DE2344681A1 - SUBSTITUTED 2-HYDROXY-2-PHENYLAETHYLAMINE - Google Patents

Description

DIPL.-INQ. H. STEHMANN

DIPL.-PHYS. DR. K. SCHWEITZER DIPL.-ING. DR. M. RAU

PATENT LAWYERS

85 NUREMBERG 2

ESSENWEINSTRASSE 4-ώ

TELEPHONE: 0911/203727

TELEGRAM ADDRESS: STANDING PATENT TELEX OÄ-23135

BANK ACCOUNTS:

DEUTSCHE BANK AG. NUREMBERG BLZ 76070012 ACCOUNT NO. 341164 CHECK ACCOUNT: NUREMBERG 67081-85?

Nuremberg, ^ .9 · 1975

20/55

Company Dr. L. Zambeletti S.p.A.j

Via L. Zambeletti, Baranzate, Milan / Italy

Substituted 2-hydroxy-2-phenylethylamines

The invention relates to some 2-hydroxy-2-phenyläthylami · ne of the general formula I.

, R ₁

3E0H

Century

H -

R = -H, -OCH ,, -OH,
R .. = —Η, —OH, —OCH ,,

= -N

N -

-N N-CH ₂ CH ₂ OH,

-NH-

, -NH-

N-CH ₀ -CH-

OH

R. R ₁ , / \ - NKCH ,, ι "\ / //

409812/1212

R -2-

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Calls on the telephone have no legally binding effect.

-NH-iso-CJiU; = -H, -CH ₃

"robe! then, when R ₂ = NHCH ,, -NKC ^ H or NH-iso-CJi-, at least one of the two substituents R and R ^ has the meaning of "methoxy"; as well as the nicicitboxy salts with organic or inorganic acids.

The invention also relates to a method of production of the compounds according to the general formula (i), which is characterized by a, preferably by means of a catalytic hydrogenation made reduction of an aminoacetophenone or aminopropiophenone salt of the general formula (II) according to the following reaction:

- IU. (HX) n

R--

PtO,

serving as starting materials in salts of the general formula (II) can be, for example, on one of the following dargeleg - th pathways condition:

409812/1212

SCHEME A

KCI \

OCl

COCH ₂ Cl RpH

C2X}

(HXJn

SCHEME B

t η.

CH ^ COOH

Cu)

409812/1212

cocz - Ml ^ R.

R- .R

CuBr ₂

CJX)

In these formulas listed above, the substituents have R, R., Rp, R_ the meaning given y °, X stands for a monovalent anion of an organic or inorganic, physiologically compatible acid and η has the value of a number equal to the number of basic nitrogen atoms in the molecule.

The compounds of general formula (I) are interesting vasoactive substances. Some of them show hypertensive, others on the other hand, hypotensive effect. The invention is illustrated by the following examples.

A09812 / 1 2 1 2

example 1

a) c ^ -Chlor - ^ - acetoxyacetophenone

A diazomethane solution that is obtained from 2-57 g of potassium hydroxide in 4oO ml v / ater, 1390 ml ethylene glycol monomethyl ether, 400 ml of diethyl ether and 850 g of N-methyl-N-nitroso-p-toluenesulfonamide in 4000 ml of diethyl ether is put into a reaction flask equipped with a stirrer, thermorne-ter,

and
The reflux condenser is equipped with a calcium chloride tube and is cooled externally by an ice / common salt mixture. A solution of 280 g of 4-acetoxybenzoic acid chloride in two liters of benzene is then added dropwise so that a temperature of −10 ° C. to -5 ° C. is maintained. The mixture is then kept at room temperature for about two hours, and dry gaseous hydrogen chloride is passed in to achieve a strongly acidic pH. Activated charcoal is then added to the solution, which is then filtered off and the solvent is then stripped off in vacuo. The residue solidifies when rubbed with diethyl ether. The end product is filtered off and washed with a little more mohr diethyl ether. Yield 230g. Mp. 84 ° - 86 ⁰ C.

