FI62052B - PROCEDURE FOR THE PHARMACOLOGICAL PROPERTIES OF VAERDEFULLA 4-AMINOPHENYLETHANOLAMINER WITH SAERSKILT BETA 2-MIMETISK OCH / ELLER ALFA 1-BLOCKER - Google Patents

Description

Γβΐ M1, ANNOUNCEMENT.Un x0nco 4ΒΓα tBi UTLÄOG N I NOSSKÄIPT 6205 2 c Pententi ny'imetty 10 11 1932 (45) intent ·: «; ; t ^ (51) K ».lk? /lnt.a.3 c 07 C 91/40 FINLAND — FINLAND (21) Pmnttihakvmut - Pmncan * 6knln | 3T70 / T3 CU) 10.12.73 'r1' (23) Alkupllvt - Glltlfh «cad * | 10.12.73 (41) TMhK JvIktMkal — Latches offmtHf i9.O6.7h

Patent and Registration Office / 44) NlhttviMpron μ k »ul. | Ulk ^ un pv, * .- Qo

Patent- och refisteratyrelsen '' AmMcm «ithfd och utl. * Krtft * n publican * 30.07 · Ö2 (32) (33) (31) Pyydetty« cuoIImiis — Sugar * priorttuc 18.12. J2 Ο8.Ο9.73, 12.10.73, 02.11.73 Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 226191U.3, P 23 ^ 5 ^ 2. U, p 2351281.Il, .P 235U961.3 (71) Dr. Karl Thomae Gesellschaft mit beschränkter Haftung, D-7950 Bibe-rach / Riss, Federal Republic of Germany Tyskland (DE) (72) Giinther Engelhardt, Biberach / Riss , Johannes Keck, Biberach / Riss,

Gerd Kruger, Biberach / Riss, Klaus-Reinhold Noll, Warthausen-Oberhofen, Helmut Pieper, Biberach / Riss, Federal Republic of Germany-Förbundsrepubliken Germany (DE) (7 * 0 Leitzinger Oy (5 * 0 Method for the preparation of pharmacologically valuable U-amino-phenylethanol amines having in particular a β-mimetic and / or a β-blocking effect - Förfarande för framställmng av pharmacologiskt vardefulla U-aminophenlethanolaminer med särskilt och c ^ -blockerande verkan

The present invention relates to a process for the preparation of pharmacologically valuable 4-amino-phenylethanolamine, in particular having a β-mimetic and / or β-blocking effect, and of the general formula I being OH R.,

R1 \ ^ \ / CH "CH2 ~ N \ (U

r2 2 62052 wherein R1 is a fluorine, chlorine, bromine, iodine atom or cyano group or also a hydrogen atom, when R2 represents hydroxyalkyl, aminoalkyl, dialkylaminoalkyl, trifluoromethyl, nitro, cyano, carboxyl, carbalkoxy - or a carbamoyl group, R2 is a fluorine atom, a straight-chain or branched alkyl group having 1 to 5 carbon atoms, a hydroxyalkyl, aminoalkyl, dialkylaminoalkyl, trifluoromethyl, alkoxy, nitro, cyano, carboxy, carbalkoxy or carbamoyl group, R3 and R4, which may be identical or different, denote hydrogen atoms, straight-chain or branched alkyl groups having 1 to 6 carbon atoms, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl or optionally substituted by hydroxy or methoxy groups phenylalkyl groups, as well as their optically active antibiotics and their physiologically acceptable acid addition salts with inorganic or organic acids.

The new compounds can be prepared by the following methods: a) reduction of acetophenone of general formula II -d {'h 3 62052 ^ R3

RiyTV co - CH2 - N (II)

IJ

H2N T R2 where R1 ~ R4 have the same meaning as above.

The reduction is best carried out in a solvent such as, for example, methanol, methanol / water, ethanol, isopropanol, ether, tetrahydrofuran or dioxane, suitably a complex metal hydride such as lithium aluminum hydride or sodium borohydride in the presence of an aqueous or secondary alcohol at temperatures between -20 ° C and the boiling point of the solvent used.

However, the reduction with complex metal hydrides is best performed with sodium borohydride and at room temperature. When a more reactive complex metal hydride, such as lithium aluminum hydride, is used and when operated at possibly elevated temperatures, the cyano, carboxy, carbalkoxy or carbamoyl groups mentioned in the group definition may be reduced simultaneously.

If the reduction with hydrogen is carried out in the presence of a catalyst such as Raney nickel, platinum or palladium / animal carbon, the alkenyl or alkynyl groups mentioned in the definition of Rg and / or R1 can be converted to the corresponding alkyl groups and / or any benzyl groups present can be hydrogenated.

b) For the preparation of compounds of general formula I in which R 1 and are as defined above except for alkynyl and alkenyl groups, and R 1 is a chlorine, bromine or iodine atom: Λ · i, · a halogenated compound of general formula III, 620S 2 OH R, I / 3

CH - CH - N

Γ X (III) I R4

V ^ V

* 2 where R0 - has the same meaning as above except for alkenyl and alkynyl groups.

The reaction is carried out with a halogenating agent, for example chlorine, bromine, iodine, tribromophenol bromine or phenyl iodide dichloride, preferably in a solvent, for example 50-100% acetic acid or tetrahydrofuran in the presence of a tertiary organic base and optionally in the presence of a heavy metal salt, e.g. C. Suitably 1 mole or a small excess of the halogenating agent is used per mole of the compound of general formula III which can be used both as a base and as a salt, for example as a mono-, di- or trihydrochloride. If a salt of hydrohalic acid is formed in the reaction, this can be isolated as such directly or, if desired, further purified via a base.

c) Cleavage of one or more protecting groups from the compound of general formula IV

0X

1 / Y2 xyvp ~ ch2 uv) xy R2 »Pf> wherein R1 'R2 and R3 have the same meaning as above, X is a hydroxyl group protecting group or a hydrogen atom, 62052 is an amino group protecting group or a hydrogen atom, Y2 is an amino group protecting group or has the same meaning as above. , wherein at least one of X, Y1 and / or Y2 must be one of the abovementioned protecting groups.

Suitable groups Y1 and / or Y2 are, in particular, an acyl group, for example an acetyl, benzoyl or p-toluenesulfonyl group, or a benzyl group, and the group X is an acyl group, for example an acetyl, benzoyl or p-toluenesulfonyl group, or trimethylsilyl, benzyl or tetrahydropyranyl. (2) group.

If Y1 and / or Y2 denote, for example, an arbitrary acyl group, the cleavage of this group takes place hydrolytically, for example with ethanolic hydrochloric acid or sodium hydroxide, at temperatures up to the boiling point of the solvent used. If in the deprotection of the general formula IV denotes a cyano group, this can be simultaneously saponified to a carbanoyl or carboxyl group, and if R 2 denotes a carbalkoxy or carbamoyl group, this can be simultaneously saponified to a carboxyl group.

If in a compound of general formula IV wherein R 2 is not a nitro group. X, Y 1 and / or Y 2 represent, for example, a Bentyl group, the cleavage of which is carried out by hydrogenolytic means, for example with hydrogen in the presence of a catalyst such as palladium, H 2 or palladium oxide hydrate with barium sulphate, platinum or Raney nickel, preferably in a solvent, such as in methanol, methanol / hydrochloric acid or ethanol, at room temperature or at slightly elevated temperatures and at normal pressure or low overpressure. The alkynyl or alkenyl groups mentioned in the definition of the group and / or R 1 can be simultaneously converted into the corresponding alkyl groups in the reaction.

For example, if X is an arbitrary acyl group, trimethylsilyl or tetrahydropyranyl (2) group, then cleavage of this group is carried out hydrolytically, preferably in the presence of an acid and at temperatures up to the boiling point of the solvent used.

6 d) For the preparation of compounds of general formula I having a hydrogen atom:

Halogen is removed from the compound of general formula V.

OH

I yS R3

HalCH - CH2 - N (V)

XJ

H 2 N 2 R 2 wherein - R 1 is as defined above and Hal is a chlorine, bromine or iodine atom.

The halogen removal is best carried out in a solvent and suitably with either triphenylphosphine in benzene or toluene or hydrogen in methanol, ethanol, ethyl acetate or tetrahydrofuran and in the presence of a hydrogenation catalyst. Depending on the method used, the reaction is carried out at room temperature or at elevated temperature, for example at temperatures between 100 ° and 150 ° C and at normal pressure or moderate overpressure. When using Raney nickel, palladium / carbon is removed by halogen, for example at room temperature and normal pressure. If, in the compound of the general formula V, R1 and / or R1 represents an alkenyl or alkynyl group, this can be hydrogenated to the corresponding alkyl group during the removal of the hydrogenolytic halogen, and / or the benzyl group, then this can be hydrogenolytically cleaved off at the same time.

If in the compound of general formula V R2 represents a nitro group, then the removal of halogen is best carried out with triphenylphosphine.

e) For the preparation of compounds of general formula I in which R2 is an aminomethyl group: 62052

Compound of general formula VI ° H π I / 3 CH - CH2 - N .____ (VI) TT ** il

CH

3!

B

wherein, R 3 and have the same meaning as above are reacted with a reducing agent and then hydrolyzed.

The reaction takes place in a solvent, preferably by reduction with sodium in pentyl alcohol at temperatures between 0 ° and 50 ° C. Subsequent hydrolysis of the 1,2,3,4-tetrahydroquinazoline thus formed, which does not need to be isolated, is best carried out with hydrochloric acid at elevated temperatures, for example at the boiling point of the hydrochloric acid used.

f) A compound of general formula VII

OH

R 1 - CH 2 - Z (VII)

XI

h2n T R2 wherein and R2 have the same meaning as above and Z 'is a chlorine, bromine or iodine atom or a p-toluenesulfonyloxy group, is reacted with an amine of general formula VIII 62052 as above.

The reaction is conveniently carried out in a solvent such as methanol, ethanol, chloroform, carbon tetrachloride, dioxane, or an excess of the amine of general formula VIII used, and preferably at temperatures between 0 ° and 100 ° C. However, the reaction can also be carried out without a solvent.

(g) For the preparation of compounds of general formula I in which Rj does not represent a nitro group:

The compound of general formula IX is reduced

° H

I / 3

R1Ny ^ ^ \ ^ CK-CH2- (IX) I R4 in R '2 and R1, R3 and have the same meaning as above and R1' means the same as the group R2 above except for the nitro group.

The reduction is conveniently carried out in a solvent such as water, methanol, ethanol, water / methanol or ethyl acetate with the most evolving hydrogen, for example zinc / glacial acetic acid or iron / hydrochloric acid, hydrogen over a catalyst such as Raney-Nikke-platinum or palladium / carbon. in the presence of a complex metal hydride such as lithium aluminum hydride or stannous chloride / hydrochloric acid, suitably at temperatures between 0 ° and 100 ° C.

9 62052 h) For the preparation of compounds of general formula I in which R1 does not represent a cyano group and R2 does not represent a nitro, cyano, carboxy, carbalkoxy or carbamoyl group:

The compound of general formula X is reduced to 0 tl y Rg

R1 is A - C - N2 (X) f h2n

V

j ossa

Rg and have the same meaning above, R1r has the same meaning as above for the group except for the cyano group.

R 2 'is the same as the group R 2 except above for a nitro, cyano, carboxy, carbalkoxy or carbamoyl group, and A is a carbonyl or hydroxymethylene group.

The reaction is carried out in a solvent such as ether, tetrahydrofuran, dioxane or tetrahydrofuran / benzene, preferably with a reducing agent such as a complex metal hydride, for example lithium aluminum hydride, sodium borohydride in the presence of Lewis acid .

i) For the preparation of compounds of general formula I in which R 1 is a hydrogen atom:

The oxazolidone of general formula XI is hydrolyzed

1 I

R1Ny ^ VSr ^ CH N - R. (XI) XJ "* '

K2N T

R2 where

R1, ia have the same meaning as above.

The hydrolysis is conveniently carried out in a solvent such as water, methanol, ethanol, ethanol / water and glacial acetic acid in the presence of an acid such as hydrochloric acid, hydrobromic acid or sulfuric acid or in the presence of a base such as sodium hydroxide or potassium hydroxide and suitably at 0 ° C to 110 ° C. depending on the nature of the agent, preferably at room temperature or at the boiling point of the solvent used.

j) For the preparation of compounds of general formula I in which R is a hydrogen atom:

The aldehyde of general formula XII is reduced

d ^ CO - CKO

(I (xii)

"T

H, N I R2 wherein R1 and R2 are as defined above, or a hydrate thereof in the presence of an amine of general formula VIIa

R

ί! ~ N 3 (Villa)

B

li 620 5 2 where

Rg means the same as above.

The reduction is conveniently carried out in a solvent such as methanol, ethanol, ether or tetrahydrofuran, preferably with a specific metal hydride such as sodium borohydride or lithium aluminum hydride, evolving hydrogen or hydrogen in the presence of a catalyst such as Raney nickel or palladium on carbon, palladium at temperatures between - 20 ° and 100 ° C, but preferably at temperatures up to the boiling point of the solvent used.

However, the reaction can also be carried out in such a way that the reduction is directed to the in situ-formed compound of the general formula Xlla R1 CO - CH = N - R3 (Xlla) r2 in which, R2 and R3 have the same meaning as above.

(k) For the preparation of compounds of general formula I in which R2 does not represent a nitro group:

The compound of general formula XIII is nitrated

OH

ri y ^ Y “c“ 2 n c; wiii) h2n where 12 62052 R, j R and R, have the same meaning as above.

15 3 J 4

The reaction is carried out with a nitrating agent, preferably nitric acid or a mixture of concentrated nitric acid and concentrated sulfuric acid, suitably at temperatures between -20 ° and 100 ° C.

The compounds of general formula I obtained by methods a to k can subsequently, if desired, be resolved into their optically active antipodes by racemate cleavage or by separating a mixture of diastomeric compounds of general formula XIV 0R? R1 'CH2 "N (XIV) T I R4

HN

R-R2 6 and O 3 S ci g R, R R and R have the same meaning as above, R is a hydrogen atom or an acyl group and R? is a chiral acyl group, followed by cleavage of the groups R 7, R 8 and, if R 8 represents an acyl group and is an optionally substituted benzyl group.

Suitable chiral acyl groups are, in particular, optically active α-aminoacyl groups protected on the nitrogen atom, for example the N-benzyloxycarbonyl-L-alanyl group, or an optically active terenyloxycarbonyl group, for example the (-) - menthyloxycarbonyl group.

The separation of the mixture of diastomeric compounds of the general formula XIV into pure d.stereomeric compounds is conveniently carried out by fractional crystallization and / or column chromatography on an inert support.

seer> .t-g

The cleavage of the Rg and subsequent groups is effected by hydrolysis or solvolysis in the presence of water or a suitable alcohol such as methanol, optionally in the presence of an acid or base, and at temperatures between 0 ° C and 100 ° C.

Cleavage of the group can also be performed with a complex metal hydride, such as lithium aluminum hydride, in a suitable solvent, for example ether, tetrahydrofuran or dioxane, and suitably at temperatures between -20 ° and 20 ° C. In this case, if R2 in the compound of the general formula IV represents a cyano group, this can be reduced simultaneously. Depending on the nature of the substituents R 9 and R 2, their cleavage can take place gradually or also all at once.

If R14 represents an optionally substituted benzyl group, it is cleaved in non-nitro compounds by hydrogenolysis in the presence of a suitable catalyst such as palladium on carbon or barium sulphate in a suitable solvent, for example an alcohol such as methanol, ethanol or acetic acid, optionally with the addition of a mineral. -acid acid, such as hydrochloric acid, and optionally at elevated hydrogen pressure, and preferably at temperatures between 20 ° and 50 ° C. If R 1 in the compound of general formula XIV represents a cyano group, this can be reduced simultaneously. Cleavage of R 1 may occur either after or before cleavage of R 8 and R 2.

The racemate cleavage of the d, 1 form of the compound of general formula I above is best accomplished by fractional crystallization of a mixture of its diastereomeric salt with an optically active acid such as D (-) - tartaric acid, L (+) - tartaric acid, dibenzoyl-D-tartaric acid. , dibenzoyl-L-tartaric acid, (+) - camphor-10-sulfonic acid, L (-) - malic acid, L (+) - mandelic acid, da-bromo-camphor-1-sulfonic acid or 1-quinic acid . Racemate cleavage can also be performed by column chromatography on an optically active carrier, for example acetylcellulose.

If methods a) to k) give a compound of general formula I in which R 2 is a cyano group, this can be converted into the corresponding carbamoyl compound and / or carbamoyl or carbalkoxy compound, then these can be converted into the corresponding carboxylic compound of general formula I by hydrolysis.

14 62052

The compounds of the general formula I obtained can, if desired, be converted with their inorganic or organic acids into their physiologically acceptable acid addition salts using 1, 2 or 3 equivalents of the acid in question. Suitable acids have, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid and fumaric acid.

The compounds of the general formulas II to XIV used as starting materials are obtained by methods known from the literature.

Thus, for example, the starting compounds of general formula II are obtained by reacting the corresponding 2-haloacetophenone with the corresponding amines.

The compounds of the general formulas III, IV and V are obtained by reacting the corresponding 2-haloacetophenones with the corresponding amines and then reducing the ketones obtained, for example with sodium borohydride. The starting compound of general formula IV is also obtained by halogenating the corresponding compound or catalytically reducing the corresponding 4-nitro-phenyl compound.

The compounds of general formula VI are obtained, for example, by reduction of the corresponding aminoacetylquinazolines with sodium borohydride.

For example, the starting compound of general formula VII is obtained by reacting the corresponding phenylethylene glycol with p-toluenesulfonic acid chloride in the presence of pyridine or by reducing the corresponding aminophenyl halide with sodium borohydride.

The starting compound of general formula X is obtained, for example, by reacting the corresponding acid with the corresponding amine in the presence of a condensing agent such as Ν, Ν'-dicyclohexylcarbodiimide or N, N1-carbonyldiimidazole, or by activation with nitric chloride or mixed anhydride and then reacting. with the corresponding amine, for example by reduction of the corresponding ketocarboxylic acid amide.

The starting compound of general formula XI is obtained, for example, by halogenating the corresponding oxazolidone in which a hydrogen atom is present or by alkylating the corresponding oxazolidone in which R3 is a hydrogen atom.

The starting compound of general formula XII is obtained, for example, by oxidizing the corresponding acetophenone with selenium dioxide or by oxidizing the corresponding phenacyl bromide with dimethyl sulfoxide.

