CS220271B1 - Substituted aryloxypropanolamines, salts and their production - Google Patents

Abstract

The invention relates to substituted aryloxypropanolamines of the general formula I OH OCH^HCH^NHR2 \Q^-NHCOOR (1')> where R1 is alkyl aleho/a alkyloxyl with 2 to 5 carbon atoms, pyrami or branched alkenyl with 2i to 5 carbon atoms aleho/a ethyloalkyl· with 3 to 6 carbon atoms and® is branched alkyl with 3 to 4 carbon atoms and/or cycloalkyl with 3 to 6 carbon atoms and their salts. These nil substances are important effective betalytics, useful in the treatment of various circulatory disorders. The invention also protects several methods of producing substances of general formula I.

Description

The invention relates to substituted aryl xypropaneolamines of general formula I

O-CHrCH-CH^NHfí

nhcoor (I) where

R ¹ is straight or branched alkyl alfetto alkoxyalkyl of 1 to 5 carbon atoms, straight or branched alkenyl of 2 to 5 carbon atoms or cycloalkyl of 3 to 6 carbon atoms and

R ² is branched alkyl of 3 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms.

The invention also relates to salts of substituted aryloxypropanolamines of the general formula I, as well as to processes by which the said substances can be prepared.

Substituted aryloxypropanolamines of the general formula I are new compounds, not previously described in the literature, which exhibit typical betalytic effects, similar to those of aryloxypropanolamines substituted in other ways (Czech Pat. No. 128,471, American Pat. No. 3,468,376, German Federal Republic Pat. No. 1,236,523, Swiss Pat. Nos. 451,114 and 453,363). All studied substances exhibit antiisoprenaline, antiarrhythmic and locally anesthetic activity and effects on the tracheal mucosa. Substances with the working designation BL-445 (example 31) and BL-443 (example 30) are fairtoakiolioglcly equivalent to the clinically used metipranolol [1-(2,3,5-trimethyl-4-ace|toxy enoxy)-3-isopropylamino-2-propanol], it is also possible to assume their application in the therapy of various disorders of the function® of the heart and blood circulation. The effectiveness of the substances of the invention is shown in table 1-3.

Substituted aryloxypropandlarains of general formula I can be prepared according to the invention by various methods, e.g. by letting it react

a) a compound of general formula II

Olympic Games

I

O-CH^CH-CH-Ci (^-nhcoor ⁴ (!/) a vain amine of the general formula NH2R ² , in which R ² means the same as in the formula

I.

b) a compound of general formula III

R ¹ means the same as in Formula I, with a primary amine of the general formula NH2R ² , in which R ² means the same as in Formula I,

c) a compound of general formula IV

OH [04-NHCOOR ⁴ in which

R ¹ has the same meaning as in formula I with a 1-alkylamino-2,3-epoxypropanium of the general formula V

CH.— CH-CH.-NHR \\Z ° IV) in which

R ² has the same meaning as in formula I, d) a compound of general formula IV in which

R ¹ has the same meaning as in formula I, with 1-alkylamino-3-chloro-2-propanol of general formula VI

Olympic Games

I

Cl—CH2—CH—CH2—NHR2 (VI), in which in which

R ¹ has the same meaning as in formula I, with R ² having the same meaning as in formula I.

In the preparation according to the invention, the reaction between the two starting components takes place in an alcohol or water environment under the catalytic action of an alkali metal hydroxide, for example sodium hydroxide, at room temperature or at the boiling point of the reaction mixture.

After the reaction is complete, the reaction mixture is most often worked up by shaking it with a dilute solution of alkali metal hydroxide, distilling off the organic solvent; and the residue, representing the crude basic ester, is purified by conversion to a salt, alkalization, and extraction into an organic, water-immiscible solvent;

From this solution, the basic ester can be converted directly to the desired solution and further purified by crystallization from water, an organic solvent, or a mixture of organic solvents. Among the salts with inorganic acids suitable for the preparation of application forms, the following are suitable: hydrochloride, hydrobromide, sulfate, phosphate, and from the salts with organic acids, e.g. oxalate, tartrate, maleate, funiate, and others.

