FI59582B - FOERFARANDE FOER FRAMSTAELLNING AV NYA TERAPEUTISKT VERKSAMMA FENOXYLPROPYLAMINDERIVAT OCH DERAS SALTER - Google Patents

Description

r l rftl ANNOUNCEMENT c Q C O O

3¾¾ M (11) uTLÄOCNINGSSKmFT by502 c (45) ra exam issued ID C9 1981 v ^ (51) Kv.lk.3 / lnt.ci'3 C 07 C; 127/17 SUOM I - FI N LAN D (21) Pwunttlhtkumu »- p * t * nttn * eknlnj βθ / 73 (22) HukumlipWvl - An * eknlnpd« | 10.01.73 (23) AlkupUvi —Glttlghutadag 10.01.73 (41) Tullut JulklMkil - Bllvlt offuntllg 29.08.73

Patent and Raccoon Administration · (44) Nlhtlvlkilpanen f ·uuL | -

Patent- och ragistarstyralaan '' Anaekan uttagd och utUkrtfUn publkand 29-05.81 (32) (33) (31) Pyydetty atuelkaua — Begird prlorltec 28.02.72

Austria-Austria (AT) A 1573/72 (71) AB Hassle, Fack, S-l + 31 20 Molndal, Sweden-Sweden (SE) (72) Gerhard Zölss, Linz / Donaii, Werner Obendorf, Linz / Donau,

Irmgard Lindner, Linz / Donau, Karl Anton Wismayr, Linz / Donau,

Austria-Österrike (AT) (7 ^) Berggren Oy Ab (5 ^) Process for the preparation of new therapeutically active phenoxypropylamine derivatives and their salts - Forfarande för framställning av nya therapeutiskt verksamma fenostjlpropylaminderivat och deras salter

The present invention relates to a process for the preparation of new therapeutically active phenoxypropylamine derivatives of the general formula R 1 X - NH - C - N f 0 R 2 (rVn I i

V

O-CH2-CH-CH2-NHR2

OH

wherein X is a straight or branched lower alkylene residue, and R 2, which may be the same or different, is a hydrogen atom, a lower alkyl, allyl, hydroxyethyl, phenyl, methoxyethyl or benzyl group, R 1 is lower alkyl, allyl, lower alkoxy -, an acetamido, nitro, amino group or halogen atom, R 1 is a branched lower alkyl group or a cyclopropyl group, and n is 0, 1 or 2, and pharmaceutically acceptable acid addition salts thereof. The compounds according to the invention have β-receptor inhibitory properties and are thus suitable for the treatment and prevention of cardiac arrhythmias, such as angina pectoris, cardiac arrhythmias and the like.

Compounds which have an inhibitory effect on the function of β-receptors are known from DE-2 040 441. These are phenylurea derivatives which, in the arbitrary position, preferably in the 4-position with respect to the ureido group, have a 2-hydroxypropylamine residue which is characteristic of compounds having β-inhibitory properties and which has the general formula R

</ x) -XCH0CHCH0N

r X = J 2! 2 10 R 2 K 4 wherein R is a ureido group, R 1 is hydrogen, halogen or lower alkyl, R 2 is hydrogen or lower alkyl, R 1 is hydrogen, lower alkyl or aryl-lower alkyl, R 1 is lower alkyl, OH-lower alkyl, lower alkoxy-lower alkyl, aryloxy-lower alkyl, cycloalkyl, lower alkenyl or aryl-lower alkyl, X is oxygen or sulfur, and the compounds below are denoted by G in Table 1 when compared to the compounds of the invention .

According to PI application 3256/71, similar 8-receptor blocking compounds are known which have the general formula: R2-NH-CO-NH- {f 'ς) v = / ^ 0-CH2-CHO-CH2-NH-R1 in which R 1 is branched or unbranched lower alkyl, alkenyl or cycloalkyl and R 2 is hydrogen, branched or unbranched lower alkyl, cycloalkyl or alkenyl, wherein the urea and alkanolamine group may be in an optional position relative to each other, and the compounds are denoted by F in Table 1.

In these two groups of cardiac compounds mentioned above, the ureido group is directly attached to the phenyl ring. Such compounds have been shown to have the property of being metabolized to anilines in humans, which can lead to a serious side effect, namely the development of autoimmunity. In the compounds of the present invention in which the alkylene group X separates the ureido group from the phenyl ring, there is no such risk.

Still known β-receptor blocking compounds are known from FI application 443/70, which have the general formula: VA_ <Q- οο „2_Λ with isopropyl or tertiary butyl, R2 is carbamoyl or alkylcarbamoyl and A is methylene, ethylene or vinylene.

However, these compounds do not contain a ureido group but in the side chain of a heteroatom (nitrogen), and are structurally quite far from the compounds of the present invention.

Surprisingly, it has now been found that the compounds according to the invention have a much stronger inhibitory effect on β-receptors. The compounds of the formula I differ from the known phenylurea derivatives, in particular in that they have a branched or straight lower alkylene group between the aromatic nucleus and the ureido group. Thus, for example, the inhibitory effect on the β-receptors of the N-4- (T3'-tert-butylamino-2'-hydroxy) -propoxy-7-benzylurea compound has been shown to be demonstrated by studying the increase in heart rate after administration of isoprotenol in dogs. when the test compound is or has not been administered before, is more than 5 times more potent than the analogous N-4- [T3, -tert-butylamino-2'-hydroxy) -propoxy7-phenylurea (example of DE-2 040 441 4), the effect of which has been particularly emphasized in that publication. The toxicity values observed in mice with the compounds of formula I are approximately the same as with the known phenylurea derivatives, so that the relationship between the effective dose and the toxic dose is considerably more favorable in the compounds of formula I. In addition, among the compounds of the formula I, those which have a particularly long-lasting effect have also been found, such as, for example, N-3-nitro-4- [13'-tert-butylamino-21-hydroxy) -propoxy] -benzylurea.

Of the compounds of formula I, the best ones are those in which in formula IX there is a branched or straight lower alkylene group having up to 4 59582 carbon atoms, R 1 is hydrogen or a lower alkyl group, R 2 is a hydrogen atom or a lower alkyl, hydroxyethyl, methoxyethyl or benzyl group , R 1 is a lower alkyl, nitro or amino group or a halogen atom, and R 1 is a branched lower alkyl group or a cyclopropyl group having in each case up to 6 carbon atoms, and pharmaceutically acceptable acid addition salts of these compounds.

