CS220271B1

CS220271B1 - Substituted aryloxypropanolamines,salts thereof and method of producing same

Info

Publication number: CS220271B1
Application number: CS617681A
Authority: CS
Inventors: Jozef Csoellei; Alois Borovansky; Ludek Benes; Eva Bederova; Jan Drimal; Jan Kozlovsky; Pavel Svec
Original assignee: Jozef Csoellei; Alois Borovansky; Ludek Benes; Eva Bederova; Jan Drimal; Jan Kozlovsky; Pavel Svec
Priority date: 1981-08-18
Filing date: 1981-08-18
Publication date: 1983-03-25

Abstract

Vynález sa týká substituovaných aryloxypropanolamínov obecného vzorca I OH OCH^HCH^NHR2 \Q^-NHCOOR (l‘)> kde R1 je alkyl aleho/a alkloxylalkyl s. 2 až 5 atómami uhlíka, piriamy alebo rozvětvený alkenyl si 2i až 5 atémami uhlíka aleho/a eyteloalkyl· s 3 až 6 atómami· uhlíka a® je rozvětvený alkyl s 3 až 4 atómami uhlíka a/ /aleblo cykloailkyl s 3 až 6 atómami uhlíka a ich siolí. Tieto nlové látky sú významné účinné betalytika, použitelná pri léčbě róznych oběhových porúch. Vynález tiež chrání niekolko spósobov výroby látok obecného vzorca I.The present invention relates to substituted aryloxypropanolamines of formula (I) OH OCH 2 HCH 2 NHR 2 Q1 -NHCOOR (l ‘)> where R 1 is alkyl and / or alkyloxyalkyl 2 to 5 carbon atoms, piriam, or branched alkenyl is 2 to 5 carbon atoms and / or eyteloalkyl · with 3 to 6 carbon atoms; branched alkyl having 3 to 4 carbon atoms and / cycloalkyl having 3 to 6 carbon atoms and their salt. These nickel substances are significant effective betalytics, useful in the treatment of rhinitis circulatory disorders. The invention also protects several ways of producing the general substances of formula I.

Description

Vynález sa týká substituovaných arylo xypropanOlamínov všeobecného vzorca IThe present invention relates to substituted aryloxypropanol amines of formula I

O-CHrCH-CH^NHfíSputum-O-CH NHfí

nhcoor (I) kdenhcoor (I) where

R¹ je priamy alebo rozvětvený alkyl alfetto alkoxyalkyl s 1 až 5 atómami uhlíka, priamy alebo rozvětvený alkenyl a 2 až 5 atómami uhlíka alebo cykloalkyl s 3 až 6 atómami uhlíka aR ¹ is a straight or branched (C 1 -C 5) alkyl or alkoxyalkyl, straight or branched (C 2 -C 5) alkenyl or (C 3 -C 6) cycloalkyl; and

R² je rozvětvený alkyl s 3 až 4 atómami uhlíka alebo cykloalkyl s 3 až 6 atómami uhlíka.R ² is a branched alkyl of 3 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms.

Vynález sa týkia tiež solí substituovaných aryloxypropanolamínov všeobecného vzorca I, ako i spóšohov, ktorými možno uvedené látky připravovat.The invention also relates to salts of the substituted aryloxypropanolamines of the formula I as well as to the spohoses with which they can be prepared.

Substituované aryloxypropanolamíny všeobecného vzorca I sú nové, v literatúre dioposial nepopísané zlůčeniny, ktoré vykazujú typické účinky betalytlk, podobné akio je tfoi u aryloxyprppanolamínov iným špósobom substituovaných (čs. pat. spis č. 128 471, americký pat, spis. č. 3 468 376, NSR pat. splS. č. 1 236 523, švajcarsky pat. spis. č. 451114 a 453 363). Všetky študované látky vykazujú antiizOprenailínovú, antiarytmickú a lokálně anestetickú aktivitu a účinky na tracheálny síval. Látky s pracovným označením BL-445 (příklad 31) a BL-443 (příklad 30) sú fairtoakiolioglcky ekvivalentně klinicky používanému metipranololu [1- (2,3,5-trimethyl-4-ace|toxyf enoxy) -3-izopropylamino-2-propanolu], taktiež možno předpokládat ich aplikáciu při terapii róznych porúch funkci® srdca a krvného oběhu. Účinnost látok padla vynálezu je uvedená v tabulke 1 — 3.Substituted aryloxypropanolamines of formula I are novel dioposial compounds not described in the literature which exhibit the typical effects of betalytes, similar to those of aryloxyproppanolamines substituted in other ways (U.S. Pat. No. 128,471, U.S. Pat. No. 3,468,376). , German Patent Application No. 1 236 523, Swiss Patent Nos. 451114 and 453 363). All study compounds exhibit antiisprenailin, antiarrhythmic and local anesthetic activity and effects on tracheal muscle. The substances designated BL-445 (Example 31) and BL-443 (Example 30) are fairlyakiologically equivalent to clinically used metipranolol [1- (2,3,5-trimethyl-4-acetoxyphenoxy) -3-isopropylamino-2 -propanol], may also be expected to be of use in the treatment of various cardiac and circulatory disorders. The efficacy of the compounds of the invention is shown in Table 1-3.

Substituované aryloxyprapandlaraíny všeobecného vzorca I je možné pódia vynálezu připravit róznymi spóSobmi, napr. tak, že sa nechá reagovatThe substituted aryloxyprapandlarains of the formula I can be prepared according to the invention in various ways, e.g. by reacting

a) zlúčenina všeobecného vzorca IIa) a compound of formula II

OHOH

II

O-CH^CH-CH-Ci (^-nhcoor⁴ (!/) márnym amíniom všeobecného vzorca NH2R², v ktorom R² znamená to isté ako· vo vzorciO-CH 2 CH-CH-C 1 (N ⁴ -hcoor ⁴ (1H)) amine of formula NH ² R ² , wherein R ² is the same as in the formula

I.I.

