DD202867A5 - PROCESS FOR THE PRODUCTION OF PHENYL ALKYLAMINES - Google Patents

Abstract

New phenylalkylamines of the general formula I where R 1 is a hydroxy group or an optionally substituted amino group, R 2 is low and R 3 is halogen atoms, trifluoromethyl, cyano or nitro groups or one of the radicals R 2 or R 3 is also a hydrogen atom R 4 is a hydrogen atom or an alkyl group, R 5 is a hydrogen atom, an alkyl, cycloalkyl, alkenyl or aralkyl group, A is the methylene, ethylene or hydroxymethylene group and B is an optionally substituted aralkyl group, which is linked to the phenyl nucleus Methylene group may be replaced by an oxygen or sulfur atom, a sulfinyl or sulfonyl group, their optically active antipodes, their diastereomeric racemates and their optical antipodes, and their Saede addition salts, which have valuable pharmacological properties, in particular an effect on the heart and circulation. The compounds of the formula I can be prepared by conventional methods for analogous compounds.

Description

03/18/1982

/ learn to produce new Phe nyla lkylaminen

Field of application of the invention

The invention relates to the preparation of novel phenylalkylamines having cardiovascular activity. The new compounds can be used in medicine as a cure #

Known technical solutions

DE-OS 2 603 417 discloses phenylalkylamines of the general formula

R'-NH

OH N CH-I II ³

CH-CH ₀ -NC-CH ² I

known which have broncholytic properties · Object of the invention

It was the object of the present invention to find "better compounds which are suitable for the treatment of cardiovascular diseases.

.Vesen the invention

The object of the invention was to provide processes for the preparation of novel phenylalkylamines.

.... rt "Ii h Λ ti

\ pi · .- m.

5 Λ 9 1 8

18.3 * 1982

AP C 07 O / 235 491/8

60 028 12

Therefore, according to the invention, novel phenylalkylamines of the general formula are prepared

A - CH -

, (D

their optically active antipodes, their diastereomeric racemates and their optical antipodes, and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids »

The new compounds have valuable pharmacological properties, in particular an effect on the heart and the circulation.

3 1-fr

In the above general formula I means

R _{1 is} a hydroxy group, an amino group optionally substituted by an alkanoyl group having 1 to 3 carbon atoms or an alkoxycarbonyl group having 2 to 4 carbon atoms in total, an alkylamino or dialkylamino group wherein each alkyl moiety may contain 1 to 3 carbon atoms and each may be substituted by a phenyl group, ;

R ₇ and R 8, which may be identical or different, halogen

atoms, trifluoromethyl, cyano or nitro groups or a 10 'of the radicals R ₂ or R _{3 is} also a hydrogen atom,

R is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

R _{5 is} a hydrogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkenyl group having 2 to 5 carbon atoms or an aralkyl group having 7 to 10 carbon atoms,

A is the methylene, ethylene or hydroxymethylene group and

B is a group of formulas

* 8 -CH- (CH ₂ ) _n -D-

or

20 where

R _{6 represents} a hydrogen or halogen atom, a hydroxy group, an alkoxy group optionally substituted by a phenyl group having 1 to 3 carbon atoms, an alkylsulfenyl or alkylsulfinyl group having in each case 1 to 3 carbon atoms

25 atoms,

5Λ 9 ~ 1

a hydrogen atom, a hydroxy group or an alkoxy group having 1 to 3 carbon atoms or R, and R- together

ο /

the methylenedioxy group,

Rg is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, D is an oxygen or sulfur atom, a sulfinyl or sulfonyl group,

η is the number 1 or 2 and

E is a straight-chain alkylene group having 3 to 5 carbon atoms optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms or when A is a methylene or ethylene group and / or R ₁ is an alkanoyl group having 1 to 3 carbon atoms or an alkoxycarbonyl group a total of 2 to 4 carbon atoms substituted amino group, a hydroxy, alkylamino or dialkylamino group, each alkyl moiety containing 1 to 3 carbon atoms and each may be substituted by a phenyl group, and / or

R is a trifluoromethyl, cyano or nitro group and / or R _{3 is} a fluorine atom and / or

R _{4 is} an alkyl group having 1 to 3 carbon atoms and / or R _{5 is} an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkenyl group having 2 to 5 carbon atoms or an aralkyl group having 7 to 10 carbon atoms and / or

R _{c is} a fluorine or chlorine atom, an alkylsulfenyl or alo

kylsulfinylgruppe each having 1 to 3 carbon atoms, an ethylene group or also, when A represents the methylene group, a group of the formula

- CH - CH ₂ -, in which R "represents an alkyl group having 1 to 3 carbon atoms.

7X5X31-8

For the meanings mentioned in the definition of the radicals R ₁ to R _g and E above, for example

R ₁ represents the hydroxyl, amino, methylamino, ethylamino, propylamino, isopropylamino, benzylamino, 1-phenylethylamino, 2-phenylethylamino, 3-phenylpropylamino, dimethylamino, diethylamino, dipropylamino, Diisopropylamino, dibenzylamino, di (2-phenylethyl) amino, di (3-phenylpropyl) amino, methylethylamino, methylpropylamino, methylisopropylamino, ethylisopropylamino, methylbenzylamino Ethylbenzylamino, propylbenzylamino, pyrrolidino, piperidino, hexamethyleneimino, formylamino, acetylamino, propionylamino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino or isopropoxycarbonylamino group,

for R "and R ₃ , which may be identical or different, in each case those of the fluorine, chlorine, bromine or iodine atom, the trifluoromethyl, cyano or nitro group or, for R- or R _3, also those of the hydrogen atom,

R. and R _3, which may be identical or different, each d _is hydrogen atom, the methyl, ethyl, propyl or isopropyl group,

for R ₅ that of the hydrogen atom, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. Butyl, cyclopropyl-cyclobutyl, cyclopentyl, cyclohexyl, allyl, crotyl, pentenyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl or 4-phenylbutyl group,

for R, the hydrogen, fluorine, chlorine or bromine atom, the hydroxy, methoxy, ethoxy, propoxy, isopropoxy, methylsulfenyl, ethylsulfenyl, methylsulfinyl, propylsulfinyl, benzyloxy, 2-phenylethoxy or 3-phenylpropoxy group,

23543T

for R_ those of the hydrogen atom, the hydroxy, methoxy, ethoxy, propoxy or isopropoxy group or for R _β and R together are those of ^the methylenedioxy group,

for R "is the methyl, ethyl, propyl or isopropyl group

and ;

for E, the ethylene, n-propylene, n-butylene, n-pentylene, 1-methyl-n-propylene, 1-ethyl-n-propylene, 1-propyl-propylene, 1,1 Dimethyl-n-propylene, 1,1-diethyl-n-propylene, 1,1-dipropyl-n-propylene, 1-methyl-1-ethyl-n-propylene, 1-methyl-i-propyl n-propylene, 1-ethyl-1-propyl-propylene, 1-methyl-n-butylene or 1-methyl-n-pentylene group.

Here, the compounds of the general formula I in which R _{1 is} an amino group optionally substituted by a benzyl group or an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, an alkylamino or 'dialkylamino group, each alkyl part may contain 1 to 3 carbon atoms,

R is a hydrogen, chlorine, bromine or iodine atom, a trifluoromethyl, cyano or nitro group,

R 1 is a fluorine, chlorine or bromine atom or a cyano group,

R. is a hydrogen atom or a methyl group,

R ,. a hydrogen atom, an optionally substituted by a phenyl group alkyl group having 1 to 3 carbon atoms, an allyl or cyclopropyl group,

A is the methylene, ethylene or hydroxymethylene group and B is a group of the formulas

R ₈

-CH- (CH ₂ J _n - ^ ^)

or

235491 8

^R 6

- E

* 7

mean, where \

Rg, D and η are defined as mentioned in the beginning, '!

Rg is a hydrogen, fluorine or chlorine atom, a hydroxy, i methoxy, ethoxy, benzyloxy, methylsulfenyl or Me | thylsulfinyl group, i

R is a hydrogen atom or a methoxy group or R, and

R- together is a methylenedioxy group and E is n-propylene, 1-methyl-n-propylene, 1,1-dimethyl-n- _; propylene or n-butylene group or, if

A is the methylene or ethenylene group and / or I

R _{1 is} an amino group optionally substituted by a benzyl group or by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, an alkylamino or dialkylamino group, wherein each alkyl moiety may contain 1 to 3 carbon atoms, and / or R _{2 is} a trifluoromethyl group , Cyano or nitro group and / or R _{3 is} a fluorine atom and / or

R _{5 is} an optionally substituted by a phenyl substituted alkyl group having 1 to 3 carbon atoms, representing allyl or cyclopropyl group, the ethylene group, particularly favorable properties.

However, particularly preferred compounds of the above-mentioned general formula I are those in which

R _{1 is} an amino group optionally substituted by an ethoxycarbonyl group, an alkylamino or dialkylamino group, each alkyl portion containing from 1 to 3 carbon atoms

R _{0 can be} a hydrogen, chlorine or bromine atom or the cyano group,

23 54 9 1 8

R 1 is a fluorine or chlorine atom or the cyano group, R _{4 is} a hydrogen atom or the methyl group, R c is a hydrogen atom, an optionally substituted by a phenyl

group substituted alkyl group having 1 to 3 carbon atoms, the allyl or cyclopropyl group, A methylene or hydroxymethylene group and B is a group of formula

- E

means, where

Έ the n-propylene, 1-methyl-n-propylene, 1,1-dimethyl-n-propylene, n-butylene group or, when R _{1 is} the ethoxycarbonylamino group and / or R _{2 is} the cyano group and / or R ₃ Fluorine atom and / or R _{5 represents} an alkyl group having 1 to 3 carbon atoms which is optionally substituted by a phenyl group and represents the allyl or cyclopropyl group, and also the ethylene group,

R _{c is} a hydrogen atom, a hydroxy or methoxy group b

and R- represents a hydrogen atom or a methoxy group.

According to the invention, the new compounds are obtained by the following processes:

a) reduction of a compound of the general formula

CU)

> s

23 5 Λ 9 1 8

in the

R ₁ to R ₃ and R _{5 are} as defined above,

B _{1 is} a group of the formula

-C- (CH ₂ ; .- // ^) ~ _and

2'k

X is a group of the formula

- A " ¹ - CH- or

B _{1 has} the meanings mentioned for B and X is a group of the formulas

* ⁴ -CO-CH-,

OH R.

I ι ⁴

-CH- CH-,

O-acyl CH-CO-,

-A " ¹ -CO-,

Z R.

II ⁴

CH - CH - or

- CH - CH ₂ -CH -, where R. , Rg and R_ are as defined above,

i 1. M Ä HQ ö 0, *: (KiUIi / »λ

235491 8

A " ^{1 is} the methylene or ethylene group, k is the number 1,2 or 3,

Acyl is an organic acyl group such as the acetyl, propionyl or Benzoylgrüppe and

Z represents a reductively cleavable group such as a bromine or iodine atom or a carbonic acid ester radical such as the methoxycarbonyloxy or ethoxycarbonyloxy group.

Depending on the importance of the radical to be reduced, the reduction is expediently carried out in a suitable solvent such as methanol, methanol / water, ethanol, ethanol / water, isopropanol, trifluoroacetic acid, butanol, diethyl ether, tetrahydrofuran, tetrahydrofuran / water, dioxane or hexamethylphosphoric triamide a hydride, with aluminum isopropylate in the presence of a primary or secondary alcohol, with catalytically-promoted hydrogen or with nascent hydrogen at temperatures between -20 C and the boiling temperature of the reaction mixture, eg at temperatures between -20 ° C and 100 ° C, carried out.

For the preparation of a compound of the general formula I in which A represents the hydroxymethylene group, the reduction is conveniently carried out, for example, with a complex metal hydride such as sodium borohydride or lithium aluminum hydride in a suitable solvent such as methanol, methanol / water, diethyl ether or tetrahydrofuran at temperatures between -20 ° and 50 C, the reduction with aluminum isopropoxide in isopropanol at the boiling point and distilling off the acetone formed, the reduction with catalytically excited hydrogen with hydrogen in the presence of a catalyst such as platinum, palladium, Raney nickel or Raney cobalt at room temperature and at a hydrogen pressure of 1 -5 bar, and the reduction with nascent hydrogen, eg with activated metallic aluminum and water or with zinc and hydrochloric acid, carried out at temperatures up to the boiling point of the solvent used.

23549 1

- ίο -

If X in this case represents the -CO-CHR group in a compound of the general formula II, the reaction is expediently carried out at temperatures between 0 and 50 ° C., preferably at room temperature, e.g. with sodium borohydride in methanol / water, ethanol / water or isopropanol or with lithium aluminum hydride in diethyl ether or tetrahydrofuran as solvent,

0-acyl

or X is the --CH - CO- group, the reaction is preferably carried out with a hydride in a suitable solvent such as ether, tetrahydrofuran or dioxane, e.g. with diborane or lithium aluminum hydride in tetrahydrofuran at lower to

slightly elevated temperatures, e.g. at temperatures between 0 and 100 C, but expediently the reaction mixture, carried out.

0 and 100 C, but expediently at the boiling point

For the preparation of a compound of general formula I in which A represents the methylene or ethylene group

Conveniently, the reduction with a hydride such as sodium borohydride, lithium aluminum hydride, sodium cyanoborohydride or pyridine-borane in a suitable solvent such as ethanol, isopropanol, tetrahydrofuran, dioxane, trifluoroacetic acid or hexamethyl-phosphoric triamide at temperatures between 0 and 100 C.

X in this case denotes in a compound of the general formula II the -A "'- CO group or B ₁ the -CO- (CH ₂ )

Group, the reaction is preferably carried out at elevated temperatures, e.g. with lithium aluminum hydride in tetrahydrofuran at the boiling point of the reaction mixture, or X.

1 IMAI 1! Jr = Ui * in <« nn <n

5 Λ 9 1 8

-1Oa-

the hydroxyethylene group, the reaction is preferably carried out with pyridine-borane in trifluoroacetic acid at temperatures between 25 and 100 ° C, the reactant components conveniently at low temperatures, e.g. at -10 ° C, or X ZR. ZR

 I, 4 Γ 14

a -CH-CH- or -CH-CH ^ -CH group, the reaction is preferably carried out with sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride in a suitable solvent such as isopropanol, hexamethyl-phosphoric triamide, tetrahydrofuran or dioxane at temperatures between 20 and 100 ° C. carried out.

b) Reaction of a carbonyl compound optionally formed in the reaction mixture of the general formula

K-L, (III)

in the

K together with an adjacent hydrogen atom in the alkyl group of the radical L denotes an oxygen atom, L has the meanings mentioned for R at the outset or with the exception of the hydrogen atom, or a group of the formula

23 5 A 9 1

- 11 -

represents, where

R ₁ to R _{4 are} as defined above and

A ^{1 is} the carbonyl, methylene or

Represents ethylene group, or their aldehyde hydrate with a

Amine of the general formula

M H - N ', (IV)

in the

M and Q are different for B and R ₁ . have meanings mentioned above or one of the radicals M or Q, the group of the formula

R /

- CH - A

represents, where

R .. to R ₄ and A are as defined above, and a reducing agent.

The reaction is preferably carried out in a suitable solvent such as methanol, methanol / water, ethanol, ethanol / water, butanol, diethyl ether, tetrahydrofuran or dioxane in the presence of a reducing agent at temperatures between -20

23 5 A 9 1

- 12 -

and 50 C, but preferably at temperatures between 0 and 25 ° C performed. As a reducing agent here is a complex metal hydride or catalytically excited hydrogen into consideration.

However, if the reaction is carried out with a secondary amine of general formula IV, this is preferably carried out in tetrahydrofuran as solvent and with sodium cyanoborohydride at pH <7, e.g. at pH 6-6.5 and then with sodium borohydride at room temperature. ;

If the reaction is carried out with a primary amine of the general formula IV, the Schiff base formed in the reaction mixture is preferably mixed with a complex metal hydride such as sodium borohydride or lithium aluminum hydride in a suitable solvent such as methanol, methanol / water, diethyl ether or tetrahydrofuran at temperatures between - 20 C and the boiling point of the solvent used, eg at temperatures between 0 and 80 ° C, or with catalytically-promoted hydrogen, e.g. with hydrogen, in the presence of a catalyst such as platinum, palladium, Raney nickel or Raney cobalt, at temperatures between and 100 ° C, but preferably at room temperature, and carried out at a hydrogen pressure of 1-5 bar.

Methylation may also be carried out with formaldehyde and formic acid as the reducing agent at elevated temperatures, e.g. at the boiling temperature of the reaction mixture, carried out.

If the reaction is carried out with a compound of the general formula IV in which R.sup.1 is an amino or alkylamino group having 1 to 3 carbon atoms, and a carbonyl compound of the general formula III in which L has the meaning for R.sub.c, then this can be carried out in particular be alkylated using an appropriate excess,

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

A "- CH - N"

 V

B '

in the

R ₁ , R ₂ and R _{4 are} as defined above, R ₁ 'has the meanings mentioned above for R ₁ or a hydroxy or protected by a protective radical

Amino group, A "has the meanings mentioned for A or hydroxymethylene protected by a protective radical

group represents,

has the meanings mentioned for R ₅ or is a protective group for an amino group and has the meanings mentioned for B or

a group of formulas

B ¹

-CH- (CH ₂ ) _n -D

or

represents, where

235491 8

- 14 -

Rg, D, E and η are as defined above and Rg ¹ and R ₇ ¹ * which may be the same or different, have the meanings mentioned for Rg and R- above or represented by protecting groups protected hydroxy groups, wherein at least one of the radicals R ₁ '/ A ", R ₅ ¹ and / or B ^{1 represents} one of the abovementioned protective radicals, or must contain.

Examples of protective radicals are acyl radicals such as the ethoxycarbonyl, acetyl, propionyl or benzoyl group or the benzyl group and ';

for A "the acetyl / methoxycarbonyl or ethoxycarbonyl

group into consideration.

The cleavage of one of the abovementioned acyl and / or alkoxycarbonyl radicals is preferably carried out hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water,

Tetrahydrofuran / water or dioxane / water, in the presence of one;

Acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 C, preferably at the boiling temperature of the reaction mixture. ι

The cleavage of a benzyl radical is preferably hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon, in a solvent such as i

Methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ⁰ C, but preferably at room temperature, and a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

d) For the preparation of a compound of the general formula I in which one of the radicals R ₂ or R _{3 represents} a hydrogen atom:

Dehalogenation of a compound of the general formula

23 5 Λ 9 1 8

- 15 -

Hal

A-CH-N

, CVI)

in the

R ₁ , R ₃ to R ₅ , A and B are as defined above and Hai represents a chlorine, bromine or iodine atom.

The dehalogenation is preferably carried out in a solvent, expediently with Tripheny!. Phosphine in benzene or toluene, with hydrogen in methanol, ethanol, ethyl acetate or tetrahydrofuran and in the presence of a hydrogenation catalyst or with a complex metal hydride such as lithium aluminum hydride or sodium diethoxy-aluminum hydride in tetrahydrofuran, dioxane or toluene. Depending on the method used, the reaction is carried out at room temperature or elevated temperature, for example at temperatures between 60 and 150 C, and at atmospheric pressure or moderate pressure; when using Raney nickel or palladium / carbon, for example, the dehalogenation is carried out at room temperature and atmospheric pressure.

e) alkylation of a compound of the general formula

R /

A-CH-N

(VII)

- 16 -

in the

R ₁ to R and A are as defined above, R ₅ ^{11 has} the meanings mentioned for R ₅ or a hydrogen atom and

B "has the meanings mentioned for B, wherein, if R ₅ ^{11 is} not a hydrogen atom, at least one of R _β or R- is a hydroxy group or R _{1 is} an amino group optionally substituted by an alkyl group having 1 to 3 carbon atoms , wherein the alkyl group may additionally be substituted by a phenyl radical must represent.

The reaction is carried out in a solvent such as water / methanol, ethanol / water, tetrahydrofuran, dioxane, acetone or dimethyl sulfoxide with an alkylating agent such as methyl iodide, dimethyl sulfate, ethyl bromide, diethyl sulfate, benzyl bromide, 2-Phenyläthylbromid or methyl p-toluenesulfonate, optionally in the presence of Base such as sodium hydroxide or potassium carbonate advantageously at temperatures between -10 and 50 C, but preferably at temperatures between 0 and 30 ° C, carried out. However, the reaction can also be carried out without a solvent.