Compounds of formula I in which R 1 and R 2 are hydrogen, n is 0 and X is a methylene or ethylidene group and R 1 is a branched alkyl group of 3 to 5 carbon atoms, or compounds in which R 1 and R 2 are hydrogen, R 1 in the m-position with respect to X and in the O-position with respect to the ether side chain is a lower alkoxy group, a nitro group, a chlorine atom or a bromine atom, a lower alkyl group or an amino group, n is 1 and X is a methylene or ethylidene group, and R is a branched alkyl group having 3 to 5 carbon atoms, or finally as compounds in which R 1 is hydrogen or lower alkyl, R 1 is hydrogen, R 2 is a lower alkyl group, a hydroxyethyl group, a phenyl or benzyl group, n is 0 and X is a methylene or ethylidene group, and R ^ is a branched alkyl group having 3 to 5 carbon atoms. As examples of such compounds, in addition to the compound already mentioned, e.g. N1- (4 '- [3 "-tert-butylamino-2" -hydroxy) -propoxy] -phenyl) -ethyl- (1) -urea, N-3-methoxy-4- [1,3'-tert-butylamino 2'-hydroxy) -propoxy-7-benzyl urea, N-3-nitro-1H-3'-tert-butylamino-2'-hydroxy) -propoxy-7-benzylurea, 'N-3-chloro-4- [T3'-tert. -butylamino-2 * -hydroxy) -propoxy-7-benzylurea, N-4- (T3'-tert-butylamino-2'-hydroxy) -propoxy-7-benzyl-N'-benzylurea, β-β-β3τ-tert. -butylamino-2'-hydroxy) -propoxy7-benzyl-N'-phenylurea, N-4- (T 3'-isopropylamino-21-hydroxy) -propoxy7-benzylurea, N-li- / T 3'-tert. -butylamino-2 * -hydroxy) -propoxy7-Benzyl-N'-dimethylurea, N-3-methyl-N- (T31-tert-butylamino-2'-hydroxy) -propoxy7-benzylurea, N- 3-Amino-tert-butyl-tert-butylamino-2'-hydroxy) -propoxy-7-benzyl-urea, N-3-ethoxy-N - [3-tert-butylamino-2'-hydroxy ) -propoxy7-benzylurea, N-3-bromo-4- [T3'-tert-butylamino-2 * -hydroxy) -propoxy7-benzylurea and N-4 - [(3'-tert-butylamino-2'-hydroxy) hydroxy) -propoxy7-benzyl-N'-methyl-N '- (β-hydroxy) -ethyl-urea.

The process according to the invention for the preparation of the compounds of the formula I is characterized in that the phenoxypropane derivative of the general formula II

5,59582

X - NH - C - N

V

OCK „- CH - CH0 - Z 2! 2 X 1 in which R 1, R 2, R 2, X and n have the same meaning as in formula I, and in which X 1 is a hydroxyl group and Z is chlorine, bromine or iodine or X 1 and Z together form an epoxy group, is reacted at room temperature or at elevated temperature. at temperature with an amine of general formula

H2N - R ^ III

wherein R 1 is as defined in formula I and the bases which precipitate as a reaction product are isolated as such or as salts or the bases are liberated from the precipitating salts and, if desired, converted into pharmaceutically acceptable salts.

The reaction can be carried out with or without a solvent. Preferred solvents are polar solvents such as lower alcohols or Ν, Ν-dimethylacetamide. An excess of the amine of the formula H2N-R1 can also be used as a solvent. Particularly good results are obtained when water is added to the reaction mixture. in which X 1 represents a hydroxyl group and Z represents a halogen, it is also possible to use a solvent or not to use it. the excess of the amine of formula III can again be used as solvent.

6,59582

Isolation of the compounds of formula I in the reaction mixture takes place in the usual manner. The salts of the compounds of the formula I from bicarboxylic acids, such as, for example, fumarate, oxalate or succinate, have a very good tendency to crystallize, so that for isolation it is particularly recommended to convert the compounds into such salts.

These compounds of formula I may have use either as a base or as pharmaceutically acceptable salts in preparations. Such pharmaceutically acceptable salts include, for example, hydrohalides, especially hydrochloride and hydrobromide, further sulphate, phosphate, acetate, fumarate, succinate, cyclohexyl sulphamate, tartrate and citrate. Such salts are prepared, for example, by reacting bases with an equivalent amount of the corresponding acid.

The compounds of formula II required as starting materials are in many cases new. In case they are halohydrins, or epoxides, they can be obtained from the corresponding phenols with epi-halide hydrides. The epoxides of the formula II are obtained in particular when the phenolate is reacted either in an anhydrous medium, e.g. using dimethylformamide or hexamethylphosphoric acid trisamide as a solvent, or in water or in an aqueous-alcoholic solution with the epihalohydride. In contrast, the halohydrin of the formula II is preferably formed when the exchange reaction starts from the corresponding free phenols, is carried out at a temperature of about 100 [deg.] C., an excess of epi-halohydride is used and a basic catalyst, e.g. piperidine, is added. The epoxides of the formula II obtained as described may contain a certain amount of the halohydrin of the formula II, which, of course, does not interfere with the subsequent exchange reaction into the compounds of the formula I.

The phenols required for the preparation of the compounds of formula II having the ureido group-containing side chain described above can also be prepared by known methods. The exchange reaction of hydroxy-substituted phenylalkylamine salts with potassium cyanate thus yields 7,59582, e.g. urea derivatives, which can already serve as starting materials for the preparation of compounds of the formula II in which and R 1 are hydrogen. If it is desired to prepare compounds of formula II in which R 1 and / or R 9 are other than hydrogen, the corresponding ureidoalkyl-substituted phenol is obtained by reacting the corresponding isocyanate whose phenolic hydroxyl group is protected with acyl or benzyl with amines of formula HNR 4 R 8. The group protecting the phenolic hydroxyl group can then be easily cleaved off.

The formation of ureaalkyl-substituted phenol from carbamic acid chlorides is also possible.