b) ^ω - (6 ^} -methylpyridyl-2 '-amino ^ (^ - hydroxy) -acetophenone hydrochloride

10 g of 4-acetoxy-o> chloroacetophenone are placed in a suitable vessel and 15 g of 2-methyl-6-aminopyridine melted zen and leave the mass in the molten: state at about 120 ° C for two hours. It is then brought to room temperature Afcga cooled and mixed with water until solidification. The crude product is dissolved in hydrochloric acid diluted in a ratio of 1: 1, the solution is treated with activated charcoal, filtered off and concentrated in vacuo to half the volume. Isopropyl alcohol is added a white solid precipitate which is filtered off and then washed first with acetone and then with diethyl ether will.

Yield: 8.0 g

0 ° C

409812/1212

M.p .: over 300 ° C.

c) 1- (4'-Hydroxyphenyl> -2- (6'-methylpyridyl-2'-amino) ethanol hydrochloride

In a vessel suitable for this purpose, a suspension of 14 g of Q- (6'-methylpyridyl-2'-amino) - (4-hydroxy) -acetophenone hydrochloride is added under atmospheric pressure and at room temperature in the presence of 0.7 g of PtO ₂ hydrogenated. The solid substance dissolves gradually and after 24 hours the uptake of the theoretically required amount of hydrogen has ended. The solution obtained is filtered to remove the catalyst and the filtrate is concentrated to dryness on a water bath under reduced pressure. The residue is carefully taken up with 100 ml · acetone, filtered off and recrystallized from ethanol.
Yield: 12.0 g
Mp. : 293 ° c

Example 2 a) 3,5-Dinahoxy-4-kydroxyacetophenone

15 S magnesium shavings, 1.4 ml carbon tetrachloride, 210 ml of anhydrous benzene and 14 ml of absolute alcohol are placed in a reaction vessel. After the reaction has started, a solution of 99% diethyl malonate is obtained in 70 ml of anhydrous benzene and 56 ml of absolute alcohol added dropwise so as to maintain a vigorous reflux. After completing the addition, the mixture is refluxed for one hour and a solution of 145 g of acetylsyringic acid chloride added in 480 ml of anhydrous benzene.

The mixture is kept under gentle reflux for a further 2 hours with stirring and then at 35 ° Chilled to 40 ° C. Then a solution of 32 ml is added Sulfuric acid in 240 ml v / water with vigorous stirring once to. The benzene layer is separated and used

-7-409812 / 1212

Evaporated dry. A mixture of 168 ml of acetic acid, 112 ml of water and 21 ml is then added to the residue strong sulfuric acid; the mixture is then refluxed for 6 hours and the pH is then adjusted with 20% soda solution to 4.5 a. The precipitate is filtered off and recrystallized from water.

Yield: 70.0 g m.p. : 122 ° to 125 ° C.

80 g of JiS-dimethoxy - ^ - hydroxy-acetophenone and 150 ml of acetic acid are refluxed for 5 hours. The mixture is then cooled, the precipitate is filtered off and washed with hexane.

Yield: 90.0 kg mp. 149 ° to 151 ⁰ C.

c) j ^ jS-dircethoxy-fy-acetoxy-qhbromoacetophenone

A mixture of 50 g of 3,5-dimethoxy- ¹ ! - acetoxyacetophenone and 250 ml of anhydrous benzene is heated to reflux, then 37 g of bromine are added dropwise so that a slight reflux is maintained. The mixture is then concentrated to a thick slurry which is then filtered. The residue is washed with hexane. ·

Yield: ¹ K), 0 g -

M.p .: 125 ° to 126 ° C.

d) < a - (N ^f -methylpiperazine) - ^, 5-dimethoxy- * l-hydroxy acetophenone

Hydrochloride

10 g of 5j5-dimethoxy ~ f ~ acetoxy-Q -bromaeetophenone are added to 20 ml of N-methylpiperazine with stirring and in small portions so that the temperature does not exceed 80. A precipitate forms on cooling. Then ho ml of isopropanol is added to the mixture, the mixture is stirred for some time and then filtered off. The residue is washed with a little ice water, dried completely, sus-

4 0 9812/1212 -8-

suspended and saturated with hydrogen chloride gas. The hydrochloride precipitate forms after a short time. He is filtered off and washed with ethyl ether.

