DE2254478A1 - SALICYLIC ACID AMIDE - Google Patents

Description

The invention relates to new salicylic acid amides which block adrenergic ß-receptors (ß-adrenergic blocking action). -

The compounds of the invention can be presented by the general formula:.

Ö ' ³ ' ^ ^ CNRR · ¹

; 2

in which R and R ^{1 can be} hydrogen atoms, alkyl, aryl, halogen-substituted aryl or alkoxy-substituted aryl groups, namely identical or different groups, B a

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Hydrogen atom or a -OCH ₂ CHOHCH ₂ H group and R * a hydrogen atom, an electron withdrawing group such as a halogen atom or an electron donating group such as an alkoxy or alkyl group and E

-NHCH (CH ₃ ) ₂ , -NHC (CH ₃ ) ₃ , -NHCH

"CH .-> CH_,

NHCH (Ar) ₂ or N \

is. In these compounds, the alkyl and alkoxy radicals are preferably lower alkyl or lower alkoxy groups having 1 to 5 carbon atoms and the aryl group (Ar) is preferably a phenyl group. The halogen

2 atones on the aryl group or the halogen atom of group E can be any suitable halogen atom such as chlorine, bromine or fluorine atom, and is preferably Chioratom.

The compounds according to the invention can be prepared as the free base or as acid addition salts. It has has shown that the free bases of these compounds are often oily liquids and therefore are the acid addition salts the preferred shape. Such salts are preferably pharmacologically suitable, non-toxic water-soluble acid addition salts of inorganic or organic acids, such as halogen acids, sulfuric acid, Shark acid, citric acid, oxalic acid and other similar

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Acids. In the examples given here, the hydrochlorides of the compounds according to the invention are described » From the description given in the examples, however, it is clear how other acid addition salts are prepared can be.

The compounds of the invention may be used in Fora of the free bases for drugs _e Preferably, however, the compounds used in the form of the crystalline acid addition salts.

It has been shown that the compounds according to the invention have a surprising and clear blocking effect exercise on the adrenergic ß-receptors (ß-adrenergic blocking action). In particular, it has been shown that these compounds can be used as antihypertensive agents, antianginal Agents and anti-arrhythmic agents are suitable.

Medicines that contain these compounds as the active ingredient can easily be prepared by mixing the compounds in appropriate dose units with Fillers, carriers, extenders and / or excipients, such as are generally used for the production of pharmaceutical preparations be used. In such a preparation the compound can be in the form of the free base and preferably are in the form of a pharmaceutically acceptable acid addition salt. The drugs can either be in solid or in liquid form and they can be as Tablets,! Powder. Capsules, suspensions and the like Dose forms prepared according to the manufacturing process. will. These drugs can be oral or parenteral, for example be administered according to known pharmacological methods.

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Although the doses can vary over a wide range, Depending on the characteristics of the patient, is for that oral administration a dose of about 50 to 200 mg / kg preferred, while for parenteral administration a dose of about 3 to 20 mg / kg is preferred. These Doses may vary depending on the pharmacological used Practice can be modified to meet specific needs for a particular patient.

The compounds of the present invention can be made according to the following Reaction scheme can be produced in which one starts out from a 2-hydroxybenzamide substituted in the 5-position. This reaction scheme can be applied similarly, if one of 3-hydroxybenzamides substituted in the 5-position and 4-hydroxybenzamides.

.-CONRR " ¹ ·
-OCH ₂ CHOHCH ₂ R ^

CONRR- ¹

OCH ₉ CH-CH,

where R, R, R, R * and R have the meaning given above have, M is an alkali or alkaline earth metal and X is a halogen atom.

The aryloxypropane derivatives are produced in essential, according to that in J.Phana. and Pharmacol. 5, 3.59 (1953) and CA. Vol. 70, p. 307, 1824, 1969

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Procedure. The solvent used in this stage of the reaction can be any solvent known to be compatible with epihalohydrin and preferably a lower alcohol or dimethylformamide (DMB ¹ ). When the solvent is a lower alcohol, a metal hydroxide such as sodium hydroxide is preferably used in the reaction sequence. When using DMF as the solvent, a metal carbonate such as potassium carbonate is preferably used.