For administration of the compounds of formula I, these may be mixed with any conventional pharmaceutically acceptable carrier. This is selected in the usual manner according to the form in which the preparation is to be administered. Both mixtures which can be processed into tablets or granules and stable solutions, e.g. the compounds of the formula I, can be prepared. Finally, the active compounds of the formula I can also be filled into capsules.

The following examples further illustrate the compounds of the invention and their preparation.

Example 1 8.0 g of N-H - [(2 ', 3'-epoxy) -propoxy] -benzylurea are reacted for one hour at room temperature with a mixture of 60 ml of tertiary butylamine and 60 ml of water. The reaction mixture is then evaporated in vacuo and the residue is post-distilled with ethanol / benzene to completely remove water. 8.5 g of Ν- · * - / (3'-tert-butylamino-2, -hydroxy) -propoxy] -benzylurea are thus obtained, which is 79.9% of theory.

The oily base is dissolved in ethanol, filtered and an equivalent amount of fumaric acid in acetone is added to the filtrate. The fumarate crystallizes and is separated after some time by suction. After recrystallization from ethanol, the melting point is 1-71-173 ° C.

The required N-H - [(2 ', 3'-epoxy) -propoxy] -benzylurea was obtained by reacting N- (p-hydroxy) -benzylurea in aqueous solution with epichlorohydrin by adding a calculated amount of sodium hydroxide. Melting point 150-157 ° C.

Example 2 13.0 g of N-3 - [(2 ', 3'-epoxy) -propoxy] -benzylurea and a mixture of 40 ml of tertiary butylamine and 40 ml of water are reacted for 2 hours at room temperature. After further work-up according to Example 1, 15.0 g of crude N-3 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea are obtained. In analogy to Example 1, the fumarate obtained from the base melts at a temperature of 157-161 ° C.

The N-3 - [(2 ', 3'-epoxy) -propoxy] -benzylurea used as a starting material was obtained by exchanging the sodium salt of N- (m-hydroxy) -benzylurea with epichlorohydrin at 50 ° C and using hexamethylphosphoric trisamide as a solvent. The product is oily.

Example 3 10.0 g of N-2 - [(2 ', 3, -epoxy) -propoxy] -benzylurea are reacted with tertiary butylamine as described in Example 2. 13.0 g of N-2 - / (3') are obtained in the form of an oily product. -tert-butylamino-2'-hydroxy) -propoxy / benzylurea.

Melting point of fumarate (from ethanol) 125-128 ° C.

Example 4 10 g of N-4 - [(2 ', 3'-epoxy) -propoxy] -benzylurea are reacted at room temperature for 4 hours with 80 ml of a 1: 1 mixture of isopropylamine and water. 12.4 g of N-4 - [(3'-isopropylamino-2'-hydroxy) -propoxy] -benzylurea are thus obtained. The melting point of the base is 103-106 ° C.

Example 5 2.0 g of N-3-methoxy-4 - [(3'-chloro-2'-hydroxy) -propoxy] -benzylurea and 20 ml of tert-butylamine are heated in a sealed vessel at 100 ° C for 2 hours. After cooling, the excess tertiary butylamine is distilled off in vacuo, a small amount of acetone is added to the residue and seeded. This crystallizes a substance which, after some time, is separated by suction. 1.7 g of N-3-methoxy-4- [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea are thus obtained, corresponding to a yield of 75.5% of theory. Melting point 134-137 ° C. The melting point of neutral fumarate is 198-200 ° C.

The starting N-3-methoxy - [(3'-chloro-2'-hydroxy) -propoxy] -benzylurea is obtained from 3-methoxy-4-hydroxy-benzylurea by an exchange reaction with epichlorohydrin at 100 ° C for a reaction time of 3 hours while piperidine is added as a catalyst.

Example 6 1.0 g of N-4 - [(2 ', 3'-epoxy) -propoxy] -benzylurea and 1.64 g of tertiary butylamine are heated at reflux for 2 hours in 20 ml of ethanol. The clear solution obtained is evaporated in vacuo and the solvent is completely removed from the residue. This gives 0.95 g of crude N-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea, which, after conversion to fumarate, melts at 171-173 ° C.

In a manner similar to Examples 1-6, the following are obtained: 7. N-4 - [(3'-isopropylamino-2'-hydroxy) -propoxy] -benzyl-N'-methylurea, melting point of neutral fumarate 170-172 ° C.

8. N-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N'-methylurea, melting point 146-149 ° C of fumarate.

9. N-4 - [(3'-isopropylamino-2'-hydroxy) -propoxy] -benzyl-N'-isopropylurea, melting point 149-153 ° C of fumarate.

10. N-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N'-isopropylurea, base melting point 135-138 ° C.

II. N-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N'-allyl-urea, base melting point 73-76 ° C.

N-4 - [(3'-isopropylamino-2'-hydroxy) -propoxy] -benzyl-N'-benzylurea, melting point 119-1 ° C of the hydrochloride.

10,59582 13. N-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N'-benzylurea, base melting point 80-82 ° C.

14. N-4 - [(3'-sec.-butylamino-2'-hydroxy) -propoxy] -benzylurea, melting point of neutral fumarate 170-173 ° C.

15. N-4 - [(3'-cyclopropylamino-2'-hydroxy) -propoxy] -benzylurea, melting point of neutral fumarate 130-134 ° C.

16. N-4 - [(3'-isopropylamino-2'-hydroxy-propoxy) -benzyl-N '- (2 "-methoxy) -ethylurea, melting point 132-133 ° C of fumarate.

17. N-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N '- (2 "-methoxy) -ethylurea, base melting point 76-79 ° C.

18. N-4 - [(3'-isopropylamino-2'-hydroxy) -propoxy] -benzyl-N '- (2 "-hydroxy) -ethylurea, melting point fumarate 138-140 ° C.

19. N-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N '- (2M-hydroxy) -ethylurea, melting point 146-149 ° C of neutral fumarate.

20. N-4 '(3' -isopropylamino-2'-hydroxy) -propoxy] -benzyl-N-phenylurea, melting point of fumarate 105-107 ° C.

21. N-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N'-phenylurea, melting point of fumarate 134-138 ° C.

22. N-4 - [(3'-isopropylamino-2'-hydroxy) -propoxy] -benzyl-N'-dimethylurea, melting point fumarate 150-153 ° C.

23. N-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N'-dimethylurea, base melting point 105-108 ° C.

24. N-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N'-methyl-N '- (2 "-hydroxy) -ethyl urea, base melting point 111-113 ° C.