b) zlúčenina všeobecného vzorca IIIb) a compound of formula III

R¹ znamená to isté akio vo vZorci I, s primárným amínom všeobecného vzorca NH2R², v ktoriom R² znamená to isté ako vo· vzorci I,R ¹ is the same as in Formula I, with the primary amine of formula NH ² R ² , wherein R ² is the same as in Formula I,

c) zlúčehina všeobecného vzorca IVc) a compound of formula IV

OH [04-NHCOOR⁴ v ktoromOH [04-NHCOOR ^4] wherein

R¹ znamená to isté ako vo vzorci I s 1-alkylaminoi-2,3-epoxypriOpániom všeobecného· vzorca VR ¹ is the same as in formula I with 1-alkylaminoalkyl-2,3-epoxypriOpániom of formula V ·

CH.— CH-CH.-NHR \\Z ° IV) v ktoromCH - CH - CH - NHR (IV) in which

R² znamená to isté ako vo vzorci I, d) zlúčenina všeobecného vzorca IV v ktorom ^R2 is the same as in formula I, d) a compound of formula IV wherein

R¹ znamená ta isté ako vo vzorci I, s 1 -alkylamino- 3-chlór-2-prOpanolbin všeobecného vzorca VIR ¹ is the same as in formula I, with 1 alkylamino- 3-chloro-2-prOpanolbin formula VI

OHOH

II

Cl—CH2—CH—CH2—NHR2 (VI), v ktoriom v ktoromCl-CH2-CH-CH2-NHR2 (VI) in which

R¹ znamená to isté akio vo vzorci I, s priR² znamená to isté ako vo vzorci I.R ¹ is the same as in formula I, with R ² is the same as in formula I.

Pri přípravě podlá vynálezu prebieha re£20271 akcia medzi obidvotma východzími zložkami v prostředí alkoholu, alebo· Vody za katalytického posioibenla hydroxidu alkalického· kovu, například hydroxidu sodného,, huď při teplote miestnosti, alebo prii teplote bodu, varu reakčnej zmesy.In the preparation according to the invention, the reaction proceeds between the two starting components in an alcoholic medium or with a catalytic posioiben of an alkali metal hydroxide, for example sodium hydroxide, at room temperature or at the boiling point of the reaction mixture.

Po skončení reakcie sa reakčná zmes najčastejšie spracuje tak, že sa pretrepe zriedeným roztokom hydroxidu·, alkalického kovu, organické nazpúšťadlo oddestiluje: a odparek predstavujúci surový bazický ester sa přečistí převedením na sol', alkalizáciOu a extrakciiou do organického s vodou nemiešateťnéhio rloizpúš ťadla;After completion of the reaction, the reaction mixture is most often worked up by shaking it with a dilute alkali metal hydroxide solution, distilling off the organic solvent, and purifying the crude base ester residue by conversion to salt, alkalization and extraction into an organic water-immiscible solvent.

Z tohoto roztoku je možné bázický ester previesf pniamio na žiadanú slof a tú dalej čistit kryštailzáciou z vody,, organického rozpúšťadla, alebo zo zmesy organických rozpúšťadiel. Zo solí- s anorganickými· kyselinami vhodnými; pre přípravu aplikačných foriem prichádzajú v úvahu: hydrochliorid, hydrioibromid, síran, fosforečnan, připadne zo stolí s organickými kyselinami napr. šťavelan, vínan, maleinát, funiarát a iné.From this solution, the basic ester can be converted into the desired slurry and further purified by crystallization from water, an organic solvent, or a mixture of organic solvents. Of salts with inorganic acids suitable; suitable for the preparation of dosage forms are: hydrochloride, hydrioibromide, sulphate, phosphate, optionally from tables with organic acids e.g. oxalate, tartrate, maleate, funiarate and others.

Podrobnosti· přípravy sú uvedené v nasledujúcich príkladoch prevedenia.Preparation details are given in the following examples.

P r í k 1 a· d 1Example 1 and 1

Etyl-4 [ (2-hydroxy-3-cyklohexylamino)-propoxy ] karbanilátEthyl 4 - [(2-hydroxy-3-cyclohexylamino) -propoxy] carbanilate

K roztoku 10,5 g (0,038 mol] etyl-4[ (2-hydroxy-3-chlór ) -propoxy J-karbanilátu v 50 ml metanolu sa přidá 4,9 g (0,05 mol) cyklohexylamínu a zahrieva sa 10 h v autokláve pri tepliote 110 °C.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. autoclave at 110 ° C.

Po vychladnutí reakčnej zmesy sa· vakuová oddestiluje metanol a cyktobexylamín, odparek rozpustí v zriedenej kyselině chloroVodíkovej, pretrepe třikrát éterlom a z oddelenej vodnej fázy sa alkalizáciOu uvolní báza,, ktorá sas vytrepe doi éteru. Po vysušení bezvodým síranom horečnatým sa a filtrátu přidáním; éterického. roztoku suchého chlorovodíka vylúči hydrochlorid,, ktorý sa prekryštalizuje zto zmesy 2-propantol-éter (t. t. 156. až 159 °G.After cooling the reaction mixture, methanol and cyctobexylamine are distilled off in vacuo, the residue is dissolved in dilute hydrochloric acid, shaken three times with ether and the base is freed from the separated aqueous phase and shaken into ether. After drying over anhydrous magnesium sulfate, and the filtrate added; ethereal. of hydrochloric acid, which is recrystallized from 2-propantol-ether (m.p. 156-159 ° C).

Příklad 2Example 2

Propyl-2[ (2-hydroxy-3-izOpropylamino·)-pr opoxy ] kar bani látPropyl 2 - [(2-hydroxy-3-isopropylamino) -propoxy] carboxylic acid