The desired compounds are obtained by amination of the aryloxypropane with the desired amine groups suitable conditions established * Advantageously this reaction is carried out in a solvent, that under the reaction conditions at one temperature is essentially inert up to reflux temperature. Preferably the solvent is a lower alcohol, such as ethanol, methanol or 2-propanol and the reaction " participants are heated to reflux temperature in order to accelerate the completion of the reaction.

The invention will be further illustrated by the following examples explained *

example 1

1- (2-Propylamino) -3- (2-carboxamidophenoxy) propan-2-ol hydrochloride .

A. 1- (2-Carboxamidophenoxy) 2,3-epoxypropane

30 g epichlorohydrin were added to a solution of 13.7 6 (0.1 mol) salicylamide in 4.8 g WaOH, 25 cm ⁵ H ₂ O, 200 cm ^ ethanol

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less than 20 ° C added. The solution was stirred at tree temperature for 16 hours and concentrated. The concentrate in a mixture of water and chloroform was filtered to remove the contaminants and the chloroform layer was evaporated to a solid. The solid was recrystallized from 2-propanol.
Yield 5 g, m.p. 107-108 ° C.

Analysis: Ber. for C ₁₀ H ₁₁ NO ₅ : C, 62.18; H 5.70; N 7

Found: C, 62.65; H 5.85; H 7.23.

B. 1- (2-Propylamino) -3- (2-carboxamidophenoxy) propan-2-ol hydrochloride

5 g (0.026 mol) 1- (2-carboxamidophenoxy) -2,3-epoxypropane, 25 car isopropylamine and 100 cmr ethanol were 1 1/2 hours heated to reflux and concentrated in vacuo. The concentrate in excess hydrogen chloride in 2-propanol was used with Diluted ether, the solid collected and extracted from methanol / 2-propanol recrystallized.

Yield 4.8 g, mp 185-186 ⁰ C (dec.) Analysis. Ber. for C ₁₅ H ₂₀ N ₂ O ₃ • HCl: C, 54.05; H 7.33; N 9.70;

Found: C, 54.33; H 7.49; N 9.88.

Example 2

1-i-Propylamino-3- (4-carboxamidophenoxy) propan-2-ol hydrochloride

The procedure of Example 1 was followed, using the following reagents and amounts. 4-Hydroxybenzamide (14 g, 0.1 mole), epichlorohydrin (30 g), NaOH (12 g), H ₂ O (75 cm), and ethanol (100 cm). That as an intermediate product

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The resulting oil was reacted with i-propanol and the product was isolated as the hydrochloride. (GH ^ OH ether). Yield 2.6 g, S ¹ P 199-200 ⁰ C (dec.).

Analysis: Ber. for C ₁₃ H ₂₀ N ₂ O ₃ - HGl: C, 54.05; H 7.33; $ 9.70; Found: 0 53.75; H 7.51; N 9.69.

B ice ρ ie 1 3 "

1- (2 ~ propylamino) -3- (3-carboxamidophenoxy) propan-2-ol-liydro chloride

16.7 g (0.16 mol) of epichlorohydrin were added to a solution of 8 g (0.056 mol) of 3-hydroxybenzamide, 2.7 g of NaOH, 10 in ^{5 /} HO, and 125 cm. Of ethanol at less than 20 g added The solution was stirred at room temperature for 16 hours and concentrated. The concentrate, in a mixture of H ₂ O and CHCl 3, was filtered to remove the undissolved solids. The chloroform layer was dried (MgSO ^) and concentrated. The concentrate ,. '25'cnr isopropylamine and 125 carbons of ethanol were refluxed for 1.5 hours and concentrated. The concentrate was dissolved in 2-propanol in excess HCl gas, diluted with ether and ... the solid was collected and recrystallized from methanol-diethyl ether. Yield 6 g, mp. 216-217 ⁰ C (dec.).

Analysis: Ber. for C ₁₅ H ₂₀ Ii ₂ O ₅ * HCl: C, 54.05; H 7.33; H 9.70;

:. 0 54.17; H 7.57; N.9.65.