25. N-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N'-diisopropylurea, melting point 141-146 ° C of neutral fumarate.

59582 26. N-3 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -4-methoxy-benzylurea, base melting point 64-67 ° C.

27. N-3-methoxy-5 - [(3'-tert-butylamino-2'-hydroxy> propoxy) -benzylurea, fumarate melting point 198-200 ° C.

28. N-3-methoxy-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N'-ethyl-urea, base melting point 132-133 ° C.

29. N-2- {4 '- [(3 "-tert-butylamino-2" -hydroxy) -propoxy] -phenyl} -ethyl- (1) -urea, melting point of neutral fumarate 105-108 ° C.

30. N-1- {4 '- [(3 "-isopropylamino-2" -hydroxy) -propoxy] -phenyl) -2-ethyl- (1) -urea, base melting point 100-102 ° C.

31. N-1- {4 '- [(3 "-tert-butylamino-2" -hydroxy) -propoxy] -phenyl} -ethyl- (1) -urea, base melting point 105-107 ° C.

32. N-1- {4 '- [(3 "-tert-butylamino-2" -hydroxy) -propoxy] -phenyl} -propyl- (2) -urea, melting point of neutral fumarate 111-114 ° C.

33. N-3-methyl-4 - [(3'-isopropylamino-2'-hydroxy) -propoxy] -benzylurea, base melting point 101-102 ° C.

34. N-3-methyl-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea, m.p. 70-72 ° C.

35. N-3-methoxy-4 - [(3'-isopropylamino-2'-hydroxy) -propoxy] -benzylurea, base melting point 132-135 ° C.

36. N-3-chloro-4 - [(3'-tert-butylamino-2'-hydroxy) -propionyl] -benzylurea, mp 127-129 ° C.

37. N-3-nitro-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea, melting point of neutral fumarate 173-175 ° C.

38. N-3-nitro-4 - [(3'-isopropylamino-2'-hydroxy) -propoxy] -benzylurea, melting point 180-185 ° C of fumarate.

39. N-3-acetylamino-4 - [(3'-isopropylamino-2'-hydroxy) -propoxy] -benzylurea, fumarate melting point 142 ° C.

59582 * 10. N-3-acetylamino- * N - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea, base melting point 191-19 ° C.

* 11. N-3,5-dichloro-* - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea, base melting point 1 * 19-151 ° C.

* 12. N-3-methoxy- * 1 - [(31-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N'-butylurea, m.p. 127-128 ° C.

* 13 · N-3-methoxy- * 1 - [(3, -tert-butylamino-2, -hydroxy) -propoxy] -benzyl-N'-dibutylurea, m.p. 7 ** - 77 ° C.

* 1 * 1. N-3-ethoxy- * 1 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea, melting point fumarate 1 * 13-1 * * * 10C.

* 15 · N-3-bromo-* - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea, m.p. 130-132 ° C.

* 16. N-3-amino-4 - [(31-tert-butylamino-2 * -hydroxy) -propoxy] -benzylurea, dihydrochloride mp 18-118-87 ° C.

* 17. N-3-allyl * 1 - [(3T-tert-butylamino-2'-hydroxyD-propoxy) -benzylurea fumarate, amorphous powder, sintering range 130-133 ° C.

Pharmacological research

The compounds prepared according to the above examples were compared in terms of their biological properties with the above-mentioned prior art compounds (F and G) by means of reserpinated, anesthetized vagotomized cats. Cats were pretreated with re-serpin 16 hours before the start of the experiment. Following anesthesia with nembutal sodium (30 mg / kg i.p.), cats underwent thoracotomy and vagotomy. Intra-arterial mean blood pressure and heart rate were recorded. The dose of isoprenaline that elicited a heart rate control response of 80% of the maximal response was determined. The test substance was administered intravenously evenly at increasing doses at 30 minute intervals. Between each dose, a control dose of blood isoprenaline was administered. The ED 2 values of the isoprenaline response block were determined from the dose-response curves by reading the block percentage from the logarithm of the test substance dose.

The results of the experiment are shown in Table 1, in which compounds A-E are compounds according to the invention and F and G are from FI application 3256/71 and resp. Compounds known from DE 0 040 441.

table 1

A compound of the formula r - // \\ -_ O-CH2-CH-CH2-NHCH (CH3) 2,

've \ i 0H

R

where

Isoprenaline- Specific effect, response to heartbeat- blockade change in density ED (-q mg / kg i.v.

Heartbeat / min.

RR stroke pressure nl density A NH2CONHCH2- H 0.7 8.5 0 b ch3nhconhch2- H 0.5 l4.l 0 C (CH3) 2CHNHCO0NHCH2- h 1.8 21 +8 D ΝΗ20ΟΝΗΟ2Η ^ - h 0.6 8 0 E NH2CONHC2H4- Cl 0.4 3 * 0 o F NH 2 CONH- h 1.3 68 +26 G CH 2 NHCONH- H 0.9 17 +43

As can be seen from the table, both the previously known compounds and the compounds according to the invention have a selective effect on heart rate relative to blood pressure. In many cases, however, the ED 2 value of the heart rate isoprenaline response is lower with the new compounds, which means that lower therapeutic doses can be used. The known compounds F and G have a strong characteristic effect on the heart rate. Especially when the patient is in a state of over-tension, the absence of a specific effect is desirable and the F and G compounds are unusable for the treatment of several cardiovascular diseases due to their high specific effect. In contrast, a limited specific effect, such as that seen with Compound C, is beneficial in several cases, especially in the treatment of angina pectoris in elderly patients.

14 59582 For use in the manufacture of a compound for the treatment of all, therapeutically active phenoxypropylamines in the form of all-forms In / R1 X-NH-C-N

II

yy / S 0 2 i

<R3> n - I

V

0 - CH2 - CH - CH2 - NHR4 OH

color X is selected from the group consisting of alkylene, alkyl and R2 »which may be contaminated with oil or hydrogen, with alkyl, allyl, hydroxyethyl, phenyl, methoxyethyl or benzyl group, R3 is selected from the group consisting of alkyl, allyl, alkoxy, acetamido, nitro, amino or halogen, R 4 is selected from the group consisting of alkyl or cyclopropyl and 0.1 or 2, as well as pharmaceutically acceptable sugar derivatives. For example, a 3-receptor blocker is used in the presence and use of a 3-receptor blocker for the treatment and use of the fungus, in the case of angina pectoris, fungi and other fungi.