The alkylation of the nitrogen atom may also be effected by means of formaldehyde / formic acid at elevated temperatures, e.g. at the boiling temperature of the reaction mixture, or with a corresponding carbonyl compound and a complex metal hydride, preferably with sodium cyanoborohydride at pH <7, e.g. at pH 6-6.5, in a solvent such as water / methanol, ethanol, ethanol / water or tetrahydrofuran at temperatures between 0 and 50 ° C, but preferably at room temperature.

235491 8

- 17 -

Furthermore, the alkylation of a phenolic hydroxy group with a corresponding diazoalkane in a solvent such as diethyl ether or tetrahydrofuran at temperatures between 0 and 50 C, but preferably at room temperature, can be carried out.

f) For the preparation of a compound of general formula I, in

R _{1 is} an amino group substituted by an alkanoyl group having 1 to 3 carbon atoms or alkoxycarbonyl group having a total of 2 to 4 carbon atoms, and R _{1 is} not a hydrogen atom:

Acylation of a compound of the general formula

A-CH-N

(VIH)

in the

Rj to R ₅ , A and B are as defined above, with a

Compound of the general formula

Y-CO-R,

, (IX)

in the

R _{10 is} a hydrogen atom, a methyl or ethyl group or an alkoxy group having 1 to 3 carbon atoms, and Y is a nucleophilically exchangeable group such as a halogen atom, a nitrophenyl group, an imidazolyl group or a group

of the formula -0-COR ₁ - represents.

23 5 Λ 9 1 8

- 18 -

The reaction is carried out, for example, with acetyl chloride, acetic anhydride, propionic anhydride or a corresponding chloroformate, e.g. Ethyl chloroformate, which may also serve as a solvent, optionally in a solvent such as water / tetrahydrofuran, diethyl ether, tetrahydrofuran or methylene chloride, optionally in the presence of a base such as triethylamine or pyridine,! wherein a tertiary organic base is also referred to as j

Solvent can serve, at temperatures between O and j

100 C, but preferably at room temperature.

The reaction can also be carried out without a solvent

the. i

g) For the preparation of a compound of general formula I, in

D represents a sulfinyl or silyl group:; -j5 oxidation of a compound of general formula j

A-CH-N

CH - (CH) ι ^{2 η}

in the

R ₁ to Rg, A and η are as defined above and m represents the number 0 or 1.

The oxidation is preferably carried out in a solvent, for example in water, water / pyridine, ethanol, methanol, acetone, glacial acetic acid, formic acid, dilute sulfuric acid or trifluoroacetic acid, depending on the oxidant used, expediently at temperatures between -80 and 100 ° C.

 1

- 19 -

For the preparation of a sulfinyl compound of the general formula I, the oxidation is conveniently carried out with one equivalent of the oxidizing agent used, e.g.

 with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20 ° C or in acetone at 0 to 60 ° C ,; with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50 ° C or with m-chloroperbenzoic acid in methylene chloride or chloroform at -20 to 60 ° C, with sodium metaperiodate in aqueous methanol or ethanol at 15

10 to 25 ° C.

To prepare a sulphonyl compound of the general research ¹ mel I the oxidation is conveniently effected with one or mitι two or more equivalents of the oxidizing agent • used, for example with hydrogen peroxide in glacial acetic acid, tri- j fluoro acetic acid or in formic acid at 20 to 100 ° C or inI acetone at 0 to 60 ° C, with a peracid such as performic acid ¹ or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid,

Methylene chloride or chloroform at temperatures between 0 ^: and 60 ° C or potassium permanganate in glacial acetic acid, water / sulfuric acid or in acetone at 0 to 20 C.

h) for the preparation of a compound of general formula I,

in which D represents an oxygen or sulfur atom and R ₅ does not represent a hydrogen atom:

Reaction of a compound of the general formula

A ^m - CH - N _t

^ - CH - (CH) - V, (XI)

^{2 n}

^R 8

5.4 9 1 8

- 20 -

in the

R- to R-, Rg and η are as defined above,

V is a nucleophile exchangeable group such as a halogen atom or a sulfonic acid ester residue, e.g. a chlorine, bromine or iodine atom, a p-toluenesulfonyloxy or methanesulfonyloxy group, and

A " ¹ denote the methylene or ethylene group, with a compound of the general formula

HD '- (f

(XII)

R 7

in the Rg and R- are as defined above and

D ^{1 represents} an oxygen or sulfur atom, or their alkali or alkaline earth metal salt.

The reaction is conveniently carried out in a solvent such as chloroform, tetrahydrofuran, dioxane or toluene, but preferably in an anhydrous aprotic solvent such as acetone, dimethylformamide or dimethyl sulfoxide, optionally in the presence of an alkali metal base such as sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride or potassium tert-butylate Temperatures between -10 ° C and the boiling point of the solvent used, eg at temperatures between -10 and 1OO ° C, but preferably at temperatures between 0 and 50 ° C performed. However, the reaction can also be carried out without a solvent.

23 5 Λ 9 1 B

- 21 -

A compound of the general formula I which is obtained according to the invention and contains one, two or three optically active carbon atoms can subsequently be separated into its optically active antipodes, their diastereomeric racemates and into their optical antipodes by conventional methods.

The cleavage of a racemate of a compound of general formula I above is preferably carried out by a fractional crystallisation of a mixture of its diastereomeric salts with an optically active acid, e.g. D (-) - tartaric acid, L (+) - tartaric acid, dibenzoyl-D-tartaric acid, dibenzoyl-L-tartaric acid, (+) - camphor-10-sulphonic acid, L (-) - malic acid, L (+) -mandelic acid , α-bromobromate er-3T-sulfonic acid or 1-quinic acid and subsequent release of the respective optically active base. However, racemate resolution can also be achieved by column chromatography on an optically active support material, e.g. on acetyl cellulose.

• *

The preparation of the diastereomeric racemates is carried out, for example, by fractional crystallization and / or column chromatography on an inert support.

Further, if desired, a new compound thus obtained can be converted into its physiologically acceptable salts with inorganic or organic acids. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

The compounds of the general formulas II to XII used as starting materials are partly new. These are obtained by methods known per se.

23 5 Λ 9 1 8 -

18 '3.1982

AP C 07 C / 235 431/8

60 028 12

Thus, for example, a compound of general formula II wherein X is a -CO-CHR.-group is obtained by reacting a corresponding oc-halogenated ketone with a corresponding amine and a compound of general formula II in which X is the Represents -CHg-CO group, by reacting a corresponding phenylacetic acid derivative with a corresponding amine.

A compound used as starting material of the general formula III, in which A 'is the carbonyl group and R, a hydrogen atom, is obtained, for example, by selenium dioxide oxidation of a corresponding acetophenone or a compound of general formula III, in which A' is a methylene or Is ethylene group, by Überfuhrung a corresponding hydroxy compound in a corresponding halogen compound or by acylation of a corresponding hydroxy compound with a corresponding chloroformate and subsequent reduction.

A compound of general formula V used as starting material is obtained, for example, by reacting a corresponding co-phenylalkyl halide with a corresponding amine.

A compound of the general formulas VI, VII and VIII used as starting material is obtained, for example, by reduction of a corresponding carboxylic acid amide or aminoacetophenone.

A compound of the general formula X used as starting material is obtained, for example, by alkylation of a corresponding mercapto compound and optionally subsequent oxidation.

A compound of the general formula XI used as starting material is obtained, for example, by alkylation of a suitable phenylalkylamine <>

235491 8

- 23 -

As already mentioned, the new compounds have valuable pharmacological properties with low acute toxicity and low side effects, namely an effect on the heart and the circulation, in particular an effect on the blood pressure, an antiarrhythmic and / or cardiotoxic

niche effect.

For example, the compounds were

A = 1- (4-amino-3,5-dichloro-phenyl) -2- / N ~ / 3- (4-methoxy-phenyl) -propyl-7-amino-7-ethanol,

B = 1- (4-amino-3-cyano-5-fluoro-phenyl) -2- _< / N-> 3- (4-methoxy-phenyl) -propyl-methyl-amino / -ethanol,

C ss 1- (4-amino-3,5-dichloro-phenyl) -2- _< / N- (3-phenylpropyl) -2-propylamine / -ethanol hydrochloride,

D = 1- (4-amino-3,5-dichloro-phenyl) -2- / N- / 3- (4-hydroxyphenyl) -1-methyl-propyl / -lina-amino / -ethanol,

E = N- / T-methyl-2- (4-amino-3,5-dichloro-phenyl) -ethyl 7-N- / J- (4-methoxy-phenyl) -propyl-amine hydrochloride,

F = N- / 2- (4-amino-3,5-dichloro-phenyl) -ethyl 7-N- / 3- (4-chloro-phenyl) -propyl-Z-isopropylamine,

20G = N- / 3- (4-chloro-phenyl) -propyl-N- _i / 2 '- (3,5-dichloro-4-iso-propyramino-phenyl) -ethyl / -isopropylamine and

H = N- / 2- (4-amino-3-bromo-5-cyano-phenyl) -ethyl 7-N- / J- (4-methoxyphenyl) -butyl / -methylamine

examined for their biological effects as follows:

31

- 24 -

1. Measurement of the contractility parameter dp / dt__ "or the heart rate in anesthetized cats. :

Male and female cats weighing approximately 2-4 kg were anesthetized with pentobarbital sodium (40 mg / kg intraperitoneally) and pentobarbital sodium (8 mg / kg / hr) was continuously infused to maintain anesthesia

 - The animals breathed spontaneously.

The body temperature was with a heating pad and a

Thermostats kept at 38 ° C.

The pressure in the left ventricle was detected with a pickup advanced via the right ί aorta into the left ventricle ^pressure] (Millar PC 350) and from the pressure signal, the rate of pressure increase dp / dt with a differentiator determined continuously.

The heart rate was continuously measured with a Grass tachograph (Model 7P4). Either an ECG or the left ventricular pressure curve was used as the trigger signal. The registration of the parameters took place on a grass polygraph.

All substances were injected as a solution (water or polyethylene glycol 200) into a V. saphena. The dose was 0.3 mg / kg i.V. in each case.

The maximum effect and the time after the application up to which effect on half of the maximum effect decreased.

The following tables contain the found values:

23 5 Λ 9 1

- 25 -

Table I:

substance % Increase of Half-life ^d P / ^dt max in minutes A + 93 38 B + 124 > 140 C + 83 112 D + 105 > 100

Table II;

10

substance % Reduction of Half-life .Herzfrequenz in minutes • E -. 27 39 F - 17 150 G - 13 > 90 H - 14 > 52

15 ² · Acute toxicity;

Male and female mice weighing approximately 20 g received a dose of the respective test substance into a V. saphena (0.1 or 0.2 ml / 10 g body weight) or into the stomach. After an observation period of 14 days, the LD, - _{Λ was determined} by the method of Lichtfield and Wilcoxon:

 1

- 26 -

substance LD ₅₀ rag / kg iv p.o. " A C 19 32 > 100 250

Because of their pharmacological properties, the compounds according to the invention are suitable for the treatment of cardiac and circulatory diseases. Thus, the compounds which have a positive inotropic action, in particular for the treatment of heart failure, and the compounds which lower the heart rate, in particular for the treatment of cardiac arrhythmias and of coronary heart diseases are suitable.

For this purpose, the new compounds, optionally in combination with other active substances. into the usual galenic preparations such as dragees, tablets, powders, suppositories, suspensions, ampoules or drops. The single dose in adults is 1 to 4 times daily, 5 to 75 mg, but preferably 10 to 50 mg.

The following examples are intended to explain the invention in more detail:

23 54 9 1 8

- 27 -

example 1

1- (4-amino-3,5-dichloro-phenyl) -2- / N- (1- (4-methoxy-phenyl) -propyl ! L7-methylamino-2-ethanol "," ___ _ ™™™

To a solution of 3.45 g (9 mmol) of 4'-amino-3 ', 5'-dichloro-2- ^ / N- / 3- (4-methoxyphenyl) -propyl]. - methyl-amino. / acetophenone in 40 ml of methanol and 15 ml of water, 0.5 g (13.5 mmol) of sodium borohydride are added in portions. The pH is maintained between 3 and 6 with 2 η hydrochloric acid. After the addition is stirred for 30 minutes and concentrated on a rotary evaporator, the solution. The residue obtained is partitioned between 100 ml of ether and 100 ml of 2N ammonia solution. The ethereal phase is washed with water, dried with sodium sulfate and concentrated. The residual oil is treated with methylene chloride: methanol = 19: 1 as eluent over silica gel (Macherey

u. Nail 7Q - 230 mesh ASTM). The fractions containing the desired compound are combined, evaporated and freed of the oil obtained in vacuo at 40 C from solvent residues.

IR spectrum (methylene chloride)

25 UV spectrum (ethanol): \ max.

NH ₂ CH-

OCH ₃

N-alkyl

C = C

243 nra (0.23) 280 nm (0.08) 300 nm (0.08)

3610 cm

* " ¹

3400 + 3490 cm 2850 + 2940 cm * ¹

28 30 cm 2800 cm 1610 cm

"" ¹

Example 2

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- (3-phenyl-propyl) -methyl- amide ^ -ethanol-hydrochj-or id

10 g (0.035 mol) of 4'-amino-2-bromo-3 ', 5'-dichloro-acetophenone, 6.7 g (0.036 mol) of N- (3-phenyl-propyl) -methylamine-hydrochloride

23549 1

- 28 -

and 10.5 ml (0.075 mol) of triethylamine are added to 250 ml of methylene chloride. This mixture is heated for 6 hours at reflux temperature and then allowed to stand overnight at room temperature, washed with water, dried over sodium sulfate and concentrated on a rotary evaporator under vacuum. The oily residue, consisting of crude 4'-amino-3 ', 5'-dichloro-2-N- (3-phenyl-propyl) -raethylamine-7-acetophenone, is dissolved in 100 ml of 90% ethanol. With stirring and external cooling with water 'is added in portions 5 g of sodium borohydride. Allow to stand for 10 hours at room temperature and destroy excess sodium borohydride with acetone. After dilution with water, it is!

Extracted methylene chloride. The methylene chloride phase is separated off \, washed with water, dried over sodium sulfate

and concentrated on a rotary evaporator under vacuum. The yellow

The remaining oily residue is treated with methylene chloride: ethyl acetate =!

Chromatographed 4: 1 as eluent over silica gel. The ,

Fractions containing the desired compound are; evaporated. The remaining oily residue is dissolved in isopropanol, acidified with ethereal hydrochloric acid and admixed with 20 ml of ether until crystallization occurs. This gives a colorless crystalline product. i

Melting point: from 85 ° C (with sintering). :

Example 3 ί

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- / β- (4-hydroxy-phenyl) -1- methyl-propyl-methyl-amino-V ^ -ethanol ______

To an ice-cooled solution of 0.1 mol of 4'-amino-3 ', 5'-dichloro-2- / N -, / [3- (4-hydroxy-phenyl) -i-methyl-propyl-methylamino / -acetophenone in 300 ml of tetrahydrofuran and 50 ml of water, 0.2 mol of sodium borohydride are added in portions with stirring. The reaction solution is stirred for 60 minutes at room temperature and, after acidification with 2 N hydrochloric acid, the tetrahydrofuran is distilled off on a rotary evaporator. The obtained aqueous-hydrochloric residue is after addition of 8.5

2354 9 1 8

N Ammonia until the basic reaction 2 χ extracted with 250 ml of ether, then the ether extracts 2 χ washed with 75 ml of water and dried with magnesium sulfate. The filtrate is concentrated on a rotary evaporator and the resulting evaporation residue is purified on silica gel 60 (Macherey u. Nagel, 70 230 mesh, ASTM). Methanol = 30:: as eluent a mixture] of methylene chloride 1 is used. The fraction obtained after fractionation and concentration on a rotary evaporator; Vapor residue crystallizes after inoculation. The crude crystallizate is recrystallized from methylene chloride and is available as! 1: 1 mixture of diastereomeric racemates before. j

Melting point: 112-115 ° C. '

Example 4

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- / 3- (4-methoxy-phenyl) -1- methyl-propyl-Z-methyl-aminoghanol

0.02 mol of 1- (4-amino-3,5-dichloro-phenyl) -2- _/ / N- _< / 1- (4-hydroxyphenyl) -1-methyl-propyl-7-methylamino / -ethanol are in Dissolved 22 ml of 1 N sodium hydroxide solution and 10 ml of water. To this solution I while stirring and cooling with ice water dropwise 0.022 mole 'added <dimethylsulfate and stirred the reaction solution after addition of 50 ml of tetrahydrofuran for 20 hours at room temperature .; Subsequently, 100 ml of ether are added, the organic phase is separated off, washed with 50 ml of 0.5N sodium hydroxide solution, washed 3 times with [ 75 ml of water and dried over magnesium sulfate. The

The organic phase is concentrated on a rotary evaporator and the resulting evaporation residue over silica gel 60 (Macherey u. Nagel, 70-230 mesh, ASTM) with methylene chloride: methanol = 30: 1 as eluent. The oily evaporation residue obtained is filtered in vacuo over sulfuric acid from solvent residues.

freed. The resulting oil is present as a 1: 1 mixture of diastereomeric racemates.

23 54

- 30 -

IR spectrum (methylene chloride): OH

NH ₂ CH ₂ OCH.

-1

3 200 - 3500 cm (below NH ₂ ) 3480 + 3390 cm "

2930, 2850 cm " ¹ -1

wide

2830 cm

-1

1580, 1510, 1485 cm '

-1

UV spectrum (ethanol):

N-alkyl 2800 cm C = C

C = C + NH ₂ deformation 1620 cm max. 244 nm (0.27)

280 nm (0.08) 300 nm (0.08)

Example 5

1- (4-Xthoxycarbonylamino-3-cyano-5-fluoro-phenyl) oxy-phenyl-propyl-amino-quinolethanol

- ^ 3- (4-meth-

In a solution of 1.16 g (0.01 mol) of selenium dioxide in 12 ml of dioxane and 0.7 ml of water at 60 ° C with stirring 0.5 g of Celite and then 2.5 g (0.01 mol) of 4 '-Ethoxycarbonylamino-3'-cyan-5'-fluoro-acetophenone added in portions. The mixture is then heated for 4 hours at reflux temperature and then filtered from the insoluble. After cooling and cooling with ice, 2.01 g (0.01 mol) of 3- (4-methoxy-phenyl) are dissolved in the solution of 4'-oxo-carbonylamino-3'-cyano-5'-fluoro-phenylglyoxal thus prepared. Propylamine hydrochloride and 1.01 g (0.01 mol) of triethylamine, dissolved in 12 ml of ethanol, added dropwise. The crude 4'-ethoxycarbonylamino-3 ¹ -cyan-5'-fluoro-phenyl-3-glyoxylidene-3- (4-methoxyphenyl) -propylamine containing solution is added with stirring and cooling with ice in portions with 1.5 g of sodium borohydride and allowed to stand overnight at room temperature. Subsequently, excess sodium borohydride is destroyed with acetone, concentrated under reduced pressure to a small volume, mixed with water and extracted with methylene chloride. The methylene chloride solution is washed with water, dried with sodium sulfate and evaporated to dryness in vacuo. The

23 5 Λ 9 1

- 31 -

residual oily residue is chromatographed over 200 g of silica gel with methylene chloride / methanol = 20: 1 as eluent. The fractions containing the desired compound are evaporated. This gives a colorless crystalline product.

Melting point: 111-112 ° C.

Example 6

1-M-ethoxycarbonylamino-S-cyano-S-fluoro-phenyl) -2- ^ N- [ 3- (4- methoxy-phenyl) -propyl] -methylamine- diethanol

In a solution of 6.6 g (0.06 mol) of selenium dioxide in 60 ml of dioxane and 2 ml of water at 60 ° C with stirring 15 g (0.06 mol) of 4'-Äthoxycarbonylainino-3'-cyan-5 ' Fluorinated acetophenone added in portions. The mixture is then heated at reflux temperature for 4 hours, then diluted with 100 ml of tetrahydrofuran and filtered off from the insoluble matter. To the thus prepared solution of 4'-ethoxycarbonylamino-3'-cyano-5'-fluoro-phenylglyoxal, after cooling at room temperature, 10.7 g (0.06 mol) of N- (3- (4-methoxy-phenyl) -propylamine / triethylamine dissolved in 100 ml of tetrahydrofuran. 8 g (0.13 mol) of sodium cyanoborohydride are added in portions to this solution, the solution being kept at pH 6 by the dropwise addition of 2N hydrochloric acid. It is allowed to stand overnight at room temperature, mixed with 5 g of sodium borohydride and allowed to stand again for 5 hours at room temperature. Subsequently, excess sodium borohydride is destroyed with acetone, diluted with water and extracted with methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The remaining oily residue is chromatographed with ethyl acetate as eluant over 700 g of silica gel. The fractions containing the desired compound are combined, evaporated and the resulting oil was freed from solvent residues in vacuo at 40.degree.