Example 4.

1- (2-Propylamino) -3- (2-N-methylcarboxamidophenoxy) propan-2-ol hydrochloride

30 g of epichlorohydrin were added to a cold solution of 16.5 g (0.11 mol) of N-methylsalicylamide, 6 g of NaOH, 30 cm ^{5 of} H ₃ O and 200 cnr of ethanol.

let stand temperature and concentrated. The concentrate in water was extracted with chloroform. The extracts were dried (MgSO /,) and concentrated. The concentrate, 30 cnr Propylamine and 150 cur ethanol were taking 2 hours Heated to reflux and concentrated. The concentrate in methanol was treated with HCl in 2-propanol and the solvent removed in vacuo. The salt was made from hot ethyl acetate.

Methanol-acetone crystallized and from 2-propanol-ethyl acetate recrystallized.

Yield 5 g, mp. 137-138 ⁰ C (dec.).

Analysis: Ber. for C ₁₄ H ₂₂ N ₂ O ₅ • HCl: C 55.53; H 7.65; N 9.25;

Found: C, 55.02; H 7.63; N 9.38.

Example 5

1- (2-Propylanino) -3- (2-N, N-diethylcarboxamidophenoxy) propan-2-ol hydrochloride

18 g of epichlorohydrin were added to a cold solution of 13 g (0.67 mol) of Ν, Ν-Diäthylsalicylamid, 4 g NaOH, 25 a ⁵ HgO and 100 cnr ethanol. After standing at room temperature for 3 days, the solvent was evaporated in vacuo. The concentrate was suspended in water and extracted with CHCl 2. The extracts were dried (MgSOy.) And concentrated. The concentrate, 40 cm ^ isopropylamine and

ζ · ■
150 cnr ethanol was refluxed for 3 hours and concentrated. The concentrate in ethyl acetate was treated with HCl in 2-propanol and concentrated, and the salt was crystallized from ethyl acetate-methanol and recrystallized from methanol-ether. Yield 12.6 g, mp. 147-148 ⁰ C (dec.). Analysis: Ber. for C 1 H ₂₀ N ₂ O, -HCl: C, 59.19; H 8.4 ?; N 8.18;

Found: C, 59.48; H 8.64; N 8.11.

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3 0 2 8 2 η, 'Hi 7 u

225447

Example 6

1 - (2-Propylamino) - 3- (2-N-phenylcarboxamidophenoxy) propane-2-ο 1-hydrochloric}.

27 g epichlorohydrin was added to a cold solution of 21.3 S (0.1 mol) salicylanilide, 6 g WaOH, 25 cm ⁵ H ₀ O and 150 cnr ethanol. After standing at room temperature for 18 hours, the mixture was concentrated, _{suspended in H 2} O and extracted with CHGl. The extracts were dried over MgSO ,, and concentrated. The concentrate, 30 cnr isopropylamine and 150 cm ^ ethanol were refluxed for 2 hours and concentrated. The concentrate was dissolved in HGl in 2-propanol and concentrated. The salt crystallized from ethyl acetate-methanol and was recrystallized from methanol-ether.

Yield 10 g, Pp. 146 to 148 ⁰ C (dec.).

Analysis: Ber. for C ₁₉ H ₂₄ N ₂ O ₅ • HCl: C, 62.54; H 6.9O / N 7.67; Found: C, 62.87; H 7.00; N 7.81.

Example 7

1 - (2-Propylamino) -3- (4-N-phenylcarboxamidophenoxy) propan- 2- olhydric chloride

21 g epichlorohydrin was added to a cold solution of 9 g (0.042 mole) 4-hydroxybenzanilide, 4 g NaOH, 25 cm. ⁵ H ₂ O and 150 cur ethanol added. The solution was stirred at room temperature for 18 hours and concentrated. The concentrate in water was extracted with chloroform and the extracts dried (MgSO ^) and concentrated. The solid concentrate was recrystallized once from benzene-nH.exane and again as benzene. The solid (5 g, 0.018 mol) and 30 cm ^ 'isopropylamine in 150 cm * ethanol were refluxed for 2 hours and concentrated. The concentrate Ln 2-propanol,

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30 98 2.0 / 107 4

holding HCl, was diluted with ethyl acetate and the salt off Recrystallized methanol-ether.