The use of a β-receptor blocker is described in DE patent-patent 2,040,441. föreningar har den allmänna formeIn / r3

v) —XCH-CHCH-NC

* A- / \ N

R is an alkyl group, R 1 is an alkyl group, a halogen or an alkyl group, an alkyl group is an alkyl group, an R 1 is an alkyl group, an aryl-alkyl group, an R 1 -alkyl alkyl group, an OH-alkyl group, an alkyl group alkoxy-alkyl-alkyl, aryloxyl-alkyl-alkyl, cycloalkyl, alkenyl or aryl-alkyl-alkyl, X is a single or hydrogen-containing, and in the case of specific compounds in Table 1, in which case the same or more are used.

is 5 9582

In particular, FI-32 32/71 is used in the form of a B-receptor blocker, in which the form R2-nh-co-nh -r \ \ - 7c ^ o-ch2-choh-ch2-nh-r1 is used to form or alkyl of alkyl, alkenyl or cycloalkyl and R2 of the alkyl group, grenadine or alkyl of alkyl, cycloalkyl or alkenyl, color of urea and alkanolamine group in the valence of the flaxAllande in the case of F.

The present reference number of the BA is very active in the case of a group of directors of the phenyl ring. For this purpose, the anaeros, which can be used for all autoimmunity activities, can be used. In this case, the same group of compounds as the phenyl group X of the alkyl group X up to the risk is used.

In this case, the 3-receptor blocker for the FI-compound 443/70, which has the following formula • OCH2CHOHCH2NHR1 is R1 is isopropyl or tert-butyl, R2 is carbamoyl or alkyl-carbamoyl and A is methylene or ethylene. In this case, the heterogeneous group is itself a heteroatom (quaternary) and a bond and a structure that is structurally relative to the same or greater than the same.

However, the present invention is based on the above-mentioned genomic uptake of the genome and the specific $-receptor blocker. For example, it is possible to form a mixture of phenylureas derived from the aromatic group, which may be aromatic from the aromatic group and which is present in the alkyl group. This exemption may be used to prevent the N-4- / 73 * tertiary. -butylamino-2'-hydroxy) -propoxy-7-benzylurea, which is often used in the presence of isoproterenols for the purposes of the present invention, in the form of 16 to 59582 compounds, in addition to 5 ginger analogues -tert.-butylamino-21-hydroxy) -propoxy-7'-phenylurea (exempt 4 and DE-patent 2,040,441) can be used in particular for the publication. Toxicity, especially in the form of a mixture of phenylurea derivatives, in which case a mixture of compounds of formula I is used to reduce the risk of toxicity. The compounds of formula (I) are used as a compound in which the N-3-nitro-4- (T3'-tert-butylamino-2'-hydroxy) -propoxy] benzylurea is specifically added to the genome.

The compounds of formula I are used in combination with a compound of formula IX having an alkyl group of up to 4 cholaters, R1 is an alkyl group or an alkyl group, R2 is an alkyl group having an alkyl, hydroxyethyl, methoxyethyl group. or a benzyl group, R 1 is an alkyl group, a nitro or an amino group or a halogen atom, and an R 1 is an alkyl group or an alkyl group, or a cyclopropyl group having a maximum of 6 colaters, as well as a pharmaceutically acceptable syrup addition salt.

Specifically, a hydrogen group is used in the preparation of formula I, in which R 1 and R 2 are attached, and in the same case X is a methyl or ethylene group and R 1 is an alkyl group having 3 to 5 carbon atoms in the case of R 2 and R 2. betecnar väte, R ^, som stirr i m-stellning till X och i o-ställning account etersidokedjan, betecknar en lgre alkoxygroup, en nitroroup, en chloro or bromatom, en lgre alkylgroup or amino-group, n betecnar 1 och X betecknar en methyl - or an ethylidene group selected from the group consisting of an alkyl group having 3 to 5 carbon atoms or an alkyl group having the same alkyl group and an alkyl group having the alkyl group, an alkyl group having an alkyl group, a hydroxyethyl group, a phenyl group or a benzyl group, betecnar O and X betecnar in methylene or ethylidene and R4 is a alkyl group having 3-5 cholatomers. Sisom exempel pi sidana föreningar kan förutom den redan ovan angivna föreningen bl.a. N-N- (4 '- / (3 "-tert-butylamino-2" -hydroxy) -propoxy-7-phenyl) -ethyl- (1) -urea, N-3-methoxy-4 - [(3'- tert-butylamino-2'-hydroxy) -propoxy-7-benzylurea, N-3-nitro-4- (73'-tert-butylamino-2'-hydroxy) -propoxy-7-benzylurea, N-3-chloro-4- T3'-tert-butylamino-2'-hydroxy) -propoxy-7-benzylurea, N-4- (73'- 17,59582 tert-butylamino-2'-hydroxy) -propoxy-7-benzyl-N'-benzylurea, N-4- / 73 (tert-butylamino-2'-hydroxy) -propoxy-7-benzyl-N'-phenyl-urea, N-4- (73'-isopropylamino-2'-hydroxy) -propoxy-7-benzyl-urea, N-4- ( 73'-tert-butylamino-2'-hydroxy) -propoxy-7-benzyl-N'-dimethylurea, N-3-methyl-4- (T3'-tert-butylamino-2'-hydroxy) -propoxy-7-benzylurea, N- 3-amino-4- (73'-tert-butylamino-2'-hydroxy) -propoxy] benzylurea, N-3-ethoxy (73'-tert-butylamino-2'-hydroxy) -propoxy] benzylurea, N-3-bromo-4 - (7'-tert-butylamino-2'-hydroxy) propoxy] benzylurea and N-4- (3'-tert-butylamino-2'-hydroxy) propoxy] benzyl-N'-methyl -N'- (β-hydroxy) ethylurea.