Yield: 7.0 g of sap. : 270 ° to 272 ° C.

e) 1- (3 ', 5'-dirnethoxy-4'-hydroxyphenyl) -2- (N'-methylpiperazine) ethanol hydrochloride

■ A solution of 10 g of & i- (N'-methylpipera-zinj-jj ^ -dimethoxy-4-hydroxy-acetophenone Hydrochloride in 200 ml of methanol and. 50 ml of water is under atmospheric pressure and at room temperature in the presence of 1 g of 1Obiger palladium carbon with hydrogen hydrogenated. The solid substance gradually dissolves, after 24 hours the theoretical amount is absorbed Hydrogen terminated. Then it is filtered to remove the catalyst, and the filtered solution under reduced -, Temp pressure concentrated to dryness. The residue is then taken up in acetone, filtered and crystallized out Isopropyl alcohol.

Yield t .8.0 g. Mp.: 225 ° C.

Example 3

a) 3j 5-difl] ethoxy-4-acetoxy-benzamide

Gaseous ammonia is passed into a solution of 68 g of acetylsyringic acid chloride in 400 ml of chloroform until it is saturated (approximately 2 hours). The temperature is maintained while below 8 ⁰ C. The precipitate formed is abfil trated, air dried, slurried with water and filtered again. The end product is recrystallized from 300 ml of ethanol.

. Yield: 4o g O mp. 185 ^{0-190 0} C.

-9-409812 / 1212

b) 3,5-dimethoxy-4-acetoxy-propiophenone

To a A'thylmagnesiumbromidlösung which have been prepared from 109 S ethyl bromide and 24.3 g of magnesium in 300 ml of anhydrous diethyl ether, 6o g of 3,5-dimethoxy-4 acetoxybenzamid added in such proportions that the mixture remains at vigorous reflux. The mixture is then refluxed for a further 5 hours, the solvent is then stripped off in vacuo and 80 ml of dilute sulfuric acid in 500 ml of ice-cold water are carefully added to the residue. After standing for a short time, the precipitate is filtered off.

Yield: 55 * 0 g c)

rap. : 105 ⁹ C.

30 g of 3 * 5-dimethoxy-4-acetoxy-propiophenone, 90 ml of thylace tat, 90 ml of chloroform and 34 g of CuBr _{2 are placed} in a suitable vessel. The suspension is then refluxed for 6 hours with vigorous stirring. The CuBr formed is then filtered off and the filtered solution is evaporated to complete dryness under reduced pressure. The oily residue solidifies when rubbed with benzene ether.

Yield: 25.0 g M.p.-. : 75 ° to 8o ° C.

d) 1- (3'j5'-dimethoxy-4'-hydroxy) -2-methylaminopropiophenone hydrochloride

20 g of 3 * 5-dimethoxy-4-acetoxy-ot-bromoacetophenone and 200 ml 4o # aqueous methylamine solution are stirred up to heated to 45 ° c to completely dissolve. The reaction mixture is then allowed to stand at 45 ° C. for 15 minutes and evaporates under reduced pressure to complete dryness. The semi-solid residue is then with a few ml Isopropanol taken up and filtered off. The solid residue thus obtained is then suspended in 50 ml of methanol

409812/1212

and acidifies with ether, that with gaseous hydrogen chloride is saturated. The solid fractions initially dissolve, and the hydrochloride then falls almost suddenly the end. The hydrochloride is filtered off and further crude product is obtained by removing the mother liquors concentrated and diluted again with diethyl ether. The two fractions of the crude hydrochloride product are made from ethanol recrystallized.