Details of the preparation are given in the following design examples.

Example 1

Ethyl 4 [(2-hydroxy-3-cyclohexylamino)-propoxy]carbanilate

To a solution of 10.5 g (0.038 mol) of ethyl 4-[(2-hydroxy-3-chloro)-propoxy]-carbanilate in 50 ml of methanol is added 4.9 g (0.05 mol) of cyclohexylamine and heated for 10 h in an autoclave at 110 °C.

After the reaction mixture has cooled, methanol and cyclohexylamine are distilled off in vacuo, the residue is dissolved in dilute hydrochloric acid, shaken three times with ether, and the base is released from the separated aqueous phase by alkalization, which is shaken into ether. After drying with anhydrous magnesium sulfate, the filtrate is treated with an ethereal solution of dry hydrogen chloride to separate the hydrochloride, which is recrystallized from a 2-propanol-ether mixture (m.p. 156 to 159 °C).

Example 2

Propyl-2[(2-hydroxy-3-isopropylamino·)-propoxy]carbanilate

To a solution of 9.0 g (0.035 mol) of propyl-2-((2,,3-epoxy)-propoxy] carbanilate in 30 ml of 2-propanol are added 3.5 g (0.06 mol) of isopropylamine and 2 ml of water. The reaction mixture is heated in an autoclave at 100 °C for 5 h. After the reaction mixture has cooled, the solvent and excess isopropylamine are distilled off in vacuo. The residue is dissolved in dilute hydrochloric acid, shaken three times with a whisk, and the base is released from the separated aqueous phase by alkalization, which is shaken into ether. After drying with anhydrous magnesium sulfate, the hydrate is separated from the filtrate by adding an ethereal solution of dry hydrogen chloride, which is recrystallized from an acetone-ether mixture (i.e. 1.115 to 118 °C).

Example 3

Isopropyl-3.[, (;2-hydr ^, Nxy'-3-tere.butylamine|O )-propoxy ] carbanilate

12.4 g _; (0.064 mol) isopropyl ester of 3-hydroxycarboxylic acid. and 8.3; g, (0.064 mol) 14-tert.butylamino-2,3-epoxypropane. in 40 ml of water and in 2 ml of 42% sodium hydroxide solution; are stirred for 6 h at room temperature., Giny· solution is. decanted. and the resinous precipitate is dissolved; in dilute, acidic, hydrochloric, pnetcepeti· tbicrats ether and from the separated aqueous phase alkalization releases the base, which is shaken into ether. After drying with lead-free.! magnesium cyanide: from: the filtrate by adding ethereal. solution of dry hydrogen chloride. hydrochloride is precipitated,, which. is recrystallized from an acetone-ethanol mixture (mp 136 — 138 °C).

Example 4

Cyclohexyl-4:[i(2-hydroxy-3-isopropylamino)-propoxy]carbanilate

5.6 g (0.023 mol) of cyclohexylethylene of 4-hydroxycarbamide acid, 4.5 g (0.023 mol) of 1-chloro-3-isopropylamino-2-propanol hydrochloride and 2.1 g of sodium hydroxide (0.054 mol) in 75 ml of ethanol are heated in a sealed tube for 10 h at a temperature of 100 °C. The solvent is distilled off from the reaction mixture under vacuum and the residue is suspended in 30 ml of 2N sodium hydroxide. The liberated base is shaken out in ether and, after drying with anhydrous magnesium sulfate, The addition of ethereal solution of dry hydrogen chloride precipitates the hydrochloride from the filtrate, which is recrystallized from an acetone-ether mixture (m.p. 151 to 153 °C).