For the purposes of this Regulation, the use of phenomena in the formulation of formulas I and the phenoxy propellants in all formulas II

^ R! X-NH-C-N 2 U Xr 2 h

(R3} n "4“ I

V

OCH, - CH - CH, - Z xi color, R2, R ^, X and n are the same as in formula I, and the color X is a hydroxyl group and Z is chlorine, bromine or iodine or X epoxy group, omsättes vid rumstemperatur eller höjd temperatur med en Amin med den allmänna formuleln

h2n - r4 III

color R ^ betecknar detsamma som i formeln I och de säsom reaktions-produkt utfällande baserna isoleras som sädana eller som salter ellera baserna befrias frän utfällande salter ocver förs, om sk önskas, til farmaceutiskt tolererbara salter.

The reaction can be carried out in a frost-free manner. The sponge with a sponge is not polished with a sponge, the alcoholic alcohol or Ν, Ν-dimethylacetamide. As a result, 59N82 compounds of the form of H2N-R4 are present. Specifically, the result is different, for example, the reaction to the reaction. The genome of the plant is ascended and reactivated by reaction time, in which case the relative card size of the reactant is fully immersed. It is possible for an epoxy-derived halogenated hydride with a formulation II to be used, the color of which is a hydroxyl group or a halogen, which may be liquid or dissolved in a solid. The reaction mixture is heated at room temperature to 50-120 ° C. In the case of amino acids of formula III at a temperature such as low temperature, it can be added to the slurry. överskottet av Amin med formeln III kan äterigen tjäna säsom lösningsmedel.

Isolation of the compounds of formula I in the reaction process is based on the same conditions. Mycket crystallization is externally exacerbated in the form of a mixture of formulation I fr & n dicarbonsyror, säsom fumarater, oxalater eller succinater, s & att en överföring av föreningarna account ädana salter is specially heated for isolationen.

In this case, the formulas I can be used in the preparation of an antimicrobial agent or a pharmaceutically acceptable salt form. Säsom sädana is a pharmaceutically acceptable salt and anhydrous hydrohalide, specifically hydrochloride and hydrobromide, vidare sulfater, phosphorus, acetater, fumarater, succinater, Cyclohexylsulfamater, tartrater och citrater. Framställningen av s & Dana salter lyckas exempelvis genom reaktion av baserna med equivalent mängd av motsvarande syra.

The use of a product derived from the formulation of Formula II is associated with a fall fall. However, a halogen hydride or an epoxide, a genomic reaction of a phenoler with an epi-halogen hydride, is present. For example, a commercially available compound in the form of an epoxide of formula II, a phenolate is reacted with an epihalohydrin solution in a water-rich medium, an exemption from dimethylformamide or hexamethylphosphorosyratrisamide to give a solution, an octane or a water-containing alcohol. The compounds in the hand halogenated hydrogens of formula II, which are reacted with a mixture of phenols, at a temperature of about 100 DEG C. to about 100 DEG C., an epihalohydrin in a mixture and a catalyst and a base catalyst, e.g. piperidin. However, the skydrade provisions of the epoxide of formula II can be carried out in which all the halogenated hydrogens of formula II are used, in which case the reaction is carried out by means of the reaction of formula I.

For the purposes of the formulation of Formula II, the phenol groups with the same name are used, in which case the group is used as a whole. The reaction of the exogenous genomic reaction with hydroxyl-substituted phenylalkylamines with potassium cyanates of urea is carried out as a starting material for the preparation of compounds of formula II, which can be carried out with R2. In the case of a compound having the formula II color, R 1 and / or R 2 are not used to give a mixture of ureidoalkyl substituents of the phenol genome reaction of the isocyanate, the phenolic hydroxyl group of which is a mixture of acyl or benzyl, . The group, with the addition of phenolic hydroxyl groups, can be treated with the same.

The phenols of the ureidoalkyl substituents of the phenol ur carbamyl chloride are optionally added.

For the purposes of this Regulation, the pharmaceutical composition may be used as an acceptable pharmaceutical form. When the head is removed from the form after which it is formed, it is readily prepared for use. A man with a dowry in the field, when he bears a tablecloth or a duck, is a stable stable, t.ex. in the case of a formulation with a formulation of I. The form of the formulation is formulated with a formulation of the capsule.

I have subsequently examined the scope of the measures and the conditions under which the aid was granted.

Example 1 8.0 g of N-4- (T2 ', 3'-epoxy) -propoxy7 "benzylurea The reaction reagent is obtained by bleaching with 60 ml of tert-butylamine and 60 ml of water at 4 times rum temperature. The reaction mixture is then stirred under vacuum and at room temperature. After distilling off a mixture of water and ethanol / benzene, 8.5 g of N-4- (73'-tert-butylamino-2'-hydroxy) -propoxy-7-benzylurea are obtained in a quantity of 79.9%. Theoretical.

59582 20

The oil is basically dissolved in ethanol, filtered and filtered with acetone to give the equivalent fumarate. Fumaratet utkristalliserar och avsugs efter nägon tid. After crystallization from ethanol, the mixture is melted at 171-173 ° C.

The starting material for N-4 - / (2 ', 3'-epoxy) -propoxy / benzylurea is a genomic reaction of N- (p-hydroxy) -benzylurea in a water-based solution of epichlorohydrin under the reaction of NaOH. The temperature is 150-157 ° C.

Exemepl 2 13.0 g of N-3- (T2 ', 3'-epoxy) -propoxy-7-benzylurea are reacted with 40 ml of tert-butylamine and 40 ml of water at room temperature. 15.0 g of N-3-7T3'-tert-butylamino-2'-hydroxy) -propoxy-7-benzylurea are then obtained. The base analogue is exempted from 1 to 16 ° C.

The starting product is N-3- (72 ', 3'-epoxy) - (propoxy) -7-benzylurea in a genomic reaction with N- (m-hydroxy) -benzylurea sodium salt in epichlorohydrin at 50 ° C in hexamethylphosphoric pyrride. This product is not available.

Exempel 3 10.0 g of N-2- (72 ', 3'-epoxy) -propoxy-7'-onsylurea brinase are added to the reaction mixture with tert-butylamine. The residue is 13.0 g of N-2- / 73'. -tert.butylamino-2'-hydroxy) -propoxy-7'-benzylurea is an oil.