K roztoku 9,0 g (0,035 mol)· propyl-2( (2,,3-epoxy)-propoxy] karbanilátu v 30 ml 2-propanolu sa přidá 3,5 g (0,06 mol) iztoprtopylamínu a 2 ml; viody; Reakčná zmes sa zahrieva v autokláve pri teplote 100 °G 5 hi Po vychladnutí reakčnej: zmesy sa vákuovo oddestiluje rozpúšťadlo a přebytek izopropylamínu. Odparek sia· rozpustí v zriedenej kyselině chlorovodíkové], pretrepe třikrát éíberom a z oddelenej Vodnej fáze alkalizáciOu uvolní báza, ktorá sa vytrepe do·· éteru. Po vysušení bezvodým síranom horečnatým sa· z filtrátu přidáním.; éterického; roztoku suchého chlertevodíka, vylúči, hydrachltarid,,, ktorý sa prekryštalujp· zo· zmesy acetón-éter (t. 1.115 až 118 °C).To a solution of 9.0 g (0.035 mol) of propyl 2 ((2,3-epoxy) propoxy) carbanilate in 30 ml of 2-propanol is added 3.5 g (0.06 mol) of istoprtopylamine and 2 ml; The reaction mixture is heated in an autoclave at 100 ° C for 5 hours. After cooling the reaction mixture, the solvent and excess isopropylamine are distilled off in vacuo, dissolved in dilute hydrochloric acid], shaken three times with ether and freeed from the aqueous phase After drying over anhydrous magnesium sulfate, the filtrate is added by adding an ethereal solution of dry hydrogen chloride, precipitating, the hydrachltaride, which is recrystallized from acetone-ether (m.p. 1.115-118 ° C). .

Příklad 3Example 3

Izopropyl-3.[, (;2-hydr^,Qxy‘-3-tere.butylamin|Oo)-propoxy ] karbaniilátIsopropyl 3 - [, (; 2-hydr ^, Qxy'-3-tert-butylamine | 10o) -propoxy] carbaniilate

12,4 g_; (0,064 moll) izopropylestoru kyseliny 3-hydtaxykarhanitovej. a 8,3; g, (0,064 mol) 14erc.butylaminoi-2,3-epO'xypmpánu·. v 40 ml Vody a v 2 ml 42% roztoku hydrtoixidu sodného; sa mieša 6 h pri tepliote miestniosti., Giny· roztek sa. zLeje. a živičná zsaženina rozpustí; v zriedenej, kyselme, chlorovodíkovej, pnetcepe· tbikráts éterom a z oddelenej vodnej fáze alkalizáciOu uvolní báza, ktorá sa vytrepe do éteru. Po vysušení bezviodým.! sinaném horečnatým: z: filtrátu přidáním éterického. roztoku suchého chlorovodíka sa. vylúči hydrochlorid,, ktorý. sa prekryštalizuje zo· zmesy acetón-etanol (t. t. 136 — 138 °C).12.4 g _; (0.064 mol) of 3-hydtaxycarhanitic acid isopropyl ester. and 8.3; g, (0.064 mol) 14-tert-butylamino-2,3-epo-xypmpane. in 40 ml of water and in 2 ml of 42% sodium hydrtoixide solution; is stirred for 6 h at room temperature., Giny · spread. bad. and dissolving the bituminous precipitate; in dilute, acidic, hydrochloric, methyl ether with ether and from the separated aqueous phase the alkalization liberates the base, which is shaken into ether. After drying dry. magnesium sulfate: z: filtrate by addition of ethereal. solution of dry hydrogen chloride. the hydrochloride, which. is recrystallized from acetone-ethanol (mp 136-138 ° C).

P r í k 1 a di 4Example 1 and di 4

Cyklohexyl-4:[i (2-hydroxy-3-izopropylamino) -propoxy ] karbanilátCyclohexyl-4: [i (2-hydroxy-3-isopropylamino) -propoxy] carbanilate

5,6 g (QjQ23t mol), cyklohexyleetenu kyseliny 4Ayddo|xykaribamÍavej',, 4$ g (0,023 mol) hydrochlloridu l-chlór-3-izopBopy<lamino-2-prtopanolu a 2,1 g hydroxidu sodného (0,054 mleli), v, 75> mi. etanolu sa zahrieva v zatavenej; trubici IQ h< pri teplote.· 1QQ °C. Z reakčnej zmesy sa« vákuovo, oddestiluje rozpúšťadlo· a zbytek sa suspenduje v 30. ml. 2N hydroxidu Sodného. Uvolněná báza sa vytrepe do éteru, a po vysušení bezvodým síranom horečnatým; ste z filtrátu přidáním éterického raatoto suchého· chlorovodíka vylúči hydrochlorid, ktorý sa prekryštalizuje Zoi zmesy acetón-éter (t. t. 151 až 153 °CJ.5.6 g (Q2O23t mol), 4Ayddroxycaribamic acid cyclohexylethene, 4.00 g (0.023 mol) of 1-chloro-3-isopropanol-2-propanol, hydrochloride and 2.1 g of sodium hydroxide (0.054 ml), at, 75> mi. ethanol is heated in a sealed; tube IQ h < 1 ° C. The solvent is distilled off under vacuum, and the residue is suspended in 30 ml. 2N sodium hydroxide. The liberated base was shaken into ether and dried over anhydrous magnesium sulfate; the hydrochloride is precipitated from the filtrate by addition of ethereal dry hydrogen chloride, which is recrystallized from acetone-ether mixtures (m.p. 151-153 ° C).

S použitím hone popísaných metod, holi připravené· tieto· nové látky (v zátvoirkách pracovné označenie·},:Using the methods described above, the following new substances have been prepared (in working brackets:

1. metyl-2[ (2-hydroxy-3-izopropylamino· )-prioipQxyjkarbaniláthydrochlorid,1. Methyl 2 - [(2-hydroxy-3-isopropylamino) - propioxy] carbanilate hydrochloride;

t. t. 125 až· 127-°G (acetémetanol);t. t. 125 DEG -127 DEG C. (acetemethanol);

(BL-123),(BL-123),

2. metyl-2[ (;2-hydrloxy-3-terc.butylamino)-pnotpoxyjkarbaniláthydEOGhltorid',2. Methyl 2 - [(2-hydrloxy-3-t-butylamino) -pentypoxy] -carbanilateHEOGltoride;

t. t. 99 až 1S£°G (acefióu), (BJi-125-j:,t. t. 99-160 ° C (acephio), (BJi-125-j :,

3. metyl-3[ (2-hydrtoxy-3-izopnopylamiao:·);-prlopoxy ] karbaniláthydr ochlorid,3. methyl-3 - [(2-hydroxy-3-isopnopylamino); - prlopoxy] carbanilate hydride chloride;

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

4. metyl-3[ (2-rhydaí0xy.--3!-terc.butylaminoi)-propoxy ] karbaniláthydr ochlorid,.4. Methyl 3 - [(2-hydroxyphenyl) -3-tert-butylamino] propoxy] carbanilate hydride chloride.