Using the methods described above, the following new substances (working designations in brackets) were prepared:

1. methyl-2[(2-hydroxy-3-isopropylamino· )-propyloxycarbanilate hydrochloride,

t. t. 125 to·127-°G (acetemethanol);

(BL-123),

2. methyl-2[(;2-hydroxy-3-tert.butylamino)-pnotoxycarbanilate ethoxylated EOGhltorid',

t. t. 99 to 1S£°G (acefióu), (BJi-125-j:,

3. methyl-3[(2-hydroxy-3-isopnopylamiao:·);-prlopoxy]carbanilate hydrochloride,

1.1. lil· to 112; °C; (acetone?.). (^-133),,

4. Methyl-3[(2-hydroxy.--3'-tert.butylamino)-propoxy]carbanilate hydrochloride.

t. t, 163 to 167 °C (2i-pnopanol) (LB-135),

5. methyl-4[(2-hydr|oxy-3-isopropylamino)-prioipoxy]carbanilate hydrochloride,

1.1. 160 to 163 °C (2-propanol ether) BL-143),

6. methyl-4[(2-hydroxy-3-tert.butylamino)-propoxy]carbanilate hydrochloride,

1.1.156 to 158 °C (acetone-ether) (BL-145),

7. ethyl-2i[ _: (2-hydroxy-3-isopropylamino)-propoxy]carbanilate hydrochloride,

1.1.102 to 104 °C (acetone-petroleum ether) (BL-223),

8. ethyl-2[(2-hydroxy-3-tert.butylamino]-propoxy]carbanlate hydrochloride,

1.1. 128 to 130 °C (acetone-ether) (BL-225),

9. Ethyl-3[(2-hydoxy-3-isopropylamino)-pnooxy]carbanilate hydrochloride,

mp 104 to 105 °C (acetone-ether) (BL-233),

10. ethyl-3[(2-hydroxy-3-tert.butylamino)-priopoxy]carthianilate hydrochloride,

t. t. 130 to 131 °C (ethanol-ether) (BL-235),

11. ethyl-4[(2-hydroxy-3-isoprlopylaminio)-priopoxy]carbanlate hydrochloride,

1.1. 141 to 142: ^Q C (2-propanol etherj (BL-243),

12. ethyl-4[(2-hydroxy-3-tert.butylamino)-propoxy] carbonylate hydrochloride, mp 86 to 88 °C (acetone-ether) (BL-245),

13. propyl-2[(2-hydroxy-3-isopropylamine©)-prlopoxy]carbanilate hydrochloride,

1.1. 115 to 118 °C (acetone-ether)

BL-323),

14. propyl-2i[(2-hydroxy-3-tert.butyliamino)-priopoxy] carhanilate hydrochloride,

mp 123 to 131 °C (acetone-ether) (BL-325),

15. propyl-3[(2-hydryoxy-3-isopropylamine©)-pnopoxy]carhanylate hydrochloride,

1.1. 94 to 95 °C (acetone-ether) (BL-333),

16. pnopyl-3[(2-hydryoxy-3-tert,butylamino)-priopoxy]carbanilate hydrochloride,

1.1. 153 to 155 °C (acetone-ether) (BL-335),

17. propyl-4[(2-hydroxy-3-isopropylamino)-propyloxy]carbanilate hydrochloride,

1.1. 140 to 141 °C (acetone-ether) (BL-343),

18. propyl-4[(2-hydnoxy-3-tert.butylamino)-prtopioxy]carhanylate hydrochloride,

mp 76 to 77 °C acetone-ether ) (BL-345),

19. isopropyl-2 ((2i-hydroxy-3-isopropylamino)-pnoploxy] caribanilate hydrochloride,

1.1. 111 to 113 °C (acetone) (BL-323izoi),

20. isopropyl-2[(2-hydroxy-3-tert.butylamino)-propoxy]carbanilate hydrochloride,

1.1. 154 to 157 °C (acetone-ether) (BL-iso325),

21. isopropyl-2|[(2-hydroxy-3-isobutylamiln)-propyloxycar bianylate hydrochloride,