Fumarate with a drop point (ethanol) of 125-1280 ^ -Exempel 4 10 g of N-4- (72 ', 3'-epoxy) -propoxy7 "benzylurea ring is reacted with 80 ml of a 1: 1 mixture of isopropylamine and watts 4 times at room temperature. 12.4 g of N-4- (73'-isopropylamino-2'-hydroxy) -propoxy-7-benzylurea are obtained at a temperature of 103-106 ° C.

Exempel 5 2.0 g of N-3-methoxy-4- (73'-chloro-2'-hydroxy) -propoxy-7-benzylurea and 20 ml of tert-butylamine are added at 2 to 59582 ° C. After distillation, the mixture is stirred tert-butylamine in vacuo, then the mixture is stirred with acetone and seed. The crystals are present after each use. The solvent is adjusted to give 1.7 g of N-3-methoxy-4 / 73'-tert-butylamino-2'-hydroxy) -propoxy-7-benzylurea, which weighs 75.5% of theory. Melting point 134-137 ° C. The neutral fumarate temperature is 198-200 ° C.

The starting material is N-3-methoxy-4- (73'-chloro-2'-hydroxy) -propoxy-7-benzylurea with 3-methoxy-4-hydroxy-benzylurea in the genomic reaction with epichlorohydrin at 100 ° C, three times the reaction temperature and under tillsats av piperidin säsom katalysator.

Exempel 6 I, 0 g of N-4- (72 ', 3'-epoxy) -propoxy-7'-benzylurea and 1.64 g of tert-butylamine are added in 20 ml of ethanol and 2 times in the mixture. For the purposes of this Regulation, vacuum cleaners and vacuum cleaners shall be completely free of frost. The product is adjusted to 0.95 g of N-4- (73'-tert-butylamino-2'-hydroxy) -propoxy-7-benzylurea, which is then obtained at a temperature of 171-173 °. C.

The analog is given in Example 1-6 as follows: 7. N-4- (73'-isopropylamino-2'-hydroxy) -propoxy7 ** benzyl-N'-methylurea, neutral temperature at 170-172 ° C .

8. N-4- (73'-tert-butylamino-2'-hydroxy) -propoxy-7-benzyl-N'-methyl-urea, m.p. 146-149 ° C.

9. N-4- (73'-isopropylamino-2'-hydroxy) -propoxy-7-benzyl-N'-isopropylurea, m.p. 149-153 ° C.

10. N-4- (73'-tert-butylamino-2'-hydroxy) -propoxy-7 "benzyl-N-isopropylurea, m.p. 135-138 ° C.

II. N-4- (73'-tert-butylamino-2'-hydroxy) -propoxy-7 "benzyl-N'-allyl-urea, m.p. 73-76 ° C.

12. N-4- (73'-isopropylamino-2'-hydroxy) -propoxy-7'-benzyl-N'-benzylurea, m.p. 119-121 ° C.

22 5 9 5 8 2 13. N-4 - [(3'-tert-butylamino-2 1-hydroxy) -propoxy] -7-benzyl-N'-benzylurea, m.p. 80-82 ° C.

14. N-4 - ((3'-sec-butylamino-2'-hydroxy) -propoxy) -benzylurea, m.p. 170-173 ° C.

15. N-4 - [(3'-cyclopropylamino-2'-hydroxy) -propoxy] -benzylurea, m.p. 130-134 ° C.

16. N-4 - [(3'-isopropylamino-2'-hydroxy) -propoxy] -benzyl-N'- (2 "-methoxy) -ethylurea, m.p. 132-133 ° C.

17. N-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N '- (2 "-methoxy) -ethylurea, m.p. 76-79 ° C.

18. N-4- (73'-isopropylamino-2'-hydroxy) -propoxy-7'-benzyl-N'- (2 "-hydroxy) -ethylurea, m.p. 138-140 ° C.

19. N-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] benzyl-N '- (2 "-hydroxy) ethylurea, m.p. 146-149 ° C.

20. N-4 - [(3'-isopropylamino-2'-hydroxy) -propoxy] benzyl-N'-phenylurea, m.p. 105-107 ° C.

21. N-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N'-phenyl-urea, m.p. 134-138 ° C.

22. N-4 - [(3'-isopropylamino-2'-hydroxy) -propoxy] -benzyl-N'-dimethylurea, m.p. 150-153 ° C.

23. N-4- (73'-tert-butylamino-2'-hydroxy) -propoxy-7-benzyl-N'-dimethylurea, m.p. 105-108 ° C.

24. N-4- (T3'-tert-butylamino-2'-hydroxy) -propoxy) -benzyl-N'-methyl-N '- (2 "-hydroxy) -ethylurea, m.p. 111-113 ° C .

25. N-4- (73'-tert-butylamino-2'-hydroxy) -propoxy-7-benzyl-N'-diisopropylurea, m.p. 141-146 ° C.

26. N-3- (73'-tert-butylamino-2'-hydroxy) -propoxy] -4-methoxybenzylurea, m.p. 64-67 ° C.

27. N-3-methoxy-5- (73'-tert-butylamino-2'-hydroxy) -propoxy-7'-benzylurea, m.p. 198-200 ° C.

23 59582 28. N-3-methoxy-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] benzyl · N'-ethylurea, m.p. 132-133 ° C.

29. N-2- {4 '- [(73'-tert-butylamino-2 "-hydroxy) -propoxy] phenyl} -ethyl- (1) -urea, m.p. 105-108 ° C.

30. N-1- {4 '- [(3 "-isopropylamino-2" -hydroxy) -propoxy] -phenyl} -ethyl- (1) -urea, m.p. 100-102 ° C.

31. N-1-'(4' - [73 "-tert. Butylamino-2" -hydroxy) -propoxy] -phenyl} -ethyl- (1) -urea, m.p. 105-107 ° C.

32. N-1- (4 '- [73 "-tert-butylamino-2" -hydroxy) -propoxy] -phenyl} -propyl- (2) -urea, having a neutral fumarate at 111-114 ° C.