t. t, 163 až 167 °C (2i-pnopanol) (LB-135),t. t, 163-167 ° C (2β-propanol) (LB-135),

5. metyl-4[ (2-hydr|oxy-3-izopropylammo)-prioipoxy ] karbaniláthydr ochlor id,5. Methyl 4 - [(2-hydroxyoxy-3-isopropylamino) -prioipoxy] carbanilate hydrochloride;

1.1. 160 až 163 °C (2-priopaniol-éter) BL-143),1.1. 160-163 ° C (2-propanol-ether) BL-143),

6. metyl-4[ (2-hydroxy-3-terc.butylamino)-prιopoxy]kaιrbaniláthydrochl©rid,6. Methyl 4 - [(2-hydroxy-3-tert-butylamino) propoxy] carbanilate hydrochloride;

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

7. etyl-2i[_: (2-hydrloxy-3-izopropylamino ) -priopoxy ] karbaniláthydrochítorid,7. Ethyl-2i [ _: (2-hydrloxy-3-isopropylamino) -propoxy] carbanilate hydrochloride;

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

8. etyl-2[ (2-hydr|oxy-3-terc.buty lamino ]-propoxy ] karbanlláthydroohlorid,8. Ethyl 2 - [(2-hydroxyoxy-3-tert-butylamino) -propoxy] carbanl-ethylhydro chloride,

1.1. 128 až 130 °C (acetón-éter) (BL-225),1.1. 128-130 ° C (acetone-ether) (BL-225),

9. etyl-3[ (2-hydhoxy-3-izopropylamino)-pnopoxy ] karbaniláthydrochílorid,9. Ethyl 3 - [(2-hydroxy-3-isopropylamino) -popoxy] carbanilate hydrochloride;

t.1. 104 až 105 °C (acetón-éter) (BL-233),T.1. 104-105 ° C (acetone-ether) (BL-233),

10. etyl-3[ (2-hydroxy-3-terc.butylamino)-priopoxy ] kartíaniláthydrochllorid,10. Ethyl 3 - [(2-hydroxy-3-tert-butylamino) -propoxy] -cartanilate hydrochloride,

t. t. 130 až 131 °C (etanol-éter) (BL-235),t. t. 130-131 ° C (ethanol-ether) (BL-235),

11. etyl-4[ (2-hydroxy-3-izoprlopylaminio)-priopoxy ] karbanlláthydr ochlorid,11. Ethyl 4 - [(2-hydroxy-3-isoprlopylaminio) -propoxy] carbanl-ethyl chloride,

1.1. 141 až 142: ^QC (2-propanol-éterj (BL-243),1.1. 141-142: ^Q C (2-propanol-éterj (BL-243),

12. etyl-4[ (2-hydroxy-3-terc.butylamino)-propoxy ] kar bianiláthydrochlorid, t, t. 86 až 88 °C (acetón-éter ) (BL-245),12. Ethyl 4 - [(2-hydroxy-3-t-butylamino) -propoxy] -carbianilate hydrochloride, m.p. 86-88 ° C (acetone-ether) (BL-245),

13. propyl-2[ (2-hydrioxy-3-izopropylamin©)-prlopoxy ] karbianiláthydrochlorid,13. Propyl 2 - [(2-hydrioxy-3-isopropylamine) - propoxy] carbianilate hydrochloride;

1.1. 115 až 118 °C (acetón-éter)1.1. 115-118 ° C (acetone-ether)

BL-323),BL-323),

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

t. it. 123 až 131 °C (acetón-éter) (BL-325),t. it. 123-131 ° C (acetone-ether) (BL-325),

15. propyl-3[ (2-hydrioxy-3-iZopropylamin©)-pnopoxy ] karhaniláthydrochlorid,15. Propyl 3 - [(2-Hydroxy-3-isopropylamino) -popoxy] carhanilate hydrochloride

1.1. 94 až 95 °C (acetón-éter) (BL-333),1.1. 94-95 ° C (acetone-ether) (BL-333),

16. pnopyl-3[ (2-hydrioxy-3-terc,butylamino )-priopoxy ] karibaniláthydrochlorid,16. 3-propyl [(2-hydroxyri-3-tert-butylamino) -propoxy] caribanilate hydrochloride;

1.1. 153 až 155 °C (acetón-éter) (BL-335),1.1. 153-155 ° C (acetone-ether) (BL-335),

17. propyl-4[ (2-hydroxy-3-izapropylamin|o)-prlopoxy ] karbaniláthydrochlorid,17. propyl 4 - [(2-hydroxy-3-isapropylamine | o) - propoxy] carbanilate hydrochloride,

1.1. 140 až 141 °C (acetón-éter) (BL-343),1.1. 140-141 ° C (acetone-ether) (BL-343),

18. propyl-4[ (2-hydnoxy-3-terc.butylamlnio)-prtopioxy ] karhaniláthydrochlorid,18. propyl 4 - [(2-hydroxy-3-tert-butylamino) -propopioxy] carhanilate hydrochloride,

t. t. 76 až 77 °C acetón-éter ) (BL-345),t. t. 76-77 ° C acetone-ether) (BL-345),

19. izopr opyl-2 ((2i-hydroxy-3-izopropylamino) -pnoploxy] karibaniláthydrochlorid,19. Isopropyl-2 ((2i-hydroxy-3-isopropylamino) -popoploxy] caribanilate hydrochloride)

1.1. 111 až 113 °C (acetón) (BL-323izoi),1.1. 111-113 ° C (acetone) (BL-323izo),

20. iziopriopyl-2[ (2-hydroxy-3-terc.butylaminoi) -propoxy ] karbaniláthydrlochlorid,20. Isiopropyl-2 - [(2-hydroxy-3-tert-butylamino) propoxy] carbanilate hydrlochloride;

1.1. 154 až 157 °C (acetón-éter) (BL-izo325),1.1. 154-157 ° C (acetone-ether) (BL-iso325),

21. izopr©pyl-2|[ (2-hydroxy-3-izobutylamiln©) -prlapoxyjkar bianiláthydrochlorid,21. Isopropyl-2 | [(2-hydroxy-3-isobutylamino) -propoxycarbianilate hydrochloride,