23 5 Λ 9 1 8

- 32 -

IR spectrum (methylene chloride): OH 3600 cm NH 3400 cm CH ₂ 2930 cm OCH ₃ 2830 cm N-alkyl 2800 ent CN 2 2 20 cm NHCCX) C ₂ H ₅ 1735 cm

UV spectrum (ethanol): Jl max.

UV spectrum (ethanol + KOH)

-1 -1 -1 -1 -1 -1 -1

228 nm (shoulder, 0.19) 240 nm (shoulder, 0.12) 285 nm (0.06)

Max. 223 nm (shoulder, 0.39)

253-265 nm (shoulder; 0.1)

318 nm (0.06)

Example 7

N- ^ 2- (4-amino-3-bromo-phenyl) -ethyl 7-N- _i / 3- (4-methoxyphenyl) -propyl-7-methylamine dihydrochloride

2.9 g (0.077 mol) of lithium aluminum hydride are suspended in a nitrogen atmosphere in 100 ml of absolute tetrahydrofuran. For this purpose, a solution of 14.4 g (0.031 mol) of 4-amino-3,5-dibromo-N- ^ 3- (4-methoxy-phenyl) -propyl7-N ~ methyl-phenylacetic acid amide in 100 ml of absolute tetrahydrofuran added dropwise with stirring at room temperature. Subsequently, one hour is heated to reflux. With ethyl acetate and water, the excess lithium aluminum hydride is decomposed and 10 η sodium hydroxide solution is added dropwise until the inorganic material precipitates as granules. The supernatant tetrahydrofuran phase is decanted off, dried over sodium sulfate and concentrated on a rotary evaporator. The mixture is chromatographed over silica gel (Macherey u. Nagel, 70-223 mesh ASTM) using methylene chloride / methanol = 19: 1 as eluent. The fractions with the desired product are combined and concentrated. The resulting oil is dissolved in a little absolute ethanol and prepared with ethanolic hydrochloric acid with the addition of ether, the crystalline dihydrochloride. Melting point: 168-171 ° C (dec.).

23 5Λ9 1 8

- 33 -

Example 8

N- £ 2- (4-Amino-3,5-dibromo-phenyl) -ethyl 7-N- ₁ / 4- (4-methoxyphenyl) - ^! butyl7-methylamine ^^ ,. " _f ... _T ,. "" ^. . "

2.9 g (0.077 mol) of lithium aluminum hydride are in a stick! suspended in 100 ml of absolute tetrahydrofuran, j To this is added a solution of 15.0 g (0.031 mol) of 4-amino-3,5-di-bromo-N - /, 4- (4-methoxyphenyl) -buty ^ 7 "" N-methyl-phenylacetic acid; amide in 100 ml of absolute tetrahydrofuran was added dropwise with stirring at room temperature. Then one hour is heated to the reflux. With ethyl acetate and water, the excess lithium aluminum hydride is decomposed and 10 η sodium hydroxide solution is added dropwise until the inorganic material precipitates as granules. The supernatant tetrahydrofuran phase is decanted off, dried over sodium sulfate and concentrated on a rotary evaporator. Methylene chloride: methanol = 19: 1 as eluent is chromatographed on silica gel (Macherey and Nagel, '70-230 mesh ASTM). The fractions containing the desired product are combined and concentrated. The resulting oil is freed from solvent residues in vacuo at 40.degree.

IR spectrum (methylene chloride): NH ₂ 3380 + 3470 cm ^-1

N-alkyl 2790 a " ¹

OCH ,. 2830 cm "" ¹

- aliphatic. CH ₂ 2850 + 2930 cm

C = C 1610 cm " ¹

UV spectrum (ethanol) i \ max. 246 nm (0.24)

281 nm (0.08)

305 nm (0.09)

23549 1

- 34 -

Example 9

N- ^ 2- (4-Amino-S-chloro-5-cyanophenyl) phenyl) -propyl-methylamine

-N- £ 3- (4-methoxy-

6.6 g (0.014 mol) of 1- (X-thoxycarbonyloxy) -1- (4-amino-3-chloro-5-cyanophenyl) -2 - ^ - / 3- (4-methoxyphenyl) -propyl V-methylamine? ethane is dissolved in 70 ml of isopropanol and stirred at room temperature overnight with 5.5 g (0.14 M sodium borohydride) The resulting solution is concentrated to dryness and taken up in 100 ml of water With 50 ml of 2N hydrochloric acid, the excess sodium borohydride is destroyed The mixture is then basified again with 100 ml of 2N ammonia and extracted twice with 150 ml of ethyl acetate The organic phase is dried with magnesium sulfate and concentrated The resulting oil is treated with methylene chloride: methanol = 19: 1 as eluant over silica gel (Macherey et al Nagel, 70-230 mesh ASTM) The fractions containing the desired compound are combined and evaporated, and the resulting oil is freed of solvent residues in vacuo at 40 ^° C. IR spectrum (methylene chloride): NH ² .

N-alkyl allphat. CEL · aromat. C = C

NH ₂ deformation

3400 + 3500 cm 2800 cm " ¹ 2860 + 2940 cm

1600 cm 1625 cm

-1

-1

UV spectrum (ethanol): λ max. 244 nm (0.23)

278 nra (0.06) 330 nra (0.13)

Example 10

N- / 2- (4-amino-3-chloro-5-cyano-phenyl) -ethyl-N- (3- (4-methoxy- phenyl) -propyl) -diethylamine

1.3 g (0.0027 mol) of 1- (4-amino-3-chloro-5-cyano-phenyl) -2- / N- / 3- (4-methoxyphenyl) -propyl-7-methylaminoy-ethyl iodide in

23 54 9 1 8

- 35 -

Dissolved 30 ml of hexamethylphosphoric triamide. To this solution is added 0.25 g (0.004 mol) of sodium cyanoborohydride and heated ^; then for 3 hours at 70 ° C. After cooling, the mixture is diluted with 100 ml of water and extracted with ether. The ethereal solution is washed with water, dried over sodium sulfate and concentrated to dryness in vacuo. The remaining oily residue is purified over silica gel with methylene chloride: methanol =; Chromatographed 20: 1 as eluent. The preserved oily | Evaporation residue is freed of solvent residues in vacuo. Mass spectrum: found M ⁺ 357/59 j

Molecular weight: 357.8. I

! i

Example 11 '

1- (4-Amino-3-fluoro-phenyl) -2- £ N- / 3- (4-methoxyphenyl) -propyl -7-methylamino-7-ethanol :

• *

A solution of 3.9 g (0.0955) of 1- (4-amino-3-bromo-5-fluorophenyl) -2- / N- / 3- (4-methoxyphenyl) -propyl-7-methyl-amino-7-ethanol in 50 ml of methanol is added 2 g of 10% palladium / carbon perl and in an autoclave at room temperature and a pressure of 3.5 bar; hydrogenated. After the theoretically calculated amount of hydrogen:

is absorbed, is filtered off and the filtrate is concentrated on a rotary evaporator. The resulting 4 g of oil are chromatographed on silica gel (Macherey u. Nagel, 70-230 mesh ASTM) with eluent chloroform: methanol = 19: 1. The ^: fractions containing the desired substance are

united and concentrated. The resulting oil is dissolved in isopropanol and the hydrochloride is precipitated with isopropanolic hydrochloric acid and ethyl acetate. The crystals are filtered off, washed with a little cold isopropanol and dried in vacuo

 Melting point: 11O ° C (dec.).

235 Λ 9 1

Example 12

1-M-A'-thoxycarbonylamino-S-bromo-phenyl) -2- / N- / J- (4-methoxy- phenyl) -butyl-methyl-amine-pyhanol

To a solution of 5.1 g (0.0125 mol) of 1- (4-amino-3-bromo-phenyl) 2-N- / 3- (4-methoxyphenyl) -butyl-7-methyl-7-aminoethanol 40 ml of absolute pyridine are added under ice-cooling at ⁰ ° C. 1.5 ml (0.015 mol) of ethyl chloroformate. The resulting solution is kept overnight at +4 ⁰ C in the refrigerator. Subsequently, the pyridine is distilled off on a rotary evaporator at 50 ° C. The resulting oil is dissolved in 100 ml of methylene chloride and washed twice with 100 ml of water. The organic phase is dried over sodium sulfate, filtered and evaporated on a rotary evaporator. The resulting oil is chromatographed over silica gel 1i (methylene chloride: methanol = 9: 1 as eluant) (Macherey & Nagel, 70-230 mesh ASTM). The fractions containing the desired substance are combined and concentrated. The resulting oil is freed from solvent residues in vacuo at 40.degree. IR spectrum (methylene chloride): OH

20 NH

OCH ₃ N-alkyl aliphatic. CH ₃ C = O

aromat. C = C UV spectrum (ethanol): Λ max. 224 nrn (0.42)

; 240 nra (0.29) 280 nm (0.04)

3610 cm 3400 era 2830 cm 2800 cm

-1

-1 -1 -1

2850 + 2940 cm

1735 cm 1610 cm '

-1 -1

235491 8

- 37 -

Example 13

N- / 2- (4-amino-3,5-dichloro-phenyl) -ethyl V-N - /! - (4- hydroxyphenyl ) -1-methyl-propyl-7-methylamine ___

0.012 mol of N - ^ - (4-amino-3,5-dichloro-phenyl) -äthyy-N - / _ 3- (4-hydroxyphenyl) -1-methyl-propyl / -amine are dissolved in 13 ml of 1 N sodium hydroxide solution solved. Under ice-water cooling, the solution of O7OI4 mol of dimethyl sulfate are added dropwise. It falls after a short time, the reaction product greasy, which is dissolved by the addition of 150 ml of tetrahydrofuran. The reaction!

The solution is stirred for 24 hours at room temperature and then extracted 2 times with 150 ml of ether. The organic extracts are washed with water, dried over magnesium sulfate and concentrated in vacuo. The resulting evaporation residue was purified over silica gel (Polygosil 60-1525, Macherey and Nagel) with methylene chloride: methanol / conc. Amraoniak-19: 1: 0.1. The oily evaporation residue is freed from adhering solvents in vacuo over potassium hydroxide.

-1

IR spectrum (methylene chloride):

OH 3580 cm cm cm NH ₂ 3 4 80 + 3380 2850 CH ₂ 2930 , 2960, cm N-alkyl 2790 cm 1480 cm C = C 1580 , 1510, 1610 C = C + NEL deformation

UV spectrum (ethanol) UV spectrum (ethanol + KOH): S

Max. 240 ran (0.26, shoulder)

288 nm (0.08)

301 nm (0.08)

Max. 241 rim (0.56)

299 nm (0.17)

23 5 4 9 1 8 - ³⁸ -

Example 14

1- (4-Amino-3,5-dichloro-phenyl) -2- ^ N- ^ 2 ~ (4-methoxyphenylsulfinyl ) ethyl / methylaminoV- ethanol · .. ·

7.0 g of 1- (4-amino-3,5-dichloro-phenyl) -2- / N- / 2- (4-methoxyphenylsulfenyl) -ethyl 7-methylamino-7-ethanol are dissolved in 100 ml of glacial acetic acid and stirred At room temperature with 2.0 g of 30% hydrogen peroxide added dropwise. The mixture is stirred overnight at the same temperature and then the solution is evaporated in vacuo. The residue is taken up in water and combined with potassium carbonate until the basic reaction. It is extracted with dichloromethane, the organic phase is washed with water, dried with magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography (column: 40 × 200 mm, Kieselgel 60, from E. Merck, particle size: 0.06-0.2 mm, methylene chloride: methanepl = 50: 1). After evaporation of the desired fractions in vacuo, the substance mentioned remains as an oil.

IR spectrum (methylene chloride): NH ₂ 3 390 + 3480 cm "

CH ₂ 2940 cm " ¹

OCH ₃ 2840 cm " ¹

N-alkyl 2800 cm " ¹ C = C 1590, x 1510 + 1480 cm" x ¹

ι S = O 1040 cm "(shoulder)

UV spectrum (ethanol): * \ max. 244 nm (0.54) 300 nm (0.07; shoulder)

2T5 4 "9T ~ 8

Example 15

t- (4-amino-3 _r 5-dichloro-phenyl) -2- £ N- £ 2- (4- methoxyphenylsulfonyl) -ethyl / methylamino / -ethanol

7.0 g of 1- (4-amino-3 ', 5-dichloro-phenyl) -2- / N- / 2- (4-ethylthiophenyl-sulfenyl) -äthy! / - methylaminoZ-ethanol, as in the example 14 | described converted into the sulfinyl derivative. The residue (4.7 g) obtained after evaporation of the dichloromethane extract is dissolved in 1 (X) ml of dioxane and 30 ml of water, and 4.0 g of magnesium sulphate are added. While stirring, 2.5 g of 10-pulverized potassium permanganate are added in portions. After completion of the addition, stirring is continued for two hours and then filtered undissolved over

Celite off. The dioxane is removed in vacuo and partitioned between dichloromethane and water. The evaporation residue of the dried organic phase is purified by chromatography 15 × (1st column: 60 × 300 mm, Al ₃ O ₃ II neutral, methylene chloride tetrahydrofuran = 5: 1, 2nd column: 35 × 300 mm, silica gel 60, from E. Merck, particle size: 0.015-0.025 mm, dichloromethane, 8.5 bar). After evaporation of the desired fractions in vacuo, the substance mentioned remains as an oil. 20 | IR spectrum (methylene chloride): NH ₃ 3395. + 3480 cm "

CH ₂ 2940 cm "" ¹

OCH ₃ 2840 cm ^-1 N-alkyl 2800 cm ^-1 C = C 1595, 1520 +

25 | '1495 cm " ¹

j. SO ₉ 1150 + 1315 cm " ¹

_: ÜV spectrum (ethanol): Λ max. 241 nm (0.59)

300 nm (0.09)

2354

% J - 40 Example 16 1- (4-Amino-3,5-dichloro-phenyl) -2- ^ N- £ 3- (4-hydroxyphenyl) -pro-

9.2 g of 1M4-amino-3,5-dichloro-phenyl) -2- £ N-3- (4-benzyloxyphenyl) -propyl-7-methylamino-7-ethanol are dissolved in 150 ml of methanol. The solution is treated with 1 g 5% palladium / carbon added and hydrogenated at room temperature under a pressure of 5 bar hydrogen. After recording the calculated amount of hydrogen, the catalyst is filtered off / the solution is evaporated ^to dryness on a rotary evaporator and the oily residue with methylene chloride / methanol = 20: 1 as the eluent chromatographed on silica gel. The fractions containing the desired compound are combined, evaporated and the resulting oil is freed of solvent residues in vacuo at 40 ° C. IR spectrum (methylene chloride): OH - 3580 cm ^-1

'' NH ₂ '' 3395 + 3495 cm ' ¹

N-alkyl 2800 cm ^-1 .

Example 17

1- (4-amino-3-bromo-phenyl) -2- ^ N-4- (4-methoxy-phenyl) -butyl -methyl-amino-7-ethanol * ___ ™ __,

3 g of 1- (4-acetamino-3-bromo-phenyl) -2- ^ - ^ 4- (4-methoxyphenyl) -butyl-7-methylamino-ethanol are heated to reflux temperature in 100 ml of half-concentrated hydrochloric acid for one hour. After cooling, it is alkalized with 10 N sodium hydroxide solution, extracted with methylene chloride, the methylene chloride solution is washed with water, dried over sodium sulfate and concentrated to dryness in a rotary evaporator. The residual oil is chromatographed over silica gel with methylene chloride / methanol = 20: 1 as eluent. From the fractions containing the desired compound, they are obtained by evaporation in vacuo at 40 ° C as an oil.

23549 1

UV spectrum (ethanol)

, λ

-

IR spectrum (methylene chloride): OH

-1

Max.

OH C = C nm 3590 cm NH 224 nm 3 3 80 + 34 70 cm 243 nm 2800 -1 cm 280 nm 2830 - I cm N-alkyl 300 2 8 50 + 29 30 cm -1 OCH ₃ 16 20 cm aliph (0.20) arom. (0.14) (0.04) (0.04)

Example 18

1- (4-amino-3-cyano-5-fluoro-phenyl) -2-_N-_l ~ (4-raethoxy-phenyl) -propyl-7-methyl-amino-7-ethanol

Prepared from 4'-amino-3'-cyano-5'-fluoro-2-_N-3- (4-methoxy)

15-phenyl) -propyl-7-methylamino-7-acetophenone and sodium borohydride

in 90% methanol analogously to Example IR spectrum (methylene chloride): OH

-1

NH

₂ OCH ₃

N-alkyl CeN

NH ₂ deformation aromat. C = C 1 25 uv spectrum (ethanol): \ max. 242 nm (0.3)

nm (0.14).

3590 cm 34 90 cm 3400 + 2 9 40 cm 2 8 50 + -1 2830 cm -1 2,800 cm - 1 2210 cm -1 -1 1635 1610 cm cm

Example 19

1- (4-Amino-3-bromo-5-cyano-phenyl) -2- propyl-7-methylamine q-ethanol

~ / j- (4-methoxyphenyl) -

30 Prepared from 4 x -Arai.no-3'-bromo-5-cyano-2-N-3- (4-methoxyphenyl) -propyl-7-methylamine-acetophenone and sodium borohydride in 80% methanol as in Example 1.

23 5 Λ 9 1 8

IR spectrum (Methylene chloride): OH 359O cm weak NH ₂ 3400 + 3480 cm " ¹ CH ₂ 2850 + 2930 on C = N 2200 cm

C = C 1640 cm

UV spectrum (ethanol): \ max. 243 run (0,20)

280 nm (0.04)

-1

334 nm (0.12).

10 Example 20

1- (4-Amino-3,5-dibromo-phenyl) -2- ^ N- ^ 3- (4-methoxyphenyl) -pro pvl7-methvlaminQ 7-ethanol · ___

Prepared from 4 · -Αιη1ηο-3 ', 5 ¹ -dibromo-2- / N- £ 3 (4-methoxy-phenyl) -propylj methylaminc-^ acetophenone and sodium borohydride in 80% methanol as in example 1

 IR spectrum (methylene chloride): OH

UV spectrum (ethanol):

Example 21

N-alkyl "OCH ₃

aliphatic. CH ₂ C = C

Max. 244 nm (0.16) 303 nm (0.06).

3590 cm 3380 2800 cm 2830 cm 2850 1610 cm

-1

34 60 cm

"ι

-1

2940 cm

-1

1- (4-amino-3,5-dichloro-phenyl) -2- / β-β, 1-dimethyl-3- (4-methoxy- phenyl) -propyl -amino- ethanol ·

Prepared from 1- (4-amino-3,5-dichloro-phenyl ) -2- / β- , 1-dimethyl-3- (4-hydroxyphenyl) -propyl-7-amino-7-ethanol, tetrahydrofuran, caustic soda and Dimethyl sulfate analogously to Example 13. Oil.

30 IR spectrum (methylene chloride): OH

3600 cm " ¹

3390 + 3490 cm "

2860 + 2960 cm '

2830 cm " ¹

* · 1 Λ 3o «m

-1

23549 1

- 43 -

UV spectrum (ethanol): Λ max. 24 3 nm (0.2 3)

280 nm (0.08)

300rim (0.0S)

Example 22

1- (4-Amino-3,5-dichloro-phenyl) -2- / N £ i, 1-dimethyl-3 ~ (4-methoxy-

phenyl) -propyl-7-methylamino-atha .nol ^ ^

Prepared from 1- (4-amino-3,5-d ± chloro-phenyl) -2- / N- ^ ¹ 1,1-dimethyl-3- (4-hydroxyphenyl) -propyl-2-ylamine. ethanol,

Tetrahydrofuran, caustic soda and dimethyl sulfate analogue example 13. Oil.