Yield 2.5g, bp 182 Ms 183 ° C (dec).

Analysis; Ber. for C ₁₉ H ₂₄ N ₂ O ₃ -HCl: C, 62.54; H 6.90; N 7.67;

Found: C, 62.06; H 6.79; N 7.56.

Example 8

1-tert-Butylamino-3- (2-carl) oxainidophenoxy) propan-2-ol hydrochloride

JO g of epichlorohydrin were added to a cold solution of 13.8 6 (0.1 mol) salicylamide, 6 g of NaOH, 30 cm ^{5 of} H ₂ O and 150 cm ^{5 of} ethanol, and the solution was stirred and concentrated for 18 hours at room temperature. The concentrate in water was extracted with ether, the extracts dried (MgSOy.) And concentrated. The concentrate, 30 cnr tert-butylamine and 150 cm * ^ ethanol were refluxed for 2 hours and concentrated. The concentrate in methanol was saturated with HCl gas and diluted with ether. A hygroscopic solid was recrystallized from methanol-ether and again from 2-propanol-ethyl acetate.
Yield 2.5 g, pp. 188 to 189 ⁰ C (dec.). Analysis: Ber. for C ₁₄ H ₂₂ N ₂ O ₃ • HCl: C 55.53; H 7.65; N 9.25;

Found: C, 55.61; H 7.64; N 9.20.

Example 9

1-tert-Butylamino-3- (3-carboxamidophenoxy) propan-2-ol hydrochloride

30 g of epichlorohydrin was added to a cold solution of 14.5 g (0.105 mol) m-hydroxybenzamide, 6 g NaOH, 25 carbons of water

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and 150 cnr ethanol added and the solution at 18 hours Room temperature stirred. The mixture was concentrated, with Water diluted and extracted with chloroform. The extracts were dried (MgSOy.) And concentrated. The concentrate, 30 cnr tert-butylamine and 150 cur ethanol were Heated under reflux for 2 hours and concentrated. The salt was crystallized from 2-propanol-methanol-ethyl acetate and recrystallized from methanol-ether.

Yield 1.8g, jp. 236 to 238 ° 0 '(dec.).

Analysis: Ber. for C ₁₄ H ₂₂ H ₂ O ₅ • HCl; C 55.535 H 7.65? H 9 _S 25;

Found: C, 55.35; H 7.80; H9.11.

Example 10 -

1-tert-butylamino-3- (4-carboxamidophenoxy) propan-2-ol hydrochloride

15 g of epiehlorohydrin was added to a cold solution of

13 S (0.1 mol) 4-hydroxybenzamide, 5 g HaOH, 30 cm ^ H ₀ O and 150 cm ethanol. The solution was stirred at room temperature for 18 hours and concentrated. The concentrate in H ₂ O was extracted with GHGl ^. The extracts were

dried (MgSOy.) and concentrated. The concentrate and 30 cnr of tert-butylamine in 150 cm ^ ethanol were used for 18 hours heated under reflux and concentrated. The concentrate was dissolved in HCl gas in 2-propanol and washed with ethyl acetate diluted. The solid was collected and extracted from 2-propanol-ethyl acetate recrystallized. -

Yield 5.2 g, m.p. 218-220 ° C (dec.).

Analysis: Ber. for C ₁₄ H ₂₂ H ₂ O ₃ • HCl: C, 55.53; H 7.65; H 9.25;

Found: C, 55.76; H "7.85; H 9.04.