1.1. 149 až 152 °C (acetón-éter) (BL-izo324),1.1. 149-152 ° C (acetone-ether) (BL-iso324),

22. izOpropyl-3[ (2-hydrOxy-3-iZopropylamino) -pnopoxy ] karblaniiáthydrochliorid,22. Isopropyl-3 - [(2-hydroxy-3-isopropylamino) -popoxy] carblaniate hydrochloride,

1.1. 108 až 110°C (acetón-éter) (BL-izo333),1.1. 108-110 ° C (acetone-ether) (BL-iso333),

23. izopropyl-3[ (a-hydnoxy-3-terc.butylamlnot)-propoxy ] karbaniláthydnochlorid,23. Isopropyl 3 - [(α-hydroxy-3-tert-butylamino) -propoxy] carbanilate hydrochloride;

t. t. 136 až 138 °C (acetón-etanol] (BL-izo335),t. t. 136 DEG-138 DEG C. (acetone-ethanol) (BL-iso335),

24. izoipr©pyl-4[ (2-hydrloxy-3-izlopr©pylamino ) -priopoxy ] karbaniláthydrochílorid,24. Isopropyl 4 - [(2-hydrloxy-3-isopropylamino) -propoxy] carbanilate hydrochloride,

t. t. 137 až 139 °C (acetón) (BL-ÍZ0343),t. t. 137-139 ° C (acetone) (BL-Z0343),

25. izopropyl-4[ (2-hydnoxy-3-terc.butylamimo·) -propoxy] karbaniláthydrochílorid,25. Isopropyl 4 - [(2-hydroxy-3-tert-butylamino) propoxy] carbanilate hydrochloride,

t. t. 98 až 100 °C (acetón) (BL-izo345),t. t. 98-100 ° C (acetone) (BL-iso345),

26. butyl-2 [ ( 2rhydroxy-3-iz©priOpylamino)-prlopioxy ] kiařfaaniláthydr ochlorid,26. Butyl 2 - [(2-hydroxy-3-isopropylpylamino) -propioxy] potassium phthalate hydride chloride

t. t. 101 až 102 °C (acetón) (BL-423),t. t. 101-102 ° C (acetone) (BL-423),

27. butyl-2[ (2-hydirioxy-3-.terc.butylaminoi)-prlopoxy ] karblaniiáthydrochliorid,27. Butyl 2 - [(2-hydroxy-3-tert-butylamino) -propoxy] carblaniate hydrochloride,

t. t. 138 až 140 °C (acetón-éter) (BL-425),t. t. 138-140 ° C (acetone-ether) (BL-425),

28. butyl-3[ (2-^,hydirιoxy-3-izιopropylamino)-pnopoxy] karbaniláthydr ochlorid,28. Butyl 3 [(2- ^, hydroxyoxy-3-isopropylamino) -popoxy] carbanilate hydride chloride

t. t. 107 až 109 °C (acetón-éter) (BL-433),t. t. 107-109 ° C (acetone-ether) (BL-433),

29. butyl-3[!(2-hydrOxy-3-terc.butylamino)-phopoxy ] karbaniláthy drochlor id,29. Butyl 3 - [(2-hydroxy-3-tert-butylamino) -phopoxy] carbanilate hydrochloride;

t. t. 140 až 144 °C (acetón-éter) (BL-435),t. t. 140-144 ° C (acetone-ether) (BL-435),

30. butyl-4[ (2-hydroxy-3-.izopropylamin©)-prlopoxy ] karbianiláthydrochlorid,30. Butyl 4 - [(2-hydroxy-3-isopropylamine) - propoxy] carbianilate hydrochloride;

t. t. 124 až 126°C (acetón-éter) (BL-443),t. t. 124-126 ° C (acetone-ether) (BL-443),

31. butyl-4[i(i2rhydroxy-3-terc.bntylamino)-priopioxy ] karbaní 1'áthy drochlorid,31. Butyl-4 - [(1-hydroxy-3-tert-butylamino) -propioxy] -carbanyl hydrochloride;

1.1. 150 až 155 °C (2-propanOl-éterj (BL-445),1.1. 150-155 ° C (2-propanol-ether) (BL-445),

32. pentenyl-2[ (2-hydroxy-3-iZopropylamino )-propoxy ] karhaniláthydroehlorid,32. Pentenyl 2 - [(2-hydroxy-3-isopropylamino) -propoxy] carhanilate hydrochloride;

t.1. 123 až 125 °C (acetón-etaniolj (BL-523),T.1. 123 DEG-125 DEG C. (acetone-ethanol) (BL-523)

33. pentyl-2(<( 2-hydr.oxy-3-terc.butylaininio)-propoxy ] kar bamiláthydr ochlorid,33. Pentyl-2 (<(2-hydroxyoxy-3-tert-butylaininio) propoxy] carboxylate hydride chloride

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

34. pentyl-3[ (2-hydroxy-3-izopropylaminoj-propoxy ] karbaniláthydrochíorid,34. Pentyl 3 - [(2-hydroxy-3-isopropylamino-propoxy) carbanilate hydrochloride,

1.1. 118 až 120 °C (acetón-éter) (BL-533),1.1. 118-120 ° C (acetone-ether) (BL-533),

35. pentyl-3[ (2-hydrloxy-3-terc.butylamino)-propoxy ] karbaniláthydrochíorid,35. Pentyl 3 - [(2-hydrloxy-3-t-butylamino) -propoxy] carbanilate hydrochloride,

t. t. 135 až 138 °C (acetón-éter) (BL-535),t. t. 135-138 ° C (acetone-ether) (BL-535),

36. penty 1-4 [ (2-hydroXy-3-izopr opy lamino)-propoxy ] karbaniláthydrochíorid,36. penty 1-4 [(2-hydroxy-3-isopropylamino) -propoxy] carbanilate hydrochloride,

1.t. 136 až 138 °C (acetón-petroléter) (BL-543),1.t. 136-138 ° C (acetone-petroleum ether) (BL-543),

37. pentyl-4[ (2-hydroxy-3-terc.butylam.inoj- propoxy ] karbaniláthydrochíorid,37. pentyl 4 - [(2-hydroxy-3-tert-butylamino) propoxy] carbanilate hydrochloride,