1.1. 149 to 152 °C (acetone-ether) (BL-iso324),

22. isopropyl-3[(2-hydroxy-3-isopropylamino)-pnooxy] carblaniate hydrochloride,

1.1. 108 to 110°C (acetone-ether) (BL-iso333),

23. isopropyl-3[(α-hydroxy-3-tert.butylamino)-propoxy]carbanilate hydrogen chloride,

mp 136 to 138 °C (acetone-ethanol] (BL-iso335),

24. isopropyl-4[(2-hydroxy-3-isopropylamino)-propoxy]carbanilate hydrochloride,

mp 137 to 139 °C (acetone) (BL-ÍZ0343),

25. isopropyl-4[(2-hydnoxy-3-tert.butylamimo·)-propoxy]carbanilate hydrochloride,

mp 98 to 100 °C (acetone) (BL-iso345),

26. butyl-2 [(2-hydroxy-3-isopropoxyamino)-propyl] phenylanilate hydrochloride,

mp 101 to 102 °C (acetone) (BL-423),

27. Butyl-2[(2-hydroxy-3-.tert.butylamino)-propyloxy]carbalniate hydrochloride,

mp 138 to 140 °C (acetone-ether) (BL-425),

28. butyl-3[ (2- ^, hydiríoxy-3-isopropylamino)-pnopoxy] carbanilate hydrochloride,

mp 107 to 109 °C (acetone-ether) (BL-433),

29. butyl-3[!(2-hydroxy-3-tert.butylamino)-phopoxy] carbanilathi drochlor id,

mp 140 to 144 °C (acetone-ether) (BL-435),

30. butyl-4[(2-hydroxy-3-.isopropylamine)-prlopoxy]carbanilate hydrochloride,

mp 124 to 126°C (acetone-ether) (BL-443),

31. Butyl-4-[i(12-hydroxy-3-tert.butylamino)-propioxy]carbaniol,

1.1. 150 to 155 °C (2-propaneol ether (BL-445),

32. pentenyl-2[ (2-hydroxy-3-isopropylamino)-propoxy] carhanylate hydrochloride,

mp 123 to 125 °C (acetone-ethanol (BL-523),

33. pentyl-2(<(2-hydr.oxy-3-tert.butylininio)-propoxy]carbamilate hydrochloride,

t. t. 148 to 150 °C (acetone) (BL-525),

34. pentyl-3[(2-hydroxy-3-isopropylamino]-propoxy] carbanilate hydrochloride,

1.1. 118 to 120 °C (acetone-ether) (BL-533),

35. pentyl-3[(2-hydroxy-3-tert.butylamino)-propoxy]carbanilate hydrochloride,

mp 135 to 138 °C (acetone-ether) (BL-535),

36. penty 1-4 [(2-hydroxy-3-isopropylamino)-propoxy]carbanilate hydrochloride,

1.m. 136 to 138 °C (acetone-petroleum ether) (BL-543),

37. pentyl-4[(2-hydroxy-3-tert.butylamino-propoxy]carbanilate hydrochloride,

1.1. 145 to 147°C (acetone-petroleum) (BL-545),

38. cyclohexyl-2[(2-hydnoxy-3-iopropylamimo)-propoxy] carbianilate hydrochloride,

1.1. 147 to 150 °C (2-propanol ether j (BL-623),

39. cyclohexyl-2[(2-hydroxy-3-tert.butylamino)-pnopotoxy]carbaniTate chloride,

t. t. 192 to 195 °C (ethanol-ether) (BL-625),

40. cyclotohexyl-3[(12,1-hydroxy-3-isopropylamino)-propoxy)carbanilate hydrochloride,

1.1. 128 to 129 ^° C (acetone-ether) (BL-633),

41. cyclohexyl-3[(2-hydroxy-3-tert-butylamino)-propyloxy]carbanilate hydrochloride, mp 138-140 ^° C (acetone-petroleum ether) (BL-635),

42. cyclohexyl-4[(2-hydroxy-3-isopropylamino)-propoxy] carbanilate hydrochloride, m.p. 151 to 153 °C (acetone-ether) (BL-643),