Yield: 12.0 g, mp. 24l ° to 244 ⁰ C.

e) 1- (3 ', 5'-Dirnethoxy-4'-hydroxyphenyl) -2-methylaminopropanol hydrochloride

A solution of 12 g of 1- (3 ^r , 5'-dirnethoxy-4'-hydroxy) -2-methylaminopropiophenone hydrochloride in 200 ml of water is reduced with hydrogen at room temperature and under atmospheric pressure in the presence of 1 * 2 g of PtOp. After one hour, the theoretical amount of hydrogen has been absorbed. The mixture is filtered to remove the catalyst and the filtrate is evaporated to dryness under reduced pressure. So that the conversion of the semi-solid residue into a crystalline solid is complete, it is heated to the boil in 100 ml of acetone for about 2 hours. It is then filtered off and dried.

Yield: 8.0 g mp: 215 ° C.

g Procedures

the Y described above is obtained in the

connections listed in the table below.

409 812/1212

£ M

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Table I (continued)

10

11

-OCE.

-OH.

-0OH.

-OH,

13th

J 4 -OH 15

16

'19

-OH

-OCK -OCE

-OH

-OSH,

-H -03.-OCH.

-H -OH

-Η -OH -OH

-QGS

V
- CH-
B OH- ^R 3 HX 1 1 I.
M.p.,
( ⁰ C) ί ° . -. ¹ FOHMEL '. Molecular
large -
weight .86 C. .03
.29 AUALYSI
Ή 4.05
4.00 C +)
Cl S. . D.
3 -NH- (H) -H. HCl 1 215 17! W ⁰ A ⁰¹ 345 .83 59
59 .65 · ■ 8.16
7.79 4.44
4.25 10.25
10.25 - Γ II Ä . 'I. -CH ₂ -H HCl. 2 t
195
■ 315 .31 60
60 .12
.74 8.30
8.r 7.02
6.60 11.23
11.45 :: ί __
I. A. / - \
-ΪΓ; H-CSg - -H HCl 2 25? ; C. 399 .34 48
47 .40
.99 "7.0
■ 6.6 6.78
6.51 17.76
17.90 B. It -H ■ HCl 1 253 .C 17 ^Η 30 ^Ε Λ ⁰¹ ₂ 413 .41 49
48 .20 7 · 3
7.0 7.36
7.34 17.16
08/17 "... I A. -H ^H 2 ^SO 4 2 270 C. H ^H 24 ^H 2 ° 8 ^S 380 .46 44
43 .27
.74 6.3
6. 3 5.03
4.90 —— - 6.43
8.53 Λ -N jST-OHL HCl 1 233 ■ ο 24 ^ß 36 ^N 2 ⁰ 8 ^C1 2 .551 τ » 52
51 35
52 6.5
. 6.8c 4.61
4.57 12.8c
13.17 B. -H HCl 1
2 217 C. _U H ₂₂ BD Cl 303 78
28 55.
55. 58
34 .7-30
■ 6.98 4.17 11.67
11.85 A. Il
-S ⁷ V-CH ₀
N- / -OH ² -H
-H KCl
HCl 2- 190
185 η HH ₂₄ IT ₂ O ₃ Ol ₂ H ₂ O 319
357 31 52.
52. Ub
50 6.93,
5.74 7.Ö4
7.82 11.09
08/11 3 -NQ-CH ₃ -K HOl ° -39 16 ^E 28 ^N 2 ° 4 ^{C; L} 2 ·, 383. 47.
47. 13th
48 7.34.
7.07 7.31;
ί 19. öS
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7.46; 10-50
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- ^l4 - 23U681

The acute toxicity of the compounds according to the invention was determined by intravenous administration to the mouse. The values for the LD _n - ^ were determined by the method of Litchfield

50

and Wilcoxon for sure.

The vasoactivity was determined "in vitro" using the Land and Rand method. The percentage reduction was added to this the high pressure induced by administration of norepinephrine to a central artery dissected from a rabbit ear determined, which is traversed by a peristaltic pump of "cancer bicarbonate".