Calc .: C 61.31 H 6.86 Cl 17.24 N 6.81 F .: 61.13 6.99 17.25 6.75

Example 23

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2- / N- (1- (4-methoxy- phenyl) -propyl-Z-methylamino) -ethanol

Prepared from 4'-amino-S'-chloro-S'-trifluoromethyl-2'-N- ^ 3- (4-methoxyphenyl) -propyl-7-methylamino-7-acetophenone and sodium borohydride in 80% methanol as in Example 1. IR spectrum (methylene chloride): OH 3590 cm ^-1

NH ₂ 3410 + 3510 cm " ¹

N-alkyl 2800 cm ^-1 OCH ₃ 2830 cm " ¹

aliphatic. CH ₂ 2850 + 2940 cm " ¹ C = C 16 30 cm" ¹

UV spectrum (ethanol): * X max. 225 nm (0.36)

245 nm (0.31 280 nm (0.05) 310 nm (0.1).

23 5 49 1 8

- 44 -

Example 24

"1- (3,5-dichloro-4-hydroxy-phenyl) -2- / Ν- 3- (4-methoxyphenyl) -propyl- 7-methylamino-7-ethanol ___ .___

Prepared from 3 ¹ , 5'-dichloro-4'-hydroxy-2- / N- / 3- (4-methoxyphenyl) -propyl_7-methylamino / acetophenone and sodium borohydride in 80% methanol as in Example 1. Melting point: 156- 157 ° C.

Example 25

1- (3,5-dibromo-4-hydroxy-phenyl) -2- / N- / 3- (4-methoxyphenyl) -propyl-7-methylamino-7-ethanol

Prepared from 3 ', 5'-dibromo-4'-hydroxy-2- / N- / 3- (4-methoxyphenyl) -propyl-7-methylamino / acetophenone and sodium borohydride in 80% methanol as in Example 1.

Melting point of the hydrochloride: 159-162 ° C.

Example 26

! 1- (4-amino-3-bromo-5-fluoro-phenyl) -2- / N- _- / 3- (4-methoxyphenyl) -propyl; L / -methylamino / ethanol

Prepared from 4-amino-3'-bromo-5'-fluoro-2- / N- / 3- (4-methoxyphenyl) -propyl-7-methylamino] -7-acetophenone and sodium borohydride in 80% methanol as in Example 1. Melting point hydrochloride (amorphous): from 60 ° C.

Example 27

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2- ^ N- / 1- (4-methoxyphenyl) -propyl-7-methylamino-7-ethanol _____

Prepared from 4'-amino-3'-chloro-5'-fluoro-2- / N- / 1- (4-methoxyphenyl) -propyl-methylamine-acetophenone and sodium borohydride

23 5 Λ 9 1 8

in 80% methanol as in Example 1. Melting point of the hydrochloride: 103-108 "" C (dec.).

Example 28

1- (4-Amino-3-chloro-5 -cyanophenyl ) -2- propyl-7-methylamine-Q7-ethanol

- £ 3- (4-methoxy ~ phenyl) -

UV spectrum (ethanol): * Xmax,

3400 + 3500 cm -1

Prepared from 4'-amino-3'-chloro-5 ^l -cyan-2 · - · / N- / 3- (4-methoxyphenyl) -propyl-7-methylamino-7-acetophenone and sodium borohydride in 80% methanol analogously to Example 1.

IR spectrum (methylene chloride): OH 3590 cm

, NH ₂

" N-alkyl 2800 cm

OCH ₃ 2830 cm '

aliphatic. CH ₉ C = N 2210 cm

15- C = C 1625 cm

Do (0.26) nm (0.06) nm (0.16).

-1

2850 + 2940 cm -1

Example 29

1- (4-amino-3-chloro-5-nitro-phenyl) - propyl7-methylaminQ / -Sthanpl · ^ _

(4-methoxy-phenyl) -

Prepared from 4'-amino-3'-chloro-5'-nitro-2 '/ _N-3- (4-methoxyphenyl) -propyl-7-methylamino-acetophenone and sodium borohydride in 80% methanol as in Example 1.

IR spectrum (methylene chloride): OH

N-alkyl OCH ₃

aliphatic

C = C

3590 cm " ¹

3390 + 3500 cm "- 1

2800 cm 2 830 cm "

 1

2850 + 2940 cm

1630 cm " ¹

1330 + 1515 cm

-46 -

UV spectrum (ethanol): \ max 227 mn (0.64)

280 nm (0.16) 400 nm (0.12)

Example 30

1- (4-Amino-3-chloro-phenyl) -2- ^ N- £ "3- (4-methoxyphenyl) -propyl / methylamino-7-ethanol

Prepared from 4'-amino-3 ^1- chloro-2 - ^ - / 1- (4-methoxyphenyl) -propyl-3-methylamino-7-acetophenone and sodium borohydride in 80%

methanol according to Example 1.

10 IR spectrum (methylene chloride):

OH

NH ₂

N-alkyl

OCH ₃

allphat.

C = C

3600 cm

-1

3380 + 3470 cm 2800 cm " ¹ 2830 cm" i 2850 + 2940 cm 1620 cm "" ¹

-1

-1 !

UV spectrum (ethanol) : \ max. 225 nm (0.44)

243 nm (0.36)

280 nm (0.09)

295 nm (0.08).

20 Example 31

1- (4-Amino-3-bromo-phenyl) -2- £ N -, / 3- (4-methoxyphenyl) -propyl / methylamino-7-ethanol

Prepared from 4'-amino-3 ¹ -bromo-2- / N- 3- (4-methoxyphenyl) -propyl-7-methylamino-acetophenone and sodium borohydride in 80% methanol analogously to Example 1.

Melting point of dihydrochloride: 137 ° C (dec.).

23 5 4 9 1 8

Example 32 .

1- (4-Amino-3,5-dicyano-phenyl) -2- / N- / 3- (4-methoxyphenyl) -methylamino / -ethanol

Prepared from 4'-amino-3 ·, 5'-dicyano ^ -, ^ - /! - (4-methoxyphenyl) -r propyl7-methylamino7-acetophenone and sodium borohydride in 80% methanol as in Example 1. j

Melting point of the hydrochloride: 167-170 ° C. ι

Ί Example 33 j

1- (4-amino-3-bromo-phenyl) -2- / N- £ 4- (4-methoxy-phenyl) -butyl- methylamine-ethanol ______ »______ ^ ™™™™ ^» ^^ ™™ - ™™ -.

Prepared from 4'-amino-3 ^l -bromo-2 - ^ - _< / 4- (4-methoxyphenyl) -butyl-1-methylamine-acetophenone and sodium borohydride in 80% methanol analogously to Example 1.

IR spectrum (methylene chloride): OH. 3590 cm " ¹ 15 'NH_ 3380 + 3470 cm" ¹

N-alkyl 2,800 cm "" ¹

: OCH, 2830 cm "" ¹

³ -1

• .aliphatic. CH ₀ 2850 + 29 30 cm

-1 C = C 16 20 cm

UV spectrum (ethanol): * \ max. 224 nm (0.44)

243 nm (0.28)

280 nm (0.08)

300 nm (0.06).

Example 34

1- (4-Amino-3-bromo-phenyl) -2- / N- (Zj- {4-methoxy-phenyl) -äthy 1 / -methylamino-7-ethanol ].

Prepared from 4 ^l -Amino-3 "'- bromo-2- ^ i- 2- (4-methoxyphenyl) ethyl ^ -methylaminc ^ acetophenone and sodium borohydride in 80 ml of methanol analogously to Example 1.

23 5 Λ 9 1 8

IR spectrum (methylene chloride): - OH

NH.

UV spectrum (ethanol): \ max.

N-alkyl

OCH ₃

aliphatic. CH ₃

C = C

nm (0.43) nm (0.36) nm (0.08) nm (0.08).

3590 cm

3380 + 3470 cm -1

2800 cm 2830 cm '

-1

2840 + 2940 cm

1620 cm

-1

Example 35

1- (4-Amino-3,5-dichloro-phenyl) -2- ^ N- / 4- (4-methoxyphenyl) -butyl-7-methylamino-7-ethanol

Prepared from 4 · amino-3 ·, 5'-dichloro-2- / N-_i4- (4-methoxy-phe-15-nyl) -butyl-7-methylamino-7-acetophenone and sodium borohydride in 80% methanol analogously to Example 1

IR spectrum (methylene chloride): OH 3590 cm ^-1

339O f 3490 cm

-1

I N-alkyl

20! OCH ₃

i is aliphatic. CH ₂

; C = C

UV spectrum (ethanol): \ max. 245 nm (0.25): 320 nm (0.48).

2800 cm 2830 cm

-1

2850 + 29 30 cm 1610 cm

Example 36

1- (4-Amino-3-bromo-5-cyano-phenyl) -2- £ N- / 4- (4-methoxyphenyl) -butyl-myhanol7-ethanol _____

Prepared from 4 '-Amino-3'-bromo-5 ¹ -cyan-2- _/ / N - ^ _ 4- (4-methoxyphenyl) -butyl ^ -methylamingy-acetophenone and sodium borohydride in 30 80% methanol analogously to Example 1.

235491

 1

3390 + 3490 cm -1

IR spectrum (methylene chloride): OH 3590 era

NH ₂

N-alkyl 2800 cm '

OCH ₃ 2830 cm "

aliphatic. CH ₂

CsN 2210 cm

C = C 1620 cm

UV spectrum (ethanol): Λ max. 245 nm (0.27)

278 nm (0.08) 330 nm (0.15).

 1

2850 + 2930 cm.-1

-

Example 37

1- (4-Amino-3-bromo-5-cyano-phenyl) -2- ^ N- / 2- (4-methoxy-phenyl) ethyl-7-methyl-amino-7-ethanol

Prepared from 4'-amino-3'-bromo-5 ^l -cyan-2- ₍ / N- _J / 2- (4-methoxy-5-phenyl) -ethyl / -methylaminoy-acetophenone and sodium borohydride in 80% methanol analogous to Example 1. IR spectrum (methylene chloride):

UV spectrum (ethanol): Λ max.

OH ' ^CH 2 3590 cm NH ₂ 3390 + 3490 cm N-alkyl 2800 cm ti OCH ₃ , 25) 2830 cm aliphatic , 09) 2850 + 2 9 50 cm C = N , 10). 2210 cm C = C 1520 cm 245 nm (0 277 nm (0 331 mn (0

Example 38

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- / 2- (4-methoxy-phenyl) -ethyl / -methylamino-7-ethanol "" ____

Prepared from 4'-amino-3 ', 5 ^t -dichloro-2- _< / N- ₍ 2- (4-methoxy-phenyl) -ethyl) -7-methylamino-7-acetophenone and sodium borohydride

2 3 5 Λ 9 1 8 -50-

80% methanol analogously to Example 1.

IR spectrum (methylene chloride): OH 3590 cm ^-1

NH ₂ 3390 + 3490 cm " ¹

N-alkyl 2800 cm ^-1

OCH ₃ 2830 cm " ¹

aliphatic. CH ₂ 2850 + 2930 cm " ¹

C = C 1610 cm "" ¹

Example 39

1- (4-amino-3-chloro-5-cyano-phenyl) -2- £ N- / 4- (4-methoxy-phenyl) - butyl ^ -methylamlnoT'-ethanol '

Prepared from 4'-amino-3 ^l -chloro-5 ^l -cyan-2- / N- / 4- (4-methoxyphenyl) -butyl-7-methylamino-7-acetophenone and sodium borohydride in 80% strength methanol analogously to Example 1.

IR spectrum (methylene chloride): OH 3590 cm ^-1

NH ₂ 3400 + 3500 cm " ¹

N-alkyl 2800 cm ^-1

OCH ₃ 2 830 cm " ¹

aliphatic. CH ₃ 2850 + 2930 cm " ¹

C = N 2210 cm " ¹

C = C 1625 era " ¹

UV spectrum (ethanol): "X max 245 nm (0.23)

280 nm (0.05) 332 nm (0.13).

Example 40

25i- (4-Amino-3-chloro-5-cyano-phenyl) -2- ^ N- £ 3- (4-methoxyphenyl) -ethyl 7-methylamino-ethanol

Prepared from 4'-amino-3'-chloro-5'-cyano-2- / N- / 2- (4-methoxyphenyl) -ethyl 7-methylamino-acetophenone and sodium borohydride in 80% methanol as in Example 1.

23549 1 8

IR spectrum (methylene chloride): OH 3590 cm *

•1

3 390 + 3490 cm 2800 cm "" ¹ 2 330 cm "'

28 50 + 2940 cm

•1

N-alkyl OCH ₃ : 5 'CH ₂

CsN 2210 cm

C = C 1620 cm

UV spectrum (ethanol): N max. 245 nm (0.24) 280 nm (0.04) 332 nm (0.13).

-1

Example 41

1- (4-Amino-3,5-dichloro-phenyl) -2- ^ N - ( 1 - (4- methoxyphenylsulfenyl) -ethyl) -methylamino-7- ethanol

Prepared from 4'-amino-3 ¹ , 5'-dichloro-2'-N- / 2 '' (4-methoxyphenylsulfenyl) ethyl 17-methylamino-acetophenone and sodium borohydride in tetrahydrofuran: water: methanol = 25: 5: 10 analog In game 1st oil.

IR spectrum (methylene chloride): 0H

20 cn.

UV spectrum (ethanol)

Max

3200-2500 cm (under

3480 + 3390 cm 2940 cm " ¹

•1

- 1

 1

-1

N-alkyl 2,800 cm

OCH ₃ 2 830 cm "

C = C 1580 + 1490 cm

, 230 nm (0.58; shoulder)

245 nm (0.54)

298 nm (0.14).

Example 42

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- (2- (4-methoxy-phenoxy) -ethyl) -methylammonium-ethanol

Prepared from 4'-amino-3 ', 5'-dichloro-2 ™ / N- / 2- (4-methoxy-phenoxy) -ethyl 7-methylamine / acetophenone and sodium borohydride in

23 5 Λ 9 1 8

- 52 -

Tetrahydrofuran: Water: methanol = 15: 5: 3 analogously to Example 1. oil.

" ¹

IR spectrum (methylene chloride): OH

NH CH

N-alkyl OCH ₃ C = C CO aryl

3200-3500 cm (below NH 3480 + 3390 cm " ¹

" ¹

2940 cm 2790 cm 2830 cm

" ¹ " ¹

1580, 1505 + 1485 cm 1250 cm " ¹

uv spectrum (ethanol): Λ max. 230 nm (0.32; shoulder)

244 nm (0.26; shoulder) 294 nm (0.12).

Example 4 3

1- (4-Amino-3,5-dichloro-phenyl) -2- / N ^ l- (4-methoxy-phenyl) -Pro-pyiy aminoy-propanol _(1).

Prepared from 4'-amino-S ^ S'-dichlor ^ - ^ N- ^ iJ- (4-methoxy-phe nyl) -propyj ^ -aminc ^ -propiophenone and sodium borohydride analogously to Example 1

 Melting point of the hydrochloride: 2O1-2O2 ° C (dec.).

20 Example 4 4

1- (4-Amino-3,5-dichloro-phenyl) -2- / Ji- (J) - (4-methoxyphenyl) -pro pyf7 "2-propylamine-7-ethanol

-1

3400 + 3490 cm -1

-1

Prepared from 4'-amino-3 ', 5'-dichloro-2-N- / I- (4-methoxyphenyl) -propyl ^^ - propylamincy-acetophenone and Natriuraborhydrid analogous to Example 1. oil.

IR spectrum (methylene chloride): OH 3600 cm

NH ₂

OCH_ 2830 cm "

UV spectrum (ethanol): f \ max. 243 nm (0.13) 280 nm (0.03)

300 nm. (0.03)

2354 9I 8 - ^ -

Example 45

1- (4-Amino-3,5-dichloro-phenyl) -2- ^ N-3- (4-methoxyphenyl) -propyl- 7-ethylaniline-7-ethanol .

Prepared from 4'-amino-3 ', 5'-dichloro-2-N, N'-3-bis (4-methoxy-phenyl) -propyl-7-ethylamino-7-acetophenone and sodium borohydride analogously to Example 1

 IR spectrum (methylene chloride)

10 UV spectrum (ethanol):% max.

OH 3 nm 3600 cm NH ₂ OCH nm 3395 + 3490 cm " ¹ 2830 cm" ¹ 243 nm. (0.13) 280 (0.04) 300 (0.04)

Example 46

1- (4-Amino-3,5-dichloro-phenyl) ·? 2- / ? - / 3- (4-methoxy-phenyl) -propyl-L-7-propylamine [? -Ethanol

Prepared from 4'-amino-3 ', 5 ^t -dichloro-2 ~ Ai- / 3 ~ (4-methoxy-phenyl) -propyl-7-propylamino-7-acetophenone and sodium borohydride analogously to Example 1. oil.

IR spectrum 20 UV spectrum (Methylene chloride): OH 3 nm 3 600 -.1 cm - NH ₂ nm 3395 + 3495 cm OCH nm. 2850 cm (Ethanol): \ max. 245 (0.10) 280 (0.03) 3OO (0.03)

25 Example 47

1- (4-Amino-3,5-dichloro-phenyl) -2 - ^ - ^ 3- (4-methoxyphenyl) -propyl- 7-cyclopropylamino-7-ethanol

Prepared from 4'-amino-3 ', 5'-dichloro-2-Äi- / 3- (4 ™ methoxy-phenyl) -propyl 7 "~ cyclopropylamino-7-acetophenone and sodium borohydride

235491 8

analogously to Example 1. oil. IR spectrura (methylene chloride)

5 UV spectrum (ethanol): Λ max.

OH 3590 cm NH ₂ 3395 + 3495 cm " ¹ -1 OCH, 2850 cm 245 nm (0.12) 280 nm (0.04) 300 nm. (0.04)

Example 4 8

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- 3- (4-methoxyphenyl) -propyl -methylamino / -propanol- (1), isomer B

Prepared from N £ 3- (4-methoxy-phenyl) -propyl? -Triethylamine, 4 ^{1-amino-2-bromo-3} ', S'-dichloro-propiophenone, triethylamine and sodium borohydride analogously to Example 2. Oil

IR spectrum (methylene chloride): OH · 3600 + 3680 cm ^-1 NH ₀ 3390 + 3490 cm " ¹ .

² -1

OCH 2835 + 2940 cm '

Aromatic 1510, 1585 + 1610 cm

UV spectrum (xthanol): ^ max. 246 nm (0.14)

278 nm (0.08)

285 nm (0.08)

J 300 nm (0.08)

NMR spectrum (CDCl 3 / D-O): signal of the proton at carbon atom 1 of the propanol part: doublet at 4.1 ppm (J = 10 Hz).

Example 49

1- (4-Araino-3,5-dichloro-phenyl) -2- / β ~ / 1- (4-methoxyphenyl) -piperyl-methylaminoT'-propanol- (1), Iso mer A.

Prepared from N £ 5- (4-methoxy-phenyl) -propyl7-methyl amine, 4 ¹ -amino-3 ^1, 5'-dichloro-2-bromo-propiophenone, triethylamine and sodium borohydride analogously to Example 2. FIG.

2354 9 1

- 55 -

Melting point of the hydrochloride: 178-181C.

NRM spectrum of the base (CDCl3 / D ₂ O): signal of the proton at carbon atom 1 of the propanol moiety: doublet at 4.6 ppm (J »4.5 Hz).

Example 5O

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- / 3- (4-ethoxy-phenyl) -propyl -methyl-amino-7-ethanol

Prepared from 4'-amino-3 ^l , 5'-dichloro-2-bromo-acetophenone, 1- (4-ethoxy-phenyl) -S-methylamino-propane hydrochloride , triethylamine and sodium borohydride analogously to Example 2. oil

 IR spectrum (methylene chloride)

OH (0 3590 cm NH ₀ (0 3395 + 3495 cm " λ N-alkyl (0 2800 cm 245 mn , 13) 280 nm , 04) 300 nm. , 04)

UV spectrum (ethanol): ^ max

 15

Example 51

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- / 3- (4-benzyloxyphenyl) -propyl-7-methylamino-7-ethanol · · -

Prepared from 4'-amino-3 ¹ , 5 ^l -dichloro-2-bromo-acetophenone, 1- (4-benzyloxyphenyl-S-methylamino-propane hydrochloride, triethyl-

amine and sodium borohydride analogously to Example 2. oil.

IR spectrum (methylene chloride): OH 3590 cm ^-1

NH_ 3395 + 3495 cm "N-alkyl 2S00 cm" ¹

23549.1 8 .- * -

Example 52

-S-JOd-S-fluoro-phenyl) -2- ^ N- ^ 1- (4-methoxyphenyl) -propyl-7-methylamine-7-ethanol · '

Prepared from 4 ^l -Amino-3 ^l -iodine-5'-fluoro-2-bromo-acetophenone, 1- (4-methoxy-pheny1) -3-methylamino-propane hydrochloride, triethylamine and sodium borohydride analogously to Example 2. oil. IR spectrum (methylene chloride): OH 3590 cm ^-1

NH ₂ 3395 + 3495 cm " ¹ N-alkyl 2800 cm" ¹

Example 53

1- (4-Amino-3-cyano-5-fluoro-phenyl) -2- ^ N- £ 3- (4-methoxy-phenyl) -propyl-1-propylamino-1-ethanol.