The starting compound of general formula XIII is conveniently obtained by any of the methods of the appended application.

The starting materials of the formulas II to XIII used in methods (a) to (k) do not have to be prepared in all cases in pure form, but can also be suitably used as crude products.

As already mentioned above, the novel compounds of the general formula I have valuable pharmacological properties, in particular a β2-mimetic and / or β-blocking effect, whichever takes precedence depending on their substitution.

In particular, <3 (+) compounds have a selective effect on β 2 receptors and 1 (-) compounds act primarily on β 2 receptors.

For example, the effect of the following compounds on β-receptors was studied: A = 1- (4-amino-3-bromo-5-fluorophenyl) -2-tert-butylamino-M-tert-hydrochloride, 16 62052 C = 1- ( 4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride, D = 1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino- ethanol hydrochloride, E = 1- (4-amino-3-fluorophenyl) -2-tert-butylamino-ethanol hydrochloride, F = 1- (4-amino-3-trifluoromethyl-phenyl) -2-tert .-pentylamino-ethanol hydrochloride, G = 1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride, H = 1- (4-amino) -3-Chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride, I = 1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol , J = 1- (4-amino-3-bromo-5-cyano-phenyl) -2-tert-butylamino-ethanol hydrochloride, K = 1- (4-amino-3-bromo-5-fluoro-phenyl) ) -2-cyclobutylamino-ethanol hydrochloride, L = 1- (4-amino-3-fluoro-5-iodo-phenyl) -2-cyclopropylamino-ethanol-hydrochloride hydrochloride, M = 1- (4-amino-3-fluoro-5-cyanophenyl) -2-isopropylaminoethanol hydrochloride, 13 62052 N = 1- (U-amino-3-fluoro-5-cyano- phenyl) -2-tert. -butylamino-ethanol hydrochloride, O = 1- (* + - amino-3-cyanophenyl) -2-cyclobutylamino-ethanol hydrobromide, P = 1- (4-amino-) 3-Cyano-phenyl) -2-tert-pentylamino-ethanol> O = 1- (4-amino-3-chloro-5-cyano-phenyl) -2-propylamino-ethanol hydrochloride, R = 1- (4 -amino-3-chloro-5-cyano-phenyl) -2-sec-butylamino-ethanol hydrochloride, S = 1- (4-amino-3-chloro-5-cyano-phenyl) -2- (hydroxy- tert-butylamino) ethanol hydrochloride, T = 1- (4-amino-3-chloro-6-cyanophenyl) -2-tert-pentylaminoethanol hydrochloride, U = 1- (U- amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol hydrochloride, V = 1- (4-amino-3-chloro-5-cyano-phenyl) -2- [1- (3 , 4-methylenedioxy-phenyl) -2-propylamino-ethanol hydrochloride, W = 1- (4-amino-3-bromo-5-cyano-phenyl) -2-cyclobutylamino-ethanol hydrochloride, X = 1- ( 4-amino-3 ',' 5-disyani-phenyl) -2-tert. - butylaminoethanol hydrochloride, Y = 1- (* 4-amino-3-bromo-5-nitro-phenyl) -2-tert. -butylamino-ethanol and Z = 1- (4-amino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol! 18 62052 l ~ blocking effect was studied in narcotic cats as an interaction against tachycardia triggered by 1.0 γ / kg i.v. With a constant dose of N-isopropyl noradrenaline sulfate. The ED 2 value (see Tables II and III) was determined graphically by extrapolation from the mean percentage reduction obtained at different doses with an increase in N-isopropyl noradrenaline sulphate-forced heart rate,

S

The 2-named effect was studied in the Konzett-Fössler experimental design i.v. after application as a vasculatory effect on cough bursts in anesthetized guinea pigs triggered by i.v. 20 γ / kg acetylcholine. The percentage reduction in cough spikes obtained at different doses was determined graphically by extrapolating the ED 2 value (see Table I). The Ö 2 -blocking effect was examined as an adverse effect against the broncholytic effect observed in the Konzett-Rossler experimental set-up in 5 kg of anesthetized guinea pigs. N'-isopropyl noradornine sulfate when triggered by cough bursts by administering a standard amount, 20 γ / kg i.v., of acetylcholine (see Table III).

The acute toxicity of the substances was determined in groups of 10 mice. According to the method of Litchfield and Wilcoxon, the LD50 value at which the compound died intravenously in 50 Z animals at 14 days of dosing was calculated.

(see Tables II and III).

Reference Compounds β- (4-Arino-3-chloro-phenyl) -2-ethylamino-ethanol hydrochloride, BB 1- (4-amino-3-bromo-phenyl) -2-n-propylamino-ethanol- hydrochlorides,.

CC 1- (e-amino-3,5-dibromo-phenyl) -2-n-propylamino-ethanol hydrochloride, DD11- (4-amino-3,5-dibromo-phenyl) -2-n-isopropylamino Ethanol Hydrochloride, EE-1- (4-Amino-3,5-dibromo-phenyl) -2-n-butylamino-ethanol hydrochloride, FF 1- (4-Amino-3,5-dibro-phenyl) - 2-sec-butylamino-ethanol hydrochloride, CC · 1- (4-amino-3,5-dichloro-phenyl) -2-tert-butylamino-ethanol hydrochloride, HH 11- (4-amino-3,5 -dibromo-phenyl) -2- (5'-hydroxy-ethylamino) -ethanol hydrochloride II 1- (1- (4-amino-3,5-dibromo-phenyl) -2-cyclopropylamino-ethanol hydrochloride, (4-Arino-3,5-dichloro-phenyl) -2-n-propylamino-ethanol hydrochloride, KK-1- (4-amino-3,5-dichloro-phenyl) -2-n-butylamino-ethanol- hydrochloride.

Compounds AA and BB are described in US-3,574,211 and Compounds CC-KK in FI-48,460.

Table I

62052

Substance β-mimetic effect Duration jq - ED50 γ / kg i.v. in minutes A 9 5 8.3 150 C 5 4 24.0 50 D 54 19.0 120 E 63 18.0 80 G 10 5 19.5 130 H 5 5 6.8 125 I 11 4 0.20 95 J 5 4 4.8 40 K 6 3 58.0 50 M 64 0.08 40 N 5 3 0.32 40 053 6.9 40 P 5 4 3.6 65 Q 5 3 27.0 50 R 5 3 5.7 80 S 53 10.0 65 T 5 3 1.9 40 U 4 4 9.8 50 V 6 4 2.7 65 W 5 3 20.5 50 X 63 11.3 65 Z 53 31.5 80 AA 4 3 5000 BB 1 3 250 CC 2 3 5000 DD 2 4 5000 EE 2 3 5000 FF 2 3 5000 GG 5 17-22 7.8 HH 2 3 5000 II 2 3 5000 JJ 2 | 3 5000 KK 2 | 3 5000 ·>. <· '·· L · -, ---- 1

Number / dose of animals; = Number of doses taken into account when calculating the EDj-Q value.

Table II

'' „62CS2 20

Always Effect on β 2 receptors ^ 50 i.v.

n2 Π) 50 γ / kg i.v.

A 3 5 18.5 34.5 C 4 5 14.0 57, 0 D 4 5 8.0 35.1 E US 13.5 69.2 F 3 5 35.0 G 5 5 11.5 36.5 H - 36.3 1 5 5 0.74 60.0 J - 67.0 K 44 1.5 26.4 L 6 5 1.3 45.2 M 5 3 0.27 66.4 fj 6 4 0.022 58 .4,055 0.070 61.8 P 5 5 0.086 62.0 Q 6 5 0, 76 53, 4 R 6 6 0.32 40, 4 S 5 4 0.76 81.8 T 5 4 0.45 33.7 U 6 4 0.70 39.1 V 6 4 1.4 13.5 W 6 5 0.078 38.5 X 6 4 0.92 166.0 Y 5 4 2.8 35.8 Z 6 4 4.5 42 , 4 00 27.6 * Number of animals / dose n2 8 Number of doses> £ [>

Table III

21 62052 - j

Substance 3β receptors received 32- r'eseP ',: orei'ta sal "L ^ so head effect head effect mg / kg i.v.

n2 ED50 Y / kS i, v * ηχ n2 ED50 Y / ks ^ v <Λ-d (+) 7 U 3,4 51> 2000 37,2 Dd (+) 6 4 6,2 51> 2000 34,2 Ed (+) 8 3 1,5 41> 2000 Gd (+) 8 4 12,5 5 1> 2000 33,2 = Number of animals n2 = Number of doses tested in individual animals

The novel compounds of the general formulas I and Ia can, if desired, be processed into customary pharmaceutical preparations in combination with other active ingredients. In this case, the single dose is 1 to 1007, preferably 5 to 50γ.

The following examples further illustrate the invention.

Example 1 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-diethylamino-ethanol 3.4 g of 4'-amino-3'-bromo-2-diethylamino-5 * -Fluoro-acetophenone hydrochloride is dissolved in 20 ml of methanol. With stirring, a solution of 570 mg of sodium borohydride in 5 ml of water is slowly added at room temperature. The pH is adjusted to between pH 3 and 6 by dropwise addition to 3N hydrochloric acid. 3N hydrochloric acid until the pH is 1. The hydrochloric acid solution is extracted twice with chloroform and the chloroform extracts are discarded, the aqueous solution is quenched with ammonia and extracted with chloroform. "which is dissolved in ethyl acetate. Ethereal hydrochloric acid is added to precipitate a colorless precipitate which is filtered off with suction and dissolved in water. The aqueous solution is basified with sodium hydroxide and extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and evaporated in vacuo. A colorless oil remains.

The structure is shown by NMR spectrum (CDCl 3): 0.85 to 1.2 ppm triplet / B proton, N (CH 2 -CII) 2 /> 2.4 to 2.9 ppm multiplet / 6 protons, M (C: 2-), β, 4.15 pp ms in, exceeded (2 protons, NK 2), 4.4-4.7 ppm multiplet (1 proton, CH), 4.85 ppm singlet (1 proton, Oli), G, 9-7.4 ppm multiplet (2 aromatic protons).

Example 2 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride 80 g of 4'-amino-2-tert. -butylamino-3'-chloro-5'-trifluoromethyl-acetophenone hydrochloride (decomposes between 223 and 231 ° C) is dissolved in 500 ml of methanol and cooled to -15 ° C. With stirring, 9.5 g of sodium borohydride are added portionwise over one hour, keeping the temperature at -5 to -15 ° C. After a further 1 hour, acidify at -15 [deg.] C. with 2N hydrochloric acid and remove the methanol in vacuo. The remaining aqueous solution is adjusted to alkaline. 2n with ammonia and extracted with ethyl acetate. The organic phase is washed with water, dried and treated with 50 ml of 4.5N hydrochloric acid in isopropanol. The precipitated hydrochloride of the above substance is filtered off with suction and washed with ethyl acetate and ether.

Melting point: 205-207 ° C (decomposes)

Concentration of the mother liquor gives more compound.

Example 3 1- (4-Amino-3-bromo-5- [trans-phenyl) -2-dimethylamino-ethanol hydrochloride _____ - 15.2 g of 4'-amino-3'-bromo-5'-cyano 2-Dimethylaminoacetophenone is dissolved in 300 ml of methanol and a solution of 10 g of sodium borohydride (7% in 100 ml of water) is added dropwise at room temperature with stirring. Allow to stand overnight, decompose the remaining sodium borohydride by acidification with hydrochloric acid, the methanol is evaporated off under vacuum, the residue is taken up in water, made up with ammonia for a while and extracted three times with about 150 ml of chloroform. to ethanol and weakly acidified with alcoholic hydrochloric acid, whereby 1- (4-amino-3-bromo-5-cyanophenyl) -2-dimethylaminoethanol hydrochloride crystallizes out.

Melting point: 187-190 ° C.

Example α- (α-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-pentyl-amino-ethanol hydrochloride-0.37 g of 1- (α-amino-3-trifluoromethyl-phenyl) -2- tert-pentylaminoethanol hydrobromide and 0.2 ml of pyridine are dissolved in 30 ml of tetrahydrofuran and cooled to 0 ° C. 0.3 g of phenyl iodide dichloride are added, kept at said temperature for 2 hours and 0.1 g of phenyl iodide dichloride are added once more. After 20 hours at about [deg.] C., the solution is evaporated, partitioned between ethyl acetate and water, the aqueous extract is made alkaline with 2N ammonia and re-extracted with ethyl acetate. The organic phase is washed with water, dried and a few drops of 4N hydrochloric acid in isopropanol are added. The precipitated hydrochloride of the above compound is filtered off with suction and washed with ether.

Melting point: 176-178 ° C (decomposes).

Example S

1- (4-Amino-3-bromo-5-phenyl-phenyl) -2-tert-butylamino-ethanol dihydrochloride _________ 2.6 g of 1- (4-amino-3-methyl-phenyl) -2-tert. -butylamino-ethanol hydrochloride is dissolved in 90 ml of 50% acetic acid and 1.6 g of bromine dissolved in a mixture of 5 ml of glacial acetic acid and 1 ml of water are added at 0-5 ° C. After 15 minutes, the unused bromine is decomposed with sodium bisulfite. Dilute with water to remove the insoluble by-product by filtration through charcoal. The filtrate is made alkaline with sodium hydroxide while cooling and extracted with chloroform. Evaporate slightly in vacuo, cool, separate 1- (4-amino-3-bromo-5-methyl-phenyl) -2-tert-butylamino-ethanol dihydrochloride by suction and recrystallize from isopropanol / ether. .

Melting point: from 148 ° C (decomposes).

Example 6 1- (4-Amino-5-bromo-3-hydroxymethyl-phenyl) -2-tert-butylanino-ethanol ________________________________________ 2.0 g of 1- (4-amino-3-hydroxymethyl-phenyl) -2-tert. -butylaminoethanol is dissolved in a mixture of 18 ml of glacial acetic acid and 2 ml of water and 1.3 g of bromine are added dropwise. The reaction mixture is then evaporated, the residue is dissolved in water, made alkaline with 2N ammonia and shaken four times with chloroform. The organic phase is evaporated after drying over sodium sulfate and the residue is purified on a silica gel column using ethanol as eluent. The fractions containing the compound are combined and evaporated in vacuo. The evaporation residue crystallizes after standing for a long time under ether.

Melting point; 121-124 ° C.

Example 7 1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol 5.05 g of 1- (4-acetylamino-3-trifluoromethyl-phenyl) -2-tert-butylamino -ethanol hydrochloride is refluxed for 3 hours in a mixture of 50 ml of ethanol and 50 ml of 4N sodium hydroxide.

The ethanol is removed in vacuo and the precipitated crystals are filtered off with suction. After recrystallization from ethanol / water, the melting point is 145 DEG-147 DEG C.

For conversion to the monohydrochloride, it is dissolved in a calculated amount of 1N hydrochloric acid, evaporated to dryness in vacuo and the solid residue is recrystallized from isopropanol / ether.

Melting point of the hydrochloride: 172-174 ° C (decomposes).

2S 62052

Example 8 1- (4-Amino-3-trifluoromethyl-phenyl) -2- (N-benzyl-N-tert-butyl) -amino-ethanol 0.5 g of 1- (4-acetylamino-3-trifluoromethyl) -phenyl) -2- (N-benzyl-N-tert-butyl) -aminoethanol (melting point 98-100 ° C) is refluxed for 1 1/2 hours in a mixture of 10 ml of ethanol and 10 .mu.l of sodium hydroxide. The ethanol is distilled off in vacuo and the aqueous phase is extracted with ethyl acetate. The organic extract is washed with water, dried and evaporated in vacuo. The oily residue is thin-layer chronographically uniform (silica gel; chloroform: methanol = 19: 1,

Rf value: / * »0.5)

Example 9 1- (U-Amino-3-carboxy-phenyl) -2-tert-butylamino-ethanol 0.3 g of 1- (U-acetylamino-3-carboxy-phenyl) -2-tert-butylamino-ethanol is dissolved in 6 to 1 ml of ethanol and add U ml of concentrated hydrochloric acid. Heat for 70 minutes at 70 ° C, evaporate to dryness in vacuo and purify the product by chromatography on silica gel using chloroform / methanol = 3: 2 as eluent. 1- (U-amino-3-carboxy-phenyl) -2-tert-butylaminoethanol is obtained, the structure of which is confirmed by nuclear resonance spectrum (CD-O): 1, U ppm singlet / 9 protons, C (Cli3> 3), 3.3 ppm multiplet (2 protons, Cl · ^), U, 5 ppm multiplet (1 proton, CH), 6.3-7.8 ppm multiplet (3 aromatic protons).

Example 10 1- (U-Amino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol 0.15 g of 1- (4-amino-3-trifluoromethyl-phenyl) -2- (N-benzyl-M tert-butyl) aminoethanol is dissolved in a solution in a hydrogenation vessel, containing 10 ml of methanol and 1.4 ml of 1N hydrochloric acid. In the presence of 50 mg of palladium / carbon catalyst (10%), hydrogenate until 1 mole has elapsed. The catalyst is filtered off, the solution is evaporated in vacuo and the residue is partitioned between ethyl acetate and 2N ammonia. The water-washed organic phase is dried and re-evaporated in vacuo. The residue is crystallized from ethanol / water.

Melting point: 145-147 ° C.

Example 11 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert. -butylamino-ethanol hydrochloride ______________ 0.76 g of 1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- (M-benzyl-N-tert-butyl) -aminoethanol is dissolved in a hydrogenation mixture with 20 ml of methanol and 1.95 ml of 1N hydrochloric acid. In the presence of 80 mg of palladium / carbon catalyst (10%), hydrogenate until 1 mole of hydrogen has been consumed. The hydrogenation is stopped, the catalyst is removed by filtration and the filtrate is evaporated to dryness in vacuo, the oily evaporation residue is purified on a silica gel column using chloroform / methanol / concentrated ammonia = 80: 20: 1 as eluent. The fractions containing the substance are combined and the solvent is removed in vacuo. The remaining crystallized base of the desired compound is converted to the hydrochloride using a calculated amount of 1.07 N hydrochloric acid in isopropanol and recrystallized from ethyl acetate / ether.

Melting point: 205-207 ° C (decomposes).