- ■. ■ "■■ - '■. - 12 -

? »Η 9 8 ? η / 1 η ι u

1-tert-butylamino-3- (2-carboxamido-4-chlorophenoxy) propan-2-ol hydrochloride

• 1- (2-Carboxamido-4-chlorophenoxy) 2,3-epoxypropaar 30 β-epichlorohydrin were added to a solution of 15.5 6 (0.09 mol) 5-chlorosalicylamide, 4.5 g NaOH, 50 cm ³ H ₅ O and 150 cm ^{3 of} ethanol at ^ 20 C added. The solution was stirred at room temperature for 16 hours and concentrated. The concentrate in a mixture of H 1 O and CHCl ₃ was filtered to remove insoluble solids. The CHClj layer was concentrated and the solid concentrate was recrystallized from benzene. Yield 6 g, melting point ₁₁₅ to 117 ^° C.

^ SäimSl Ber. for C ₁₀ H ₁₀ ClNO ₃ : C, 52.79; H 4.43; N 6.16; ^Vascular: C 53.45; H 4.54; N 6.24.

B. 1-tert -Butylamino-3- (2-carboxamido-4-chlorophenoxy) propan-2-ol hydrochloride

P? Y) 2,3Qpoxypr ■ cert.-butylamine and 125 cm ^ ethanol were 5 hours

Heated to reflux and concentrated. The concentrate was dissolved ^{ln Met} * ianol and HCl gas was added in 2-propanol to give a solid. The solid was recrystallized from ethanol-ethanol-ethyl acetate. Yield ^{6 '6} 6, mp. 225-226 ⁰ C (dec.).

Ber. for C ₁₄ H ₂₁ ClN ₂ O ₃ -HCl: C 49.86; H 6.58; N 8.30;

^Found · ': C, 50.05; H 6.70; U 3,; 7.

Example 12

1-teft.Butylamino-3- (2-N-phenylcarboxamidophenoxy) propan-2-ol hydrochloride

20 g epichlorohydrin was added to a cold solution of 26 g (0.12 mol) salicylanilide, 6 g NaOH, 30 cm ⁵ H ₅ O and 150 cnr ethanol. The solution was stirred at room temperature for 18 hours and concentrated. The concentrate in H ₂ Q was extracted with CHGl ;. The extracts were dried (MgSO _7. ) And concentrated. The concentrate, 50 cnr tert-butylamine and 150 cnr ethanol were refluxed for 2 hours and concentrated. The concentrate was in HGl gas

dissolved in 2-propanol, diluted with ethyl acetate-ether and the solid recrystallized from methanol-diethyl ether Yield 8.8 g, bp 187-189 ° C (dec.).

Analysis: Calculated for G ₂₀ H ₂₀ N ₂ O ₃ * HGl: C 63.39; H 7.18; N 7.39; Found: C, 63.79; H 7.24; N 7.27-

Example 1j5.

1-ter b.-Butylamino-3 / ~ 2-N- (4-methoxyphenyl) carboxamido-phenoxy-7-propan-2-ol hydrochloride .

A mixture of 12.3 g (0.05 mol) N ~ 4-methoxyphenylsalicylamide, 15 g K ₂ GO ₅ , 20 g epichlorohydrin and 100 cm ⁵ "dimethyl- 'formamide was heated with stirring on the steam bath for 2 hours and in water The mixture was _{extracted with CHCl 5} , the extracts dried (MgSO ^,) and concentrated. The concentrate and 30 ciü ^ terb.-butylarain in dry ethanol was refluxed for 2 hours and concentrated. The concentrate in acetone was mixed with 30% chk 2.5 η HGl in 2-propanol. The solid which formed was collected and recrystallized from methanol-ether _{or the like}

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U ^{ ) 8 2 0/1 D 7 / ₊

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Yield 8.9 g, mp. 200-201 ⁰ C (dec.).

Analysis: Ber. for C ₂₁ H ₂₈ N ₂ O ^ • HCl: C, 61.68; H 7.14; N 6.85;

Found: C, 61.76; H 7.30; N 6.67.

Example 14

1-tert-Butylamino-3- (2- carboxamido-4-methoxyphenoxy) propan-2-ol hydrochloride

13 g epichlorohydrin was added to a solution of 14.5 g (0.087 mol) 5-methoxysalicylaiaid, 5.2 g NaOH, 50 cm ^ H ₂ O and 100 cm ^ ethanol. The solution was stirred at tree temperature for 16 hours and concentrated. The concentrate in a mixture of H ₀ O and CHCl ₂ was filtered to remove insoluble solids and the CHCl ^ layer was concentrated.