1.1. 145 až 147°C (aceton-petrpléfer) (BL-545),1.1. 145-147 ° C (acetone-petroleum ether) (BL-545),

38. cyklohexyl-2[ (2-hydnoxy-3-iaopropylamimo)-propoxy ] karbíaniláthydriochlorid,38. cyclohexyl 2 - [(2-hydroxy-3-iaopropylamimo) -propoxy] carbanilate hydrochloride,

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

39. cyklohexyl-2í[ (2-hydrioxy-3-terc.butylamino) -pnopotxy JkarbaniTáthydnochliorid,39. cyclohexyl-2H - [(2-hydrioxy-3-tert-butylamino) -popopoxy] carbamate hydrochloride,

t. t. 192 až 195 °C (etanol-éter) (BL-625),t. t. 192-195 ° C (ethanol-ether) (BL-625),

40. cykltoihexyl-3[ (i2!-hydroxy-3-izioprlapylamino) -propoxy) karbaniláthydrochíorid,40. cycltohexyl 3 - [(1,2-hydroxy-3-isopropylamino) -propoxy) carbanilate hydrochloride,

1.1. 128 až 129 ^qC (acetón-éter) (BL-633),1.1. 128 to 129 ^q C (acetone-ether) (BL-633),

41. cyklohexyl-3[ (2-hydroxy-3-terc.butylamino) -prlopoxy ] karbaniiláthydroichlorid, t. t. 138 až 140 ^aC (acetón-petroléter) (BL-635),41. Cyclohexyl 3 - [(2-hydroxy-3-t-butylamino) -propoxy] carbaniilate hydroichloride, mp 138-140 ^and C (acetone-petroleum ether) (BL-635),

42. cyktohexyl-4[ (2-hydroxy-34zopropylamino) -propoxy ] karbaniláthydrochíorid, t. t. 151 až 153 °C (acetón-éter) (BL-643),42. Cychexyl 4 - [(2-hydroxy-34-isopropylamino) -propoxy] carbanilate hydrochloride, m.p. t. 151-153 ° C (acetone-ether) (BL-643),

43. etoxyetyl-2[ (2-hydroxy-3-izoprlopylamino) -propoxy ] karbaniláthydrochíorid, t. it. 102 až 105 °C (acetón-éter) (BL-723),43. Ethoxyethyl 2 - [(2-hydroxy-3-isoprlopylamino) propoxy] carbanilate hydrochloride, i. it. 102-105 ° C (acetone-ether) (BL-723),

44. ettoxyetyl-2[ (2-hydroxy-3-terc.butylamino) -propioxy ] karbaniláthydrochíorid,44. ettoxyethyl 2 - [(2-hydroxy-3-tert-butylamino) -propioxy] carbanilate hydrochloride,

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

45. etoxyetyl-3[ (2-hydroxy-3-izopropylamimo) -propioxy ] karbaniláthydrochíorid,45. ethoxyethyl 3 - [(2-hydroxy-3-isopropylamimo) -propioxy] carbanilate hydrochloride,

1.1. 147 až 150 °C (metanol-éter) (BL-733),1.1. 147-150 ° C (methanol-ether) (BL-733),

46. etOxyetyl-3[ (2-hydnoxy-3-terc.butylamimo) -propioxy ] karbanilátfumarát, t. t. 143 al 146 °C (etanol-éter) (BL-735),46. Ethoxyethyl 3 - [(2-hydroxy-3-tert-butylamimo) -propioxy] carbanilate fumarate, m.p. t. 143 and 146 ° C (ethanol-ether) (BL-735),

47. et'Oxyetyl-3 [ (2-hydroxy-3-izobutylamino) -propoxy ] karbaniláthydrochíorid,47. et'Oxyethyl 3 - [(2-hydroxy-3-isobutylamino) propoxy] carbanilate hydrochloride,

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

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

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

49. etoxye:tyl-4[ (2-hydr oxy-3-terc.butylamíno>) -pr oploxy ] karbanilátfumarát, t. t. 177 až 179 °C (metanol-éter) (BL-745),49. ethoxyethyl 4 - [(2-hydroxy-3-tert-butylamino) -proploxy] carbanilate fumarate, m.p. t. 177-179 ° C (methanol-ether) (BL-745),

50. etoxyetyl-4[ (2-hydroxy-3-izobutyla.mino j -propoxy ] karbaniláthydrochíorid,50. ethoxyethyl 4 - [(2-hydroxy-3-isobutylamino) propoxy] carbanilate hydrochloride,

1.1. 158 al 160 °C (acetén-etanolj (BL-744),1.1. 158 and 160 ° C (acetene-ethanol) (BL-744),

51. etoxyetyl-2[ (2-hydroxy-3-iziobutylaminioj -prlopoxy] karbanilátioxalát,51. ethoxyethyl 2 - [(2-hydroxy-3-isobutylamino) propoxy] carbanilate dioxalate;

t. t. 138 až 143 °C (etanol-éter) (BL-724),t. t. 138-143 ° C (ethanol-ether) (BL-724),

52. alyl-2[ (2-hydroxy-3-izobutylaminioj- propoxy ] karbamiláthydr ochlorid, . t. t. 119 až 121 °C (acetón-petroléter) (BL-323),52. allyl-2 [(2-hydroxy-3-isobutylamino-propoxy) carbamilate hydride, mp 119-121 ° C (acetone-petroleum ether) (BL-323),

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

t. t. 166 až 168 °C (2-propanol-éterj (BL-325)t. t. 166-168 ° C (2-propanol-ether) (BL-325)

54. etyl-4 [ 2-hydr oxy-3-cyklopropylaminio) -propoxy ] karbaniláthydrochíorid,54. Ethyl 4- [2-hydroxy-3-cyclopropylaminio) -propoxy] carbanilate hydrochloride,

t. t. 156 až 160 °C (acetón-etaniolj (BL-246),t. t. 156-160 ° C (acetone ethanol (BL-246)),

55. etyl-4[ (2-hy droxy-3-cyklopenty lamino)-propoxy ] karhaniláthydroehlorid,55. Ethyl 4 - [(2-hydroxy-3-cyclopentylamino) -propoxy] carhanilate hydrochloride,