Prepared from 4'-amino-3'-cyano-5'-fluoro-2-bromo-acetophenone _f 1- (4-methoxyphenyl) -3- (2-propylamino) -propane hydrochloride and ^ 5 sodium borohydride analogously to Example 2. oil. IR spectrum (methylene chloride): OH 3600 cm ^-1 NH ₂ 3395 + 3495 cm ^-1 OCH ₃ 2830 cm ^-1 N-alkyl 2800 cm ^-1 C = N 2220 cm ^-1

Example 54

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- / 3- (2-methoxyphenyl) -propylZ- methylaminoy-ethanol- hydrochloride «_-.

Prepared from 4'-amino-3 ', 5'-dichloro-2-bromo-acetophenone, 1- (2-methoxy-phenyD-3-methylamino-propane hydrochloride, triethylamine and sodium borohydride analogously to Example 2. Melting point: from 7 5 ° C (under sintering).

23 5 Λ 9 1

- 57 -

Example 55

1- (4-amino-3,5-dichloro-phenyl) -2- ^ N- ^ 3 ™ (3,4-dimethoxyphenyl) -propyl-7-methyl-7-amino-ethanol

Prepared from 4'-amino-3 ¹ , 5 ⁱ -dichloro-2-bromo · »acetophenone, 1- (3,4-dimethoxy-phenyl) -3-methylamino-propane-quathromethyl-d, triethylamine and sodium borohydride analogously to Example 2 IR spectrum (methylene chloride): OH 3600 era "

NH ₂ 3390 + 3485 cm "" ¹ OCH-2830 cm " ¹ N-alkyl 2800 era" ¹

Example 56

1 - (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2- ^ N- £ "2 ~ (4-raethoxy- phenyl) -H- thyl-L - methyl-yl-amine - H-ethanol _In ._ .. ^

Prepared from 4'-amino-3'-chloro-5'-trifluoromethylr2- / N- / 2- (4-methoxyphenyl) -ethyl 7-methyl-amino-7-acetophenone and sodium borohydride in 80% methanol analogously to Example 1 » IR spectrum (methylene chloride): OH

OH 3600 - 1 cm cm NH 3410 + 3510 N-alkyl 2800 cm 0-CH, 2830 cm cm 3 allphat. CH ₂ 2350 + 2940 C = C 16 30 mm * t cm

UV spectrum (ethanol): λ max. 225 nm (0.38)

244 nm (0.34)

280 mn (0.07)

307 nxn (0,10)

235491 8

Example 57

pyiy-amincj-ethanol hydrochloride

Prepared from 4 · amino-3 ·, 5'-dichloro- 2-Jβ-ß- (4-methoxyphenyl) -propylj-aininc ^ acetophenone and sodium borohydride in 90% ethanol as in Example 1

 Melting point of the hydrochloride: 185-186 ° C (ethanol / xther).

Example 58

1- (4-Amino-3,5-dichloro-phenyl) -2- £ N- (3-phenyl-propyl) -2-propyl ^ araino7 »ethanol hydrochloride

Prepared from 4'-amino-3 ¹ , 5'-dichloro-2-bromo-acetophenone, 1-phenyl-3- (2-propylamino) -propane hydrochloride, triethylamine and sodium borohydride analogously to Example 2

 Melting point: 124-128 ° C.

Example 59

1- (4-amino-3,5-dichloro-phenyl) -2- / N- / 3- (4-fluoro-phenyl) -propyl- methylamino-ethanol- hydrochloride _ »____________« -_ «_ »» »__» _ «« -.

Prepared from 4'-AmInO-S ', 5'-dichloro-2-bromo-acetophenone, 1- (4-fluoro-phenyl) -3-methylamino-propane hydrochloride / triethylamine and sodium borohydride analogously to Example 2.

Melting point: 185-188 ° C (dec.). _r "

Example 60

1- (4-Amino-3,5-dichloro-phenyl) -2- / β- / β- (4 -hydroxyphenyl ) -1- methyl-propyl- 7-amylQ7.-ethanol · .

Prepared from 4 '-amino-3' _f 5'-dichloro-2 - / _ N- / l- (4-hydroxy-phenyl) -i-methyl-propyj ^ -aminoy-acetophenone and sodium borohydride in aqueous tetrahydrofuran analogously to Example 4. FIG. As eluent for the chromatographic purification over silica gel

23549 1

- 59

is a mixture of dichloromethane / methanol / conc. Ammonia 19: 1: 0.05 used.

(Oil: 1: 1 mixture of diastereomeric racemates).

IR spectrum (KBr): OH 2300 - 3500 cm ^-1 "(broad, associated) NH ₂ 3460 + 3370 ctT" ¹

CH ₂ 2920 + 2960 cm "" ¹ C = C 1580, 1510 + 1480 cm " ¹

UV spectrum (ethanol): S max 244 nm (0.28) 280 nm (0.08) 300 nm (0.08) UV spectrum (ethanol + KOHj ^ max 243 nm (0.54)

299 nm (0.15)

Example 61

1 - '(4-amino-3,5-dichloro-phenyl) -2''N- ₍ 3-p-4-methoxy-p-hexyl) -1-

methyl-pro.pyl7-aminQ7 Ethanol

Prepared from 4'-amino-3 ', 5'-dichloro-2- / N- £ 3 ~ (4-methoxyphenyl) -1-methyl-propyl] .- / - amino-7-acetophenone and sodium borohydride in aqueous tetrahydrofuran analogously to Example 4. oil. The compound is a 1: 1 mixture of diastereomeric racemic

20 mats ago.

-1 IR spectrum (methylene chloride): OH 3600 cm

NH ₂ 3480 + 3390 cm

, , CH ₀ 29 30 cm

OCH ₃ 28 30 cm

, C = C 1580, 1510 + 148 5 cm " ¹

UV spectrum (ethanol): \ max. 244 ran (0,28)

280 nm (0.08)

300 nm (0.09)

23 5 Λ 9 1

Example 62

1- (4-amino-3-cyano-5-fluoro-phenyl) -2- / U- / 2- (3,4-dimethoxyphenyl) ethyl / -amine-Q7-ethanol hydrochloride

Prepared from 4'-amino-S'-fluoro-5'-cyan-acetophenone, selenium dioxide, 2- (3,4-dimethoxy-phenyl) ethylamine and sodium borohydride analogously to Example 5

 Melting point: 196-197 ° C (dec.).

Example 63

1- (4-amino-3-fluoro-5-iodo-phenyl) -2- ^ N- £ 2- (3,4-dimethoxyphenyl) -äthy ^ -amln ^ -äthanol hydrochloride

Prepared from 4'-amino-3 * -fluoro-5'-iodo-acetophenone, selenium dioxide, 2- (3,4-dimethoxy-phenyl) -ethylamine and sodium borohydride analogously to Example 5.! • Melting point: 192-193 ° C (decomp.).

15 Example 64

1- (4-Amino-S-chloro-5-fluoro-phenyl) -2- / N-2 (3,4-dimethoxy- phenyl) -ethyl-7-amyl-7-ethanol-hydrochloride.

Prepared from 4'-amino-S'-chloro-S'-fluoro-acetophenone, selenium dioxide, 2- (3,4-dimethoxy-phenyl) -ethylamine and sodium borohydride analogously to Example 5.

Melting point: 184-186 ° C (dec.).

Example 65

1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-β- {2- (3,4-dimethoxy- phenyl) -ethyl-7-amidin-7-ethanol hydrochloride.

Prepared from 4'-amino-3'-bromo-5'-fluoro-acetophenone, selenium dioxide, 2- (3,4-dimethoxyphenyl) ethylamine and sodium borohydride

23 5 4 9 1 9 - ⁶¹ -

analogously to Example 5.

Melting point: 194-195 ° C (dec.).

Example 66

1- (4-Amino-3-fluoro-5-cyano-phenyl) -2- / N - / ^ 3- (4-methoxy-phenyl) -propyl-7-amine-Q7-ethanol

Prepared from 4 ^{l of} amino-3 ^l -fluoro-5'-cyan-acetophenone _/ selenium dioxide, 3- (4-methoxy-phenyl) -propylamine and sodium borohydride analogously to Example 5

 Melting point: 119-121 ° C.

Example 67

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- (3-phenyl-propyl) amino / - ethanol hydrochloride _ _ ^, _{r mm} ·

Prepared from 4'-amino-3 ', 5'-dichloroacetophenone, selenium dioxide, 3-phenyl-propylamine and sodium borohydride analogously to Example 5. Melting point: 180-181 ° C (dec.).

Example 68

1- (4-iunino-3-chloro-5-fluoro-phenyl) -2- / N- (1-methyl-1- ethyl) -amino-7-ethanol dihydrochloride

Prepared from 4'-amino-3'-chloro-5 ¹ -fluoro-acetophenone, selenium dioxide, .i-methyl-2-phenoxy-ethylamine and sodium borohydride analogously to Example 5

 Melting point: 158-160 ° C (dec.).

235491

Example 69

1- (4-amino-3-cyano-5-fluoro-phenyl) -2 - / - N - (1-methyl-2-phenoxy- ethyl) -amino-7-ethanol-hydrochloride

Prepared from 4 ^f -Amino-3'-cyano-5'-fluoro-acetophenone, selenium-5 oxide, i-methyl-2-phenoxy-ethylamine and sodium borohydride analogously to Example 5. Melting point: 178-184 ° C (dec.) ,

Example 70

1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-N- (1-methyl-2- phenoxyethyl) amino? -Ethanol dihydrochloride

Prepared from 4-amino-S'-bromo-S'-fluoro-acetophenone, selenium dioxide, 1-methyl-2-phenoxy-ethylarain and sodium borohydride analogously to Example 5. Melting point: 156-158 ° C. (dec.).

Example 71

N-_5- (4-amino-3,5-dibromo-phenyl) -ethyl-N- / 3- (4-methoxy-phenyl) -propyl-methyl on . _________ "___________" ______ "_" __ "" _

Prepared from 4-amino-3,5-dibromo-N-_V3- (4-methoxy-phenyl) -propyl / -N-methyl-phenylacetic acid amide and lithium aluminum hydride analogous to Example melting point of the hydrochloride: 149-153 C.

Example 72

N- / 2- (4-amino-3,5-dichloro-phenyl) ethyl-N-1- (4-methoxy-phenyl) -propyl-7-methylamine

² ^ Prepared from 4-amino-3,5-dichloro-N- ^ 1- (4-methoxyphenyl) -

23549 1 8 - «

propyl 7-N -ethylphenylacetic acid amide and lithium aluminum hydride

analogously to Example 7.

Melting point of hydrochloride: 90-94 C. Example 73 N - ^ - (4-amino-3,5-diGhlor-phenyl) -äthyl7-N- / 2- (

äthyj7-methylamine

Prepared from 4-amino-3,5-dichloro-N-2- (4-methoxyphenyl) -ethyl 7-N-methylphenylacetic acid amide and lithium aluminum hydride analogously to Example 8.

IR spectrum (methylene chloride) s NH ₂ 3380 + 3470 cm ^-1

N-alkyl 2780 cm ^-1

OCH, 2830 cm

aliphatic. CH ₂ 2850 + 2930 cm

C = C 1610 cm

UV spectrum (ethanol): ^ max. 245 nm (0.24)

281 nm (0.08) 305 nm (0.07)

Example 74

N- £ 2- (4-amino-3,5-dichloro-phenyl) ~ ethyl-7 "N - / 4- (4-methoxy-phenyl) -butyl-7-methyl-1-amine ______

Prepared from 4-amino-3,5-dichloro-N- 4- (4-methoxyphenyl) -butyl-N-methyl-phenylacetic acid amide and lithium aluminum hydride analogously to Example 8

 IR spectrum (methylene chloride)

UV spectrum (ethanol): Λ max. 30

NH ₂ OCH ₃ (0 , CH ₂ 3380 2830 + 3480 -1 cm cm (0 2850 + 2930 cm aliphatic (0 2100 - 2 500 cm NH ⁺ , 22) 16 30 cm C = C , 07) 24 5 nm , 08) 2 80 nm 304 nm

23 5 Λ 9 1

- 64 -

Example 75

N- £ 5- (4-AnLLnO-S, 5-dichloro-phenyl-1) -propyl7-2- (3,4-dimethoxyphenyl ) -ethylamine hydrochloride ______ «» ___-_ «"

Prepared from 3- (4-amino-3,5-dichloro-phenyl) -N-2- (3,4-dimeth-5-oxy-phenyl) -äthy £? -Propionamide and lithium aluminum hydride analogously to Example 7

 Melting point: 142-145 ° C.

Example 76

N- / 3- (4-amino-3,5-dichloro-phenyl) -propyl7 " ^N " ZJ- (3,4-dimethoxy-10- phenyl) ethyl / triethylamine

Prepared from 3- (4-amino-3,5-dichloro-phenyl) -N-2- (3,4-dimethoxyphenyl-ethyl-N-methyl-propionic acid anide and lithium aluminum hydride analogously to Example 8. oil.

IR spectrum 20 Example 77 (Methylene chloride) : NH ₂ OCH ₃ NCH ₃ 3400 2835 2800 + era 3500 cm "2960 cm" ¹ -1 1510 + 1590/1615 UV spectrum (Ethanol): Λ max. Aromat (Shoulder) 239 nm (0, 281 nm (O ₁ 300 nm .11) , 08).

N- / β- (4-amino-3-bromo-phenyl) -propyl / -2- (3,4-dimethoxyphenyl) ethylamine hydrochloride

Prepared from 3- (4-amino-3,5-dibromo-phenyl) -N- / 2- (3,4-dimethacrylate ^J oxy-phenyl) -athyV-propionsaureamid and lithium aluminum hydride analogously to Example 7

 Melting point: 131-134 ° C.

23 5 Λ 9 1 8 - ⁶⁵ , -

Example 78

N- / J- (4-amino-3,5-dichloro-phenyl) -ethyl-7-N- / 3- (4-hydroxyphenyl) -1-methyl-propyl / -amine

Prepared from 4-amino-3,5-dichloro-N- / 3 ~ (4-hydroxy-phenyl) -1-methyl-propylphenylacetic acid amide and lithium aluminum hydride in tetrahydrofuran analogously to Example 8. The chromatographic purification is carried out by means of medium pressure chromatography on silica gel (particle size 0.015-0.025 mm) with methylene chloride: methanol: conc. Ammonia 19: 1: 0.1 as eluent. Foam. IR spectrum (methylene chloride); OH 3580 cm

NH. 3480 + 3385 cm " ¹

-1 CH ₂ 2920 am

C = C 1580, 1510 + 1480 cm ^-1

UV spectrum (ethanol): \ max. 242 mn (0.24; shoulder). 280n (0.07)

303 nm (0.08)

UV spectrum (ethanol + KOH): ^ max. 242 nm (0.53)

3oo mn (0.16).

Example 79

N- / 2- (4-amino-3,5-dichloro-phenyl) -ethyl / '- N- • /! (4-methoxy- phenyl) -1-methyl -propyl / amine

Prepared from 4-AmInO-SjS-UiChIOr-N-ZB- (4-methoxyphenyl) -1-methyl-propyl-7-phenylacetic acid amide and lithium aluminum hydride in tetrahydrofuran analogously to Example 8. oil.

IR spectrum (methylene chloride): NH ₀ 3480 + 3385 cm ^-1

- 1

CH- 2 930 cm * -ι

-ι

OCH ₁ 28 30 cm

C = C ~ 1580, 1510 + 1485 cm UV spectrum (ethanol): "X max 242 nm (0.25; shoulder)

280 nm (0.07)

302 nm (0.08)

2354 9 1 8

- 66 -

3390 + 3490 cm " ¹ 2800 mm * | cm (O , 10) (0 , 04) (0 , 04)

Example 80

N- / 2- (4-amino-3,5-dichloro-phenyl) -ethyl-T-N - / - (4-benzyloxy- phenyl) -propyl-7-methylamine

Prepared from 4-amino-3,5-dichloro-N- / 3- (4-benzyloxy-phenyl) -propyl7-N-methyl-phenylacetic acid amide and lithium aluminum hydride analogously to Example 8. oil

IR spectrum (methylene chloride): NH ₃

N-alkyl

UV spectrum (ethanol): \ max 245 nm 280 nm

300 nm.

Example 81

N, -2- (4-Amino-3,5-dichloro-phenyl) -ethyl, N'''''''- (3,4-dimethoxy- phenyl) -propyl-methyl-amine

Prepared from 4-amino-3,5-dichloro-N- / 1- (3,4-dlmethoxy-phenyl) -propyl-N-methyl-phenylacetic acid amide and lithium aluminum hydride analogously to Example 8. Oil

IR spectrum (methylene chloride): NH ₃ 3395 + 3495 cm ^-1

OCH ₃ 2830 cm " ¹

N-alkyl 2800 cm " ¹ UV spectrum (ethanol):" k max. 230 nm (shoulder, 0.18)

245 nm (shoulder, 0.12)

282 nm (0.04)

302 nm. (0.03)

Example 82

N- / 2- (4-amino-3,5-dichloro-phenyl) -ethyl7 "-N- / 3- (2-methoxy-phenyl- 1) -propyl-methylamine hydrochloride

Prepared from 4-amino-3, S-dichloro-N - /! - (2-methoxy-phenyl) -

23549

- 67 -

propylZ-N-methylphenylacetic acid amide and lithium aluminum hydride analogue Example melting point: 16O-164 ° C.

Example 83

N- / 2- (4-Araino-3,5-dichloro-phenyl) -äthy1? -N- (3-phenyl-propyl) -methylamine _m . _{| m τ n} . _rr ..._

Prepared from 4-amino-3,5-dichloro-N- (3-phenyl-propyl) -N-methyl-phenylacetic acid amide and lithium aluminum hydride analogously to Example 8. oil. 10iR spectrum (methylene chloride): NH ₂ 3390 + 3490 cm "

N-alkyl 2800 cm ^-1

UV spectrum (ethanol): % max. 245 nm (0.12)

300 rxm. (0.03)

Example 84

N- [§ - (4-amino- 3,5 -dichloro-phenyl) -äthyf / -N - /! - (4-methoxyphenyl) -propyl-amine hydrochloride

Prepared from 4-amino-3,5-dichloro-N ™ £ 3 "- (4-methoxyphenyl) propyl-7-phenylacetic acid and lithium aluminum hydride analogous to Example 7. Melting point: 2O3-2O5 ° C.

Example 85

N- / 2- (4-Amino-3,5-dichloro-phenyl) -äthy £ / -Ν- / 1- (4-methoxyphenyl) -propyl-cyclopropylamine

Prepared from 4-amino-3,5-dichloro N- / 3 ~ (4-methoxy-phenyl) 25-propyl-N-cyclopropyl-phenylacetic acid-cimide and lithium aluminum hydride analogously to Example 8. Oil. IR spectrum (methylene chloride): NH_ 3390 + 3490 cm ^-1

OCH- 2 8 30 cm

23 54 9 1

- 68 -

UV spectrum (ethanol):

Max. 245 nm (0.15) 280 ran (0.04) 300 ran. (0.05)

Example 86

N- / 2- (4-amino-3,5-dichloro-phenyl) -äthy 1 / -N- / 3- (4-methoxy- phenyl) -propyl-propylamine

Prepared from 4-amino-3, B-dicyclo-N - / ^ - (4-methoxy-phenyl) -propyl-7-N-propyl-phenylacetic acid amide and lithium aluminum hydride analogously to Example 8. oil.

IR spectrum (methylene chloride): NH ₀ 3390 + 3490 cm

-1

OCH

2830 cm "

N-alkyl 2800 cm

UV spectrum (ethanol): \ max. 243 nm (0.13)

280 nm (0.04) nm. (0 * 04)

-1

Example 87

N- ^ 2- (4-Amino-3,5-dichloro-phenyl) -äthy17-N- / 3- (4- raethoxyphenyl) -propyl-7-ethylamine.

Prepared from 4-amino-3, S-dichloro-N - ^ - (4-methoxy-phenyl) -propyl7-N-ethyl-phenylacetic acid amide and lithium aluminum hydride analogous to Example 8. oil.

