CH539606A - Substd. 1-phenoxy 2-hydroxy-3-alkyl aminopropanes - beta-adrenolytics, antiarrhythmics and hypotensives substd. 1-phenoxy 2-hydroxy-3-alkyl aminopropanes - beta-adrenolytics, anti-arrhythmics and hypotensives substitute phenoxy hydroxy alkyl aminopropan - Google Patents

Abstract

Cpds. of general formula (I) R = Pri or But R' = (CH2)xCN, (CH2)XNH2, (CH2)x+1OH or CO2R4 where x = 1-3 and R4 = H or (1-4C)alkyl R2 = (1-4C)O- or S-alkyl, (2-4C)alkenyl, (2-4C)alkynyl, CN, or H (if R' is not = a cyano or amino gp.) R3 = H, halogen, (1-4C)alkyl or (1-4C)Alkyl. beta-Adrenolytics, anti-arrhythmics, and hypotensives.

Description

       

  
 



   The invention relates to a process for the preparation of new, optically active or racemic 1-aryloxy-2-hydroxy-3-isopropylamino-propanes of the formula 1
EMI1.1
 or their salts, in which X is an integer from 1 to 3 and R is a halogen atom, a straight or branched alkyl or alkoxy group having 1 to 4 carbon atoms, a nitro, amino, hydroxy or nitrile group, an acyl group having 2 to 4 carbon atoms, or a methylenedioxy group or an aralkyloxy radical in twofold substitution, where for X = 2 or 3 the substituents R can be identical or different, except for X = 1 the 2'-halogen, 2'-methyl, 2 ' -Methoxy, 2'-nitro, 2 'hydroxy and 2'-acyl compounds and for X = 2 the 2', 6'-dimethyl compound.



   The process according to the invention is characterized in that a compound of the formula 2
EMI1.2
 where Z is the group
EMI1.3
   wobç al represents a halogen atom, means, reacts with isopropylamine.



   The starting compounds of formula 2 can be obtained by known processes.



   The compounds of formula 2 prepared according to the invention occur in optically active isomers in accordance with the center of asymmetry in the 2-position, which isomers can be separated by known processes. The optically active compounds, like the racemates, have valuable pharmacological properties.



   The new 1-aryloxy-2-hydroxy-3-isopropylamino-propanes of the formula 1 obtainable by the process according to the invention can be converted into their acid addition salts in a manner known per se. Suitable acids for salt formation are, for. B. the following: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, lactic acid, tartaric acid, ascorbic acid.



   The 1-aryloxy-2-hydroxy3-isopropylamino-propanes obtainable according to the invention have valuable pharmacological properties. They cause bradycardia and at the same time act as N-isopropyl-noradrenaline antagonists. The tachyardia caused by N-isopropyl-noradrenaline can be suppressed (eliminated) with prior administration of one of the compounds which can be prepared according to the invention; Cardiac arrhythmias can be balanced with them, for example. With the substances that can be produced according to the invention it is possible to block the sympathetic nervous system of the heart, which was previously not possible with chemotherapeutic agents. The areas of indication are: high blood pressure, angina pectoris, cardiac arrhythmias, digitalis intoxication and pheochromocytoma disease.



   The known dichloroisoproterenol (A) of the formula was used as a comparison substance for the pharmacological investigations
EMI1.4
 which shows a very similar pattern of action as the compounds that can be prepared according to the invention are used. Furthermore, two other already known compounds, 1- (2'-chlorophenoxy) -2-hydroxy3-isopropylamino-propane (B) and 1- (2'-methylphenoxy) -2-hydroxy-3-isopropyl- aminopropane (C) included.



   The two last-mentioned compounds are structurally very similar to the new compounds which can be prepared according to the invention, although it was not known that these compounds force or cause bradycardia.



  act as antagonists towards N-isopropyl noradrenaline.



   The results of the comparative tests are compiled in the table below.



   Substance Bradycardic N-isopropylnor toxicity mg / kg
Own effect of adrenaline antagonism white mouse see p. c.



   A 1 1 235
B 0.5 4.5 770
C 1.2 1.5 700 1- (4'-nitrilophenoxy) -2-hydroxy-3-isopropylaminopropane 36 3.4 585 1- (2'-aminophenoxy) -2-hydroxy-3-isopropylaminopropane 14 1.3 1220 1- (3 ', 4'-methylenedioxyphenoxy) -2-hydroxy-3-isopropyl-3.51450 aminopropane
As can be seen from the table, the compounds which can be prepared according to the invention are superior to the known compounds both in terms of their bradycardic effect and also in terms of their antagonistic effect towards N-isopropyl-noradrenaline.



   In the case of parenteral use, the compounds which can be prepared by the process according to the invention are dosed as follows: intravenously 0.5-10 mg, preferably 1-5 mg, subcutaneously 1-50 mg, preferably 5-15 mg
The dosage for oral use is 25-200 mg, preferably 50-150 mg.



   example
1- (3 '-Nitrilophenoxy) -2-hydroxy-3-isopropylamino propane maleate
35.4 g (0.6 mol) of isopropylamine are dissolved in 150 ml of ethanol and mixed with a solution of 24.5 g (0.14 mol) of 1- (3'-nitrilophenoxy) -2,3 -epoxypropane with 100 ml of ethanol Left to stand for 48 hours at 20 ° C. After two hours of heating at 60 ° C., the solvent is distilled off in vacuo and the crystalline residue is recrystallized from ethyl acetate / petroleum ether. Yield 27.5 g = 84% of theory, melting point 69-71 ° C. .

 

   The base is dissolved in acetone and one equivalent of maleic acid in acetone solution is added. The maleate melts at 88-92 "C.



   Further compounds of formula 1, which were also prepared by the process according to the invention, are listed in the following table: Compound R X F (C) No.



   1 4'-NH2 1 240-241
2 3 ', 4'-O-CH2-O- 2 127-127.5
3 2'-NH2 1 216-219
4 3'-NH2 1 91-92
5 4'-CN 1 157-159
All of the melting points given for the above compounds relate to the hydrochlorides.


    

Claims (1)

PATENT CLAIM Process for the preparation of new, optically active or racemic 1-aryloxy-2-hydroxy-3-isopropylaminopropanes of the formula 1 EMI2.1 or their salts, in which X is an integer from 1 to 3 and R is a halogen atom, a straight or branched alkyl or alkoxy group having 1 to 4 carbon atoms, a nitro, amino, hydroxy or nitrile group, an acyl group having 2 to 4 carbon atoms, or in twofold substitution denote a methylenedioxy group or an aralkyloxy radical, where for X = 2 or 3 the substituents R can be identical or different, except for X = 1 the 2'-halogen, 2'-methyl, 2 ' -Methoxy, 2'-nitro, 2 'hydroxy and 2'-acyl compounds and for X = 2 the 2', 6'-dimethyl compound, characterized in that a compound of the formula 2 EMI2.2 where Z is the group EMI2.3 where Hal represents a halogen atom, means with isopropylamine. SUBClaim Process according to patent claim, characterized in that the compounds obtained are converted into their salts.