The vasoactivity of these compounds "in vivo" was determined in cats anesthetized with "chloralose urethane". For this purpose, the changes in the carotid artery pressure after intravenous administration of doses which correspond to about 1/10 of the LDc _{0 were} determined with an apparatus for graphical blood pressure determination using a "Sanborr ^ Efrueküberträger.

As comparison compounds, 1-noradrenaline phenylephrine was used in doses which corresponded to 1/10 of the corresponding value of the LDk ₀ and dl-isoprenaline in doses of 1/10 of the corresponding Wr - _n .

The results are compiled in Table 2 below. In both tests, the results are given as the percentage change from before administration of the appropriate compound prevailing pressure, reproduced.

- 15-

409812/1212

Table II

Activity "in vitro" and "in vivo"

Connection no. ^Ld rq ^:

3
4th

5
6th

7th
8th

9
10
11
12th
13th

452 574 100 336 128 72

activity
"in vitro"
A $ activity
"in vivo"
Λ % ■ «be
there was pressure
modification . - 5th + 18 - 19th - 30 - 18th + 22 - 12 ■ ■ - 59 - 28 - 38 - 54 + 58 - 65 - 26th - 62 - 32 - 28 - 6 - 35 -15 - 27. - 22 0 - 9 - 16 - 21st

Table Ii (port setting)

link

No.

: mg / kg

Activity "in vitro" Δ%

Activity "in vivo" caused pressure change: ■ Δ %

> w

§ ■

14th

15 16

17 18

19 20 21 22

23 24

25 26

509 279 190 588 385 325 163

153 17 51

262

228

69

10

135

- 4th

+ 7

- 13

- 5th

- 37

- 2

- 94

- β

- 2

- 24 + 38

- 4l

- 45

- 35

- 24th

- 29

- 38

- 10

+ 9

- 13 + 9

- 24 + 14

- 21st

- 25 + 44 + 49

- 15

Claims (1)