Example 12 1- (4-Amino-3-chloro-5-methyl-phenyl) -2-tert-butylamino-ethanol dihydrochloride __________ 0.7 g of 1- (4-amino-3-chloro-5-methyl-f- enyl) -2- (α-benzyl-E-tert-butyl) -anino-ethanol hydrochloride is dissolved in a mixture of 50 ml of methanol and 0.92 ml of 2N hydrochloric acid and hydrogenated in the presence of 50 mg of palladium on carbon (10 %). The hydrogenation is stopped after 41 Nml of hydrogen have been consumed; the catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in ethanol and precipitated as the dihydrochloride by adding ether.

.Melting point: from 95 ° C (decomposes).

Example. 13 '62052 27 1- (4-amino-3-methoxy-phenyl) -2-tert. -butyl anino-ethanol 8.5 2 1- (4-Amino-3-methoxy-phenyl) -2- (N-benzyl-Π-tert-butyl) -aminoethanol is dissolved in 150 ml of methanol and acidified. ) .si to pH 5 with ethanolic hydrochloric acid. To this solution is added 1 g of palladium on carbon (10%) and hydrogenated in a shaker at room temperature and atmospheric pressure until the calculated amount of hydrogen has elapsed. After filtering off the catalyst, it is evaporated to a small volume. The separated crystals are filtered off with suction and recrystallized from ethanol. The colorless crystals of the hydrochloride obtained in the desired compound melt at 174-176 [deg.] C. (decomposition).

Example 14 1- (4-Amino-3-trifluoromethyl-phenyl) -2-cyclopropylamino-ethanol-dihydrochloride 4.1 g of 1- (4-amino-3-bromo-5-trifluoromethyl-phenyl) -2-cyclopropyl- aminoethanol is dissolved in 200 ml of methanol in a hydrogenation vessel and 2 g of palladium oxide / barium sulphate catalyst (5%) are added. Stir until 1 mole of hydrogen has passed, filter off the catalyst and evaporate the filtrate to dryness in vacuo. The residue is taken up in water, made alkaline with 2N ammonia and the aqueous phase is extracted with ethyl acetate. The organic extracts are washed with water, dried and re-evaporated. The solid residue is dissolved in isopropanol and 2 equivalents of 4N hydrochloric acid in isopropanol are added to the solution. The crystallized dihydrochloride of said compound is filtered off with suction and washed with isopropane and ether.

Melting point: 141.5-142 ° C (decomposes).

Example 15 1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol hydrobromide (1-amino-3-bromo-5-trifluoromethyl-phenyl) -2-tert. -pentylaminoethanol hydrochloride is partitioned between ethyl acetate and 2N ammonia. The organic phase is dried and evaporated in vacuo. The remaining base is dissolved in 100 ml of methanol in a hydrogenation vessel, 2.5 g of palladium oxide / barium sulphate catalyst (5%) are added and hydrogenated, 28 62052, until 1 mol of hydrogen has been consumed. After removal of the catalyst by filtration, the filtrate is evaporated in vacuo and the solid residue is recrystallized from isopropanol. The obtained hydrobromide of said compound melts at 174-175 ° C (decomposes).

Example 16 1- (1,4-Amino-3-methyl-phenyl) -2- (N-Benzyl-N-tert-butyl) -amino-ethanol, 5 g of 1- (4-amino-3- Bromo-5-methyl-phenyl) -2- (N-benzyl-N-tert-butyl) -aminoethanol is dissolved in a mixture of 100 ml of methanol and 11.6 ml of 2N hydrochloric acid. The mixture is hydrogenated in the presence of 250 mg of palladium on carbon (5%). After 315 ml of hydrogen have been consumed, the hydrogenation is stopped, the catalyst is filtered off with suction, the solvent is distilled off under reduced pressure, the residue is taken up in water and the base is liberated with ammonia. This is extracted with chloroform and chromatographed on a silica gel column. A base with a melting point of 96-98 ° C and a dihydrochloride decomposing from 145 ° C are obtained.

Example 17 1- (α-Amino-5-aminomethyl-phenyl) -2-tert-butylamino-ethanol 2.0 g of 6- (2-tert-butylamino-1-hydroxy-ethyl) -3,4-dihydro Dissolve 2-methylquinazoline in 80 ml of pentyl alcohol, add 7.5 g of sodium portionwise over one hour and bring to the boil after 1/2 hour. After boiling for 5 hours, the solution is cooled and 100 ml of water are added.

60 ml of concentrated hydrochloric acid are then added dropwise, the reaction mixture is stirred for 2 hours and shaken twice with ether. The acidic phase is made alkaline with 10% sodium hydroxide, the base is extracted with ether, the ether phase is dried over sodium sulfate and evaporated. The crude product is purified by column chromatography on silica with 1: 2% and eluting with methanol: chloroform (2: 1). After evaporation of the corresponding fractions, 1- (α-amino-3-aminomethylphenyl) -2-tert-butylaminoethanol is obtained as an amorphous compound.

29 62052 '

Elemental analysis i: k j C13H23M3 ° <237 · 3 ,,>

Calculated: C 65.78 H 9.76 N 17.70

Found: 65.50 9.61 17.58

Example 18 1- (4-Amino-3-bromo-5-carbamoyl-phenyl) -2-dimethylamino-ethanol 2 g of 1- (4-amino-3-bromo-5-cyano-phenyl) -2-dimethylamino -ethanol is boiled for 4 hours together with a solution of 5 g of sodium hydroxide in 120 ml of 50% ethanol. The ethanol is distilled off, the remaining aqueous solution is diluted with 100 ml of water and extracted three times with chloroform. The chloroform solution is dried over sodium sulfate and evaporated in vacuo. The residue solidifies and is then recrystallized from chloroform.

Melting point: from 93 ° C (decomposes).

Example 19 1- (4-Amino-3-bromo-3-carboxy-phenyl) -2-dimethylamino-ethanol 2 g of 1- (4-amino-3-bromo-5-cyano-phenyl) -2-dimethylamino-ethanol boil for 4 hours in a solution of 5 g of sodium hydroxide in 120 ml of 50% ethanol. The ethanol is distilled off, the remaining aqueous solution is diluted with 100 ml of water and extracted three times with chloroform. The aqueous phase is neutralized and evaporated to dryness. The residue is taken up in ethanol, filtered, the filtrate is evaporated, the residue is taken up in ethanol and filtered. Evaporation of the last filtrate leaves a residue of 1- (4-amino-3-bromo-5-carboxyphenyl) -2-dimethylaminoethanol, melting at 240-250 ° C (decomposes) and confirmed by IR and UV spectra: IR (KBr): C00 "1620 cm -1", NH + 2000 - 3500 cm -1, UV (ethanol): max 220 and 330-340 nm, shoulder 250 nm.

SM, * fc

Example 20 62052 1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol

Melting point of hydrochloride: 196-197 ° C (decomposes).

Prepared according to Example 1 by a) 4'-amino-2-tert-butylamino-3'-fluoroacetophenone hydrochloride and sodium borohydride.

Example 21 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol Melting point of hydrochloride: 207-208 ° C (decomposes).

Prepared according to Example 1 by method a) from 4'-amino-3'-bromo-2-tert-butylamino-5'-fluoroacetophenone hydrochloride and sodium borohydride.

Example 22 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol__

Melting point of the hydrochloride: 177-178 ° C.

Prepared according to Example 2 by a) 4'-amino-3'-chloro-2-cyclobutylamino-5'-trifluoromethylacetophenone hydrochloride and sodium borohydride.

Example 23 1- (4-Amino-3-fluoro-phenyl) -2-cyclopropylamino-ethanol Melting point of the hydrochloride: 157-158 ° C (decomposes).

Prepared according to Example 7 by method c) from 1- (4-acetylamino-3-fluoro-phenyl) -2-cyclopropylamino-ethanol and sodium hydroxide.

^ · ‘A νΓ

Example 24 31 62052 1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol Melting point of hydrochloride: 196-197 ° C (decomposes).

Prepared according to Example 13 by method c) 1- (4-amino-3-fluorophenyl) -2- (N-benzyl-N-tert-butyl) aminoethanol hydrochloride and catalytically activated hydrogen.

Example 25 2-Ethylamino-1- (4-amino-3-chloro-5-fluoro-phenyl) -ethanol Hydrochloride melting point: 186-188 ° C (decomposes).

Prepared according to Example 1 from 2-ethylamino-41-amino-3'-chloro-5'-fluoroacetophenone and sodium borohydride according to process a).

Example 26 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol Melting point of the hydrochloride: 152-154 ° C (decomposes).

Prepared according to Example 1 by a) 4'-amino-3'-chloro-5'-fluoro-2-isopropylaminoacetophenone hydrochloride and sodium borohydride.

Example 27 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol Melting point of the hydrochloride: 175-177 ° C (decomposes).

Prepared according to Example 1 by a) 4'-amino-3'-chloro-2-cyclopropylamino-5'-fluoroacetophenone hydrochloride and sodium borohydride.

ST; C <.Λ, ·?

Example 28 32 62052 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol

Melting point of hydrochloride: 206-208 ° C (decomposes).

Prepared according to Example 1 by a) 4'-amino-2-tert-butylamino-3'-chloro-5'-fluoroacetophenone hydrochloride and sodium borohydride.

Example 29 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-pentylamino-ethanol Hydrochloride melting point: 187-188 ° C (decomposes).

Prepared according to Example 1 by a) 4, -amino-3'-chloro-5'-fluoro-2-tert-pentylaminoacetophenone hydrochloride and sodium borohydride.

Example 30 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino-ethanol]

Melting point of hydrochloride: 119-121 ° C (decomposes).

Prepared according to Example 1 by a) 4'-amino-3'-chloro-5'-fluoro-2- [1- (3,4-methylenedioxyphenyl) -2-propylamino] acetophenone and sodium hydride.

Example 31 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-dimethylamino-ethanol Melting point of hydrochloride: 208-210 ° C (decomposes).

Prepared according to Example 1 by a) 4'-amino-3'-chloro-2-dimethylamino-5'-fluoroacetophenone hydrochloride and 620i> 333 sodium borohydride.

Example 32 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-diethylamino-ethanol

Melting point: 39-41 ° C.

Prepared according to Example 1 by method a) from 4'-amino-3'-chloro-2-diethylamino-5'-fluoroacetophenone hydrochloride and sodium borohydride.

Example 33 2-Ethylamino-1- (4-amino-3-bromo-5-fluoro-phenyl) -ethanol Melting point of hydrochloride: 167-169 ° C (decomposes).

Prepared by method a) according to Example 1 from 2-ethylamino-4'-amino-3'-bromo-5'-fluoroacetophenone hydrochloride and sodium borohydride.

Example 34 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol Melting point of the hydrochloride: 171-173 ° C (decomposes).

Prepared according to Example 1 by a) 4 * -amino-3'-bromo-5'-fluoro-2-isopropylaminoacetophenone hydrochloride and sodium borohydride.

Example 35 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclopropylamino-ethanol Melting point of the hydrochloride: 185-187 ° C (decomposes).

Prepared according to Example 1 by method a) H'-amino-S'-br'-N, N-cyclopropylamino-5 * -fluoroacetophenone and sodium borohydride.

, k 62052

Example 36 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2- (hydroxy-tert-butylamino) -ethanol

Melting point: 122-125 ° C.

Prepared according to Example 1 by a) 4'-amino-3'-bromo-5 * -fluoro-2- (hydroxy-tert-butylamino) -acetophenone hydrochloride and sodium borohydride.

Example 37 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-pentylamino-ethanol Melting point of the hydrochloride: 185-187 ° C (decomposes).

Prepared according to Example 1 by a) 4'-amino-3T-bromo-5'-fluoro-2-tert-pentylaminoacetophenone hydrochloride and sodium borohydride.

Example 38 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2- [1- (3,4-methylenedioxy-phenyl)-(2-fluoro-phenyl) -2- [1- [3,4-methylenedioxy-phenyl] -2- [

Melting point: 126-128 ° C.

Prepared according to Example 1 by a) from 4, -amino-3'-bromo-5'-fluoro-2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] -acetophenone and sodium borohydride.

Example 39 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol

Melting point: 104-106 ° C.

Melting point of the hydrochloride: 185-187 ° C.

Prepared according to Example 2 by method a) 4, -amino-3'-chloro-2-isopropyl, amino-5'-trifluoromethylacetophenone hydrochloride and sodium borohydride.

Example 40 35201 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclopropylamino-Melting point: 138-139 ° C.

Prepared according to Example 2 by a)> 4'-amino-3'-chloro-2-cyclopropylamino-5'-trifluoromethylacetophenone and sodium borohydride.

Example 41 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2- (hydroxy-tert-butylamino) -ethanol

Melting point of the hydrochloride: 219-220 ° C.

Prepared according to Example 2 by a) H * -amino-3'-chloro-2-hydroxy-tert-butylamino) -5'-trifluoromethyl-aceto-phenone hydrochloride and sodium borohydride.

Example 42 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol

Hydrochloride melting point: 176-178 ° C (decomposes).

Prepared by method a) according to Example 2 from 4'-amino-3'-chloro-2-tert-pentylamino-51-trifluoromethylacetophenone hydrochloride and sodium borohydride.

»

Example 43 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2- [2-methyl-4-hydroxybutyl- (2) -amino] -ethanol_

Melting point of the hydrochloride: 148-150 ° C (decomposes).

Prepared according to Example 2 by method a) 4'-amino-3'-chloro-2- [2-methyl-4-hydroxybutyl- (2) -amino] -51-trifluoromethylacetophenone and sodium borohydride.

36 62052

Example 44 2-Z'3-Ethynyl-pentyl- (3) -amino-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -ethanol

Melting point of the hydrochloride: 185-187 ° C (decomposes).

Prepared according to Example 2 by method a) from 2 - [(?-Ethynyl-pentyl- (3) -amino] -7'-amino-3'-chloro-51-trifluoromethyl-aceto-phenone hydrochloride and sodium borohydride.

Example 45 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2- [(3,4-methylenedioxy-phenyl) -2-propylamino] -ethanol]

Melting point of hydrochloride: 206-207 ° C (decomposes).

Prepared according to Example 2 by a) 4 * -amino-3'-chloro-2- [1- (3,4-methylenedioxyphenyl) -2-propylamino] -5 * -trifluoromethylacetophenone hydrochloride and sodium borohydride.

Example 46 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-dimethylamino-ethanol

Melting point of the hydrochloride: 162-164 ° C.

Prepared according to Example 2 by a) 4'-amino-31-chloro-2-dimethylamino-51-trifluoromethylacetophenone hydrochloride and sodium borohydride.

Example 47 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2- (N-methyl-ethylamino) -ethanol M # \ β

Melting point: 48-> 49 ° C,

Prepared according to Example 2 by method a) 4, -amino-3'-chloro-2- (N-methylethylamino) -5'-trifluoromethylacetophenone hydrochloride and sodium borohydride.

Example 48 37 62052 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-diethylamino-ethanol____

Melting point of the hydrochloride: 149-151 ° C.

Prepared according to Example 2 by a) 4'-amino-3 * -chloro-2-diethylamino-5'-trifluoromethylacetophenone hydrochloride and sodium borohydride.

Example 49 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2- (N-benzyl-N-tert-butyl) -aminoethanol oil, thin layer chromatographically uniform (SiO 2; chloroform: ol = 15 : 1; Rf value: 0, 0.75).

Prepared according to Example 2 by a) 21-amino-2- (N-benzyl-N-tert-butyl) -amino-3'-chloro-5'-trifluoromethyl-acetophenone and sodium borohydride.

Example 50 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol

Melting point: 102-103 ° C.

Melting point of hydrochloride: 177-179 ° C (decomposes).

Prepared by method a) according to Example 2 from 4'-amino-3'-bromo-2-isopropylamino-5'-trifluoromethylacetophenone hydrochloride and sodium borohydride.

Example 51 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-cyclopropylamino ------

Melting point: 141.5 ° C 142.5 ° C.

Melting point of the hydrochloride: 195-195.5 ° C (decomposes), * 38 62052

Prepared according to Example 2 by a) t1'-amino-S'-bromo-2-cyclopropylamino-51-trifluoromethylacetophenone hydrochloride and sodium borohydride.

Example 52 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol

Melting point: 85-87 ° C.

Melting point of hydrochloride: 205-206 ° C (decomposes).

Prepared according to Example 2 by a) 4'-amino-3'-bromo-2-tert-butylamino-5'-trifluoromethylacetophenone hydrochloride and sodium borohydride.

Esenkenk 53 x- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol _______________________________

Melting point of hydrochloride: 189-191 ° C (decomposes).

Prepared according to the procedure of Example 2 by a) 4f-amino-31-bromo-2-cyclobutylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride.

Example 54 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol. ___________

Hydrochloride melting point: 1E6.5 - 168.5 ° C (decomposes).

Prepared according to Example 2 by a) 4'-amino-3'-bromo-2-tert-pentylamino-5'-trifluoromethylacetophenone hydrochloride and sodium borohydride.

55 2-Z3-Ethynyl-pentyl-(3) -amino-7- (4-amino-3-bromo-5-trifluoromethyl-phenyl) -ethanol 39,62052

Melting point of hydrochloride: 189-190 ° C (decomposes).

Prepared by method a) according to Example 2 from 2- [3-ethynyl-pentyl- (3) -amino] - <+ '-amino-3'-bromo-5'-trifluoromethyl-aceto-phenone hydrochloride and sodium borohydride.

Example 56 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-dimethylamino-ethanol_

Melting point of the hydrochloride: mp 9-151 ° C.

Prepared according to Example 2 by a) k'-amino-3'-bromo-2-dimethylamino-5'-trifluoromethylacetophenone hydrochloride and sodium borohydride.

Example 57 1- (k-Amino-3-bromo-5-trifluoromethyl-phenyl) -2- (N-methyl-ethylamino) -ethanol_

Melting point: 52-53.5 ° C.

Prepared according to Example 2 by a) k'-amino-3'-bromo-2- (N-methylethylamino) -5'-trifluoromethylacetophenone hydrochloride and sodium borohydride.

Example 58 1- (k-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-diethylamino-ethanol

Melting point of hydrochloride: 159-160 ° C.

Prepared according to Example 2 by a) k'-amino-3'-bromo-2-diethylamino-5'-trifluoromethylacetophenone hydrochloride and sodium borohydride.

Example 59 1- (k-Amino-3-methyl-phenyl) -2-tert-butylamino-ethanol 62052

Melting point of dihydrochloride: 108 ° C (decomposes).

According to Example 3, process a) is prepared from 4'-amino-3'-methyl-2-tert-butylaminoacetophenone and sodium borohydride.