43. ethoxyethyl-2[(2-hydroxy-3-isopropylamino)-propoxy] carbanilat hydrochloride, m.p. 102 to 105 °C (acetone-ether) (BL-723),

44. ethoxyethyl-2[(2-hydroxy-3-tert.butylamino)-propiooxy]carbanilate hydrochloride,

1.1. 133 al 135 “C (2-propanol-ether) (BL-725),

45. ethoxyethyl-3[(2-hydroxy-3-isopropylamino)-propioxy] carbanilate hydrochloride,

1.1. 147 to 150 °C (methanol-ether) (BL-733),

46. ethOxyethyl-3[(2-hydnoxy-3-tert.butylamimo)-propioxy]carbanilate fumarate, t. t. 143 al 146 °C (ethanol-ether) (BL-735),

47. Et'Oxyethyl-3 [(2-hydroxy-3-isobutylamino)-propoxy]carbanilate hydrochloride,

t. t. 124 al 126 °C (acetone-ether) (BL-734),

48. ethoxyethyl-4[(2-hydroxy-3-isopropylamino)-propoxy]carbanilate fumarate,

1.1. 175'al 178 °C (methanol-ether) (BL-743),

49. ethoxyethyl-4[(2-hydroxy-3-tert-butylamino)-propoxy]carbanilate fumarate, m.p. 177 to 179 °C (methanol-ether) (BL-745),

50. ethoxyethyl-4[(2-hydroxy-3-isobutylamino-propoxy]carbanilate hydrochloride,

1.1. 158 and 160 °C (acetene-ethanolj (BL-744),

51. ethoxyethyl-2[(2-hydroxy-3-isobutylamino-propyloxy]carbanylthiooxalate,

t. t. 138 to 143 °C (ethanol-ether) (BL-724),

52. Allyl-2[(2-hydroxy-3-isobutylaminoj-propoxy]carbamylate hydrochloride, . m.p. 119 to 121 °C (acetone-petroleum ether) (BL-323),

53. allyl-2[(2-hydroxy-34-tert..butylamino)-propoxy]carbanilate hydrochloride,

t. t. 166 to 168 °C (2-propanol etherj (BL-325)

54. ethyl-4 [2-hydroxy-3-cyclopropylamino)-propoxy]carbanilate hydrochloride,

mp 156 to 160 °C (acetone-ethanol (BL-246),

55. Ethyl-4[(2-hydroxy-3-cyclopentylamino)-propoxy]carhanylate hydrochloride,

t. t. 152 to 155 °C (2-propanol ether) (BL-248),

56. ethyl-2[(2-hydroxy-3-cyclohexylamino-propoxy] carbonate hydrochloride,

t. t. 156 to 159 °C (2-propanol-etherj (BL-249),

57. Ethyl-3[(2-hydroxy-3-cyclobexylpropoxy]carbonate hydrochloride, m.p. 157 to 160 °C (2-propanol ether (BL-239),

2'2ΌΖ'7Γ

TTabuh-řfeai 1

Effect of tested substances and metipranolol in can. 10 mg/20 mb on isoprenaline-induced tachycardia in isolated guinea pig atria.

Substance % reduction of TF after the test % reduction positive chryonotr.