IR spectrum (Methylene chloride): NH ₂ (0 3390 + 3490 cm OCH (0 2830 cm 3N-alkyl (0 2800 cm 25 UV spectrum (Ethanol): λ max. 243 nm , 13) 280 nm , 04) 300 nm. , 04)

2 3 5 4 9 1

Example 88

N- £ 2- (4-Amino-3,5-dichloro-phenyl) -äthy1 / -N- / 3- (4-methoxyphenyl) -propyl7-2-propylamine

Prepared from 4-amino-3,5-dichloro-N- / 3- (4-methoxy-phenyl) -propyl / -N- (2-propyl) -phenylacetic acid amide and. Lithium aluminum hydride analogously to Example 8. oil

IR spectrum (methylene chloride): NH, 3390 + 3490 cm ^-1

UV spectrum (ethanol): K max. 10

Example 89

N- / 2- (4-amino-3,5-dichloro-phenyl) -äthyi7-N-Z3 - '(4-ethoxy-phenyl) propyl / -methylamine ^ .. ^, ^ - -, -

OCH ₃ nm 2830 - 1 cm 243 nm (0, 13) 280 nm (0, 04) 300 (0, 04)

Prepared from 4-amino-3, S-dichloro-N-, /! - (4-ethoxy-phenyl) -propyl-7-N-methylphenylacetic acid amide ^and lithium aluminum hydride analogously to Example 8. oil.

IR spectrum 20 DV-spotting Tram (Methylene chloride) s NH ₂ mn 3390 + 3490 cm OCH ₃ ώ.τϊϊ 2830 " N-alkyl nm. 2800 cm "* ¹ (Ethanol) s "X max 245 (0.12) 280 (0.03) 300 (0.04)

Example 90

N- / 2- (4-amino-3,5-dichloro-phenyl) -äthyl7 ^"N ~ / ^ ™ ^ ~ ^{4 Methox} y" P ^he ~ nyl) -1 -methyl-

Prepared from i-ethoxycarbonyloxy-1- (4-amino-3,5-dichloro-phenyl) -2- / N- / J- (4-methoxyphenyl) -1-methyl-propyl-7-methyl amino / sane and sodium borohydride in isopropanol analogously to Example 9. oil,

23549 1

- 70

IR spectrum (methylene chloride):

OCH-C = C

3480th + 3380 cm

2930 cm

N-alkyl '2790 cm

2840 cm

-1

-1 -1

1580, 1510 + 1480 cm

Example 91

N- ^ 2- (4-amino-3-bromo-5-cyano-phenyl) -ethyl J-N - / - (4-methoxy- phenyl) -butyl-methyl-amine,

Prepared from 1-ethoxycarbonyloxy-1- (4-aminc-3-bromo-5-cyanophenyl) -2- ^ N- ^ 4- (4-methoxyphenyl) -butyl-7-methylamino-7-ethane and sodium borohydride analogously to Example 9. Analysis :

Calc .: C 60.6 H 6.3 Br 19.2 N 10.1 Found: .60.5 .6.1 19.2 10.1

15 Example 92

N- / 2- (4-amino-3-chloro-5-cyano-phenyl) -ethyl / -N-2- (4-methoxyphenyl) ethyl-7-methylamine

+ 3490 cm

-1

-1

Prepared from 1-ethoxycarbonyloxy-1- (4-a.mino-3-chloro-5-cyanophenyl) ~ 2- / N- £ 2- (4-methoxy-phenyl) -ethyl / methylamino-T-ethane and sodium borohydride analogously to Example 9.

IR spectrum (methylene chloride): NH ₂ 3400

N-alkyl 3790 cm OCH ₃ 2830 cm

aliphatic. CH ₂

CsN 2210 cm "

C = C 1620 cm

UV spectrum (ethanol): Λ max. 244 nm (0.26)

280 nm (0.04) 335 nm (0.15)

2850 + 2940 cm

-1

-1

23 5 Λ 9 1

- 71

Example 93

N- {* ί ~ (4-Amino-3-bromo-5-cyanophenyl) -ethyl-N- ₁ /3 "- (4-methoxyphenyl) -propyl-1-methylamine

Prepared from 1-ethoxycarbonyloxy-i- (4-amino-3-hromo-5-cyano-5-phenyl) -2- / VI- / β- (4-methoxy-phenyl) -propyl-7-methylamino-7-ethane

and sodium borohydride analogous to Example IR spectrum (methylene chloride): NH-.

3790 cm 3830 -cm

UV spectrum (ethanol)

Max

N-alkyl

OCH ₃ aliphatic · CH-,

CsN

C = C

, 244 nm (0.2) mn (0.04) nm (0.13).

3390 + 3490 cm -1

2850 + 2940 era 2210 cm " ¹ 1620 cm"'

Example e1_94

N- / 2- (4-amino-3-chloro-5-cyanophenyl) phenyl) "butyl / -methylamine

J- / 1- (4-methoxy-

Prepared from 1-Xthoxycarbonyloxy-i- (4-sino-3-chloro-5-cyanophenyl) -2- / β- ~ / J- (4-methoxy-phenyl) -bitty-17-methyl-amino-7-methyl

and sodium borohydride analogous to Example Analysis:

Calc .: C 67.5 H 7.3 Cl 9.53 N 11.25 V: 67.5 7.14 9.65 11.34

Example 95

1- (4-Amino-3-chloro-5-trifluoromethylphenyl) -2-phenyl) -butyl-7-diethylamino-ethanol

! - (/ 4- (4-methoxy)

Prepared from 4'-amino-3'-chloro-5'-trifluoromethyl-2- ^ N- / 4- (4-

235491

- 72 ~

Methoxy-phenyD-butyV-methylaminoy-acetophenone and sodium borohydride in 80% methanol as in Example 1. IR spectrum (methylene chloride): OH

cm

-1

UV spectrum (ethanol):

NH

+ 3510 cm

-1

-1

cm

cm

+ 2930 cm

" ¹

N-alkyl

OCH ₃

aliphatic. CH ₂

aromat. C = C 1630 cm

Max. 225 nm (0.32)

nm (0.31)

ran (0.06)

nm (0,10)

-1

-1

example

1- (4-amino-3-cyano-phenyl) -2- / N- / 3- (4-methoxy-phenyl) -propyl _< 1/15 methylamino-ethanol

Prepared from 1- (4-Amino-3-bromo-5-cyano-phenyl) -2- / N- / 3- (4-methoxy-phenyl) -propyl-7-methylamino) ethane in the presence of palladium / carbon and hydrogen analogously Example 11. IR spectrum (methylene chloride): ~ ¹

UV spectrum (ethanol): Λ

Max.

NH ₂

N-alkyl

aliphatic. CH ₂

C-C

nm (0.31)

nm (0.6)

rrm (0.12).

3610 cm 3400 2800 cm 2830 cm 2850 + 2210 cm 1630 cm

+ 34 90 cm

-1

-1

2940 cm "

-1

-1

2 3 5 Λ 9 1 8 - ⁷³ -

Example 97

N-_2- (4-amino-3-chloro-phenyl) -ethyl / -N-3-ε (4-benzyloxy-phenyl) -poxy γ7 -ine-thy 1-am in in

Prepared from N- / 2- (4-amino-3,5-dichloro-phenyl) -äthy JV-N - /! - (4-benzyloxy-phenyl) -propyl-7-methylamine and hydrogen analogously to Example 11. Oil.

IR spectrum (methylene chloride): NH ₂ 3390 + 3490 cm ^-1

N-alkyl 2790 cm " ¹

Example 98

N- / 2- (4-amino-3,5-dichloro-phenyl) -äthylJ-N-ZSI (4-hydroxy-phenyl) - prop yl7 -meth yl am in

Prepared from N -, / 2- (4-amino-3,5-dichloro-phenyl) -ethyl 7-N- / 3- (4-benzyloxy-phenyl) -propyl / -methylamine and hydrogen analogously to Example 16. Oil

IR spectrum (methylene chloride): OH 3 580 cm ^-1

NH ₂ 3390 + 3490 cm "N-alkyl 2800 cm" ¹

Example 99

1- (4-Amino-3-fluoro-phenyl) -2-_N- (i-methyl-2-phenoxy-ethyl) -amine-7-thio- 1-tosylate

Prepared from 1- (4-acetamido-3-fluoro-phenyl) -2- / N- (1-methyl-2-phenoxy) -ethyl-7-aminoethanol and sodium hydroxide analogously to Example 17

 Melting point: 124-128 ° C.

2 3 5 U 9 1

Example 100

N->> - (4-Amino-3,5-dichloro-phenyl) -ethyl / -N-3 ~ (4-methoxy- phenoxy) -propyl-methylamine

Dissolve 1,74 g (0.014 mol) of 4-methoxy-phenol in 60 ml of dry tetrahydrofuran, the solution is cooled to -5 ° C and falls under

Stir 0.67 g (0.014 mol) of a 50% dispersion of sodium hydride in oil. The mixture is stirred for 2 hours at ^{0 0} C on and then added dropwise at the same temperature with a solution of 4.2 g of N- ^ 2- (4-amino-3,5-dichloro-phenyl) -äthyl7-N- (3 10-chloro-propyl) -methylamine in 50 ml of dry tetrahydrofuran. The mixture is stirred for 18 hours at about 20 ⁰ C. The reaction mixture is then concentrated in vacuo, and the evaporation residue is partitioned between ether and water. The phases are separated and the aqueous layer is extracted three times with ether. The washed with water, combined ether extracts are dried and evaporated in vacuo. The oily evaporation residue is purified by chromatography on a silica gel column (eluent: ether). After evaporation of the desired fractions gives the above compound as an oil.

IR spectrum (methylene chloride): NH ₀ 3390 + 3480 cm ^-1

1 CH ₀ 2 9 50 cm

-1 N-alkyl 2800 cm

C = C 1585 + 1560 + 1505 cm " ¹

DV spectrum (ethanol): \ max. 230 nm (0.18, shoulder)

246 nm (0.085; shoulder)

295 nm (0.05).

23549

Example 101

- 75 -

1- (4-AININO-3, 5-dichloro-phenyl) -2- / N- (3-phenyl-propyl) -ethylamino- ethanol-hydrochloride . «___________________ ™™ _ ™ _____.

2 g of 1- (4-amino-3,5-dichloro-phenyl) -2- / N- (3-phenyl-propyl) -amino-7-ethanol-hydrochloride are dissolved in 50 ml of ethanol. To this solution is added 0.4 ml of acetaldehyde and then with stirring at room temperature, 1.2 g of sodium cyanoborohydride, being careful by the addition of 2 η hydrochloric acid, that a pH of 6-6.5 set and maintained. At this pH, it is stirred for another 2 hours. The solution is poured into water

1C and acidified with 2N hydrochloric acid to destroy excess sodium cyanoborohydride. 2N sodium hydroxide solution is then added until the reaction is very alkaline, the mixture is extracted twice with methylene chloride, the combined methylene chloride phases are washed with water, dried over sodium sulphate and concentrated to dryness in vacuo. It leaves an almost colorless oil, which is dissolved in ethanol. This ethanolic solution is acidified to pH 5 with ethereal hydrochloric acid. The solvents are then removed on a rotary evaporator in vacuo. The residual oily residue is converted into ethyl acetate in vacuo.

2C brought lization. This gives colorless crystals of melting point 1O2-1O5 ° C.

Example 102

1- (4-Xthoxycarbonylamino-3-cyano-5-fluoro-phenyl) -2-Al-2- (2- (3,4- dime-thioxy -phenyl) -ethyl) -ethyl-sthanol-hy_drogh_lqrid__

2i Prepared from 4'-ethoxycarbonylamino-3'-cyano-5'-fluoro-acetophenone, selenium dioxide, 2- (3,4-dimethoxyphenyl) ethylamine and sodium borohydride analogously to Example 4

 Melting point: 19O-191 ° C (dec.).

23 54 9

- 76 -

example

1- (4-amino-3-cyano-5-fluoro-phenyl) -2- / N- / 4- (4-methoxyphenyl) -butyl / -methylamino-7-ethanol

Prepared from 4'-amino-3'-cyan-5'-fluoro-2 - ^ - / 4- (4-methoxy-5-phenyl) -butyi7-methylaininoy-acetophenone and Natriumfoorhydrid in 80% methanol "analogous to Example 1 ,

IR spectrum (methylene chloride):

ÜV spectrum (ethanol): "X

OH NH ₂

N-alkyl OCH ₃

aliphatic. CH ₃ CsN C = C

, 241 nm (0.27) • 280 nm (0.07) 322 nm (0.14)

3590 cm 3400 2800 cm 2830 cm 2850 2210 cm

+ 34 90 cm -1

+ 2930 cm

1635 cm

example

1- (4-Acetamino-3-bromo-phenyl) -2- / N - ^ - 4- (4-methoxy-phenyl) -butyl-1-methyl-amino / -ethanol

Prepared from 4'-acetamino-3'-bromo-2 - / β- / J- (4-methoxyphenyl) butyl-7-methylamino-7-acetophenone and sodium borohydride in 80% methanol as in Example 1.

IR spectrum (methylene chloride): OH 3590 cm

NH 3410 cm

25 N-alkyl 2,800 cm '

OCH 2830 cm aliphatic. CH ₂ 2850 aroraat. C = C 1610 cm C = O

+ 2930 cm -1

Amide II

1700 cm 1510 cm

2 3 5 Λ 3 1

Example 105

Racemates A and B of 1- (4-amino-3,5-dichloro-phenyl) -2- / N- / 3- (4- hydroxy-phenyl) -1-methyl-propyl / -methylamino: o / - ethanol

36 g of 1- (4-amino-3,5-dichloro-phenyl) -2- ^ - / 3- (4-hydroxyphenyl) -1-methyl-propyl-1-methylamino-7-ethanol (1: 1 mixture of Diastereomeric racemates A and B) are dissolved in ether and treated with 0.5 equivalents of 3 η hydrogen chloride in ether. The resulting crude crystals of the hydrochloride of racemate A is first recrystallized from isopropanol and then twice by dissolving in much methanol and then evaporating until incipient crystallization

 Melting point of the hydrochloride: 248-249 ° C (dec.).

¹ 3c-NMR spectrum of the base (CDCl ₃ ZCD ₃ OD):

-CH ₂ -CH ₂ -CH- 37.50 ppm

CH ₃ -CH ₀ -CH-CH- 58.36 ppm

.CH-CH ₃ 13.91 ppm

N-CH ₃ 36.33 ppm

, N-CH ₂ - 61.03 ppm

-CH- 68.89 ppm

The isopropanolic mother liquor is evaporated and partitioned between ether and 2 η ammonia. The evaporation residue of the dried organic phase is separated to isolate the racemate B by means of HPLC of adhering racemate A (SiO ₂ 60;

2 3 5 U 9 1

Merck; 0.015-0.025 mm; Ether: methanol = 10: 1). The crystalline evaporation residue is recrystallized from much ether by concentrating in boiling heat

 Melting point: 128-131 ° C.

C-NMR spectrum (CDCl-j / CE

CH ₃

-CH ₂ -CH ₂ -CH- 35.61 ppm

CH

-CH ₂ -CH ₂ -CH- 59.21 ppm ^ CH-CH ₃ 14.56 ppm > N-CH ₃ 35.03 ppm • 5N-CH, - 63.11 ppm OH I -CH- 69.08 ppm Example 106

1- (4-Amino-3-bromo-5-cyano-phenyl) -2- / N- ^ 4- (4-methoxy-phenyl) -butyl-benzylaminoy-ethanol-hydrochloride

Prepared from 4'-amino-3 ^l -bromo-5'-cyano-2- / N- _/ / 4- (4-methoxyphenyl) -butylZ-benzylamincy-acetophenone and sodium borohydride in 90% methanol as in Example 1. Melting point of Hydrochlorides: 122-126 ° C.

- 79 -

Example 107

1- (4-Amino-3-bromo-5-cyano-phenyl) -2- / N- / J- (4-methoxy -phenyl) butyl / -allylamino / -ethanol

Prepared from 4'-amino-3'-bromo-5'-cyano-2- / N- / 4- (4-methoxyphenyl) -butyj ₁ / -allylamino-7-acetophenone and sodium borohydride in 90% methanol as in Example 1. Resin

IR 1 spectrum (methylene chloride): NH ₂ 3390 + 3490 cm ^-1

OCH ₃ 2830 + 2940 cm " ¹

CN 2210 cm " ¹

- 1 arom. C = C 1610 cm

UV spectrum (ethanol): \ max. 223 nm (0.43)

244 nm (shoulder, wide, 0.07) 330 nm (wide, 0 ^ 05)

Example 108

1- (4-Amino-3-bromo-5-cyano-phenyl) -2- £ N - / _ 4- (4-methoxy-phenyl) -butyl-isopropylamino-ethanol-hydrochloride

Prepared from 4'-amino-3 'bromo-5'-cyanogen ~ 2- / N - / _ 4- (4-methoxyphenyl) -butyl / -isopropylamine_o / acetophenone and sodium borohydride in 90% methanol as in Example 1

 Melting point of the hydrochloride: sintering from 40 C.

Calc .: C 55.6 H 6.29 Br 16.2 Cl 2.14 N 8.46 F .: 55.3 6.37 15.4 6.84 8.83

Example 109

1- (4-Amino-3-bromo-5-cyano-phenyl) -2- / N- / 4- (4-methoxy-phenyl) -butyXZ-n-propyl-amino- ethanol -ethanol- hydrochloride

Prepared from 4'-amino-3'-bromo-5'-cyano-2- ^ N- ^ 4- (4-methoxy-

3

- 80 -

phenyl) -butylZ-n-propylaminoy-acetophenone and sodium borohydride in 90% methanol as in Example 1. Melting point of the hydrochloride: sintering from 40 ° C. Calc .: C 55.60 H 6,29 N 8,46 F .: 55,52 6,32 8,39

Example 110

1- (4-Amino-3-bromo-5-cyano-phenyl) -2- / N- / 4 * - (4-methoxy-phenyl) -butyl-7-ethylamine-7-ethanol-hydrochloride

Prepared from 4'-amino-3'-bromo-5 ^f -cyan-2-N- / J- (4-methoxyphenyl) -butylJL7-ethylamino-7-acetophenone and sodium borohydride in 90% methanol as in Example 1. Melting point of the hydrochloride : 139-142 ° C.

Example 111

1- (4-Amino-3-bromo-5-trifluoromethylphenyl) -2- ^ N- / J- (4-methoxy- phenyl) -propyl / -methylamino / -ethanol

Prepared from 4'-amino-3'-bromo-5'-trifluoromethyl-2- / N- / J- (4-methoxyphenyl) -propyl_ / methylamino / -acetophenone and sodium borohydride in 90% methanol analogously to Example 1 oil. IR spectrum (methylene chloride): NH-3400 + 3490 cm " ¹ OCH 2840 + 2940 cm"

  -1 'arom. C = C 1610 cm

UV spectrum (ethanol): \ max. 223 nm (0.26)

244 nm (0.1) 310 nm (very wide, 0.04)

- 81 -

Example 112

1- (4-Amino-3-bromo-5-cyano-phenyl) -2- / N- (4-phenyl-butyl) -methyl-amino-7-ethanol-hydrochloride

Prepared from 4'-amino-3'-bromo-5'-cyano-2-_N- (4-phenyl-butyl) -methylamine »/ - acetophenone and sodium borohydride in 90% methanol analogously to Example 1

 Melting point of the hydrochloride: 153-155 ° C.

Example 113

1- (4-Amino-3-cyano-5-fluoro-phenyl) -2- / N- / 2- (4-methoxy-phenyl) 1Q- methyl-methyl-aminothanol hydrochloride

Prepared from 4'-amino-3 '-cyan-5 ^l -fluoro-2- / N- / 2'- (4-methoxyphenyl) -äthyjy-methylaminoy-acetophenone and sodium borohydride in 90% methanol as in Example 1. Melting point of Hydrochloride: sintering from 68 ° C. 1.5 Calc .: C 60.1 H 6.12 Cl 9.35 N 11.05 F .: 59.91 6.07 9.40 10.69

Example 114

1- (4-Amino-3,5-dichloro-phenyl) -2- / Ή- (3-phenylsulfenyl-propyl) -

methylamino7 Ethanol

Prepared from 4'-amino-2-bromo-3 ', 5'-dichloro-acetophenone, N- / 3- (4-methoxyphenylsulfenyl) -propyl-methylamine and sodium borohydride in 80% methanol as in Example 2. oil. IR spectrum (methylene chloride): NH 3 3 90 + 34 90 cm * " ¹

OH 3600 + 3680 cm "uv spectrum (ethanol) : \ max 246 nm (0.18)

300 nm (0.05)

Example 115

1- (4-Amino-3,5-dichloro-phenyl) -2- £ N- ^ 3- (4-hydroxyphenyl) -propyl / -amine / -ethanol "____ __________-____" _ "__.

