colored substituents with chlorine, trifluoromethyl, methoxy, ethoxy or acetylamino or disubstituted phenyl, colored substituents from dimethyl or chloromethyl, 60201 R1 is alkyl having 1-5 cholatomers, phenyl, phenylalkyl, alkyl radicals having 1 to 3 chelates, 2-hydroxymethyl-2-propyl, hydroxyethyl, adamantyl, dimethylphenyl cycloalkyl of 5-8 cholaters or methylcyclopentyl, 2 R of the same or a different alkyl group 1-5 cholomaters, 1 2 or R and R of the same equivalents of the same quaternary biliary moiety of which are morpholino, 3,5- dimethylmorpholinyl, piperidino, 4-phenylpiperidine, 4-phenylpiperazino, 1,2,3,4-tet rhydroisoquinolyl, 4-phenyl-1,2,3,6-tetrahydro-1-pyridine, 4- (2-pyridyl) piperazine, 1- (2,6-dimethyl) morpholine, cyclopentylamino, 1-adamantylamine, 1-decahydroquinoline or phthalimide 2 with the addition of R-acid can be substituted with 1-naphthyl, phenyl or with chlorine or methoxy substituted with phenyl and R1 with isopropyl, phenylpropyl or cyclohexyl, or with the addition of a pharmaceutical formulation , as well as -alkylate of 1-aryloxy-4-chloro-2-butanol with formula IV erhilles nya l-aryloxy-yl-amino-2-butanoler, i vilka formler Ί 2 Ar, R "1 · and R betecknar samma som ovan. 6. A preferred embodiment of claim 3, wherein the monosubstituted phenyl is 2-ethoxyphenyl, and R and if