account IP' after lWbke with regard to Ife controls, qualities

Control Q,6±3)Jt 4.4 + 4.7 MTP 20.8 + 3.1 24.3 + 7.4* BL-223 5.1-+1.6 6.3^+-4.5 BL-225 7.8 + 2.6; 16.6 + 7.2 BL-233 3.9/-+- 2.5 17.6 + 6.7 BL-235 4.8 + 0.9 11.6:+2(8: BL-243 7.0 + 2.1 8.3' + 6.4: BL-245 7.8 + 0.9 17.7 + 5.9* BL-423 11.4 + 0.6; 7.8 + 6.0 BL-425 4.7 +1.6 9.8 + 6.0 BL-433 10.6 + 2.0 5.6.+ 6.1 BLr4S5 9)6(-2.0 3.7- + 4:.0 BL-443 13.0 + 3.2 24.0 + 4.9* BL-445 9.6 + 1.21 18.0 + 4.5* BL-6‘23 6)βί+ 4)2. 19.0 + 3.8* BL-6'33 9.8 + 3.2 16.7 + 3^6 BL-6‘43 14.3 + 3.2 18)6+3)2*' BL-3‘23 19.0)+ 2.2 11.9:--1-4.8 BL-3‘25 13.4 + 1.7' 15.0 + 4.0

Table ¹ 2.

Protective effect of metipranolol at a dose of 1 mg kg ^-1 on aconitine consumption during induction of arrhythmia, fibrillation and lethal cardiac arrest in anesthetized guinea pigs.

Substance· Arrhythmias Fibrillation They flew Saline solution 67.1+ 5.5. 138.8 + 13.1 218.2 + 21.1 Metípranolioir 110.4 + 7.3* 238.1 + 13.1* 430.0 + 30.7* BL-223 80.2+ 6.3 142.7+ 9.8 263.6+ 9)2* BL-225 84.6+ 8.2 151.4+ 5.2. 250.5)+ 10.1 BL-233 94.7 +14.6* 226.8 + 11.6* 274.8.+ 42.0* BL-235 9.4.5+ 3.7* 208.7 + 11.9* 306.2'+ 12.4* BL-243 74.7+ 5.3 139.9 + 14.4 252.9 + 13.1* BL-245 83.4+ 7.1 158.6+ 6.8/ 317.9.+ 12.8/ BL-423 106.7 + 10.6-* 191.6 + 16.7* 272.8-+ 26.6- BL-425 105.9+ 8.1* 199.9 + 14.3* 286.6+ 27.7 BL-433 183.4+ 11.9/ 265.5 + 20.9* 409.4+ 17.3* BL-435 123.9 +10.9* 251.5 + 23.2* 381.9 + 14.6* BL-443 69.2+ 9.0 188.1 + 10.7* 321.4+ 31.6* BL-445- 95.4 + 7.0/ 276.9 + 29.4* 407.6 + 21.0* BL-6‘23 Flow Tox Tox. BL-6'33 Tox Tox Tox BL-6‘43' 94.6+12.9* 243.0 + 31.7* 474.0 + 70.0* BL-3‘23 93.4 +18.3* 276.2 + 55.1* 364.1+44.6* BL-3'25. 71.2+ 6.6 277.8 + 42.0/ 429.6.+ 43.(L*

Table 1' and 3

Acute toxicity of substances after s. c. application of 1% solution to mice.

Substance LD50 (Mg. kg ^-1 ]

BL-223 250 — 400 BL-225 300 — 400 BL-233 50 — 100 BL-235 50 — 100 BL-243 300 — 400 BL-245 300 — 400 BL-423 50 — 100 BL-425 50 — 100 BL-433 < 50 BL-435 < 50 BL-443 200 — 250 BL-445 150 — 200 BL-6‘43 100 — 200 BL-6‘23 50 — 100 BL-6'33 < 50 BL-3‘23 100 — 200 BL-3‘25 100 — 300 MTP 250 — 300

Local anesthetic activity

Fabric

Efficacy index LD50/mg.kg ^-1 superficial anesthesia infiltration anesthesia

BL-223 7.1 BL-225 2.3 BL-235 <1 BL-233 1.8 BL-243 2.1 BL-245 1.9 BL-423 9.1 BL-425 7.9 BL-433 10.6 BL-435 10.8 BL-443 3.1 BL-445 4.5 BL-6‘23 11.1 BL-6'33 4.5 BL-6‘43 3.6 BL-3‘23 2.3 BL-3‘25 7.5 metipranol <1

2.0

1.0 <1

1.0

2.2

1.0

4.0

7.0

4.4

4.2

1.0 <1

7.7 =5

4.2 =2

3.6

5.8

Claims (4)