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

56. etyl-2[ (2-hydrioxy-3-cyklohexylamlnoj-propoxy] kar hanlláthydrochlior id,56. Ethyl 2 - [(2-hydrioxy-3-cyclohexylamino-propoxy) -carbonyl] -hydrochrochloride;

t. t. 156 až 159 °C (2-propanol-éterj (BL-249),t. t. 156-159 ° C (2-propanol-ether) (BL-249),

57. etyl-3[ (2-hydrtoxy-3-cyklobexylamlnoj-propoxy ] kar banlláthydr ochllorid, 't. t. 157 až 160 °C (2-propanol-éterj (BL-239),57. Ethyl 3 - [(2-hydrtoxy-3-cyclobexylaminobutyl-propoxy) -carbonyl allyl chloride, m.p. 157-160 ° C (2-propanol-ether) (BL-239);

2'2ΌΖ'7Γ2'2ΌΖ'7Γ

TTabuh-řfeai 1TTabuh-rfeai 1

Efekt testovaných. látok a metípranololu. v kane. 10 mg/20 mb na. Izoprenalínom indukovaná tachykardiu na izolované predsiene morčiat.Effect of tested. substances and metipranolol. in the canoe. 10 mg / 20 mb per. Isoprenaline-induced tachycardia on isolated guinea pig atria.

Látka % zníženia TF po láitke % redukcle pozitivně chrionotr.The% TF reduction after the% reductioncle positive chrionotr.

úč. IP' po» lWbke vzhíádfom Ife kontrol, hodtiotám·acc. IP 'lwbke on Ife controls, values ·

Kontrola inspection Q,6±3)Jt Q, 6 ± 3) J t 4,4 + 4,7 4.4 + 4.7 MTP MTP 20,8 + 3,1 20.8 + 3.1 24,3 + 7,4* 24.3 + 7.4 * BL-223 BL-223 5,1-+1,6 5,1-+ 1.6 6,3^+-4,5 ^ 6.3 + - 4.5 BL-225 BL-225 7,8 + 2,6; 7.8 + 2.6; 16,6 + 7,2 16.6 + 7.2 BL-233 BL-233 3,9/-+- 2,5 3.9 / - + - 2.5 17,6 + 6,7 17.6 + 6.7 BL-235 BL-235 4,8 + 0,9 4.8 + 0.9 11,6:+2(8: 11.6 +2 (8: BL-243 BL-243 7,0 + 2,1 7.0 + 2.1 8,3' + 6,4: 8.3 '+ 6.4: BL-245 BL-245 7,8 + 0,9 7.8 + 0.9 17,7 + 5,9* 17.7 + 5.9 * BL-423 BL-423 11,4 + 0,6; 11.4 + 0.6; 7,8 + 6,0 7.8 + 6.0 BL-425 BL-425 4,7 +1,6 4.7 +1.6 9,8 + 6,0 9.8 + 6.0 BL-433 BL-433 10,6 + 2,0 10.6 + 2.0 5,6.+ 6,1 5.6. + 6.1 BLr4S5 BLr4S5 9)6(-2,0 9) 6 (-2.0 3,7- + 4:,0 3.7- + 4: 0 BL-443 BL-443 13,0 + 3,2 13.0 + 3.2 24,0 + 4,9* 24.0 + 4.9 * BL-445 BL-445 9,6 + 1,21 9.6 + 1.21 18,0 + 4,5* 18.0 + 4.5 * BL-6‘23 BL-6'23 6)βί+ 4)2. 6) βί + 4) 2. 19,0 + 3,8* 19.0 + 3.8 * BL-6‘33 BL-6'33 9,8 + 3,2 9.8 + 3.2 16,7 + 3^6 16.7 + 3 ^ 6 BL-6‘43 BL-6'43 14,3 + 3,2 14.3 + 3.2 18)6+3)2*' 18) 6 + 3) * 2 ' BL-3‘23 BL-3'23 19,0)+ 2,2 19.0) + 2.2 11,9:--1-4,8 11.9 - from 1 to 4.8 BL-3‘25 BL-3'25 13,4 + 1,7' 13.4 + 1.7 ' 15,0 + 4,0 15.0 + 4.0

Tabulka¹ 2.Table ¹ 2.

Ochranný efekt- látok a metípranololu v· dávke 1 mg . kg^-1 i; v: vyjadrenef spotřebouakonitinu pri indukcii arytmii, fibrilácii a letálnej zástavy srdca u anestezovanýcfr morčiat.Protective effect of 1 mg of metipranolol. kg ^-1 i; v: expressed as aconitine consumption in the induction of arrhythmia, fibrillation, and lethal cardiac arrest in anesthetized guinea pigs.