Example 60 1- (4-Amino-3-chloro-5-methyl-phenyl) -2-methylamino-ethanol Melting point: 95-9G ° C.

Prepared by method a) according to Example 3 from 4'-amino-3'-chloro-5'-methyl-2-methylaminoacetophenone and sodium borohydride.

Example 61 2-Ethylamino-1- (4-amino-3-chloro-5-phenyl-phenyl) -ethanol Melting point: 107-108.5 ° C.

Prepared according to Example 3 by method a) from 2-ethylamino-4'-amino-3'-chloro-5'-methylacetophenone and sodium borohydride.

Example 62 1- (4-Amino-3-chloro-5-methyl-phenyl) -2-dimethylamino-ethanol Hydrochloride melting point: 120-125 ° C (decomposes).

Prepared according to Example 1 by a) 4'-amino-3'-chloro-2-dimethylamino-5'-methylacetophenone hydrochloride and sodium borohydride.

Example 63, N- (4-amino-3-chloro-5-methyl-phenyl) -2- (X'-methyl-ethylamino) -ethanol ---- m.p. 9 3-9 6 ° C.

Prepared according to Example 1 by method a) from 4'-amino-3'-chloro-5'-methyl-2- (N-methylethylamino) acetophenone hydrochloride and sodium borohydride.

4i 62052

Example 64 1- (4-Amino-3-chloro-5-methyl-phenyl) -2-diethylamino-ethanol Melting point of hydrochloride: 118-122 ° C (decomposes).

Prepared according to Example 1 by a) 4f-amino-3 · -chloro-2-diethylimino-5'-methylacetophenone hydrochloride and sodium borohydride.

Example 65 1- (4-Amino-3-chloro-5-methyl-phenyl) -2- (N-benzyl-N-tert-butylamino-ethanol _______

Melting point of hydrochloride: 2Q0-201 ° C.

Prepared according to Example 3 by a) 4'-amino-2- (H-benzyl-N-tert-butyl) -amino-3'-chloro-5'-methylacetophenone and sodium borohydride.

Example 66 1- (4-Amino-3-bromo-5-methyl-phenyl) -2-dimethylamino-ethanol Melting point of the hydrochloride: 123-125 ° C (decomposes).

Prepared according to Example 3 by a) 4'-amino-3'-bromo-2-dimethylamino-5'-methylacetophenone and sodium borohydride.

Example 67 1- (4-Amino-3-bromo-5-methyl-phenyl) -2-diethylamino-ethanol Melting point: 48-50 ° C.

Prepared by method a) according to Example 3 from 4'-amino-3'-bromo-2-diethylamino-51-methylacetophenone and sodium borohydride.

Example 68 1- (4-Amino-3-bromo-5-methyl-phenyl) -2- (N-benzyl-N-tert-butyl) -amino-ethanol __________ h 2,6205 2

Prepared according to Example 3 by method a) 4'-amino-3'-bromo-2- (N-benzyl-N-tert-butyl) -amino-5'-methyl-acetofer.or.is and sodium borohydride.

The material is pure by thin layer chromatography (SiO 2; chloroform: methanol =): 1, RF value: * '* 0, S).

Example 69 1- (S-Ethyl-N-amino-S-chloro-phenyl) -2-diethylamino-ethanol 1 Hydrochloride melting point: 121-124 ° C.

Prepared according to Example 3 by a) 3'-ethyl-4'-amino-5'-chloro-2-diethylaminoacetophenone and sodium bocrihydride.

Example 70 1- (3-Ethyl-4-amino-5-bromo-phenyl) -2-diethylamino-ethanol Hydrochloride melting point: 132-134 ° C.

Prepared according to Example 3 by a) 3r-ethyl-4f-amino-5 * -bromo-2-diethylaminoacetophenone and sodium borohydride.

Example 71 1- (4-Amino-3-tert-butyl-5-chloro-phenyl) -2-tert-butylamino-ethanol

Melting point of hydrochloride: from 218 ° C (decomposes).

Prepared according to Example 1 by a) U'-amino-S'-tert-butyl-2-tert-butylamino-5'-chloroacetophenone and sodium borohydride.

Example 72 1- (4-Amino-3-hydroxymethyl-phenyl) -2-dimethylamino-ethanol

Prepared according to Example 1 from 41-amino-2-dimethylamino-3 · -hydroxymethylacetophenone and sodium borohydride.

«3 62052

The structure is indicated by UV and IR spectra. UV (ethanol): maximum 250 nm (E = 0.5), shoulder 275-305 nm (E = 0.11); IR (CH 2 Cl 2): OH 3500 cm -1, NH 2 3380 and 3450 cm -1, N (CH 3) 2 2780 and 2830 cm -1.

Example 73 1- (4-Amino-3-hydroxymethyl-phenyl) -2-diethylamino-ethanol

Melting point of hydrochloride: from 125 ° C (decomposes).

Prepared according to Example 1 by a) 4'-amino-2-diethylamino-2'-hydroxymethylacetophenone and sodium borohydride.

Example 74 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-isopropylamino-ethanol Melting point of the hydrochloride: 185-188 ° C ·.

Prepared by method a) according to Example 3 from 4'-amino-31-chloro-5'-cyano-2-isopropylaminoacetophenone and sodium borohydride.

Example 75 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol Melting point: 125-133 ° C.

Prepared by method a) according to Example 3 from 4'-amino-3'-choir-5'-cyano-2-tert-butylaminoacetophenone and sodium borohydride.

Example 76 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-dimethylamino-ethanol

Melting point of the hydrochloride: 187-189 ° C.

The compound is prepared according to Example 3 by method a) 4'-amino-3'-O * 4-chloro-5'-cyano-2-dimethylaminoacetophenone and sodium boron-e 2 'hybrid.

Example 77 62052 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-diethylamino-ethanol Melting point: 69-71 ° C.

Prepared according to Example 3 by a) from U'-amino-S * -chloro-5'-cyano-2-diethylaminoacetophenone and sodium borohydride.

Example__78 1- (H-Amino-3-bromo-5-cyano-phenyl) -2-isopropylamino-methanol Melting point of the hydrochloride: 186-189 ° C.

Prepared according to Example 3 by method a) 4'-amino-3'-bram-5'-cyano-2-isopropylamino-acetophenyl? and sodium borohydride.

Example 79 1- (k-Amino-3-bromo-5-cyano-phenyl) -2-tert-butyl-amino-ethanol Hydrochloride Melting point: 213-125 ° C.

Prepared according to Example 3 by method a) from 41-amino-31-bromo-2-tert-butylamino-5'-cyanoacetophenone and sodium borohydride.

Example 80 1- (u-Amino-3-bromo-5-cyano-phenyl) -2-diethylamino-ethanol E u1am and mp: 72-74 ° C.

Prepared according to Example 3 by method a) from 4'-anino-3'-bromo-5'-cyano-2-diethylaminoacetophenone and sodium borohydride.

Example 81 1 S-1H-Amino-3-Eron-5-carboxy-phenyl) -2-tert-butylamino-ethanol Melting point: from 218 ° C (decomposes).

115 62052

Prepared according to Example 3 by a) from 4'-ar.-3'-bromo-2-tert-butylamino-5'-carboxyacetophenone and borohydride.

Example 82 1- (U-Amino-3-chloro-5-methoxy-phenyl) -2-tert-butylamino-ethane. Melting point of the hydrochloride: 175-178 ° C (decomposes).

Prepared according to Example 1 by method a) 41-Amino-2-tert-butylamino-31-chloro-5'-methoxy-acetophenone hydrochloride and sodium borohydride.

Example 83 1- (α-Amino-5-bromo-3-hydroxymethyl-phenyl) -2-dimethylamino-ethanol ___

Melting point: 87-92 ° C.

According to Example 6, bronamal i- (U-amino-3-hydroxymethyl-phenyl) -2-dimethylamino-ethanol is prepared according to Example 6.

Example 84 1- (4-Amino-5-bromo-3-dimethylaminomethyl-phenyl) -2-tert-rutylamino-ethanol

Melting point: 127-129 ° C.

Prepared according to Example 6 by method b) with bromine. L- (4-amino-3-dimethylaminomethyl-phenyl) -2-tert-butyylianino-ethanol.

Example 85 1- (N, N-n-n-S-bromo-1-dimethylaminomethyl-phenyl) -2-dimethylamine; - - - -, - - —- · --- —- _ - - -

Prepared according to Example 6 by method b) by bromination of 1- (4-amino-3-dimethylaminomethyl-phenyl) -2-dimethylamino-ethanol.

1.6 62052

The structure is shown by NMR spectrum (DCCl 3, / DC, 0D): 2.2 nprr SinS * · ** 1/6 protons, NCCK 6), 2.35 ppm singlet / 6 protons, NCCK 6 3.0 ppm multiplet (2 protons, CI ί 2), 3.45 ppm singlet (2 motons and CH0), 4.4-4.3 ppm multiplet (1 proton, Cl), G, 9t PP771 doublet and 7 , 4 ppm doublet (2 aeromatic protons).

Example R-Ethylamino-1- (4-amino-3-fluoro-phenyl) -ethanol Melting point of hydrochloride: 187-12 8 ° C (decomposes).

Prepared according to Example 7 by method c) from 1- (4-acetyl-1-amino-3-fluoro-phenyl) -2-ethylamino-ethanol and sodium p-phenyl-di-di.

Example 8 7 1- (4-Amino-3-fluoro-phenyl) -2-isopropylamino-anthanol Hydrochloride melting point: 156-158 ° C (decomposes).

Prepared according to Example 7 by method c) from 1- (4-acetyl-amino-3-fluorophenyl) -2-isopropylarinoethanol and sodium hydroxide.

Example 88 1- (4-Amino-3-fluoro-phenyl) -2-tert-pentylamino-ethanol Melting point of Hydrochlorocline: 153-155 ° C (decomposes).

Prepared according to Example 7 by method c) 1- (4-acetylamino-3-fluoro-phenyl) -2-tert. pentylaryrino-otanol and sodium oxide.

Esi n e r k k i. 89. '. BE'.

Prepared according to Example 7 by method c) from 1- (4-acetyl-aryl-3-fluorophenyl) -2-dimethylamino-α-anol and sodium hydroxide. „62052 oil; the structure is indicated by IR and UV spectra. IR (CE 2 Cl 2): Was free 3550 cm -1, NH 2 3370 and 3450 cm -1, OH associated 3200 to 3500 cm 2780 and 2830 cm aromatic C = C 1635 cm -1 UV (ethanol): max 238 nm (E = 0.6) and 288 nm (E = 0.13).

Example 9Q

1- (4-amino-3-fluoro-phenyl) -2-diethylamino-ethanol Melting point of the hydrochloride: 122-125 ° C (decomposes).

Prepared according to Example 7 by method c) from 1- (4-acetylamino-3-fluoro-phenyl) -2-diethylamino-ethanol and sodium hydroxide.

Example 91 1- (4-Amino-3-dimethylaminomethyl-phenyl) -2-tert-butylamino-ethanol

Melting point: 55-59 ° C.

Prepared according to Example 7 by method c) by saponification with 1- (4-acetylamino-3-dimethylaminomethyl-phenyl) -2-tert-butylamino-ethanol with ethanolic sodium hydroxide.

Example 92 1- (4-Amino-3-dimethylaminomethyl-phenyl) -2-dimethylamino-ethanol

Prepared according to Example 7 by method c) by saponification with 1- (4-acetylamino-3-dimethylaminomethyl-phenyl) -2-dimethylamino-ethanol with ethanolic sodium hydroxide.

The structure is shown by NMR spectrum (CDCl 3): 2.2 ppm singlet / 6 protons, N (CH 3) 2 /> 2.35 ppm singlet / 6 protons, N (CH 3) 2 / »1.6-2.9 ppm multiplet (2 protons, CII2) 3.42 ppm singlet (2 protons, CH2>, 4.41-4 ', S1 ppm multiplet (1 proton, CH), 6.6-7.18 ppm multiplet (3 aromatic protons).

l, s 62052

Example 93 1- (4-Amino-3-hydroxy-ethyl-phenyl) -2-tert. -butylamino-ethanol Melting point: 123-12 ° C.

Prepared according to Example 13 by methods c) 1- (H-amino-3-hydroxyethylphenyl) -2- (N-benzyl-1'-tert-butyl) ) -aninoethanol using hydrogen in the presence of palladium activated carbon.

Example. 94 1- (N-amino-3-chloro-5-hydroxymethyl) -2-tert-butylaminoethanol

Prepared according to Example 13 by method c) 1- (4-aniro-3-chloro-5-hydroxymethyl-1-phenyl) -2- (N-Benzyl) tert-one bu style) -arino-ethanol using hydrogenated palladium-Akti-vi in the presence of carbon.

The structure is indicated by the MliR spectrum 11 ^ (CDCl 3): 1.1 nn; y. n: 'rmvlot ti 12 -.- 0-pus, C (Ca 2) 3 /, 2.0-3.6 onm multiplet (2 protons, CK?), 4.6 ppr. singlet (2 protons, Cl 2), 4.2-4.6 ppm multiplet (1 proton, CK), 6.9 ppm doublet, and 7.2 ppm doublet (2 aromatic protons).

Example 95 1 - (4 - is in 3 - tr '' fluoro] i {{-yl i **. F er.y vl i) - 2 - big no rp'vl i an ien - s ρ a no i kk -facial-: 13 Γ-1 7 7, 5 ° C.

It is possible to carry out according to the pre-miarW r 14 method by the method s) 1- (4-or 3-ro-3-bromo-5-trifluoride is absorbed by 1 if envy 1 i) - 2-1 soorory or. -tarol 'et a] a viewed s s vvsti activated hydrogenpa.

I ime rkl '- 96 1- (4-url-3-trifluoromethyl-fertyl) -2-dimethyl-1-ethenol en u 1 s mi: · ρ into: 64- 66.6 ° C.

According to the example of Example 1n, mr-etelm ”lv.“ E) 1- (4-erir-3-brop-i-5-fluoro-fluorophenyl) phenyl) - 2 - d ΐηοΐν'Ί iomino-ethanol hydrochlorides and catalytically activated hydrogen.

62052 49

Example 97 1- (4-Amino-3-trifluoromethyl-phenyl) -2- (N-methyl-ethylamino) -ethanol _____

Prepared according to Example 14 by method d) from 1- (4-amino-3-bromo-5-trifluoromethyl-phenyl) -2- (N-methylethylamino) -ethanol and catalytically activated hydrogen.

oil, uniform by TLC (Rf value: 0.2; SiO 2; chloroform-methanol: concentrated ammonia = 90: 10: 1);

Elemental analysis: C12H17r3N2O (262.3)

Calculated: C 54.95 H 6.53 N 10.68

Found: C 54.70 H 6.55 N 10.68

Example 98 1- (4-Amino-3-trifluoromethyl-phenyl) -2-diethylamino-ethanol

Prepared according to Example 14 by process d) 1- (4-amino-3-bromo-5-trifluoromethyl-phenyl) -2-diethylamino-ethanol hydrochloride and catalytically activated hydrogen.

oil; TLC uniform (Rf value: ^ 0.3, SiO 2, chloroform: methanol: concentrated ammonia = 90: 10: 1); the structure is shown by NMR spectrum (CDCl 3): 1.1 ppm triplet / 6 protons, iKCF 2 -CH 2) 2 /> 2.55 ppm multiplet / 6 protons, N (CK 2 ~) 3 /, 4.5 ppm multiplet, (1 proton, CH), 6.7 ppm dutlet and 7.3 ppm doublet (2 aromatic protons).

Example 99 1- (4-Amino-3-methyl-phenyl) -2- (N-benzyl-N-tert-butyl) -amino-ethanol _, ______

Melting point of dihydrochloride: from 145 ° C (decomposes).

Prepared according to Example 16 by method d) from 1- (4-amino-3-bromo-{(S'-methylphenyl) -2- (N-benzyl-N-tert-butyl) -aminoethanol and catalytically , activated hydrogen.

• \ · · so 62052

Example 100 1- (4-Amino-3-cyano-phenyl) -2-isopropylamino-ethanol Melting point: 159-161 ° C.

Prepared according to Example 16 by d) from 1- (4-anino-3-bromo-5-cyanophenyl) -2-isopropylaminoethanol 3a from catalytically activated hydrogen.

Example 101 1- (14-Amino-3-cyano-phenyl) -2-tert. -butylamino-ethanol Melting point: 181-185 ° C.

Prepared according to Example 16 by method d) from 1- (4-amino-3-bromo-1-cyano-phenyl) -2-tert-butylamino-ethanol and catalytic activated hydrogen.

Example 102 1- (4-Amino-3-cyano-phenyl) -2-dimethylamino-ethanol Melting point of the dihydrochloride: 130-133 ° C (decomposes).

Prepared according to Example 16 by process d) 1 - C * + - a.m ± n - -3 - bromo-5-cyano- (phenyl) -2-dimethylaminoethanol using catalytic activated hydrogen.

Example 103 1- (4-Amino-3-cyano-phenyl) -2-diethylamino-ethanol

Prepared according to Example 16 by method d) from 1- (1+ bromo-5-cyanophenyl) -2-diethylaminoethanol and catalytically activated hydrogen.

"Oil; Elemental analysis: C., H.P N.0 (233.3) li i 3 'ÖaskeHu: C 67.00 H 8.20 N 18.00

Found: 67.00 8.40 17.81.

51

Example 104 62052 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol_

Melting point of hydrochloride: 205-207 ° C (decomposes). Prepared according to Example 8 by method c) from 2-tert-butylamino-1-C3-chloro-4- (p-chlorobenzoylamino) -5-trifluoromethylphenyl} ethanol and sodium hydroxide.

Example 105 1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol.

Melting point of hydrochloride: 196-197 ° C (decomposes). Prepared according to Example 7 by method c) from 1- (4-benzoylamino-3-fluoro-phenyl) -2-tert-butylamino-ethanol and sodium hydroxide.

Example 106 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol

Melting point of hydrochloride: 206-208 ° C (decomposes). Prepared according to Example 7 by method c) from 2-tert-butylamino-1- (3-chloro-5-fluoro-4-propionylamino-phenyl) -ethanol and sodium hydroxide.

Example 107 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-cyclopentylamino-ethanol_

Melting point: 100-102.5 ° C (decomposes), prepared according to Example 2 by a) 4'-amino-3'-bromo-2-cyclopentylamino-5'-trifluoromethylacetophenone hydrochloride and sodium borohydride.