33. N-3-methyl-4- (7'-isopropylamino-2'-hydroxy) -propoxy] -benzylurea, m.p. 101-102 ° C.

34. N-3-methyl-4- (73'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea, m.p. 70-72 ° C.

35. N-3-methoxy-4- (731-isopropylamino-2'-hydroxy) -propoxy] benzylurea, m.p. 132-135 ° C.

36. N-3-chloro-4- [73'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea, m.p. 127-129 ° C.

37. N-3-nitro-4- [73'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea, m.p. 173-175 ° C.

38. N-3-nitro-4- [73'-isopropylamino-2'-hydroxy) -propoxy] -benzylurea, m.p. 180-185 ° C.

39. N-3-acetylamino-4- (73'-isopropylamino-2'-hydroxy) -propoxy] -benzylurea, m.p. 142-144 ° C.

40. N-3-acetylamino-4- (73'-tert-butylamino-2'-hydroxy) -propoxy-7'-benzylurea, m.p. 191-194 ° C.

41. N-3,5-dichloro-4- (73'-tert-butylamino-2'-hydroxy) -propoxy-7-benzylurea, m.p. 149-151 ° C.

42. N-3-methoxy-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzyl-N'-butylurea, m.p. 127-128 ° C.

24 5 9 5 8 2 43. N-3-methoxy-4- (73'-tert-butylamino-2'-hydroxy) -propoxy-7-benzyl-N'-dibutylurea, m.p. 74-77 ° C.

44. N-3-ethoxy-4- [73'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea, m.p. 143-144 ° C.

45. N-3-bromo-4 - [(3'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea, m.p. 130-132 ° C.

46. N-3-amino-4- (73'-tert-butylamino-2'-hydroxy) -propoxy) -benzylurea, m.p. 184-187 ° C.

47. N-3-allyl-4- [73'-tert-butylamino-2'-hydroxy) -propoxy] -benzylurea-fumarate, amorphous powder, sintering point 130-133 ° C.

Pharmacological action in the field of pharmacovigilance may be exempted from the use of other biological agents (F and G), in the case of active technical means of treatment, in which case they may be used in other ways. Katterna förbehandlades med reserpin 16 timmar före experimentet. After anesthesia with nembutal sodium (30 mg / kg i.p.), the toraco-tom and vagotomy were removed. Intraarteriella medelblodtrycket och hjärtfrekvensen registrerades. The isoprenal fasted to the control weight at a constant frequency of up to 80% of the maximum weight. With an interval of 30 minutes, an intra-Russian test is performed. Mellan varje dos got control of the iso-prenalin. ED ^ q is used for blocking the isoprenal uptake by adding the response genome to the percentage blocking of the logarithm for the test substance.

The results are set out in Table 1, color A-E and in the case of additions to F and G and are in the form of F1 annexes 3256/71, respecting DE patent claim 2 040 441.

In the case of the formula R-F \ -O-CH2-CH-CH2-NHCH (CH2) 2,

OH

25

Table 1 ^ R1 color

Blockade of the effect of isoprenaline on the EDcq mg / kg i.v. hjärtfre-

Hjärt- Blod- quant RR ^ frequency tryck slag / minute A NH2CONHCH2- H 0.7 8.5 0 B CH3NHCONHCH2- H 0.5 14.1 0 C (CH3) 2CHNHCONHCH2- H 1.8 21 +8 D NH2CONHC2H4- H 0.6 8 0 E NH2CONHC2H4- Cl 0.4 3.0 0 F NH2CONH- H 1.3 68 +26 G CH3NHCONH- H 0.9 17 +43 This subset of the table contains a selection of the inverse frequency of the inverted head frequency in relation to the main blank of the blank. I flertalet fall ligger emellertid EDj.q för blockad av isoprenalinsvaret pä hjärtfrekvens lägre för de nya föreningarna, vilket ger en lägre terapeutisk dos. In particular, the F and G har emellers are used to control the external frequency. Specifically, the hypertensive effect is limited to the effect of the self-test and the effect of the self-test effect and the effect of the self-test on the fixture. In addition, the effect of this effect is to be achieved in the event of a fall, especially in the case of angina pectoris.

Claims (2)

A process for the preparation of new therapeutically active phenoxypropylamine derivatives having a β-receptor blocking effect and their pharmaceutically acceptable acid addition salts, the derivatives of which have the general formula R 1 X - NH - C - N 1 O 2 R 2 (R3, n ~ T II IV 0. CH0-CH-CH9-NHRa OH wherein X is a straight or branched lower alkylene residue, and Rp, which may be the same or different, are a hydrogen atom, a lower alkyl, allyl, hydroxyethyl, phenyl, methoxyethyl or benzyl group, R 1 is a lower alkyl, allyl, lower alkoxy, acetamido, nitro, amino or halogen atom, R 1 is a branched lower alkyl group or a cyclopropyl group, and n is zero, 1 or 2, characterized in that the phenoxypropane derivative of the general formula is . X - NH - C - N I! R3 n 11 OCHp - CH - CHp - Z xi wherein R1, R2, Rj, X and n are as defined in formula I, and wherein Xq_ is a hydroxyl group and Z is chlorine, bromine or iodine or X and Z together form an epoxy group, is reacted at room temperature or at elevated temperature with an amine of the general formula HpN - R 2 III 59582 27 wherein R 1 represents the same as in formula I and the bases which precipitate as reaction product are isolated as such or as salts or liberated from the precipitated salts and converted into a pharmaceutically acceptable salt if desired. For the preparation of a therapeutic agent with a phenoxy-propylamine derivative as well as a pharmaceutically acceptable syrup addition salt, a derivative of the formulation * 1 X - NH - C - N l ^ R2 «Vn - I 1 0. CH0 - CH - CH ~ - NHR ,. 2 | 2 M OH for X is not present in the alkylene group, R 1 and R 2, in the same column as in the case of alkylate, alkyl, allyl, hydroxyethyl, phenyl, methoxyethyl or benzyl, R 1 is alkyl, allyl, alkoxy, acetamido, nitro, amino or halogen, R 1 is a form of alkyl or cyclopropyl, och n is no, 1 or 2, converted to a phenoxy, phenoxypropyl derivative, having the formula X - NH - C - N 2> 5 II __ 0 R2 <R3 n OCH, - CH - CH, - Z 2 I 2 x for R ^, Rp, R ^, X and the same group of compounds as I and for X ^ betecnar en hydroxylgrupp och Z betecknar chloro, Bromo or iodine or X ^ och Z tillsammans bildar en epoxygrupp, bringas i omlagringsre -action at rumstemperature or at room temperature with amine, with the exception of the formulation