Lát ka· Fabric · Arytmie arrhythmias Fibrilácie fibrillation Létali tta They flew tta Fyzioí.. roztok Physical solution 67,1+ 5,5. 67.1+ 5.5. 138,8 + 13,1 138.8 + 13.1 218,2 + 21,1 218.2 + 21.1 Metípranolioir Metípranolioir 110,4 + 7,3* 110.4 + 7.3 * 238,1 + 13,1* 238.1 + 13.1 * 430,0 + 30,7* 430.0 + 30.7 * BL-223 BL-223 80,2+ 6,3 80.2+ 6.3 142,7+ 9,8 142.7+ 9.8 263,6+ 9)2* 263.6+ 9) 2 * BL-225 BL-225 84,6+ 8,2 84.6+ 8.2 151,4+ 5,2. 151.4+ 5.2. 250,5)+ 10,1 250.5) + 10.1 BL-233 BL-233 94,7 +14,6* 94.7 + 14.6 * 226,8 + 11,6* 226.8 + 11.6 * 274,8.+ 42,0* 274.8. + 42.0 * BL-235 BL-235 9.4,5+ 3,7* 9.4,5+ 3,7 * 208,7 + 11,9* 208.7 + 11.9 * 306,2'+ 12,4* 306.2 '+ 12.4 * BL-243 BL-243 74,7+ 5,3 74.7+ 5.3 139,9 + 14,4 139.9 + 14.4 252,9 + 13,1* 252.9 + 13.1 * BL-245 BL-245 83,4+ 7,1 83.4+ 7.1 158,6+ 6,8/ 158,6+ 6,8 / 317,9.+ 12,8/ 317.9. + 12.8 / BL-423 BL-423 106,7 + 10,6-* 106.7 + 10.6- * 191,6 + 16,7* 191.6 + 16.7 * 272,8-+ 26,6- 272.8- + 26.6- BL-425 BL-425 105,9+ 8,1* 105.9+ 8.1 * 199,9 + 14,3* 199.9 + 14.3 * 286,6+ 27,7 286.6+ 27.7 BL-433 BL-433 183,4+ 11,9/ 183,4+ 11,9 / 265,5 + 20,9* 265.5 + 20.9 * 409,4+ 17,3* 409.4+ 17.3 * BL-435 BL-435 123,9 +10,9* 123.9 + 10.9 * 251,5 + 23,2* 251.5 + 23.2 * 381,9 + 14,6* 381.9 + 14.6 * BL-443 BL-443 69,2+ 9,0 69.2+ 9.0 188,1 + 10,7* 188.1 + 10.7 * 321,4+ 31,6* 321.4+ 31.6 * BL-445- BL-445- 95,4 + 7,0/ 95.4 + 7.0 / 276,9 + 29,4* 276.9 + 29.4 * 407,6 + 21,0* 407.6 + 21.0 * BL-6‘23 BL-6'23 Tok flow Tox Tox Tox. Tox. BL-6‘33 BL-6'33 Tox Tox Tox Tox Tox Tox BL-6‘43' BL-6'43 ' 94,6+12,9* 94.6 + 12.9 * 243,0 + 31,7* 243.0 + 31.7 * 474,0 + 70,0* 474.0 + 70.0 * BL-3‘23 BL-3'23 93,4 +18,3* 93.4 + 18.3 * 276,2 + 55,1* 276.2 + 55.1 * 364,1+44,6* 364.1 + 44.6 * BL-3‘25. BL-3'25. 71,2+ 6,6 71.2+ 6.6 277,8 + 42,0/ 277.8 + 42.0 / 429,6.+ 43,(L* 429.6. + 43, (L *

T a b u 1' k a 3T and b at 1 'k and 3

Akútna toxicita látok po s. c. aplikácii 1% roztoku myšiam.Acute toxicity of substances after s. c. application of 1% solution to mice.

Látka LDso (Mg. kg^-1]Substance LD 50 (Mg. Kg ^-1 )

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

Lokálně anestetická aktivitaLocal anesthetic activity

Látkasubstance

Index účinnosti LDso/mg .kg^-1 povrchová anestézía infiltračná anestéziaEffectiveness index LD 50 / mg .kg ^-1 surface anesthesia and infiltration anesthesia

BL-223 BL-223 7,1 7.1 BL-225 BL-225 2,3 2.3 BL-235 BL-235 <1 <1 BL-233 BL-233 1,8 1.8 BL-243 BL-243 2,1 2.1 BL-245 BL-245 1,9 1.9 BL-423 BL-423 9,1 9.1 BL-425 BL-425 7,9 7.9 BL-433 BL-433 10,6 10.6 BL-435 BL-435 10,8 10.8 BL-443 BL-443 3,1 3.1 BL-445 BL-445 4,5 4.5 BL-6‘23 BL-6'23 11,1 11.1 BL-6‘33 BL-6'33 4,5 4.5 BL-6‘43 BL-6'43 3,6 3.6 BL-3‘23 BL-3'23 2,3 2.3 BL-3‘25 BL-3'25 7,5 7.5 metipranol Metipranol <1 <1

2,02.0

1,0 <11.0 <1

1,01.0

2,22.2

1,01.0

4,04.0

7,07.0

4,44.4

4,24.2

1,0 <11.0 <1

7.7 =57.7 = 5

4,2 =24.2 = 2

3,63.6

5.85.8

Claims

SUBJECT

Substituted aryloxypropanolamines of the general formula I

OH

O-CH-CH-CH-NHR 2

INVENTION it is a (C 1 -C 5) alkoxyalkyl, a (C 2 -C 5) straight or branched alkenyl or (C 3 -C 6) cycloalkyl

NHCOOR (I) mom carbon and

R ² is a branched alkyl of 3 to 4 carbon atoms or a cycloalkyl of 3 to 6 carbon atoms, as well as their tables with inorganic and organic acids.

2. A process for the preparation of substituted aryloxypropanialamines of the formula I according to claim 1, which comprises reacting a compound of the formula II.

R ¹ is straight or branched alkyl or R 4

2 2Q27>]>

113

OH

I

The compound of formula (I) as defined in claim 1, wherein the compound of formula (IV) is not reacted more frequently.

N HCOOR

OH (II)

NHCOOR in which

R &^lt; ¹ > as in. of formula I, with a primary amine of formula

H2NHR ² , (IV) wherein

R ² is the same as the tol · Formula I in prloistredí alkanloilu of 1 to 3 carbon atoms at a temperature of 100 to 120 DEG C. in a sealed nádoibe.

3. Method of preparation; The compound of formula (I) as defined in claim 1, wherein a compound of formula (III):

R ¹ is the same as yo of the formula t, s. 1-Alkylamino-2,3-epocyclopropane of formula V

0 '

0-CHgCH -CH _£

NHCOOR (III) wherein

R ¹ is t (i ¹ as in formula I) with the primary amines of formula

H2NR2, / \ 9

CHf-CH-CH2-NHR (V) wherein

R2 is the same as in. of alkali metal hydroxide, preferably sodium hydroxide.

5. Spésoto preparing substituted aryloxyprloipaiBOlamínoV of, formula I as claimed in one stabs characterized by reacting a compound according to Formula IV, wherein R ¹ is the same as R in the formula of l-amino-3-chloro-2- of formula VI

OH

I

Cl-CH2-CH-CH2-NHfi® (VI) in which

R ² means that the ISLT; of formula I, in an alkanol having 1 to 3 carbon atoms at a temperature of 100 to 120 ° C, in a closed vessel.

4. A process for the preparation of substituted aryl R @ ² is the same as in formula I, in an alkanol having 1 to 3 carbon atoms, by catalytic treatment of the alkali metal hydroxide in a sealed vessel at a temperature of 100 to 120 ° C.