Example 108 1- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclopropylamino-ethanol 52 62052 3 g of sodium borohydride are added to a solution containing 7.5 g of 4'-amino-31-bromo-5 ' -cyano-2-cyclopropylamino-acetophenone, 200 ml of tetrahydrofuran and 100 ml of water, and stirred for one hour; the excess sodium borohydride is decomposed by adding acetone. The insolubles are filtered off and the solvent is distilled off in vacuo; the residue is dissolved in hot isopropanol. Addition of isopropanol-containing hydrochloric acid gives 1- (4-amino-3-bromo-5-cyano-phenyl) -2-cyclopropylamino-ethanol hydrochloride, which is recrystallized from isopropanol. Melting point: 190-193 ° C (decomposes).

Example 109 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol a) 20 g of 4'-amino-3'-bromo-5'-fluoroacetophenone are dissolved in 300 ml. of chloroform. While stirring, a solution of 4.3 ml of bromine in 20 ml of chloroform is slowly added dropwise with stirring. When the addition is complete, stir for an additional 5 minutes at reflux temperature and then cool to room temperature. A mixture of 15 g of cyclobutylamine and 14 ml of triethylamine is further added dropwise to a crude solution of 4'-amino-3 ', 2-dibromo-5'-fluoroacetophenone with stirring and ice-cooling. After the addition, heat at reflux for 2 hours. After cooling, it is washed with water and the organic phase is evaporated to dryness in vacuo. The residue is crude 4 1 -amino-3 '- * bromo-2-cyclobutylamino-5'-fluoroacetophenone.

b) The crude ketone obtained in a) is dissolved in 30 ml of tetrahydrofuran. To the solution is added 5 ml of water, followed by the portionwise addition of 4.5 g of sodium borohydride under stirring and ice-cooling. The solution is stirred under cooling for 3 hours and then allowed to stand at room temperature overnight. The excess sodium borohydride is then decomposed with acetone and the solution is evaporated to dryness in vacuo. The residue is partitioned between water and chloroform, the organic phase is extracted three times with 100 ml of 2N hydrochloric acid, the combined hydrochloric acid extracts are made alkaline with sodium hydroxide and extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The remaining crude 1- (4-amino-3-bromo-5-fluorophenyl) -2-cyclobutylamino-ethanol residue is dissolved in isopropanol and acidified to pH 5 with ethereal hydrochloric acid. Crystallization occurs upon addition of ether. The separated hydrochloride of the desired compound is recrystallized from isopropanol. Melting point: 164-166 ° C (decomposes).

Example 110 1- (4-Amino-3-bromo-5-iodo-phenyl) -2-isopropylamino-ethanol hydrochloride 5.15 g of 1- (4-amino-3-fluoro-phenyl) -2-isopropylamino-ethanol dissolved in 300 ml of acetic acid, 80 g of iodine and 4.0 g of mercuric oxide are added and the mixture is stirred vigorously at room temperature for 2.5 hours. The solids are then filtered off, the dark brown filtrate is decolorized with saturated sodium hydrogen sulfite solution and diluted with water to about 1 liter. Make alkaline with 10η of sodium hydroxide and cooling and extract with chloroform. The chloroform phase is dried over sodium sulfate and evaporated to dryness in vacuo. The residue is dissolved in methanol and acidified to pH 4.5 with ethereal hydrochloric acid. The solution is evaporated to dryness in vacuo and the solid residue is crystallized from absolute ethanol. Melting point: 203-205 ° C (decomposes).

Example 111 1- (4-Amino-3-diethylaminomethyl-phenyl) -2-tert-butylamino-ethanol 6.0 g of 1- (4-acetylamino-3-diethylaminomethyl-phenyl) -2-tert-butylamino-ethanol boil at reflux for 35 hours in a mixture of 50 ml of ethanol and 50 ml of 4N sodium hydroxide. The ethanol is then distilled off, diluted with water and extracted twice with chloroform. The organic phase is dried over sodium sulfate and evaporated. Purify by column chromatography (silica gel} methanol) and crystallize 1- (4-amino-3-diethylaminomethylphenyl) -2-tert-butylaminoethanol from petroleum ether. Melting point: 86-90 ° C.

54

Example 112 62052 1- (4-Amino-3-cyano-phenyl) -2-cyclopropylamino-ethanol 4 g of 1- (4-amino-3-bromo-5-cyano-phenyl) -2-cyclopropylamino-ethanol are dissolved in methanol and is hydrogenated at room temperature and under hydrogen pressure of 3-5 aty after adding 1 g of palladium on carbon (10%). After hydrogen consumption has ceased, the catalyst is filtered off, the filtrate is evaporated to dryness in vacuo and the residue is partitioned between dilute sodium hydroxide and chloroform. Evaporation of the chloroform phase gives 1- (4-amino-3-cyanophenyl) -2-cyclopropylaminoethanol as an oil which is purified by chromatography on silica gel (eluent: chloroform: methanol = 9: 1) and crystallized from isopropanol as the dihydrochloride by adding ethereal hydrochloric acid . Melting point: 148-151 ° C (decomposes).

Example 113 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclopentylamino-ethanol

Melting point of hydrochloride: 167-170 ° C (decomposes). Prepared according to example 109 by method a) from 4'-amino-3'-bromo-2-cyclopentylamino-5'-fluoroacetophenone and sodium borohydride.

Example 114 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclohexylamino-ethanol.

Melting point of hydrochloride: 191-195 ° C (decomposes). Prepared by method a) according to Example 109 from 4'-amino-3'-bromo-2-cyclohexylamino-5'-fluoroacetophenone and sodium borohydride

Example 115 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cycloheptylamino-ethanol

Hydrochloride melting point: 187-189 ° C (decomposes). Prepared according to Example 109 by a) 4'-amino-31-bromo-2-cycloheptylamino-5'-fluoroacetophenone and sodium borohydride.

55 62052

Example 116 1- (4-Amino-3-fluoro-5-iodo-phenyl) -2-cyclopropylamino-ethanol Melting point of the hydrochloride: 199-201 ° C (decomposes).

Prepared according to Example 109 by method a) from 4, -amino-2-cyclopropylamino-3'-fluoro-5'-iodoacetophenone and sodium borohydride,

Example 117 1- (4-Amino-3-fluoro-5-iodo-phenyl) -2-isonropylamino-ethanol Melting point of the hydrochloride: 203-205 ° C (decomposes).

Prepared according to Example 109 by method a) from 4'-amino-31-fluoro-2-isopropylamino-5'-iodoacetophenone and sodium borohydride.

Example 118 1- (H-Amino-3-fluoro-5-iodo-phenyl) -2-cyclobutylamino-ethanol Hydrochloride melting point: 197-199 ° C (decomposes).

Prepared by method a) according to Example 109 from 4'-amino-2-cyclobutylamino-31-fluoro-5'-iodoacetophenone and sodium borohydride.

Example 119 '1- (4-Amino-3-fluoro-5-iodo-phenyl) -2-tert. -butylaminoethanol Melting point of hydrochloride: 207-209 ° C (decomposes).

Prepared according to Example 109r by method a) from 4'-amino-2-tert-butylamino-3'-fluoro-5'-iodoacetophenone and sodium borohydride.

filtration rate 120 l - (4-amino-3-fluoro-5-iodophenyl) -2- (hydroxy-tert-butylamino) -ethanol ________ 56 62052

Melting point of hydrochloride: 200-202 ° C (decomposes).

Prepared according to Example 111 by method a) from 41-amino-31-fluoro-2- (hydroxy-tert-butylamino) -5'-iodoacetophenone and sodium borohydride.

Example 121 2-Ethylamino-1- (4-amino-3-cyano-5-fluoro-phenyl) -ethanol Hydrochloride melting point: 216-218 ° C (decomposes).

Prepared by method a) according to Example 109 from 2-ethylamino-4'-amino-3'-cyano-5'-fluoroacetophenone and sodium borohydride.

Example 122 1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-cyclopropylamino-ethanol Melting point of the hydrochloride: 188-190 ° (decomposes).

Prepared according to Example 109 by a) 4'-amino-3'-cyano-2-cyclopropylamino-51-fluoroacetophenone and sodium borohydride.

Example 123 1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-isopropylamino-ethanol Melting point of hydrochloride: 182-184 ° C (decomposes).

Prepared according to Example 109 by method a) from 4, -amino-3'-cyano-5'-fluoro-2-isopropylaminoacetophenone and sodium borohydride.

Example 124 N - [(Amino-3-cyano-5-fluoro-phenyl) -2-cyclobutylamino-ethanol Hydrochloride melting point: 222-224 ° C (decomposes).

Prepared according to Example 109 by method a) 4 '** amino-3'-cyano-2-cyclobutylamino-51-fluoroacetophenone and sodium borohydride.

Example 125 57 6 2 0 5 2 1- (k-amino-3-cyano-5-fluorophenyl) -2-tert-butylaminoethanol Hydrochloride melting point: 2k2-2k3 ° C (decomposes).

Prepared according to Example 109 by method a) from k'-amino-2-tert-butylamino-3 * -cyano-5'-fluoroacetophenone and sodium borohydride.

Example 126 1- (k-Amino-3-cyano-5-fluoro-phenyl) -2-cyclopentylamino-ethanol Hydrochloride melting point: 18k-186 ° C (decomposes).

Prepared according to Example 109 by method a) 4'-amino-3'-cyano-2-cyclopentylamino-5'-fluoroacetophenone and sodium borohydride.

Example 127 1- (k-Amino-3-cyano-5-fluoro-phenyl) -2-tert-pentylamino-ethanol Hydrochloride Melting point: 172-175 ° C (decomposes).

Prepared according to Example 109 by method a) from k'-amino-3'-cyano-5 * -fluoro-2-tert-pentylaminoacetophenone and sodium borohydride.

Example 128 1- (k-Amino-3-cyano-5-fluoro-phenyl) -2-dimethylamino-ethanol

Prepared according to Example 109 by method a) from 1-amino-31-cyano-2-dimethylamino-51-fluoroacetophenone and sodium borohydride.

oil, structure indicated by NMR spectrum (CD-OD): 2.2 to 2.65 ppm

h OH

Ι'ί,,, l_ multitflet, / 8 protons, N-CH 2 and N-CH-Cl - ^ - N v /; k, 6 - k, 9 ppm 58 6 2 0 5 2

OH

multiplet, / 4 protons; 3 exchange protons and -CH-CH 2 -NX 2; 7.15 - 7.4 ppm raultiplet (2 aromatic protons).

Example 129-1- (u-Amino-3-cyano-5-fluoro-phenyl) -2-diethylamino-ethanol

Prepared according to Example 109 from method 1'-amino-3'-cyano-2-diethylamino-5'-fluoroacetophenone and sodium borohydride.

Oil, structure shown by NMR spectrum (CD 2 OD): 0.35 to 1.2 ppm tri silicon, / 6 protons; -N (CH 2 -C 13) 2 H; 2.45 to 2.85 ppm multiplet / S proton, -N (CH2-Cl3) 2 and -CH-CH2-NC I '> 4.5 to 4.35 ppm singlet

OH

i and triplet / 4 protons; 3 exchange protons and -Cri - Crl2- /; 7.1 to 7.4 ppm multiplet (2 aromatic protons).

Example 130 1- (4-Amino-3-trifluoromethyl-phenyl) -2- (cyclopropylmethyl-amino) -ethanol __________

Hydrochloride melting point: 122-127 ° C (decomposes; stains from 110 ° C)

Prepared according to Example 112 by method d) from 1- (4-amino-3-bromo-5-trifluoromethyl-phenyl) -2- (cyclopropylmethylamino) -ethanol and catalytic activated hydrogen.

Example 131 1- (4-Amino-3-trifluoromethyl-phenyl) -2-cyclopentylamino-ethanol Hydrochloride melting point: 144-145 ° C.

Prepared according to Example 112 by method d) 1- (4-amino-3-bromo-5-trifluoromethyl-phenyl) -2-cyclopentylamino-ethanol and catalytic activated hydrogen.

Example 132 '62052 59 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2- (cyclopropylmethylamino) -ethanol __________

Melting point of hydrochloride: 186-187 ° C (decomposes).

Prepared by method a) according to Example 108 from 4'-amino-3'-chloro-2- (cyclopropylmethylamino) -5'-trifluoromethylacetophenone and sodium borohydride.

Example 133 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclopentylamino-ethanol ____.

Melting point of hydrochloride: 188-190 ° C (decomposes).

Prepared according to Example 108 by method a) from 4'-amino-3'-chloro-2-cyclopentylamino-5'-trifluoromethylacetophenone and sodium borohydride.

Example 134 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclohexylamino-ethanol __________________

Melting point of the hydrochloride: 213-124 ° C (decomposes).

Prepared according to Example 108 by a) 4'-amino-3'-chloro-2-cyclohexylamino-5'-trifluoromethylacetophenone and sodium borohydride.

Example 135 1- (k-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cycloheptylamino-ethanol __________ 'Melting point of the hydrochloride: 163-165 ° C.

Prepared according to Example 108 by method a) from 4'-amino-3'-chloro-2-cycloheptylamino-5'-trifluoromethylacetophenone and sodium borohydride.

60

Example 136 62052 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2- (cyclopropylethyl-amino) -ethanol _______________

Melting point of hydrochloride: 173-175 ° C (decomposes).

Prepared according to Example 108 by method a) k'-amino-3 '♦ * bromo-2- (cyclopropylmethylamino) -51-trifluoromethylacetophenone and sodium borohydride.

Example 137 Melting point of 1- (k-amino-3-cyanophenyl) -2-cyclobutylamino-ethanol bromide: decomposes at 193 ° C.

Prepare according to Example 108 by method d) 1-Cu-amino (2-bromo-5-cyano-phenyl) -2-cyclobutylamino-ethanol and catalyst from activated hydrogen.

Example 138_ 1- (c-Amino-3-cyano-phenyl) -2-cyclopentylamino-ethanol

Melting point: 158-160 ° C.

Prepared according to Example 108 by method d) 1- (4-arino-3-bromo-5-cyano-phenyl) -2-cyclopentylaninool from ethanol and k from analytically activated hydrogen.

E s im e rkl i 139 1 - (k - a m i n o - 3 - s y a n i - fa n y y 1 ij> -2-tert. -Per, styliar.lnc - ύ t ar o 1:

Melting point: Ik3 ° C.

Prepared according to Example 108, seas el m "11" e) 1 - (! I -,: r m no-3 -., Iron: - O-syar.i-f eny-Ί i) - 2-tert. -pentyl emi no-at -:. 0 'and l.at ai ^ · * 4-! i - ‘v.

: seribi 'is activated. hydrogen.

Eslmerkt i | 140 1- (· Ί -a;: tinc-3 - ?: loorl-S - cyano-f er.yy 1 i) - 2-cylooproxy-1-ethanol 61 62052

Melting point of the hydrochloride: 175-177 ° C.

Prepared according to Example 108 'by method a) from 4'-amino-3'-chloro-5'-cyano-2-cyclopropylarinoacetophenone and sodium borohydride.

Example 141 1- (U-Amino-3-chloro-5-cyano-phenyl) -2-propylamino-ethanol Melting point of the hydrochloride: 187-189 ° C.

Prepared according to Example 108 by method a) from 4'-amino-3'-chloro-5'-cyano-2-propylaminoacetophenone and sodium borohydride.

Example 142 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclobutylamino-ethanol Melting point of the hydrochloride: 178-180 ° C (decomposes).

Prepared according to Example 108 by method a) 4'-amino-3'-chloro-5'-cyano-2-cyclobutylaminoacetophenone and sodium borohydride.

Example 143 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-sec-butylamino-ethanol Melting point of the dihydrochloride: 190-191 ° C.

Prepared according to Example 108 by method a) from 4'-amino-2-sec-butylamino-3'-chloro-51-cyanoacetophenone and sodium borohydride.

Example 144, 1- (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert-butylamino) -N: ethanol T __>

Mp of the hydrochloride: 228-230 ° C (decomposes).

Prepared according to Example 108 by method a) from 4'-amino-3'-chloro-5'-cyano-2- (hydroxy-tert-butylamino) -acetophenone and. /. '"\ 62 62052 n at r i umbo or ihyd r i d i c t ä.

Example 145 Melting point of 1- (H-amino-3-chloro-5-cyanophenyl) -2-cyclopentylaminoethane hydrochloride: 138-144 ° C.

Prepared according to Example 108 by method a) from 4'-amino-3'-chloro-5'-cyano-2-cyclopentylaminoacetophenone and sodium borohydride.

Example 146 Melting point of 1- (4-amino-3-chloro-5-cyanophenyl) -2-tert-pentylaminoethanol hydrochloride: 213-220 ° C (decomposes).

Prepared according to Example 108 by method a) 4'-amino-3'-chloro-5'-cyano-2-tert-pentylaminoacetophenone and sodium borohydride.

Example 147 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cycloheptylamino-ethanol Hydrochloride melting point: 2 3 5-237 ° C (decomposes).

Prepared according to Example 108 from "a) 4 * -amino-3H-chloro-5'-cyano-2-cycloheptylamino-acetophenone and sodium borohydride].

Example 148 1- (4-Amino-3-chloro-5-cyano-phenyl) -2- [1- (3,4-methylenedioxy-phenyl) -2-propyl] -pyrene i no7 - e t an o 1 i_________ hydrochloride melting point: 189-192 ° C. Prepared according to Example 108 by method a) 4'-α-amino-3'-chloro-5'-cyano-2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] -acetophenone and sodium hydrochloride.

Example 149 63 62052 1- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclobutylamino-ethanol Melting point of hydrochloride: 215-216 ° C (decomposes).

Prepared according to Example 108 by method a) from 4'-amino-3'-bromo-5'-cyano-2-cyclobutylaminoacetophenone and rhodium borohydride.

Example 150 1 - (, 1-Amino-3-bromo-5-cyano-phenyl) -2- (hydroxy-tert-butylamino) -ethanol _______

Melting point of the hydrochloride: 221-222 ° C.

Prepared by the method of Example 108 a) from M 1 -amino-3'-bromo-5'-cyano-2- (hydroxy-tert-butylamino) -acetophenone and sodium borohydride.

Example 151 1- (U-Amino-3-bromo-5-cyano-phenyl) -2-cyclopentylamino-ethanol Hydrochloride melting point: 177 ° C.

Prepared according to Example 108 from M'-amino-31-bromo-5'-cyano-2-cyclopentylaminoacetophenone and sodium borohydride.