τ. y ⁷ J-

The concentrate, 30 cur tert-butylamine and 150 cnr ethanol were refluxed for two hours and concentrated. The concentrate was dissolved in HCl gas in methanol. This solution was concentrated and the concentrate triturated in hot acetone, the oil solidifying. The solid was recrystallized twice from mebhanol diethyl ether.

Yield 3 g, mp. 207-208 ⁰ C (dec.).

Analysis: Ber. for C _{1 r} H ₂₄ N ₂ O 1 HCl: C, 54.13; H 7.57; H 8.41; Found ": C 53.86; H 7.66; N 8.60,

Example 15

1 ~ (1-piperidyl) -3- (2-carboxamidophenoxy) propan-2-ol hydrochloride

A. 1- (1-Piperidyl) -3- (2-carboxajnidophenoxy) propan-2 ~ ol

A mixture of 13.8 g (0.1 mol) salicylamide, 20 g K ₂ CO ,,

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i (J iJ B? 0 / I Γ) 7. ofttö * N * ^L INSPECTED j

28 g of ISpichlorohydrin and 150 cm of dimethylfoimamide were heated on a steam bath with stirring for 2 hours and poured into water. The mixture was ", extracted with CHCl, the extracts dried (MgSO ..) and concentrated. The concentrate and 8.5 g of piperidine in 150 cr & ^y of ethanol were heated for 2 hours under reflux and evaporated to dryness. The solid concentrate was prepared from 2 -Propanol-n-iIexane recrystallized.

Yield 11g, 5p. 166 to 168 ⁰ C.

Analysis: Ber. for ^c ₁ cH ₂ 2 ^N 2 ⁰ 3 * HOl * ■ C-64.75; H 7.91; Έ 10.07; Found: C, 64.16; H 7.90; N 9.52.

B. 1- (1-piperidyl) - $ - (2-carboxamidophenoxy) propan-2-ol hydrochloride

6 g of the free base in ethyl acetate was treated with HCl in 2-propanol and the mixture concentrated until the salt began to solidify. The salt was recrystallized twice from 2-propanol-ethyl acetate. Yield 1.5 g, ίρ · 157j8 ° C (dec.) Analysis: Calc. for C ₁₅ H ₂₂ N ₂ O ₅ - HCl: C 57 _S 22 ", H 7.36; W 8.89;

Found: C, 57.24; H 7.42; N 9.18.

Example 16

1- (i-Piperidyl) -3- (2-N-phenylcarboxamidophenoxy) propan-2-olhydric chloride

■ s'

A mixture of 21.3 g (0.1 mol) of salicylanilide, 20 g of K ₂ CO-, 28 g of epichlorohydrin and 150 cm of dimethylformamide was heated on a steam bath for 4 hours with gentle stirring. The mixture was poured into v / water and extracted with chloroform. The extracts were. ^ t ".-cJoiet (Vr '^ Qj > and a-

■ - 16 -

3 0-98 20 / TO 7Ä

tight. The concentrate and 8.5 6 piperidine in ethanol was made heated under reflux for two hours and concentrated. The concentrate was dissolved in 2-propanol containing HCl gas and diluted with ethyl acetate. The salt was collected and recrystallized from 2-propanol-ethyl acetate.

Yield 4.2 g, mp 156-157 ° C (dec.).

Analysis: Ber. for C ₂₁ H ₂₆ N ₂ O, * HGl: C 64.52; H 6.96; N 6.17;

Found; C 64.61; H 6.93; N 6.94.

Example 1 £

1-sec-Butylamino-3- (2-N-phenylcarboxamidophenoxy) propan-2-ol hydrochloride

The procedure of Example 1 was followed, using the following reagents and amounts. 21 g (0.1 Mol) salicylanilide, 8 g NaOH, 29 g epichlorohydrin, 75 cm ^ Water and 150 cur ethanol. The intermediate product oil was reacted with sec-butylamine and the product as the hydrochloride (2-propanol-methanol-ether) isolated.