Prepared from 4'-amino-3 ', 5'-dichloro-2 - ^ - ^ 3 "- (4-hydroxyphenyl) -propy 1 / -amino-acetophenone and sodium borohydride in aqueous tetrahydrofuran analogously to Example 3. oil.

IR spectrum (KBr): OH, NH ₀ 3300-3,600 cm ^-1

- 1

aroma C = C 1615 cm

UV spectrum (ethanol + KOH): fs. Max. 244 nm (0.26) 299 nm (0.08)

Example 116

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- / J3- (4-chlorophenyl) -propyl- 7-amyl-ethanol

Prepared from 4'-amino-3 ', 5 • -dichlor ^ - ^ N - /! - (4-chlorophenylJ-propyV-aminoy'-acetophenone and sodium borohydride in aqueous tetrahydrofuran analogously to Example 3. Melting point: 1O3-1O6 ° C.

Example 117

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- / J- (4 -hydroxyphenyl ) -1 -methylpropyl-isopropylaminoyethanol

Prepared from 4'-amino-3 ', 5'-dichloro-2 - ^ - / J- (4-hydroxyphenyl) -i-methyl-propylZ-isopropylaminoy-acetophenone and sodium borohydride analogously to Example 3. oil.

Calcd .: C, 61.31; H, 6.86; Cl, 17.24; N, 6.81; 25; Fe: 61.07, 6.86, 16.67, 6. 53

- 83 -

Example 118

1- (4-Amino-3,5-dichloro-phenyl) -2- {N - / _ 3- (4- hydroxyphenyl ) -1- methyl-propyl-ethyl-methyl-ethanol] ___> ___________ ™ ____

Prepared from 4'-amino-3 ', 5'-dichloro-2- / N- / 3 "- (4-hydroxyphenyl) -1-methyl-propyl-i-ethylamino-acetophenone and sodium borohydride analogously to Example 3. Oil

  Beer .: C 60.45 H 6.60 Cl 17.85 N 7.05 Found: 60.45 6.76 17.70 6.86

Example 119

101- (4-Methylamino-3,5-dichloro-phenyl) -2- / N- / 3- (4 -hydroxyphenyl ) -i-methyl-propyl-Z-methylaminoythanol

Prepared from 4'-methylamino-3 ', 5'-dichloro-2- / N- / 3- (4-hydroxyphenyl) -1-methyl-propyl 1 / -methylaminoy-acetophenone and sodium borohydride analogously to Example 3. Oil

 15Ber .: C 60.45 H 6,60 Cl 17,85 N 7,05 Gef .: 60,68 6,73 17,50 6,71

Example 120

1- (4-Dimethylamino-3,5-dichloro-phenyl) -2- / N- / 3- (4-hydroxy- phenyl) -1-methyl-propyl-methyl-amino Z-ethano l

Prepared from 4 '-Dime thy lamino-3 ·, 5'-dichloro-2- ^ N- / Ji- (4-hydroxy-phenyl) -1-methyl-propyl / -methylamino / acetophenone and sodium borohydride analogous to Example 3. oil. Calc .: C 61.31 H 6.86 Cl 17.24 N 6.81 F .: 61.28 6.57 16.80 6.42

O - 84 -

Example 121

1- (4-Acetylamino-3,5-dichloro-phenyl) -2- / N - / ^ - (4-hydroxy-phenyl) -1-methyl-propyl-7-methylamine-ethyl-ethanol _______ »____

Prepared from 4'-acetylamino-3 ', 5'-dichloro-2- / N- / 3- (4-hydroxyphenyl) -1-methyl-propyl / -methylamine £ 7-acetophenone and sodium borohydride analogously to Example 3. Foam.

IR spectrum (methylene chloride): OH 3580 cm "

NH 3410 cm " ¹

N-alkyl 2800 cm ^-1 C = 0 1700 cm " ¹

C = C 1610, 1595 cm " ¹ amide II 1515 cm" ¹ UV spectrum (ethanol) : \ max. 230 nm (0.3; shoulder)

280 nm (0.04) (ethanol + KOH) O ^ nax. 243 nm (0.46)

294 nm (0.08)

Example 122

1- (4-ethoxycarbonylamino-3,5-dichloro-phenyl) -2- / N- / J- > (4-hydroxy-

phenyl) -1-methyl-propyl / -methylamlno7 Ethanol

Prepared from 4'-ethoxycarbonylamino-3 ', 5'-dichloro-2- / N - / "3- (4-hydroxyphenyl) -1-methyl-propyl-7-methylamino-7-acetophenone and sodium borohydride analogously to Example 3. oil .: C 58.02 H 6,20 Cl 15,57 N 6,15 Found: '58,20 6,32 15,32 6,03

23 5 43 "

Example 123

Racemates A and B of 1 ^ 4-amino-3-cyano-5-fluoro-phenyl) -2- ^ N- ^ 7- methyl-3- (4-hydroxyphenyl) -propylmethylamine-ethane ol

Prepared from 4'-amino-3'-cyano-5'-fluoro-2- ^ i- ^ T-methyl-3- (4-hydroxyphenyl) -propyl-methylaminpT'acetophenon and sodium borohydride analogously to Example 3. The resulting mixture of diastereomeric racemates is separated by column chromatography methylene chloride: methanol conc. Ammonia = 50: 1: 0.1).

Racemate A:

Melting point: 161-163 ° C.

¹³ C-NMR spectrum (dg-dimethylsulfoxide)

-CH ₂ -CH ₂ -CH- 37.17 ppm

CH ₃

-CH ₂ -CH ₂ -CH- 57.91 ppm

^ CH-CH ₃ 13.26 ppm

^, N-CH ₃ 35.74 ppm

- 60.90 ppm

OH -CH- 69.21 ppm

235497

- 86 -

Racemate B:

Melting point: 92-98 ° C.

¹³ C-NMR spectrum (dg-dimethylsulfoxide)

-CH ₂ -CH ₂ -CH- 36.52.ppm

-CH ₂ -CH ₂ -CH- 57.78 ppm

ICH-CH ₃ 13.19 ppm

N-CH ₃ 35.74 ppm

.N-CH ₂ - 61, 48 ppm

OH

CH- 69.02 ppm

Example 124

1- (4-amino-3-cyano-5-fluoro-phenyl) -2- ^ N- ₍ / T-methyl-3- (4-methoxy- phenyl) -propyl-amino-7-ethanol

Prepared from 4'-amino-3'-cyano-5'-fluoro-2- / N- / T-methyl-3- (4-methoxy-phenyl) -propyl-amino-p-acetophenone and sodium borohydride analogously to Example 3 ,

Melting point: 108-110 ° C.

23549 1

Example 125

1- (4-amino-3-cyano-5-fluoro- phenyl) -phenyl) -propyl -7-alpha- ethanol

methyl-3- (4-hydroxy

Prepared from 4'-amino-S'-cyano-S ^l -fluoro ~ 2- _< / N- ₍ / J-methyl-3- (4-5-hydroxy-phenyl) -propyl-7-amine £ / acetophenone and Ifetriumborhydrid analog Example 3

 Melting point: 162-164 ° C.

Example 126

1- (4-amino-3-cyano-5-fluoro-phenyl) -2- £ 7 -, / T-10-phenyl) -propyl-7-ylamine / -ethanol

-3- (4-methoxy-

Prepared from 1- * (4-amino-3-cyano-5-fluoro-p.-phenyl) -2- ^ N- / J-methyl-3- (4-hydroxy-phenyl) -propyl-methyl-amino-ethanol and dimethylsulfate / 1 N sodium hydroxide in tetrahydrofuran analogously to Example 4. oil.

IR spectrum (methylene chloride): NH

UV spectrum (ethanol) ih max,

0-CH ₃

N-alkyl

C = N

C = C

C = C + NH nm nm (0.05) nm (0.05) nm (0.12)

3400 2 830 cm

+ 3500 cm

-1

-1

2800 cm 2210 cm

-1

_ ·1

1580, 1510 cm

-1

'2 (0.27)

Deformation 1620 cm

- 88 -

Example 127

1- (4-Amino-3,5-dichloro-phenyl) -2-N- (1-methyl-2-phenoxy-ethyl) -amino-ethanol-hydrochlor id ____________

Prepared from 4-amino-3 ', 5-dichloro-acetophenone, selenium dioxide, 1-methyl-2-phenoxy-ethylamine and sodium borohydride analogously to Example 5. Amorphous hydrochloride.

IR spectrum (methylene chloride): 3390 + 3490 cm NH_ ^"1 UV spectrum (ethanol):. Fr max 245 nm (0.15)

300 nm (0.04)

Example 128

1- (4-Amino-3,5-dichloro-phenyl) -2- / 13- / 3- (4-fluoro-phenyl) -propyl / "· aming-V-ethanol-hydrochloride /

Prepared from 4 ^ AmInO-S *, 5-dichloro-acetophenone, selenium dioxide, 3- (4-fluoro-phenyl) -propylamine and sodium borohydride analogously to Example 5.

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

Example 129

1- (4-Amino-3,5-dichloro-phenyl) -2- / Ή- (3-phenyl-i-methyl-propyl) -methylamino-ethanol -

Prepared from 4'-amino-3 ', S'-dichloro-acetophenone, selenium dioxide, 3-phenyl-i-methyl-propylamine and sodium borohydride analogously to Example 5. oil.

IR spectrum (methylene chloride): NH ₃ 3390 + 3490 cm ^-1

OH 3600 + 3680 cm " ¹ UV spectrum (ethanol): * \ max 245 nm (0.18)

300 nm (0.06)

23549 1

Example 130

- 89 -

1- (4-Amino-3,5-dichloro-phenyl) -2-_N- (1-methyl-2-phenoxy-ethyl) -amino-ethanol-hydrochloride

Prepared from 4-amino-3,5-dichloro-acetophenone, selenium dioxide, 1-methyl-2-phenoxy-ethylamine and sodium borohydride analogously to Example 5

 Melting point of the hydrochloride: 122-125 ° C.

Example 131

N- / 3- (4-amino-3-bromo-phenyl) -propyl / -N-_2- (3,4-dimethoxy- phenyl) -ethyl / methylamine hydrochloride

Prepared from N-methyl-N- / 2- (3,4-dimethoxy-phenyl) ethyl J-3- (4-amino-3,5-dibromophenyl) -propionamide and lithium aluminum hydride in absolute tetrahydrofuran analogously to Example 7.

he '-1

Melting point of the hydrochloride: 70-12O ⁰ C (sintering).

IR spectrum (KBr): NH ^ ⁰ 2500 - 2650 cm

Alkyl 2800 - 3000 cm " ¹ UV spectrum (ethanol): * \ max 234 nm (0.17)

280 nm (0.04) 300 nm (shoulder; 0.03)

Example 132

N-_2- (4-amino-3-chlorophenyl) ethyl-N- (1-methyl-3-phenylpropyl) isopropylamine

Prepared from 4-amino-3, S-dichloro-N-isopropyl-N- (1-methyl-3-phenyl-propyl) -phenylacetic acid amide and lithium aluminum hydride in tetrahydrofuran analogously to Example 7. oil.

IR spectrum (methylene chloride): NH 3 390 + 34 90 cm "UV spectrum (ethanol): \ max 241 nm (0.15)

3OO nm (O, O3)

23 5 4 9 18 - ⁹⁰ -

Example 133

N- / 2- (4-amino-3,5-dichloro-phenyl) ethyl-N- (1-methyl-3-phenyl- propyl-isopropylamine ·

Prepared from 4-amino-3,5-dichloro-N-isopropyl-N- (1-methyl-3-phenyl-propyl-phenyl-acetic acid amide and lithium aluminum hydride in tetrahydrofuran analogously to Example 7. oil.

Ir spectrum (methylene chloride): NH ₃ 3390 + 3490 cm ^-1 UV spectrum (ethanol) : \ max 245 nm (0.15)

302 nm (0.04)

Example 134

N- £ 2- (4-Amino-3,5-dichloro-phenyl) -ethyl / - ^ - (4-fluoro-phenyl) -propylamine hydrochloride '

Prepared from 4-amino-3 _/ 5-dichloro-N- ^ 3- (4-fluoro-phenyl) -propyl / -phenylacetic acid amide and lithium aluminum hydride in tetra ^ .5 hydrofuran analogously to Example 7.

Melting point of hydrochloride: 2O5-2O6 ° C.

Example 135

N- / 2- (4-amino-3,5-dichloro-phenyl) -äthy "Q -N- (1-methyl-3-phenylpropyl -1) -methylamine

Prepared from 4-amino-3,5-dichloro-N- (1-methyl-3-phenyl-propyl) -phenylacetic acid amide and lithium aluminum hydride in tetrahydrofuran analogously to Example 7. oil.

IR spectrum (methylene chloride): NH ₂ 3 390 + 3490 cm "UV spectrum (ethanol): *% max 243 nm (0.14)

300 nm (0.05)

23 5 U 9H

Example 136

ι _Λ - l

N- / 2- (4-amino-3,5-dichloro-phenyl) -äthy] L / -N - /, 3- (4-methoxyphenyl-i- sulfenyl) -propyl-methylamine . ·

Prepared from 4-amino-3,5-dichloro-N- / 3- (4-methoxyphenylsulfenyl) -propyl-N-methylphenylacetic acid amide and lithium aluminum hydride in tetrahydrofuran analogously to Example 7. oil. XR spectrum (methylene chloride): NH-3390 + 3490 cm ^-1 UV spectrum (ethanol): X max. 245 nm (0.16)

300 nm (0.04)

10 Example 137

N - / _ 2- (4-amirio-3-bromo-phenyl) -ethyl / -N - ^ - 4- (4-methoxy-phenyl) -

Prepared from 4-amino-3-bromo-N - / _ 2- (4-methoxyphenyl) -butyl / -N-methyl-phenylacetic acid amide and lithium aluminum hydride in absolute tetrahydrofuran analogously to Example 8. IR spectrum (methylene chloride): NH_ 3380 + 34 70 cm "

"" ¹

NMR spectrum

20

OCH ₃ 283O + 293O cm 7H) arom. C = C 16 20 cm -1 arom. H 6.4-7.3 ppm (M, OCH ₃ 3.7 ppm (S, 3H) 8H) NCH ₃ 2.2 ppm (S, 3H) aliph. H 1.3-2.8 ppm (M,

Example 138

N- / 2- (4-amino-3-bromo-phenyl) -ethyl / -N-2- (4-methoxyphenyl) -ethyl-7-methylamine

Prepared from 4-amino-3-bromo-N- _; £ 2- (4-methoxyphenyl) ethylV-

 1

N-methyl-phenylacetic acid amide and lithium aluminum hydride in absolute tetrahydrofuran analogously to Example 8.

IR spectrum (methylene chloride): NH ₂

üV spectrum (ethanol): Λ max.

arom. C = C

3380 + 3480 cm 2840 + 2940 cm "1620 cm" ¹

224 nm (0.24)

242 nm (0.15)

280 nm (wide, 0.03)

300 nm (wide, 0.03)

1.0 Example 139

N- ^ 2- (4-amino-3-fluoro-phenyl) propyl / triethylamine

LZ-N - / ^ - (4-methoxy-phenyl) -

Prepared from 4-amino-3-fluoro-N- / 3- (4-methoxyphenyl) -N-methyl-phenylacetic acid amide and lithium aluminum hydride in 15 absolute tetrahydrofuran analogously to Example 8. oil.

IR spectrum (Methylene chloride) : NH ₂ , C = C nm (0 3390 + 3460 cm OCH ₃ 227 nm (0 2840 + 2940 cm arom 279 nm (0 1610 cm UV spectrum (Ethanol): \ Max. 285 , 3) , 06) , 06)

Example 140

N- / 2- (4-amino-3- chlorophenyl ) propyl / -methylamine

i7-N- 3- (4-methoxyphenyl) -

25 Prepared from 4-amino-3-chloro-N-methyl-N- _{ A3- (4-methoxyphenyl) propyl-7-phenylacetic acid amide and lithium aluminum hydride in absolute tetrahydrofuran analogously to Example 8. Resin.

2 1

- 93 -

IR spectrum (methylene chloride):

3390 + 3470 cm

2840 + 2940 cm

-1

-1

aroma C = C 1610 cm

UV spectrum (ethanol): A max. 224 nm (0.25) '240 nm (0.18)

280 nm (0.04) 300 nm (0.03)

Example 141

N- ( 3- (4-Amino-3,5-dichloro-phenyl) -10-nyl) -propyl) -ammine hydrochloride

N ^ p- (4-methoxy-phe

Prepared from 3- (4-amino-3,5-dichloro-phenyl) -N- ^ 3- (4-methoxyphenyl) -propyl / -propionamide and lithium aluminum hydride in absolute tetrahydrofuran analogously to Example 8. Melting point of the hydrochloride:

138-142 ^W C.

15 Example 142

N- £ 5- (4-amino-3,5-dichloro-phenyl) -propylV-N - / - (4-methoxyphenyl) ethyl methylamine dihydrochloride?

Prepared from 3- (4-amino-3,5-dichloro-phenyl) -N-methyl-N - / _ 2- (4-methoxyphenyl) -äthy ^? - Propionsäureamid and lithium aluminum hydride in absolute tetrahydrofuran analogous example melting point of dihydrochloride : 147-157 c.

23 5 Λ 9 1

Example 143

N- ^ 2- (4-Amino-3,5-dichloro-phenyl) -ethyl-N-J- (4-methoxy-phenyl) -butyl-L- amine hydrochloride ___________

Prepared from N- £ 2- (4-amino-3,5-dichloro-phenyl) -ethyl / -4- (4-methoxyphenyl) -butyramide and lithiuraaluminum hydride in absolute tetrahydrofuran analogously to Example 8. Melting point of the hydrochlorides: 186- 189 ° C.

Example 144 . :

N- / J- (4-amino-3,5-dichloro-phenyl) -ethyl / -N-_3- (4-chloro-phenyl) -propyl-amine hydrochloride , '

Prepared from 4-amino-3,5-dichloro-N- / 3- (4-chlorophenyl) -propyl / -phenylacetic acid amide and lithium aluminum hydride in absolute tetrahydrofuran analogously to Example 8

 Melting point of the hydrochloride: 186-190 ° C.

Example 145

N- £ 2- (4-amino-3,5-dichloro-phenyl) -ethyl / -N-_4- (4-methoxy-phenyl) -butyl-isopropylamine

Prepared from N- £ 2- (4-amino-3,5-dichloro-phenylJ-ethyl-N-isopropyl-4- (4-methoxyphenyl) -butyramide and lithium aluminum hydride in absolute tetrahydrofuran analogously to Example 8. Oil. Spectrum (methylene chloride): NH _ 3390 + 3490 cm

OCH-2850 + 2930 cm ~ ¹

-1 arom. C = C 1610 cm

UV spectrum (ethanol): Λ max. 242 nm (0.12) 280 nm (shoulder; 0.04)

301 nm (0.04)

2.3 5 A 9 1 8 ^^

Example 146

N- / 2- (4-amino-3,5-dichloro-phenyl) -ethyl / ^ -N- ^ J- (4-methoxyphenyl) ethyl-7-isopropylamine

Prepared from N-_2- (4-amino-3,5-dichloro-phenyl) -äthy1 / -N-isopropyl-4-methoxyphenylacetic acid amide and lithium aluminum hydride in absolute tetrahydrofuran analogously to Example 8. oil. IR spectrum (methylene chloride): NH ₂ 3390 + 3490 cm ^-1

OCH-2830 + 2960 cm " ¹

-1 arom. C = C 1610 cm UV spectrum (ethanol): \ max. 244 nm (shoulder; 0.12)

280 nm (shoulder, 0.05) 301 nm (0.05)

Example 147

N- £ 2- (4-Amino-3,5-dichloro-phenyl) -äthyV-N- / J- (4-methoxy- phenyl) -äthy ^ Z-amine hydrochloride

Prepared from 4-amino-3,5-dichloro-N- / 2- (4-methoxyphenyl) -äthyjV-phenylacetic acid amide and lithium aluminum hydride in absolute tetrahydrofuran analogously to Example 8. Melting point of the hydrochloride: 2O6-2O8 ° C.