A- Claims 1.) A 2-hydroxy-2-phenylethylamine of the general formula mel I: CHOH CH - R = -H, -OCH ,, -OH; R ₁ = -H, -OH, -OCH, · R ₂ = / λ -N N - -NH- CH-: , -NH -N N-CH ₂ CH ₂ OH, N-CH ₂ -CH- OH R ₁ , -NO, - NHCH ,, -NHC ^ H ₉ \ / -NH-iso-C = -H, -CH where, when R ₂ = -NHCH ,, -NHC ^ Hq or -NH-IsO-C ₅ H ₇ means at least one of the two substituents R and R ₁ 409812/1212 has the meaning of "methoxy"; as well as the nontoxic salts formed by addition of these connections. 2.} 1- (4 * -Hydroxyphenyl) -2- (N ¹ -methylpiperazino) ethanol and its non-toxic salts formed by addition. 5.) 1- (3 ', 5 ^t -dimethoxy-4 ^t -hydroxyphenyl) -2- (N ¹ -methylpi perazino) ethanol and its non-toxic salts formed by addition. 4th ) 1- (3 ', 5'-bimethoxyphenyl) -2- (N'-methylpiperazino) ethanol and its non-toxic, addition-formed salts. , 5.) 1- (3 ', 5'-dihydroxyphenyl) -2- (N'-methylpiperazino) ethanol and its nontoxic, addition-formed salts. 6.) 1- (5'j5 ^! -Bimethoxy-4'-hydroxyphenyl) -2- (6'-methylpyridy1-2'-amino) ethanol and its non-toxic salts formed by addition. 7.) 1- (V r-hydroxyphenyl) -2- (6 ^! -Methylpyridyl-2 '- amino) ethanol and its non-toxic salts formed by addition. 8.) 1- (3 ', ^ - DimethoxyplienylJ ^ -ie ¹ -methylpyridyl-2'-amino) ethanol and its non-toxic salts formed by addition. 9.) l- (3 '* ^ ^f * 5 ^T -Trimethoxyphenyl) -2- (6' -me thylpyridy1-2'-amino) ■ ethanol and its non-toxic addition salts formed by. 10 « ) l-O ', 5 ^f -dimethoxy-4' -hydroxyphenyl) -2- (cyclohexy lamino) ethanol and its non-toxic salts formed by addition. 11.) 1- (3 ', 4', 5-trimethoxyphenyl) -2- (cyclohexylamine) ethanol and its non-toxic, addition-formed salts. 40981271212 12 *) 1- (3 ', 5 ^f -Dimethoxyphenyl) -2- (cyclohexylamine) -ethanol and its non-toxic salts formed by addition. 13.) 1- (3 ', 5' -Dimethoxy-4 ¹ -hydroxyphenyl) -2- [V - (ß-hydroxyethyl) ■ piperazine] ethanol and its non-toxic salts formed by addition. 14.) 1- (3 ^f , 4 ', 5' -trimethoxyphenyl) -2- [N ^f -p * ydroxyethyl) -piperazinol -ethanol and its non-toxic salts formed by addition. 15.) 1- (3 ^f >5'-dihydroxyphenyl) -2- [N '- (ß-hydroxyethyl) -piperazinoj-ethanol and its nontoxic salts formed by addition. 16.) N, N ^f -Bis-r2-hydroxy-2- (3 ', 5' -dimethoxy-4 '-hydroxyphenyl) -äthyy -piperazine and its non-toxic salts formed by addition. 17.) 1- (3 ', 5'-Dimethoxyphenyl) -2-morpholino-ethanol and its non-toxic salts formed by addition. 18.) 1- (3 ', 5'-Dimethoxy-4 ^f -hydroxyphenyl) -2-morpholinoethanol and its non-toxic salts formed by addition. 19.) 1- (4 ^! -Hydroxyphenyl) -2-Γν '- (ß-hydroxyethyl) -pipera2ino] ethanol and its non-toxic salts formed by addition. " 20.) l- (3 ', 4 ¹ , 5 * -trimethoxyphenyl) -2-fN ^f - (ß-hydroxyethyl) -piperazinol-ethanol and its non-toxic salts formed by addition. - 21.) 1- (3 ', 5'-hydroxyphenyl) -2- (6'-methylpyridyl-2 ¹ -amino) ethanol and its non-toxic salts formed by addition. 22.) 1- (3 '# 5'-Dimethoxyphenyl) -2- (N ¹ -methylpiperazino) ethanol and its non-toxic salts formed by addition. -4-409812 / 1212 23 ·) 1- (3S5 ^f -Dimethoxyphenyl) -2- (6'-methylpyridyl-2 ^f -amino.) Propanol and its non-toxic salts formed by addition. 24.) 1- (3 ', 5'-Dimethoxyphenyl) -2 ^ -n-butyjaminopropanol and its non-toxic salts formed by addition. 25.) i- (3 ^f »5 ¹ -dimethoxy-4'-hydroxyphenyl) -2-methylaminopropanol and its non-toxic salts formed by addition. 26.) 1- (3 *, 5'-dimethoxy ~ 4 ^l -hydroxyphenyl) -2-iso-propylaminopropanol and its non-toxic salts formed by addition. 27.) 1- (3 ' * 5 '-Dimethoxy-4'-hydroxyphenyl) -2-n-butylaminopropanol and its non-toxic salts formed by addition 28.) Process for the preparation of a compound according to claim 1, characterized by reducing an aminoketone salt of the general formula III "where R, Rj, Rp and R, the" meaning defined in claim 1 have, X is an anion and η = corresponds to the number of basic nitrogen atoms in the molecule. 29.) The method according to claim 28, characterized in that the reduction is carried out with Viasserstoff in Gegemvart of a catalyst. 4098 127 1212 23 * 4681 30.) The method according to claim 28, characterized by the features set out in Examples 1 to 3. 31 ·) Connection according to claim 1, characterized in that it has been produced by a method according to one of claims 28 to 30. 32.) Pharmaceutical mixture containing a compound according to one of claims 1 to 27 or 31 and contains an acceptable pharmaceutical carrier substance (carrier). 40981 2/1212