Yield 11.5 Si * £ 168 to 169 ° C (dec.). Analysis: Ber. for C ₂₀ N ₃ Ji ₂ O ₃ -HCl: C, 63.39; H 7.18; N7.39; Found: C, 63.47; H 7.19; K7.20.

Example IjS

1-tert. -Butylamino-3- / ~ "2-N- (3-chlorophenyl) carboxaaidophenoxy_7-propan-2-ol hydrochloride

The procedure was as in Example 15, with the exception that the following reagents and amounts were used: 12.5 g (0.05 mol) of N-3-chlorophenylsalicylamide, 15 g of K ₂ CO ^, 20 g of epichlorohydrin and 150 cm ^ Dimethylformamide.

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The oil formed as an intermediate product was reacted with tert-butylanine and the product was isolated as the hydrochloride (2-propanol ether).
Yield 5.8 g, mp. 176-177 ⁰ C ■ (dec.).

Analysis: Ber. for C ₂₀ H ₂₅ CHi ₂ O ₃ -HpI: C 58.10; H 6.34; K 6.77; Found: C, 57.97; H 6.58; H 6.76.

Example 19

1-tert. -Butylaiaino-3- / ~ 2-Ii- (3 '-tolyl) carboxamidophenoxy ^ Z-propan-2-ol hydrochloride .

The procedure was as in Example 1, using the following reagents and amounts: 27 g (0.12 mol) of N-3-methylphenylsalicylamide, 30 g of epichlorohydrin, 8 g of HaOH, 50 CBi ^ H ₂ O and 100 cm ^ ethanol. The oil formed as an intermediate product was reacted with tert-butylamine and the product was isolated as the hydrochloride (2-propanol). Yield 4.5g, m.p. 191-192 ° C (dec.).

Analysis: Ber. for ^ ₂ Λ ^ 2 ^ 2 ° 3 * ^HC1: ° ⁶⁴ » ^ι9 ί H 7.43; N 7.13; Found: C, 64.29; H 7.68; N 7.04.

Example 20 .

1-tert-Butylamino-3- / ~ 2-N- (4-trifluoromethylphenyl) carboxamido-phenoxy-7-propan-2-ol hydrochloride

The procedure was as in Example 1, using the following reagents and reagents : 23 g (0.08 mol) of N-4-trifluoromethylphenyl salicylamide, 30 g of epichlorohydrin, 8 g of NaOH, 50 ca ^ H ₃ O and 100 cm ⁵ ethanol. The oil occurring as an intermediate product was reacted with tert-butylamine and the product was isolated as the hydrochloride (2-propanol).

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225447a

Yield 4.5 g, Pp. 209-210 ⁰ C (dec.).

Analysis: Ber. for ^O 21 ^H 25 ^F 3 ^N 2 ° 3 * ^HC1: ° ^ ^{6 '48} * » ^{H 5} > ⁸⁷ > ^{N 6} ' ² ? 5 Found: C 56.32; H 6.19; N 6.35.

Example 21

1-tert. -Butylamino-3- / ~ 2-N- (4-dimethylaminophenyl) carboxaraidophenoxy_7-propan-2-ol dihydrochloride

The procedure was as in Example 15, using the following proportions and amounts: 13 g (0.05 mol) of H- (4'-dimethylaminophenyl) salicylamide, 20 g of K ₂ CO, 20 g of epichlorohydrin and 100 cm * dimethylformamide. The oil occurring as an intermediate product was reacted with tert-butylamine and the product was isolated as dihydrochloride (2-propanol).

Yield 3.3 g, mp. 181 to 183 ⁰ C (dec.).

Analysis: Ber. for ^Ο ₂ 2 ^Η 31 ^Ν 3 ° 3 ^{# 2HC1: c} 57.64; H 7.24; N 9.16; Found: C, 57.73; H 6.84; N 8.96.