220271 11 12 T a b u c a 3 Acute Toxic Toxic Toxic To Apply 1% Solution To Mice. Fabric LDso (Mg kg-1) BL-223 250 - 400 BL-225 300 - 400 BL-233 50 - 100 BL-235 50 - 100 BL-243 300 - 400 BL-245 300 - 400 BL-423 50 - 100 BL-425 50 - 100 BL-433 <50 BL-435 <50 BL-443 200 - 250 BL-445 150 - 200 BL-6'43 100 - 200 BL-6'23 50 - 100 BL-6'33 <50 BL-3'23 100 - 200 BL-3'25 100 - 300 MTP 250 - 300 Locally anesthetic activity Substance Efficiency Index LD 50 / mg .kg-1 Surface Anesthesia Infiltration Anesthesia BL-223 7.1 BL-225 2 3 BL-235 <1 BL-233 1.8 BL-243 2.1 BL-245 1.9 BL-423 9.1 BL-425 7.9 BL-433 10.6 BL-435 10.8 BL- 443 3.1 BL-445 4.5 BL-6'23 11.1 BL-6'33 4.5 BL-6'43 3.6 BL-3'23 2.3 BL-3'25 7.5 metipranol <1 2.0 1.0 <1 1.0 2.2 1.0 4.0 7.0 4.4 4.2 1.0 <1 7.7 = 5 4.2 = 2 3.6 5.8 SUBJECT 1. Substituted aryloxypropanolamines of the general formula I-O-CH-CH-CH2-NHR2, which is substituted by an alkaxyalkyl of 1 to 5 carbon atoms, straight or branched alkenyl of 2 to 5 carbon atoms, and a cycloalkyl of 3 to 6-NHCOOR ( 1) wherein R 1 is a straight or branched alkyl carbon atom and R 2 is a tri-branched alkyl of 3 to 4 carbon atoms, or a cycloalkyl of 3 to 6 carbon atoms, as well as their salts with inorganic and inorganic acids. 2. The process of claim 1, wherein the compound of formula IV (OH) (II) NHCOOR is not reacted in the covalent. R1 denotes ieite; as in. of formula (I), with a primary amine of formula H2NHR2, in which R2 represents a thiol in the formula I, in the middle of an alkanol of 1 to 3 carbon atoms, adhere to 100 to 120 DEG C. in a sealed tube. 2. A process for the preparation of substituted aryl-oxypriopanalamines of the general formula I according to claim 1, characterized in that the compound of general formula II 114 is not reacted. 3. Preparation method; of substituted aryl oxypropanolamines of the formula I according to claim 1, characterized in that a compound of the formula III is not reacted with O-O-CHfCH-CH 2 NHCOOR (III) in which R 1 represents t (other than formula I, 9 for primary amines of the general formula H2NR 2, (IV) in which R 1 represents the same as vio of formula t, s - alkylamino | o-2, The 3-eploxypropane of the general formula V / 9 CHf-CH-CH3-NHR (V) in which R2 is the same as in formula I, in the middle of the alkali metal catalysis, S sodium hydroxide. 5. A process for the preparation of substituted aryl-oxypropanolamines of the general formula (I) according to claim 1, characterized in that a compound of the general formula (IV) in which R1 represents the same as in the formula for 9-alkylamino-3-chloro-2- a propanol of formula (VI) OH (CI) -CH 2 -CH-CH 2 -NH (R) (VI) in which R 2 is as yellow as in the formula; of formula (I), at a temperature of from 100 to 120 ° C, in a sealed vessel at a temperature of from 1 to 3 carbon atoms. 4. A process for the preparation of substituted aryl-R2 is the same as in formula I, in the middle of an alkanol having 1 to 3 carbon atoms, a catalytic base of an alkali metal hydroxide in a closed vessel at a temperature of 100 to 120 ° C. Severografia, n. P., Závod 7, Most Price 2,40 Kcs