Example 152 1- (H-Amino-3-bromo-5-cyano-phenyl) -2-tert-pentylamino-ethanol Hydrochloride melting point: 202-20 * 4 ° C (decomposes).

Prepared according to Example 108 by method a) from 4-1-amino-3 * -bromo-51-cyano-2-tert-pentylaminoacetophenone and sodium borohydride.

64 6 2 0 5 2

Example 153 1- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclohexylamino-ethano3.1 Melting point of hydrochloride: 209-210 ° C (decomposes).

Prepared according to Example 108 by method a) from 4'-anino-3'-bromo-5'-cyano-2-cyclohexylaminoacetophenone and sodium borohydride.

Example 154 Melting point of 1- (4-amino-3,5-dicyanophenyl) -2-cyclopropylaminoethanol hydrochloride: 22-223 ° C (decomposes).

Prepared according to Example 108 by method a) from 41-amino-2-cyclopropylamino-3 ', 5'-dicyanoacetophenone and sodium borohydride.

Example 155 1- (4-Anino-3,5-diacyano-phenyl) -2-isopropylamino-ethanol Melting point of the hydrochloride: 224-226 ° C (decomposes).

Prepared according to Example 108 by method a) from 4'-amino-3 ', 5'-dicyano-2-isopropylaminoacetophenone and sodium borohydride.

Example 156 1- (4-Amino-3,5-diacyanophenyl) -2-cyclobutylaminoethanol Hydrochloride melting point: 258 ° C (decomposes).

Method 11 'is prepared according to Example 108. a) 4'-Amino-2-cyclobutylamino-3 ', 5 * -dicyanoacetophenone and sodium ibor or ihyc.

'F? Melting point of 1- (4-amino-3,5-dicyanophenyl) -2-sec-butylaminoethanol hydrochloride: 197-199 ° C.

65 62052

Prepared according to Example 108 by method a) 4'-arir.o-2 sec. -butylamino-3 ', 5'-dicyanoacetophenone and sodium borohydride d1 πΐΊ.

Example 158 1- (4-Amino-3,5-dicyano-phenyl) -2-tert-butylamino-ethanol Melting point of the hydrochloride: 251-253 ° C (decomposes).

Prepared according to Example 108 by method a) from 4'-anino-2-tert-butylamino-31,5'-dicyanoacetophenone and sodium borohydride.

Example 159 1- (4-Amino-3,5-dicyano-phenyl) -2- (hydroxy-tert-butylamino) -ethanol _______

Melting point of the hydrochloride: 240-241 ° (decomposes).

Prepared according to Example 108 by method a) 4'-tinc-S ', dicyano-2- (hydroxys-tert-butylamino) acetone from enone and sodium borohydride.

Example 160 1- (4-Amino-3,5-dicyano-phenyl) -2-cyclopentylamino-ethanol Melting point of the hydrochloride: 214-216 ° C.

Prepared according to Example 108 by method a) from 4 'trans-2-cyclopentylamino-3', 5'-dicyanoacetophenone and sodium unboor dihydride.

Example 161 1- (4-Amino-3,5-dicyano-phenyl) -2-tert-pentylamino-ethanol, F-. λ '' • 'Melting point of solid chloride: 231-233 C (decomposes).

Prepared by method a) according to Example 108 from 4'-amino-3,5'-dicyano-2-tert-pentylaminoacetophenone and sodium borohydride.

Example 162 6 2 05 2 66 1- (4-Amino-3,5-dicyano-phenyl) -2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] -ethanol]

Melting point of hydrochloride: 219-222 ° C (decomposes). Prepared according to Example 108 by method a) from 4'-amino-3 ', 5'-dicyano-2- (3,4-methylenedioxy-phenyl) -2-propylamino] -acetophenone and sodium borohydride.

Example 163 1- (4-Amino-3-chloro-5-diethylaminomethyl-phenyl) -2-tert-butyl-amino-ethanol_

Melting point: 65-69 ° C. Prepared according to Example 108 by method a) from 4'amino-2-tert-butylamino-3'-chloro-5-diethylaminomethyl-acetophenone and sodium borohydride.

Example 164 1- (4-Amino-3-bromo-5-diethylaminomethyl-phenyl) -2-tert-butylamino-ethanol__

Melting point: 96-100 ° C. Prepared according to Example 108 by a) 4'-amino-31-bromo-2-tert-butylamino-5'-diethylaminomethylacetophenone and sodium borohydride.

Example 165 1- (4-Amino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol

Melting point: 148-149 ° C. Prepared according to Example 108 by method a) from 4'-amino-2-tert-butylamino-3 * -chloro-5'-nitroacetophenone and sodium borohydride.

Example 166 1- (4-Amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol # 62052

Melting point: 151-152 ° C. Prepared according to Example 108 by method a) from 4'-amino-3'-bromo-2-tert-butylamino-5'-nitroacetophenone and sodium borohydride.

Example 167 1-1- (4-Amino-3 · * fluoro-phenyl) -2-tert. -butylaminoethanol and 1-1- (4-amino-3-fluorophenyl) -2-tert. -butylanin ·: -ethanol.___ a) 1-1- (H-Acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) -amino- O- (N-carbobenzoxy, -L-alanyl) -ethanolx and d-1-α-acetylamino-3-fluorophenyl) -2- (N-benzyl-N-tert-butyl) - amino-O-Q1-carbobenzoxy-L-alanyl) -ethanol _

To a solution of 15 g of N-carbobenzoxy-L-alanine and 300 l of absolute tetrahydrofuran is added 14.5 g of N, N'-carbonyldiimidazole and stirred at room temperature for 3 hours. A solution of 10 gd of 1-1- (4-acetylamino-3-fluorophenyl) -2- (N-benzyl-N-tert-butyl) aminoethanol in 200 ml of absolute tetrahydrofuran is then added, and pea-sized piece of sodium and stir at room temperature for 12 days. It is then evaporated to dryness in vacuo and the residue is partitioned between chloroform and water. The chloroform phase is dried over sodium sulfate and evaporated to dryness in vacuo. The two diastereomeric esters thus obtained in the mixture have different Rf values in thin-layer chromatography (silica gel G, Merck; chloroform: acetone = 10: 1).

The above evaporation residue is purified on a silica gel chromatography column without separating the diastereomeric esters. (500 g of silica gel; eluent: chloroform: acetone = 10: 1).

The fractions containing the compound are evaporated to dryness in vacuo and recrystallized from ether. Colorless crystals are obtained which are pure 1-1- (4-acetylamino-3-fluorophenyl) -2- (N-benzyl-N-tert-butyl) amino-O- (N-carbobenzoxy-L-alanyl) ) ethanol.

[.alpha.] D @ 20 = -101 DEG (c = 2.0; methanol); Rf value = 0.27

The mother liquor obtained above is evaporated to dryness in vacuo. The diastereomeric ester with a higher Rf value (Rf = 0.33) is isolated on a chromatography column (100 g of silica gel; eluent: chloroform: acetone = 20: 1): Colorless oil which is dl- ( 4-acetylamino-3-fluoro-phenyl) -2-n-benzyl-n-tert-butyl) amino-0- (n-carbobenzoxy-L-alanyl) ethanol.

[.alpha.] D @ 20 = -65 DEG (c = 2.0; methanol); Rf value = 0.33.

b) 1-1- (N-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol 2 g of 1--1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl) -N-tert-butyl) -amino-O- (N-carbobenzoxy-L-alanyl) -ethanol is dissolved in 60 ethanol. To the solution is added 20 ml of 5N sodium hydroxide and heated at reflux for U hours. After cooling, partition between chloroform or water and extraction of the aqueous phase four more times with chloroform. The combined chloroform solutions are dried over sodium sulfate and evaporated to dryness in vacuo. The residue, 1- (1- (4-amino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) -aminoethanol, is dissolved in 50 ml of methanol and acidified to pH 6 with ethanolic hydrochloric acid. Add 0.2 g of palladium on carbon (10%) and stir in a Parr apparatus at room temperature and 5 atm. under pressure until no more hydrogen is consumed. The catalyst is filtered off with suction, evaporated to dryness in vacuo and the solid residue which is 1-1- (4-amino-3-fluoro-phenyl) -β-tert-butylamino-ethanol hydrochloride is crystallized from isopropanol by adding ether.

Melting point; 199-200 ° C (decomposes) [α] 25 D = -123.3 ° (c = 1.0; methanol).

e) d-1- ('1-amino-5-fluorophenyl) -2-tert-butylaminoethanol

The oily dl- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) -amino-O- (N-carbobenzoxide-L-alanyl) -ethanol obtained above is dissolved in nothing. ethanol. To the solution is added 10 ml of 5N sodium hydroxide and heated for 4 hours at reflux temperature. between water and the aqueous phase is extracted four more times with chloroform. The combined chloroform solutions are dried over sodium sulfate and evaporated to dryness in vacuo. The residue, which is dl- (4-amino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) -aminoethanol, is dissolved in any 69,62052 methanol and acidified to pH 6. ether end with another hydrochloric acid. Add 0.1 g of palladium on carbon (10%) and hydrogenate in a Parr apparatus at room temperature and 5 atmospheres until no more hydrogen is consumed. The catalyst is filtered off with suction, evaporated to dryness in vacuo and the solid residue, d-1- (4-amino-3-fluorophenyl) -2-tert. -butylamino-ethanol hydrochloride.i. crystallized from isopropanol by adding ether.

Melting point: 198-200 ° C (decomposes).

Δ 364 = + 124.4 ° (c = 1.142; methanol).

Example 168 dl- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butyl-amino-ethanol and 1-1- (4-amino-3-chloro-5-trifluoromethyl- phenyl) -2-tert. -butylamino-ethanol ______________ a) d, 1- (1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-O - [(-) - methoxycarbonyl] -ethanol __________

To a solution of 8.8 gd of 1-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol in 50 ml of pyridine is added dropwise with stirring and at 20 ° C: 56.5 ml of a 0.5 molar solution of chloroformic acid - (-) - menthyl ester in toluene. After two hours, the solution is evaporated to dryness in vacuo. The oily residue is first triturated with water and taken up in ether after decanting the supernatant solution. The ether solution is washed successively with water, 2N ammonia (whereby the precipitate precipitated between the phases dissolves) and again with water. The ether solution, dried over magnesium sulphate, is adjusted to pH 6 with 4N hydrochloric acid in isopropanol. In this case, a mixture of the hydrochlorides of said diastereomeric compounds crystallizes. Separate with suction and wash with ether.

For thin layer chromatography, silica gel G, Merck, butyl acetate: cyclohexane = 9: 1, the crystals are found to have two equal t “n- ..s with Rf values of about 0.45 and 0.55.

B) d- and 1-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-O-Z (-) - menthoxycarbonyl-117- Separation of ethanol__ 70 6 2 0 5 2 D- and 1-1- (4-amino-3-chloro-trifluoromethyl-phenyl) -2-tert-butylamino-O - [(-) - menthoxycarbonyl] -ethanol the mixture of hydrochlorides cdell · 'is suspended in 3.0 g of a small amount of water, covered with ether, 5.0 ml of 2N ammonia are added and shaken until all is dissolved. The ether phase is separated, washed with water, dried over magnesium sulphate and evaporated in vacuo, the oily residue is chromatographed (flow rate 120 ml / hour) on a silica gel column (diameter 6.5 cm, length 107 cm, silica gel 2.2 kg) using butyl acetate (hexane : 1). The fractions of pure compound with an Rf value of 0.55 are combined and the solvent is removed in vacuo. The residue is crystallized from petroleum ether (b.p. 40-60 ° C). There is obtained d-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-O-Li-) -nentoxycarbonyl] -ethanol.

Melting point 95.5-96.5 ° C

[α] 25 D = + 74.1 ° (c = 1.0; chloroform).

After separating the fractions containing the mixture of diastereomeric compounds and carrying out the second chromatographic separation, the fractions containing the pure solid with an Rf value of 0.45 are combined and evaporated in vacuo. After recrystallization once from petroleum ether, chromatographically pure 1-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-O - [(-) - menthoxycarbonyl is obtained. / ethanol. Melting point: 102-104 ° C.

/ a / 364 = _273> 3 ° = chloroform).

c) dl- (4-Amino-3-chloro-5-trifluoromethyl-3-phenyl) -2-tert-butylamino-ethanol ____ 1.6 g of d-] - (4-amino-3-chloro-5 -trifluoromethyl-phenyl) -2-tert. β-Ethylamino-O-Z (-) - menthoxycarbonyl] ethanol is dissolved in 16 ml of methanol and allowed to stand for 65 hours at about 20 ° C. Evaporate in vacuo and purify the residue by column chromatography (silica gel; chloroform-methanol: concentrated ammonia = 90: 10: 1). The residues of the desired residue are combined and evaporated in vacuo. The residue is dissolved in ethyl acetate, and a calculated amount of 4N hydrochloric acid in isopropanol is added to the solution, whereby the hydrochloride of said compound crystallizes.

71 620 5 2

Melting point: above 194 ° C, decomposes slowly.

/ a / 364 s +151+ »90 (c = i» 0 »methanol).

d) 1-1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol

Prepared from 1.58 g of 1-1- (4-amino-3-chloro-5-trifluoroxymethyl-phenyl) -2-tert-butylamino-O - [(-) - menthoxy] carbonyl] carbonyl by solvolysis with methanol and purification by chromatography. The preparation takes place in the same way as in the example given for the enantiomeric compound,

Hydrochloride melting point: above 194 ° C, decomposes slowly.

[Α] D = -154.8 ° (c = 1.0; methanol).

Example 169 dl- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol and 1-1- (4-amino-3-bromo-5-fluoro-phenyl) -2 -tert-butylamino-ethanol 205 gd of 1-1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol and 118 g of dibenzoyl-D-tartaric acid are dissolved in 2.5 g of to a liter of hot ethanol, filter and allow to stand for one day at room temperature for crystallization. The product obtained is recrystallized six times from methanol-ether to give pure d-N- (α-amino-3-bromo-5-fluorophenyl) -2-tert. -butylamino-ethanol N-di-benzoyl-D-tartrate with a melting point of 206-208 ° C (decomposes).

[α] 25 D = * 332.9 ° (c = 2.0; methanol).

The salt is dissolved in methanol and concentrated ammonia by heating and the base is crystallized by adding water. The obtained base is dissolved in absolute ethanol, neutralized with absolute ethanolic hydrochloric acid, and crystallization of d-1- (4-amino-3-bromo-5-fluorophenyl) -2-tert-butylaminoethanol hydrochloride is completed by adding ether.

..j.PtulänSispiste: 234-235 ° C (decomposes).

/ a / 364 = +132> 0 ° (° = 2> ° »methanol).

72 62052

The salt is dissolved in methanol and concentrated ammonia by heating and the base is mixed with water. The base obtained is dissolved in absolute ethanol, neutralized with absolute ethanolic hydrochloric acid and 11- (4-amino-3-bromo-5-fluorophenyl) -2-tert-butylaminoethanol the hydrochloride is crystallized by adding ether. Melting point: 218-220 ° C (decomposes).

/ a / 36U = 133> 9 ° (c = 2 »°» »ethanol).

Example d-1- (H-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol

Hydrochloride melting point: 210-211 ° C (decomposes) / 0 ^ 364 = +139> 7 ° = 2.0; »Ethanol).

Prepared according to Example 175 by fractional crystallization of d, 1-1- (4-amino-3-chloro-5-fluorophenyl) -2-tert-butylaminoethanol from dibenzoyl D-tartrate.

l-L- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol

Hydrochloride melting point: 209-210 ° C (decomposes) 364 = -139> 2 ° = 2.0; methanol).

Prepared according to Example 175 from d, 1-1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol by fractional crystallization of di-benzoyl L-tartrate.

Example 171 d-1 - (- 4-Amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol

Melting point of the hydrochloride: 197-199 ° C (decomposes) [α] 25 D = +59> 9 ° (c = 2.0 * ethanol).

Prepared according to Example 175 by fractional crystallization of d, 1-1- (4-amino-3-chloro-5-cyanophenyl) -2-tert-butylaminoethanol from dibenzoyl D-tartrate.

73 6205 2 1-1- (U-amino-3-chloro-5-cyanophenyl) -2-tert. -butylamino-danol

Melting point of the hydrochloride: 199-202 ° C (decomposes) [α] 25 D -59.85 ° (c = 2.0; methanol).

Prepared according to Example 175 by fractional crystallization of d, l-1- (* + - amino-3-chloro-5-cyanophenyl) -2-tert-butylaminoethanol from dibenzoyl L-tartrate.

Example 172 d-1- (H-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol 0.26 g of dl- (4-amino-3-fluoro-phenyl) ) -2-tert-butylamino-ethanol hydrochloride and 0.2 ml of pyridine are dissolved in 30 ml of tetrahydrofuran and cooled to 0 ° C. 0.3 g of phenyl iodide chloride are added, kept at said temperature for 2 hours and 0.1 g of phenyl iodide chloride is added once more. After 20 hours at about 4 ° C, the solution is evaporated, partitioned between ethyl acetate and water, the aqueous extract is made alkaline with 2N ammonia and re-extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated to dryness in vacuo. The residue is dissolved in absolute ethanol, neutralized with ethanolic hydrochloric acid, and the hydrochloride of said compound is crystallized by adding ether.

Melting point: 210-211 ° C (decomposes).

/ a / 364 = +139 »6 ° <c = 2.0; methanol).

Example 173 dl - (* + - Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ebnol 0.26 g of dl- (t-amino-3-fluoro-phenyl) -2-tert-butylamino-ebnol , -butylamino-ethanol-lyl chloride is dissolved in 30 ml of 50% acetic acid and at 0-5 ° C 0.16 g of bromine dissolved in a mixture of 5 ml of glacial acetic acid and 1 ml of water are added dropwise, after 15 minutes the reaction mixture evaporated, the residue is dissolved in water, made alkaline with 2N ammonia and extracted with chloroform. The chloroform solution is dried over 74 62052 sodium sulfate and evaporated to dryness in vacuo. The residue is converted into the hydrochloride of said compound by dissolving in ethanol, neutralizing with ethanolic hydrochloric acid and adding ether.

Melting point: 234-235 ° C (decomposes).

364 = + 132.0 ° (c = 2.0; methanol).

Example 174 1- (4-Amino-3-cyano-phenyl) -2-cyclobutylamino-ethanol

Melting point of hydrobromide: from 193 ° C (decomposes).