Example 22

1-tert-Butylamino-3- / ~ 4-chloro-2- (N-phenylcarboxamido) phenoxy-7-propan-2-ol hydrochloride

The procedure was as in Example 15 except that the following Heagentien and amounts were used: 12 g (0.05 mole) of 5-Chlorsalicylanilid, 20 g K ₂ CO _5, 20 g of epichlorohydrin and 100 cur ⁵ dimethylformamide. The oil occurring as an intermediate product was reacted with tert-butylamine and the product was isolated as the hydrochloride (2-propanol ether).
Yield 4.5 g, mp. 241-242 ⁰ C (dec.).

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Analysis: Ber. for C ₂₀ H ₂₅ Cl N ₃ O ₃ 'HCl: C 58.10; H 6.34-; N 6.77 γ Found: C 58.36; H 6.37; N 6.82.

Example 25

1-tert-Butylamino-2- / ~ "4-meth.oxy-2- (N-phenylcaiiboxamido) -pheno: xy-7-propan-2-ol hydrochloride

The procedure was as in Example 15 with the exception that the following. Agents and amounts used were: 12 g (0.05 mol) 5-Hetkoxysalicylanilid, 20 g K ₀ CO ₇ , 20 g epichlorohydrin and 100 cnr dimethylformamide. The oil occurring as an intermediate product was reacted with tert-butylamine and the product was isolated as the hydrochloride (methanol-ether). Yield 6.0g, ip. 200 to 201 ⁰ C (dec.). Analysis: Ber. for C ₂₁ H ₂₈ N ₂ O ₄ '• HCl: C, 61.68; H 7 / IAi N 6.85;

Found: C, 61.40; H 7.19; N 7.00.

Example 24

The blocking effect of the compounds according to the invention on the adrenergic ß-receptors was iia essentially after that of Poster, E.V., in J. Pharm. and Pharmacol, 18: 1-12, 1968. A bed was formed from transverse sections of the trachea of a guinea pig. The chain was attached at one end to the floor of a bath and that other end was attached to an isotonic lever. The chain was placed in a bath of Krebs solution at 37 ° C Stabilized for 90 minutes without tension and then became a voltage of 287 mg was applied.

The compounds to be tested were added to the bath

- 2.0 -

309820 / T074.

225U78

and observed the effect for 15 minutes. 0.01 / Ug / cm ^ isoproterenol was added to the bath and the Effect observed.

The activity of the compounds was determined by their ability to control the response of the tracheal chain to isoproterenol to block. The compounds according to the invention blocked this reaction at concentrations of 0.12 to 8.3 / Ug / cnr clear.

Example 25

The blocking effect of the compounds according to the invention on the adrenergic β-receptors was also determined by a method at which the heart rate of anesthetized cats was determined by IV treatment with hecamylamine (3.1 mg / kg · ^) had been stabilized. The one to be examined Connection was i.v. administered to cats and the antagonism to that resulting from subsequent i.v. administration caused by isoproterenol (0.31 / Ug / kg) Increase in speed was observed. The compounds according to the invention showed a clear blocking Effect on response to isoproterenol at doses of 0.04 to 0.3 mg / kg i.v.

Example 26

The antiarhythmic activity of the compounds according to the invention was essentially based on that described by Lawson, J.W., in J.Pharmacol. Exp. Ther. 160: 22-31, 1968 certainly. The activity of the compounds examined was determined by their ability to develop Avoid arrhythmias in mice that inhaled chloroform

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0RK3INAL fNSPECTEO

The effective dose 50 to chloroform-induced arythenia was 50 to 100 mg / kg for the compounds of the invention when administered orally.

PATENT CLAIMS:

30 9 8 20 /

Claims (1)

PATENT CLAIM Salicylic acid amides of the general formula GNRR ¹ in which R and R V / ass he substance atoms, alkyl, aryl, halogen-substituted Be aryl or alkoxy substituted aryl groups 2 can be identical or different groups, R a hydrogen atom or a -OCH ₂ CHOHCH ₂ R- group and ΈΓ a hydrogen atom, an electron withdrawing group such as a halogen atom or an electron alkoxy or alkyl group and R a - NHCH (CH ₃ ) ₂ , -NHC Halogen atom or an electron donating group such as a .CH, - NHCH HpCH-2 NHCH (Ar) ₂ or N \ - group is. 6 2 / XI 309820/1074