Prepared according to Example 1 from 4'-amino-3'-cyano-3-cyclobutylaminoacetophenone hydrochloride and sodium borohydride.

The following compounds were prepared analogously: 1- (4-amino-3-cyano-phenyl) -2-tert-pentylamino-ethanol Melting point: 143 ° C.

1- (4-amino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol Melting point of the hydrochloride: 172-174 ° C (decomposes).

1- (4-amino-3-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol Melting point of hydrobromide: 174-175 ° C (decomposes).

Example 175 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol Melting point of the hydrochloride: 152-154 ° C (decomposes).

Prepared according to Example 4 from 1- (4-amino-3-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride and chlorine.

The following compounds were prepared analogously to Examples 4, 5 or 110: 1- (4-amino-3-chloro-5-fluorophenyl) -2-cyclopropylaminoethanol hydrochloride

Melting point: 175-177 ° C (decomposes).

75,620 5 2 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 206-208 ° C (decomposes).

1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol hydrochloride

Melting point: 187-188 ° C (decomposes).

L- (4-amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol The hydrochloride

Melting point: 171-173 ° C (decomposes).

L- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 207-208 ° C (decomposes).

1- (M-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 164-166 ° C (decomposes).

1- (4-Amino-3-fluoro-5-iodo-phenyl) -2-cyclopropylamino-ethanol hydrochloride

Melting point: 199-201 ° C (decomposes).

L- (4-amino-3-chloro-5-syani-phenyl) -2-propylamino-ethanol The hydro-chloride

Melting point: 187-189 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-sec-butylamino-ethanol dihydrochloride

Melting point: 190-191 ° C.

1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol Melting point: 125-133 ° C.

1R * (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert-butylamino) -ethanol hydrochloride

Melting point: 228-230 ° C (decomposes).

76 62052 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert-pentylamino-ethanol hydrochloride

Melting point: 218-220 ° C (decomposes).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol hydrochloride

Melting point: 138-144 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] -ethanol hydrochloride Melting point: 189-192 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 186-189 ° C.

1- (U-Amino-3-bromo-5-cyano-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 213-215 ° C.

1- (4-amino-3-bromo-5-syani-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 215-216 ° C (decomposes).

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol

Melting point: 104-106 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 205-207 ° C (decomposes).

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 177-178 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol hydrochloride

Melting point: 176-178 ° C (decomposes).

/ · Ο Γ 'K 9

77 O ^ LOZ

1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 177-179 ° C (decomposes).

1- (4-amino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol Melting point: 148-149 ° C.

1- (4-amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol Melting point: 1S1-152 ° C.

Example 176 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol Melting point of the hydrochloride: 152-154 ° C (decomposes).

Prepared according to Example 7 from 1- (4-acetylamino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride or according to Example 10 1- (4-amino-3-chloro-5-fluoro-phenyl) 2- (n-benzyl-n-isopropyl) amino-ethanol.

The following compounds were prepared analogously: 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride

Melting point: 175-177 ° C (decomposes).

L- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol hydrochloride

Melting point: 187-188 ° C (decomposes).

L- (4-amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 171-173 ° C (decomposes).

L- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 207-208 ° C (decomposes).

1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 164-166 ° C (decomposes).

78 6 2 C b 2 1- (4-Amino-3-fluoro-5-iodo-phenyl) -2-cyclopropylamino-ethanol hydrochloride

Melting point: 199-201 ° C (decomposes).

1- (U-Amino-5-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol hydrobromide

Melting point: 17H-175 ° C (decomposes).

1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol

Melting point: 10 * + - 106 ° C.

1- (U-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 205-207 ° C (decomposes).

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 177-178 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol hydrochloride

Melting point: 176-178 ° C (decomposes).

1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 177-179 ° C (decomposes).

Example 177 1- (4-Amino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol Melting point: 148-149 ° C.

Prepared according to Example 7 from 1- (4-acetylamino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol hydrochloride.

The following compounds were prepared analogously: 1- (4-amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol-Melting point: 151-152 ° C.

/ ^ r, c · ') 79

Example 178 1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol Melting point of the hydrochloride: 196-197 ° C (decomposes).

Prepared according to Example 14 from 1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol.

The following compound was prepared analogously: 1- (4-amino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol Hydrochloride melting point: 172-174 ° C (decomposes).

Example 179 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol 3.4 g of 1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) - 2-Bromoethanol is dissolved in 25 ml of tert-butylamine and allowed to stand for 20 hours at room temperature. The excess tert-butylamine is evaporated in vacuo and the residue is taken up in ether. The ether solution is washed with water, dried over magnesium sulphate and evaporated in vacuo. The evaporation residue is purified by chromatography on silica gel using chloroform-methanol: concentrated ammonia = 90: 10: 1 as the system. The combined fractions thus obtained, containing the desired compound, are evaporated to dryness in vacuo. The residue is dissolved in ether and the pH of the solution is adjusted to 4 by adding isopropanolic hydrochloric acid. The 1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride crystallizes out, which is filtered off with suction and washed with ether. Melting point: 205-207 ° C (decomposes).

Example 180 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol

Melting point of hydrochloride: 205-207 ° C (decomposes).

Prepared according to Example 185 by method f) 1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- (p-toluenesulfonyloxy) -azo 62052 and excess tert-butylamine.

The following compounds were prepared according to Examples 179 and 180: 1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride Melting point: 196-197 ° C (decomposes).

1- (U-amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 152-154 ° C (decomposes).

L- (4-amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride

Melting point: 175-177 ° C (decomposes).

1- (* + - Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 206-208 ° C (decomposes).

L- (9-amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol hydrochloride

Melting point: 187-188 ° C (decomposes).

L- (4-amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 171-173 ° C (decomposes).

1- (9-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 207-208 ° C (decomposes).

1- (> + - Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 164-1660C (decomposes).

1- (U-Amino-3-fluoro-5-iodo-phenyl) -2-cyclopropylamino-ethanol hydrochloride

Melting point: 199-201 ° C (decomposes).

1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 182-184 ° C (decomposes).

81 6 2 O 5 2 1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 242-243 ° C (decomposes).

1- (4-Amino-3-cyano-phenyl) -2-cyclobutylamino-ethanol hydrobromide Melting point from 193 ° C (decomposes).

1- (4-amino-3-cyano-phenyl) -2-tert-pentylamino-ethanol Melting point: 143 ° C.

L- (4-amino-3-chloro-5-syani-phenyl) -2-propylamino-ethanol hydro chloride

Melting point: 187-189 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-sec-butylamino-ethanol dihydrochloride

Melting point: 190-191 ° C.

1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol Melting point: 125-133 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert-butylamino) -ethanol hydrochloride

Melting point: 228-230 ° C (decomposes).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert-pentylamino-ethanol hydrochloride

Melting point: 218-220 ° C (decomposes).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol hydrochloride

Melting point: 138-144 ° C.

82 6 2 G 5 2 1- (4-Amino-3-chloro-5-cyano-phenyl) -2- [1- (3,1-methylenedioxy-phenyl) -2-propylamino] -ethanol hydrochloride Melting point : 189-192 ° C.

1- (H-Amino-3-bromo-5-cyano-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 186-189 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 213-215 ° C.

L- (4-amino-3-bromo-5-syani-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 215-216 ° C (decomposes).

L- (4-amino-3,5-disyani-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 251-253 ° C (decomposes).

1- (* + - amino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 172-174 ° C (decomposes).

L- (4-amino-3-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol hydrobromide

Melting point: 174-175 ° C (decomposes).

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 185-187 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 177-178 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol hydrochloride

Melting point: 176-178 ° C (decomposes).

83 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 177-179 ° C (decomposes).

62052 1- (4-amino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol Melting point: 148-149 ° C.

1- (4-amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol Melting point: 151-152 ° C.

Example 181 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride 1.5 g of 2-tert-butylamino-1- (3-bromo-5- fluoro-4-nitro-phenyl) -ethanol hydrochloride is dissolved in 40 ml of methanol. 0.6 g of platinum dioxide is added and the mixture is hydrogenated with shaking at room temperature and normal pressure until the theoretical amount of hydrogen has been consumed. The catalyst is removed and the solution is evaporated to dryness in vacuo. The crude solid 1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride residue is partitioned between 2N sodium hydroxide and methylene chloride. The organic phase is separated, washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residual oily residue is chromatographed on a chromatography column packed with 80 g of silica gel using a 10: 1 mixture of chloroform and methanol as eluent. The eluates containing the compound are combined and evaporated to dryness in vacuo. The residue is taken up in a small amount of isopropanol and acidified to pH 5 with ethereal hydrochloric acid. Crystallization occurs upon addition of a small amount of ether. The crystals are filtered off with suction and washed with a mixture of isopropanol and ether.

Melting point: 207-208 ° C (decomposes).

The following compounds were prepared according to Example 181: 1- [(4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point; 196-197 ° C (decomposes).

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 152-1S4 ° C (decomposes).

84 62052 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride

Melting point: 17S-177 ° C (decomposes).

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 206-208 ° C (decomposes).

1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol hydrochloride

Melting point: 187-188 ° C (decomposes).

1- (4-amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 171-173 ° C (decomposes).

1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 164-166 ° C (decomposes).

L- (4-amino-3-fluoro-5-iodo-phenyl) -2-cyclopropylamino-ethanol hydrochloride

Melting point: 199-201 ° C (decomposes).

1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 182-184 ° C (decomposes).

1- (4-amino-3-syani-5-fluoro-phenyl) -2-tert., butylamino-ethanol hydrochloride

Melting point: 242-243 ° C (decomposes).

1- (4-Amino-3-cyano-phenyl) -2-cyclobutylamino-ethanol hydrobromide Melting point: from 193 ° C (decomposes).

85 62052 1- (4-Amino-3-cyano-phenyl) -2-tert-pentylamino-ethanol

Melting point: 143 ° C.

1- (4-amino-3-chloro-5-syani-phenyl) -2-propyyliamiro-ethanol hydro-chloride.

Melting point: 187-189 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-sec-butylamino-ethanol dihydrochloride

Melting point: 190-191 ° C.

1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol Melting point: 125-133 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert-butylamino) -ethanol hydrochloride

Melting point: 228-230 ° C (decomposes).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert-pentylamino-ethanol hydrochloride

Melting point: 218-220 ° C (decomposes).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol hydrochloride

Melting point: 138-144 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] -ethanol hydrochloride

Melting point: 189-192 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-isopropylamino-ethanol hydrochloride Melting point: 186-189 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 213-125 ° C.

62052 1- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 215-216 ° C (decomposes), 86 1- (4-amino-3,5-dicyanophenyl) -2-tert-butylaminoethanol hydrochloride

Melting point: 251-253 ° C (decomposes).

1- (H-Amino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 172-174 ° C (decomposes).

1- (4-amino-3-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol hydrobromide

Melting point: 174-175 ° C (decomposes).

1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol

Melting point: 104-106 ° C.

1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert. -butylaminoethanol hydrochloride Melting point: 205-207 ° C (decomposes).

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 177-178 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol hydrochloride

Melting point: 176-178 ° C (decomposes).

1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 177-179 ° C.

of 620 5 2

Example 182 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol 4.8 g of 4-amino-3-bromo-5-fluoro-phenylglycolic acid tert-butylamide add to 100 ml of absolute ether containing 1.2 g of lithium aluminum hydride and heat at reflux for 2 hours with stirring. The excess lithium aluminum hydride is then decomposed with ethyl acetate, water and 2N sodium hydroxide are added and the phases are separated. The aqueous layer is extracted with chloroform and the combined organic phases are dried and evaporated in vacuo. The residue is purified by column chromatography on silica gel using chloroform-methanol: concentrated ammonia = 90: 10: 1 as the system. The evaporation residue of the fractions containing the compound is dissolved in isopropanol and acidified to pH 5 with ethereal hydrochloric acid. Crystallization occurs upon addition of ether. The separated hydrochloride of the desired compound is recrystallized from isopropanol. Melting point: 207-208 ° C (decomposes).

According to Example 182, the following compounds were prepared: 1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 196-197 ° C (decomposes).

1- (4-amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 152-154 ° C (decomposes).

L- (4-amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride

Melting point: 175-177 ° C (decomposes).

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 206-208 ° C (decomposes).

88 62052 1- (4-amino-3-chloro-5-fluorophenyl) -2-tert. -päätyyliamino-ethanol The hydrochloride

Melting point: 187-188 ° C (decomposes).

1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 171-173 ° C (decomposes).

L- (4-amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 164-166 ° C (decomposes).

1- (H-Amino-3-fluoro-5-iodo-phenyl) -2-cyclopropylamino ** ethanol hydrochloride

Melting point: 199-201 ° C (decomposes).

1- (4-amino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 172-174 ° C (decomposes).

L- (4-amino-3-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol hydrobromide

Melting point: 174-175 ° C (decomposes).

L- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol

Melting point: 104-106 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 205-207 ° C (decomposes).

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 177-178 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol hydrochloride

Melting point: 176-178 ° C (decomposes).

89 6 2 0 5 2 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 177-179 ° C (decomposes).

Example 183 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol 4.2 g of 4-amino-3-bromo-5-fluoro-phenylglyoxylic acid tert-butyl -amide is added to 100 ml of absolute ether containing 0.75 g of ground lithium aluminum hydride, stirred mechanically and heated at reflux for 2 hours. Then 2.0 ml of water, 2.4 ml of 2N sodium hydroxide and 6.0 ml of water are carefully added successively to the reaction mixture. Separate with suction, wash the inorganic residue with chloroform and evaporate the combined filtrate in vacuo. The residue is purified by chromatography on a column of silica gel (eluent = chloroform: methanol: concentrated ammonia = 90: 10: 1). The evaporation residue of the desired crystals obtained by distilling off the solvent in vacuo is dissolved in isopropanol, ethereal hydrochloric acid is added to pH 5 and more ether is added. The crystallized hydrochloride of the above compound is filtered off with suction and recrystallized from isopropanol.

Melting point: 207-208 ° C (decomposes).

The following compounds were prepared according to Example 183: 1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 196-197 ° C (decomposes).

L- (4-amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 152-154 ° C (decomposes).

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride

Melting point: 175-177 ° C (decomposes).

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 206-208 ° C (decomposes).

90 oZOb z 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-pentylamino-ethanol hydrochloride

Melting point: 187-188 ° C (decomposes).

1- (4-amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 171-173 ° C (decomposes).

1- (9-amino-3-bromo-S-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 164-166 ° C (decomposes).

1- (4-amino-3-fluoro-5-iodo-phenyl) -2-cyclopropylamino-ethanol hydrochloride

Melting point: 199-201 ° C (decomposes).

1- (4-amino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 172-174 ° C (decomposes).

1- (4-amino-3-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol hydrobromide

Melting point: 174-175 ° C (decomposes).

1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-isopropylamino-ethanol

Melting point: 104-106 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 205-207 ° C (decomposes).

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 177-178 ° C.

91 6 2 ϋ 5 2 1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-pentylaminoethanol hydrochloride

Melting point: 176-178 ° C (decomposes).

1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 177-179 ° C (decomposes).

Example 184 1- (* 4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol ______ 3.5 g of 5- (4-amino-3-chloro-5-trifluoromethyl- phenyl) -3-tert-butyl-oxazolidone- (2) is dissolved in 13 ml of glacial acetic acid, 13 ml of 45% hydrobromic acid in glacial acetic acid are added at room temperature and allowed to stand for 1 hour. It is then poured onto ice, made alkaline with concentrated ammonia and extracted with ethyl acetate. The organic phase is extracted with 2N hydrochloric acid, the acidic solution is made alkaline with concentrated ammonia and re-extracted with ethyl acetate. After evaporation of the organic solvent in vacuo, the crude product remains, from which, after chromatographic chromatography on silica gel (eluent = chloroform: methanol: concentrated ammonia = 90: 10: 1), pure 1- (4-amino-3-chloro-5 (trifluoromethyl-phenyl) -2-tert-butylamino-ethanol. Dissolution in ether and addition of isopropanolic hydrochloric acid gives the hydrochloride, m.p. 205-207 ° C (decomposes).

Example 185 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol 1.5 g of 5- (4-amino-3-bromo-5-fluoro-phenyl) -3- tert-butyl-oxazolidone (2) is heated in 25 ml of 3N hydrochloric acid for 3 hours at 90 ° C. After cooling, the slightly cloudy solution is filtered, adjusted to pH 9 with sodium hydroxide and extracted with chloroform. The chloroform phase is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo, the oily residue is taken up in a small amount of isopropanol and acidified to pH 5. Crystallization occurs with the addition of a little ether The crystals are filtered off with suction and washed with a mixture of isopropanol and ether Melting point: 207-208 ° C (decomposes).

Example 186 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert. -butylamino-ethanol 0.5 g of 5- (4-amino-3-chloro-5-cyano-phenyl) -3-tert-butyl-oxazolidone- (2) (melting point: 115-119 ° C) and 5 ml of concentrated hydrochloric acid are heated at reflux for 30 minutes. Cool, add ice, make alkaline with sodium hydroxide and extract 1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol with chloroform. The product is purified by chromatography on silica gel (eluent chloroform: methanol = 7: 3).

Melting point: 131-135 ° C; melting point of the hydrochloride: 204-207 ° C. The following compounds were prepared according to Examples 184-186: 1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 196-197 ° C (decomposes).

L- (4-amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 152-154 ° C (decomposes).

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride

Melting point: 175-177 ° C (decomposes).

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanal hydrochloride

Melting point: 206-208 ° C (decomposes).

1 - (, 4-amino-3-chloro-5-fluorophenyl) -2-tert. pentylamino-elanoli hydrochloride

Melting point: 187-188 ° C (decomposes).

1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 171-173 ° C (decomposes).

93,620 5 2 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 164-166 ° C (decomposes).

1- (4-amino-3-fluoro-5-iodo-phenyl) -2-cyclopropylamino-ethanol hydrochloride

Melting point: 199-201 ° C (decomposes).

1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 182-184 ° C (decomposes).

L- (4-amino-3-syani-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 242-243 ° C (decomposes).

1- (4-Amino-3-cyano-phenyl) -2-cyclobutylamino-ethanol hydrobromide Melting point: from 193 ° C (decomposes).

1- (4-amino-3-cyano-phenyl) -2-tert-pentylamino-ethanol Melting point: 143 ° C.

1- (4-amino-3-chloro-5-syani-phenyl) -2-propylamino-ethanol hydro chloride

Melting point: 187-189 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-sec-butylamino-ethanol dihydrochloride

Melting point: 190-191 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert-butylamino) -ethanol hydrochloride

Melting point: 228-230 ° C (decomposes).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert-pentylamino-ethanol hydrochloride

Melting point: 218-220 ° C (decomposes).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol hydrochloride

Melting point: 138-144 ° C.

94 62052 1- (4-Amino-3-chloro-5-cyano-phenyl) -2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] -ethanol hydrochloride Melting point: 189-192 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-isopropylamino-ethanol hydrochloride Melting point: 186-189 ° C, 1- (4-amino-3-bromo-5-cyano-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 213-125 ° C (decomposes).

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 215-216 ° C (decomposes).

1- (4-amino-3,5-disyani-phenyl) -2-tert-butylamino-ethanol-tetrahydro-töoridi

Melting point: 251-253 ° C (decomposes).

1- (4-amino-3-trifluoromethyl-phenyl) -2-tert. butylamino-ethanol hydrochloride

Melting point: 172-174 ° C (decomposes).

1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol hydrobromide

Melting point: 174-175 ° C (decomposes).

1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol

Melting point: 104-106 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 177-178 ° C.

'' *.

95 6205 2 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol hydrochloride

Melting point: 176-178 ° C (decomposes).

1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 177-179 ° C (decomposes).

1- (4-amino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol Melting point: 148-149 ° C.

1- (4-amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol Melting point: 151-152 ° C.

Example 187 1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-tert-butylamino-ethanol 10 g of 4 * -amino-3'-cyano-5'-fluoroacetophenone are added portionwise with stirring. At 60 ° C to a solution of 6 g of selenium dioxide, 36 ml of dioxane and 1 ml of water. It is then heated at reflux for 4 hours. To the solution of 4-amino-3-cyano-5-fluorophenylglyoxal thus prepared, 30 ml of tert-butylamine are added dropwise after cooling and from the outside under ice-cooling. After the addition, it is diluted with 150 ml of ethanol and the insolubles are filtered off. To a solution of crude 4-amino-3-cyano-5-fluorophenylglyoxyl-diene-tert-butylamine, 6 g of sodium borohydride are added portionwise with stirring and ice-cooling, and the mixture is allowed to stand overnight at room temperature. The excess sodium borohydride is then decomposed with acetone, water is added and the organic solvent is removed in vacuo. The precipitate formed is filtered off with suction, washed with water and taken up in 200 ml of 2N hydrochloric acid. The hydrochloric acid solution is filtered and then enough 10 N sodium hydroxide is added to bring the pH to 6. The aqueous phase is washed with chloroform and then a further 10 N sodium hydroxide is added until the reaction is clearly early. The precipitate formed is extracted with chloroform, the chloroform solution is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The solid residue, 1- (4-amino-3-cyano-5-fluorophenyl) -2-tert-butylaminoethanol, is taken up in 100 ml of absolute 96 6 2 0 5 2 ethanol and acidified to pH to 6 with ethereal hydrochloric acid. Already during acidification with ethereal hydrochloric acid, the hydrochloride begins to separate as colorless crystals. Crystallization is completed by the addition of ether. The crystals are filtered off with suction and washed with ether.

Melting point: 242-243 ° C (decomposes).

Example 188 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol 0.4 g of 4-amino-3-chloro-5-trifluoromethyl-phenylglyoxal hydrate is dissolved. To 10 ml of methanol, add 0.23 g of tert-butylamine and allow to stand for 3 hours at room temperature. The solution is then cooled to -20 ° C, 0.1 g of sodium borohydride is added and stirred for 20 minutes at -10 to -20 ° C. Acidify to pH 2 with 2N hydrochloric acid and then adjust to pH 9 with 2n ammonia, dilute with water and remove the methanol in vacuo. The aqueous mixture is extracted with ether, the ether extract is washed with water, dried over magnesium sulphate and evaporated in vacuo, the oily evaporation residue is dissolved in a small amount of ether and the pH is adjusted to 4 with isopropanolic hydrochloric acid. Crystalline 1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride is obtained, which is filtered off with suction and washed with ether. Melting point: 205-207 ° C (decomposes).

The following compounds were prepared according to Examples 187 and 188: 1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 196-197 ° C (decomposes).

1- ('4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 152-154 ° C (decomposes).

6r \ rs r r *

ZUDZ

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride

Melting point: 175-177 ° C (decomposes).

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 206-208 ° C (decomposes).

1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol hydrochloride

Melting point: 187-188 ° C (decomposes).

1- (4-amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 171-173 ° C (decomposes).

L- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 207-208 ° C (decomposes).

1- (4-amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 164-166 ° C (decomposes).

1- (4-Amino-3-fluoro-5-iodo-phenyl) -2-cyclopropylamino-ethanol hydrochloride

Melting point: 199-201 ° C (decomposes).

1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 182-184 ° C (decomposes).

1- (4-Amino-3-cyano-phenyl) -2-cyclobutylamino-ethanol hydrobromide Melting point: from 193 ° C (decomposes).

1- (4-amino-3-cyano-phenyl) -2-tert-pentylamino-ethanol Melting point: 143 ° C.

PACO

98 1- (H-Amino-3-chloro-b-cyano-phenyl) -2-propylamino-ethanol hydrochloride

Melting point: 187-189 ° C.

1- (U-Amino-3-chloro-5-cyano-phenyl) -2-sec-butylamino-ethanol dihydrochloride

Melting point: 190-191 ° C.

1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol Melting point: 125-133 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert-butylamino) -ethanol hydrochloride

Melting point: 228-230 ° C (decomposes).

L- (4-amino-3-chloro-5-syani-phenyl) -2-tert.-pentylamino-ethanol hydrochloride

Melting point: 218-220 ° C (decomposes).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol hydrochloride

Melting point: 138-144 ° C.

1- (4-amino-3-chloro-5-cyanophenyl) -2- [1- (3,4-methylenedioxyphenyl) -2-propylamino] ethanol hydrochloride Melting point: 189-192 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 186-189 ° C.

1- (4-amino-3-bromo-5-cyano-phenyl) -2-tert-butylamino-ethanol hydrochloride Melting point: 213-215 ° C.

L- (4-amino-3-bromo-5-syani-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 215-126 ° C (decomposes).

99 62052 1- (4-Amino-3,5-dicyano-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 251-253 ° C (decomposes).

1- (4-amino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 172-174 ° C (decomposes).

1- (9-amino-3-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol hydrobromide

Melting point: 174-175 ° C (decomposes).

1- (9-amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol

Melting point: 104-106 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 177-178 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol hydrochloride

Melting point: 176-178 ° C (decomposes).

1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 177-179 ° C (decomposes).

1- (4-amino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol Melting point: 148-149 ° C.

1- (4-amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol Melting point: 151-152 ° C.

Example 189 1- (4-Amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol 2.9 g of 1- (4-amino-3-bromo-phenyl) -2-tert-butylamino-ethanol. .-Butylaminoethanol is dissolved in 15 ml of a mixture of concentrated nitric acid and concentrated sulfuric acid.

c 9 η ξ 9 100 ο ζ ^ u ζ.

The solution is heated at 80-85 ° C for one minute and then poured onto ice. Addition of ammonia makes the mixture alkaline and then extracted with chloroform. The chloroform solution is washed with water, dried and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: chloroform: methanol = 8: 2), and the crude product thus obtained is recrystallized from ethyl acetate, 1- (* 4-amino-3-bromo-5-nitro-phenyl) -2-tert. -butylamino »ethanol melting point: 151-152 ° C.

Example 190 1- (14-Amino-3-chloro-5-nitro-phenyl) -2-tert. -butylamino-ethanol Melting point: 149-149 ° C.

Prepared according to Example 189 from 1- (9-amino-3-chloro-phenyl) -2-tert-butylamino-ethanol and nitric acid / sulfuric acid.

Example 191 1-C9-Amino-3-chloro-5-cyano-phenyl) -2-dimethylamino-ethanol 0.5 g of 1-acetoxy-1- (4-amino-3-chloro-5-cyano-phenyl) - 2-Dimethylaminoethane (melting point: 120-129 ° C) is stirred for 1 hour at 20 ° C in methanolic sodium hydroxide. Add water, distill off the methanol in vacuo, extract the remaining aqueous phase with chloroform, dry the chloroform phase over sodium sulphate, evaporate to dryness in vacuo and take up the residue in isopropanol. 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-dimethylamino-ethanol hydrochloride is crystallized by adding isopropanol-containing hydrochloric acid.

Melting point: 187-189 ° C.

Example 192 1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-dimethylamino-ethanol 7g-1-acetoxy- (9-amino-3-cyano-5-fluoro-phenyl) -2 -Dimethylamino-ethane is dissolved in 100 ml of methanol. To this solution is added 5 ml of 10% aqueous NaOH solution and allowed to stand for 1 hour at room temperature. It is then darkened with saturated brine and extracted with chloroform. The chloroform- <2C z o kuivat - C £ solution is washed with saturated brine, dried over sodium sulfate and evaporated to dryness in vacuo. A colorless oil is obtained.

The structure is shown by NMR spectrum (CDgOD):

OH

f ^ 2.2 - 2.65 ppm multiplet / 8 protons; N-CH 2 and N-CH-CH 2 -N ..__ /; 4.6 to 4.9 ppm multiplet / 4 protons; 3 exchange protons and

OH

-CH -ch2-n <T /; 7.15 to 7.4 ppm multiplet (2 aromatic protons).

Example 193 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol 0.5 g of N-acetyl-N- [2-acetoxy-2- (4-amino- 3-Chloro-5-cyano-phenyl) -ethyl-7-tert-butylamine (melting point: 160-162 ° C) and methanolic sodium hydroxide are stirred for 1/2 hour at 20 ° C. Add water and distill off the methanol in vacuo. The remaining aqueous phase is extracted with chloroform, the chloroform phase is dried over sodium sulfate, evaporated to dryness in vacuo and the residue is crystallized from ethanol. 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol is obtained.

Melting point: 131-135 ° C; melting point of the hydrochloride: 204-207 ° C. The following compounds were prepared according to Examples 191-193: 1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 196-197 ° C (decomposes).

L- (4-amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 152-154 ° C (decomposes). 1 (* + amino-3-chloro-5-fluorophenyl) -2-cyclopropylaminoethanol hydrochloride

Melting point: 175-177 ° C (decomposes).

102 6205 2 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 206-208 ° C (decomposes).

1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol hydrochloride

Melting point: 187-188 ° C (decomposes).

1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 171-173 ° C (decomposes).

1- (4-amino-3-bromo-5-fluorophenyl) -2-ter *. butylamino-ethanol hydrochloride

Melting point: 207-208 ° C (decomposes).

1- (4-amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 164-166 ° C (decomposes).

L- (4-amino-3-fluoro-5-iodo-phenyl) -2-cyclopropylamino-efenoli hydrochloride

Melting point: 199-201 ° C (decomposes).

1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 182-184 ° C (decomposes).

L- (4-amino-3-syani-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 242-243 ° C (decomposes).

1- (4-Amino-3-cyano-phenyl) -2-cyclobutylamino-ethanol hydrobromide Melting point: from 193 ° C (decomposes).

1- (4-amino-3-cyano-phenyl) -2-tert-p-phenylamino-ethanol Melting point: 143 ° C.

1- Γ λ 103 o ^ ubz 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-propylamino-ethanol hydrochloride

Melting point: 187-189 ° C, 1- (4-amino-3-chloro-5-cyanophenyl) -2-sec-butylaminoethanol dihydrochloride

Melting point: 190-191 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert-butylamino) -ethanol hydrochloride

Melting point: 228-230 ° C (decomposes).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert-pentylamino-ethanol hydrochloride

Melting point: 218-220 ° C (decomposes).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol hydrochloride

Melting point: 138-144 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] -ethanol hydrochloride

Melting point: 189-192 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 186-189 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-tert-butylamino-ethanol hydrochloride Melting point: 213-215 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 215-216 ° C (decomposes).

1- (4-Amino-3,5-dicyano-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 251-253 ° C (decomposes).

104 62052 1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 172-174 ° C (decomposes).

1- (4-amino-3-trifluoromethyl-phenyl) -2-tert. «* Pentylamino-ethanol hydrobromide

Melting point: 172-175 ° C (decomposes).

1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol

Melting point: 104-106 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride

Melting point: 20S-207 ° C (decomposes).

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride

Melting point: 177-178 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol hydrochloride

Melting point: 176-178 ° C (decomposes).

1- (4-Amino-3-bromo-3-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride

Melting point: 177-179 ° C (decomposes).

1- (4-amino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol Melting point: 148-149 ° C.

1- (4-amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol Melting point: 151-152 ° C.

'**. ϊ »Λ

Claims (8)

A process for the preparation of pharmacologist valuable 4-amino-phenylethanolamines having particular / 32-antiretroviral and / or β-blocking activity and of general formula IH. R3 is CH1 - CH2 - NTI * 4 (I) R2 where R; 1 represents a fluorine, chlorine, bromine, iodine atom or a cyano group, or also a hydrogen atom, where R2 represents a hydroxyalkyl, aminoalkyl, dialkylaminoalkyl, , trifluoromethyl, nitro, cyano, carboxy, carbalkoxy or carbamoyl group, r 2 represents a fluorine atom, a straight or branched alkyl group having 1 to 5 carbon atoms, a hydroxyalkyl, aminoalkyl, dialkylaminoalkyl, trifluoromethyl, alkoxy -, nitro, cyano, carboxy, carbalkoxy or carbamoyl group, R 3 and R 4, which may be the same or different, denote hydrogen atoms, straight or branched alkyl groups having 1-6 carbon atoms, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, , alkenyl, alkinyl or optionally substituted phenylacyl groups with a hydroxy or methoxy group, as well as their optically active antipodes and their physiologically acceptable acid addition salts with inorganic or organic acids, characterized in that a) an acetophenone of general formula II γγ " R 2 is R 1 -R 4 is as defined above, reduced or b) for the preparation of compounds of general formula I wherein R 3 and R 4 are as defined above with the exception of alkenyl and alkinyl groups and R 2 represents a chlorine, bromine or iodine atom, halogenates a compound of the general formula lii, OH, R 3 - CH 2 - N f li R 4 (HD », - V R 2 where R 2 -R 4 is as defined above with the exception of alkenyl and alkinyl groups, or c) from a compound of the general formula IV, x x 1 ch - ch 2 - n II 2 r 3 (iy) Y 1 - H 2 R 2, R 2 and R 3 are as defined above, X represents a protecting group for a hydroxy group or a hydrogen atom, Υχ represents a protecting group for a an amino group or a hydrogen atom, Y2 represents a protecting group for an amino group or has the meaning given for R4 above, however, at least one of the groups X, Y 2 and / or Y 2 must form the above-mentioned protecting group, one or more protecting groups are split off or d) for the preparation of compounds with the gen Formula I, where R 2 is a hydrogen atom, a compound of general formula V, H CH 2 - CH 2 - N, XT · - R2 115 620 wherein R2-R4 is as defined above and Hai represents a chlorine, bromine or iodine atom, or e) for the preparation of compounds of general formula I, wherein R 2 is an aminomethyl group, then a compound of the general formula VI is reduced, and hydrolyzed, and the compound of the general formula VI, OK 3 R 3 "Cl 2 2" N n AJ R 4 (vi) CH N 1m 3 in H where R ) a compound of the general formula VII, OH R CH - CH 2 - Z; jpr R2 wherein R 2 and R 2 are as defined above, and Z is a chloro, bromo or iodo atom or a p-toluenesulfonyloxy group, is reacted with an amine of the general formula Vili, r3 H - KK (Vili) of R3 and R4 are as defined above, or g) for the preparation of compounds of the general formula I, where R 2 is not a nitro group, a compound of the general formula IX, OH, R 3 R 2 CH - CH 2 - NV 62052 116 wherein R 2, R 3 and R 4 are as defined above, and R 2 or h) for the preparation of compounds of general formula X, wherein R 2 is not a cyano group and R 2 is not a nitro, cyan, carboxy, carbalkoxy or carbamoyl group, a compound is reduced by the general formula X, S / "3 r 1 - c - VT 1 R 4 h 2 n <*> V where r 3 and R 4 are as defined above, R 1 'has the meaning given for R 3 above with the exception of the cyano group, R2" has the meaning given for R 1 above with the exception of nitro, cyano, carboxy, carbalkoxy or carbamoyl groups and A is a carbonyl or a hydroxymethyl group, or i) for the preparation of compounds of general formula I wherein R 4 is a hydrogen atom , an oxazolidone of the general formula XI, O - C = O A - * 3 M 2 CH 2 X (XI) h 2n AyJ R2 of R 1, R 2 and R 3 is as defined above, or j) for the preparation of compounds of the general formula I, where R 4 is a hydrogen atom, an aldehyde of the general form is reduced and XII, r CO - CHO .xr 2 J (XII) R 2 wherein R 1 and R 2 are as defined above, or its hydrate in the presence of an amine of the general formula Villa, 117 62Γ. (W) where R 3 is as defined above, or k) for the preparation of compounds of general formula I, wherein R 2 is a nitro group, a compound of the general formula is nitrated. Formula XIII, OH R3 'CH2 - N \ II ^ I> 4 (XIII) h constitutes a cyano group, then, if desired, is transferred by hydrolysis into the corresponding compound of general formula 1, wherein R 2 is a carbamoyl or carboxyl group, and / or a obtained compound of general formula I, wherein R 2 is a carbamoyl or if desired, by hydrolysis in the corresponding compound of general formula I, wherein R2 is a carboxyl group and / or a recovered compound of general formula I is cleaved if desired in its optically active antipodes and / or a recovered racemate with the general formula I then, if desired, sp is calibrated by racemate digestion or a mixture of the diastereomeric compounds of general formula XIV, OR7 R3 'CH2' N \ T | T ^ R4 (XIV) 'V R 2 is R 3, R 2, R 3 and R 4 are as defined above, R 9 is a hydrogen atom or an acyl group and R 7 is a chiral acyl group, is cleaved in its sinus diastereomers and then the group R 7 and optionally R 4, if it is an optionally substituted benzyl group, and Rg, if not hydrogen, is cleaved and / or a obtained compound of formula I is transferred, if desired, into a physiologically acceptable acid addition salt with an inorganic or organic acid.