Example 148

N- ^ 3- (4-amino-3,5-dibromo-phenyl) -propyl-N - ^ - (3,4-dimethoxy- phenyl) -äthyjQ-methylamine

Prepared from N-methyl-N- / J- (3,4-dimethoxy-phenyl) -äthyj / "3- (4-amino-3,5-dibromo-phenyl) -propionsäureamid and Lithlumaluminiumhydrid in absolute tetrahydrofuran analogously to Example 8. oil.

IR spectrum (methylene chloride): NH ₂ 34 80 + 3380 cm ^-1

OCH ₃ 2840 + 2940 cm " ¹

NMR spectrum (CDCl ₃ ZD ₂ O): 0-CH ₃ 4.85 ppm (s, 6H)

N-CH ₃ 2.25 ppm (s, 3H) arom. H 6.75 ppm (d, 3H)

7.2 ppm (s, 2H) aliph.H 1.5-2.9 ppm (m, 12H)

Example 149

N- / 2- (4-amino-3,5-dichloro-phenyl) -ethyl J-S-phenyl-propylamine hydrochloride

Prepared from 4-amino-3,5-dichloro-N- (3-phenyl-propyl) -phenylacetic acid amide and lithium aluminum hydride in tetrahydrofuran analogously to Example 8

 Melting point of the hydrochlorides: 197-199 ° C.

Example 150

N- £ 2- (4-Amino-3-bromo-5-cyano-phenyl) -ethyl / -N-J- (4-methoxy- phenyl) -butyl-7-benzylamine

Prepared from 1-ethoxycarbonyloxy-1- (4-amino-3-bromo-5-cyanophenyl) -2- ^ N- ^ T- (4-methoxyphenyl) butyl / benzylamino / ethane and sodium borohydride in isopropanol analogously Example 9. Oil. IR spectrum (methylene chloride): NH ₃ 3390 + 3490 cm ^-1

OCH ₃ 2830 + 2930 cm " ¹ CN 2210 cm" ¹

Arom. C = C 16 20 cm UV spectrum (ethanol): ^ max. 222 nm (0.42)

244 nm (shoulder, 0.09) 335 nm (wide, 0.05)

23 5 Λ 9 1 8 - ⁹⁷ -

Example 151

Ν-2- (4-amino-3-bromo-5-cyanophenyl) -ethyl / -N-4- (4-methoxy- phenyl) -butyl-allylamine

Prepared from 1-ethoxycarbonyloxy-1- (4-amino-3-bromo-5-cyanophenyl) -2- ^ N- ^ J- (4-methoxyphenyl) -butyl-allylamino-7-ethane and sodium borohydride in isopropanol analogously to Example 9 oil. -range (methylene chloride): NH-3390 + 3490 cm " ¹

UV spectrum (ethanol): OCH C = C 2830 + 293C 3 CN nm 2210 cm 10 arom. nm 1620 cm, Λ max. 222 nm (0.49) 244 (Shoulder ; 0.1) 335 (wide; 0 , 06)

Example 152

N- £ 2- (4-Amino-3-bromo-5- cyanophenyl ) -äthyf / - ^ - / l ~ (4-methoxy- phenyl) -butyl-ethylamine

Prepared from 1-ethoxycarbonyloxy-1- (4-amino-3-bromo-5-cyanophenyl) -2- ^ N - ^ [- (4-methoxy-phenyl) -butyl-ethylamine] -ethane and sodium borohydride in isopropanol analogously Example 9. Oil. IR spectrum (methylene chloride): NH ₂ 3390 + 3490 cm "

OCH ₃ 2830 + 2960 cm " ¹

CN 2210 cm " ¹

aroma C = C 1620 cm

UV spectrum (ethanol): * \ max. 222 nm (0.49) 244 nm (shoulder; 0.08)

333 nm (wide, 0.06)

25 I

- 98 -

Example 153

N- (J.- (4-Amino-3-bromo-5-cyanophenyl) -äthyiy-N-) J- (4-methoxy- phenyl) -butyl-isopropylamine «_________-______

Prepared from 1-ethoxycarbonyloxy-1-M-phenyl) -2- / N- / 4- (4-methoxy-phenyl) -butyl-7-isopropyl-amino-7-ethane and sodium borohydride in isopropanol analogously to Example 9. Resin. IR spectrum (methylene chloride): NH ₂ 3390 + 3490 cm ^-1

OCH 2830 + 2960 cm " ¹

UV spectrum (ethanol): CN C = C mm % * n * »N« r ι mm ^ W> · 2210 cm " ¹ 10 arom. nm 1620 cm " K max. 221 nm (0.53) 244 nm (Shoulder; 0.1) 330 (wide, 0.07)

Example 154

N- £ 2- (4-Amino-3-bromo-5-cyano-phenyl) -ethyl / -N-J- (4-methoxy- phenyl) -butylZ-n-propylamino

Prepared from 1-ethoxycarbonyloxy-1- (4-amino-3-bromo-5-cyanophenyl) -2- ^ N- (4- (4-methoxyphenyl) -butyl) [7-n-propylamino] -ethane and sodium borohydride in isopropanol analogously to Example 9. oil. IR spectrum (methylene chloride): NH ₂ 3390 + 3490 cm ^-1

CN 2210 cm " ¹

OCH, 2830 + 2950 cm " ¹

-1 arom. C = C 1620 cm

UV spectrum (ethanol): Λ max. 222 nm (0.46) 244 nm (shoulder; 0.08)

330 nm (wide, 0.05)

 1

- 99 -

Example 155

N- / 2- (4-amino-3-bromo-5-cyano-phenyl) -äthy ^ VN- (4-phenyl-butyl) -methyl-amine

Prepared from 1-ethoxycarbonyloxy-i - (^ - phenyl) -2- / J7- (4-phenyl-butyl) -methylaminciyethane and sodium borohydride in isopropanol analogously to Example 9. Oil. NMB spectrum (CDCl-): arom. H 7,0-7,4 ppm (m, 7H)

NCH ₃ 2.2 ppm (s, 3H)

aliph. H 1.3-2.7 ppm (m, 12H)

Example 156

N- / 2- (4-amino-3-cyano-5-fluoro-phenyl) -ethyl-7-N- / T- (4-methoxy- phenyl) -äthyQ-rmethylamine

Prepared from 1-ethoxycarbonyloxy-i- (4-amino-3-cyano-5-fluorophenyl) -2- / N- / J 2 - (4-methoxyphenyl) -ethyl 7-methylamine-p-ethane and sodium borohydride in isopropanol analogously to Example 9 oil. NMR spectrum (CDCl ₃ ZCH ₃ OD): arom. H 6.7-7.2 ppm (m, 6H)

OCH ₃ 3.75 ppm (s, 3H) NCH ₃ 2.3 ppm (s, 3H) aliph. H 2.4-2.7 ppm (m, 8H)

Example 157

N- / 2- (4-amino-3-cyano-5-fluoro-phenyl) -ethyl-7- ^N, -4- (4-methoxy- phenyl) -propyl-7-methylamine hydrochloride

Prepared from 1-ethoxycarbonyloxy-i- (4-amino-3-cyano-5-fluorophenyl) -2- / J5- / 3- (4-methoxyphenyl) -propyl-7-methylamine-butane and sodium borohydride in isopropanol analogously to Example 9. hydrochloride as a resin.

23 54

- 100 -

NMR spectrum (CDCl ₃ ): arom. H 6.7-7.2 ppm (m, 6H)

OCH ₃ 3.75 ppm (s, 3H)

® NCH ₃ 2.8 ppm (s, 3H)

aliph. H 1.5-3.5 ppm (m; 10H)

5 Example 158

JSt £ 2- (4-amino-3-cyano-5-fluoro-phenyl) -äthyjJ-N- ^! ⁴ "(4-methoxy- phenyl) -butyl-methylamine

Prepared from 1-ethoxycarbonyloxy-1- (4-amino-3-cyano-5-fluoro-\ phenyl) -2- / β- / J- (4-methoxy-phenyl) -butylj-methylaminc ^ ethane and sodium borohydride in Isopropanol analogously to Example 9. Resin.

NMR spectrum (CDCl ₃ ZD ₂ O): arom. H 7.2 ppm (s; 2H):

6.85 ppm (q; 4H) j

OCH ₃ 3.8 ppm (s; 3H) j

'NCH ₃ . 2.25 ppm (s, 3H).

aliph. H 1.5-2.7 ppm (m; 12H) ^;

Example 159

N- £ 2- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -ethyl-N, 4- (4- methoxyphenyl) -butyl-7-methylamine

Prepared from 1-ethoxycarbonyloxy-1- (4-amino-3-chloro-5-tri- · "-

fluoromethyl-phenyl) -2-N / N - / - 4- (4-methoxyphenyl) -butyl-1-methylaminoyethane and sodium borohydride in isopropanol analogously to Example 9

 Melting point: 29 ° C

23 5 Λ 9 1

- 101 "-"

Example 160

Ν- / 2- (4-amino-3-chloro-5-trifluoromethylphenyl) ethylT-N- (2- (4- methoxyphenyl) ethyl) -7-ethylamine

Prepared from 1-ethoxycarbonyloxy-1 - (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- / N- / J- (4-methoxy-phenyl) ethyl-ethylamino-7-ethane and sodium borohydride Isopropanol analogously to Example 9. Resin.

IR spectrum (methylene chloride): NH_ 3400 + 3500 cm ^-1

-1 OCH- 2840 + 2960 cm

Arom. C = C 1610 cm UV spectrum (ethanol): K max. 228 nm (shoulder; 0.10)

244 nm (0.10) 310 nm (0.03)

Example 161

N- / 2- (4-Amino-3,5-dichloro-phenyl) -äthyf / -N- / 1- (4-fluoro-phenyl) -propyl-7-methylamino "™"

Prepared from 1-ethoxycarbonyloxy ~ 1- (4 ~ amino-3, 5-dichloro ~ phenyl) -2- / 17- / 3 * - (4-f luor-phenyl) ~ ethane and sodium borohydride in propyl / ~ methylamino / ~ Isopropanol analogously to Example 9. Oil. IR spectrum (methylene chloride): NH ₂ 3390 + 3490 cm ^-1 UV spectrum (ethanol): \ max 243 nm (0.13)

300 nm (0.03)

Example 162

1 - (4-amino-3-trifluoromethyl-phenyl) -2- / N - / - * - (4-methoxy-phenyl-1) -propyl-methyl-amine, o-ethanol

Prepared from 1- (4-amino-3-bromo-5-trifluoromethyl-phenyl) -2- / N- (1- (4-methoxyphenyl) -propyl-7-methylamine-7-ethanol and water;

235491

- 102 -

substance in the presence of palladium oxide on barium sulfate in methanol analogously to Example 11. oil. ι

NMR spectrum (COCl 2 / DJO) : arom. H

arom. H 6,6- 7.3 ppm (M; 7H) CH-OH 4.5 PPm (T; 1H) OCH ₃ 3.7 ppm (S; 3H) NCH ₃  2.3 ppm (S; 3H) aliph. H  2,2- 2.7 ppm (M; 6H) -CH ₂ - 1.8 ppm (Q; 2H)

Example 163

10 N- / J3 (4-acetamido-3,5-dichloro-phenyl) -propyj./'-N-/2- (3, 4-dimethoxy phenyl) -äthyjL / -methylamine ^j

Prepared from N- / T- (4-amino-3,5-dichloro-phenyl) -propyl / -N- ^ 2-; (3,4-dimethoxy-phenyl) -ethyl / -methylamine, acetyl chloride and triethylamine in toluene analogously to Example 12. oil. , \

15 IR spectrum (methylene chloride): NH 3405 cm ^-1 OCH ₃

CO 1700 cm

Max. 228 nm (shoulder, 0.17) nm (0.04)

+ 2940 cm -1

UV spectrum (ethanol): K Example 164

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- / 3- (4-hydroxy-pheny1) -1-methyl-propyi7-allylaminp7 Ethanol

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N-_3- (4-

hydroxy-phenyl) -1-methyl-propylphosphine / ethanol with allyl bromide / sodium carbonate in absolute ethanol analogously to Example 13. Oil.

  - "I

IR spectrum (methylene chloride):

1): OH CH ₂ 3580 cm cm NH ₂ 3390 + 3480 cm aliph. 18 50 + 2930 C = C 1615 cm

235 / ;?

(Ethanol + KOH):

Example 165

-

UV spectrum (ethanol): * \ max.

Max,

nm (0.26)

nm (0/08)

nm (0.08)

2 nm (O _f 47)

nm (0.19)

1- (4-Amino-3,5-dichloro-phenyl) -2 - / _ N - / _ 3- (4-hydroxyphenyl) -pro-Pyl / 'isopropylamino-ethanol-hydrochloride

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N - ^ _ 3- (4-10-benzyloxy-phenyl) -propyl / -isopropyl-amino-ethanol and hydrogen in the presence of palladium on carbon analogously to Example 16

O.

Melting point of the hydrochloride: 90-110 C.

Example 166

1- (4-amino-3-chloro-phenyl) -2- ethylamino-T-ethanol

/ 3- (4-hydroxy-phenyl) propyl / -

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N- / 3- (4-benzyloxyphenyl) -propyl-7-ethylamino) ethanol and hydrogen in the presence of palladium on carbon analogously to Example 16 Resin.

-1

IR spectrum (methylene chloride): UV spectrum (ethanol)

Max.

(Ethanol + KOH): X max

-1

2840 + 2940 cm "1625 cm" ¹

OH 3 595 cm NH ₂ 3400 + 3490 cm

aliphatic. CH C = C

227 nm (0.19)

244 nm (0.17)

290 mn (0.04)

243 nm (0.32)

297 nm (0.08)

23 5 Λ 9 1 8 ^ ~ - ~~!

Example 167 j

1- (4-Amino-3,5-dichloro-phenyl) -2- ^ - 3- (4-hydroxy-phenyl) -propyl 1 /

ethylamino / -ethanol _r , ,

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / i "- / 3- (4-benzyl-5-oxy-phenyl) -propyl-7-ethylamine-7-ethanol and hydrogen in the presence of palladium Coal analogous to Example 16. Resin, XBr spectrum (methylene chloride): OH 3590, 3620 + 3680 cm '

NH 3390 + 3480 cm

-1 arom. C = C 1615 cm

UV spectrum (ethanol): N max. 244 nm (0.17)

284 nm (0.06)

200 nm (0.05)

(Ethanol + KOH): ^ max. 243 nm (0.31)

298 nm (0.08)

15 Example 168

N - / - (4-dimethylamino-3, 5-dichloro-phenyl) -propyl 1 / -N -, __ 3- (4- methoxy-phenyl-1) -propylj / -methyl on in _________________ "__» ____

Prepared from N- / J- (4-amino-3,5-dichloro-phenyl) -propylJL / -N-3- (4-methoxy-phenyl) -propyl-3-amine, paraformaldehyde and sodium cyanoborohydride in ethanol analogously to Example 101 oil. IR spectrum (methylene chloride):

25 NMR spectrum (CDC1-./D-0)

): OCH ₃ > c 7 2830 + 2940 cm ppm 4H) NCH ₃ 7 2790 cm (s; 2H) NH 3 ppm 3H) 2 arom. C 2 1610 cm"" 6H) arom. H 2 , 0 ppm (Q; (m; 8H) "2 , 1 ppm (S; 3H) OCH ₃ 1 , 75 ppm (s; (q; 4H) N (CH ₃ ) ₂ , 85 ppm (s; aliph. H. , 2-2.8 N-CH ₃ , 2 ppm __- ("* T-I *. , 6 to 1.8

23 5 Λ 9 1

- 105 -

Example 169

N- 13- (4-amino-3,5-dichloro-phenyl) propyl / -N-_3- (4-methoxy- phenyl) -propyl-7-methylamine- _i

Prepared from N- / T- (4-amino-3,5-dichloro-phenyl) -propyl / -N- / 3- (4-methoxy-phenyl) -propyl-amine, paraformaldehyde and sodium cyanoborohydride in ethanol analogously to Example 101. oil. "Tfr spectrum (methylene chloride): NH

10 UV-sensitive (ethanol)

Max

2 OCH.

3390 + 3490 cm

2830 + 2940 cm

-1

Arom. C = C 1610 cm 230 run (shoulder; 0.21) 242 nm (0.1)

278 + 285 nm (wide, 0.03) 302 nm (wide, 0.03)

Example 170

U- / j- (4-dimethylamino-3,5-dichloro-phenyl) -ethyl-N- / 3- (4-chlorophenyl) -propyl-methylamine

Prepared from N- / 2- (4-amino-3,5-dichloro-phenyl) -ethyl / -U- / J- (4-chloro-phenyl) -propyl / amine, paraformaldehyde and sodium cyanoborohydride in ethanol analogously to Example 101. Oil.

²⁰ IR spectrum (methylene chloride): NCH

UV spectrum (ethanol):

2790 cm

-1

NH ₂ NH max. 273 nm (wide, 0.04)

23 b A 9 1 8 - ¹⁰⁶ -

Example 171

N- £ 2- (4-Amino-3,5-dichloro-phenyl) -ethyl J-N-> 1- (4-chloro-phenyl) -propyl-7-2-phenviathylamine hydrochloride

Prepared from N- ^ J- (4-amino-3,5-dichloro-phenyl) -äthyf7-U- / 3- (4-chloro-phenyl) -propyl / -aia.in, phenylacetaldehyde and sodium cyanoborohydride in ethanol analogously Example 101.

Melting point of the hydrochloride: 158-161 ⁰ C.

Example 172

N- / J- (4-amino-3,5-dichloro-phenyl) -ethyl7 "-N-_J- (4-methoxy- phenyl) -butyl-7-ethyl-amine ___________________________

Prepared from N- / T- (4-amino-3,5-dichloro-phenyl) -thathyiCT-N- / J- (4-methoxyphenyl) -butyl / -amine, acetaldehyde and sodium cyanoborohydride in ethanol analogously to Example 101. oil.

IR spectrum (methylene chloride): 0CH_ 2860 + 2930 cm "

-, arom. C = C 1610 cm

UV spectrum (ethanol): S max. 24 5 nra (0.09)

278 nm (0.02)

28 2 nm (0.02)

300 nm (0.01)

Example 173

N- ^ 2- (4-amino-3,5-dichloro-phenyl) -ethyl / -N-3- (4-chloro-phenyl) -propyl17-benzylamine hydrochloride

Prepared from K-ß- (4-amino-3,5-dichloro-phenyl) -äthyj7 ~ N- / J- (4-chloro-phenyl) -propyl / amine, benzaldehyde and sodium cyanoborohydride in ethanol analogous to Example 101.

Melting point of the hydrochloride: 164-168 ° C.

3 1

- 107 -

Example 174

N- / 2- (4-amino-3, 5-dichloro-phenyl) -äthy ^ -N - ^ - (4-chloro-phenyl) -propyl-isopropylamine

Prepared from N- / 2- (4-amino-3,5-dichloro-phenyl) -äthyi7 ~ N- / T- (4-chloro-phenyl) -propyl ^ -amine, acetone and sodium cyanoborohydride in absolute methanol analogous to Example 101 oil. ZRr spectrum (methylene chloride): NH ₀ 3390 + 3480 cm ^-1

-1 arora. C = C 1615 cm

UV spectrum (ethanol): Ov max. 241 nm (0.13) 300 nm (0.05)

Example 175

N- ^ T-methyl-2- (4-amino-3,5-dichloro-phenyl) -äthyjfZ-N - /! - (4- methoxyphenyl) -propyiy-amine hydrochloride _Mii _ __ , ^^ _ ^

Prepared from 1- (4'-amino-3 ', 5'-dichloro-phenyl) -acetone, 3- (4-methoxyphenyl) -propylamine and sodium cyanoborohydride in ethanol analogously to Example 101

 Melting point of the hydrochloride: 193-195 ° C ·

Example 176

N- £ 2- (4-Amino-3,5-dichloro-phenyl) -ethyl. N- / 3 ~ (4-chloro-phenyl) -propyl-7-n-propylamine

Prepared from N- / J- (4-amino-3,5-dichloro-phenyl) -äthy ^ VN-Zp- (4-chloro-phenyl) -propyl7-amine, propionaldehyde and sodium cyanoborohydride in ethanol as in Example 10 !. oil. IR spectrum (methylene chloride): MH ₂ 3380 + 3480 cm "Arom. C = C 1610 cm" ¹ UV spectrum (ethanol): \ max 242 nm (0.13)

301 nm (0.05)

235491

- 108 -

Example 177

N- ^ 2- (4-amino-3,5-dichloro-phenyl) -äthyJ ^ -N - ^ - (4-ehlor-phenyl) - propy ^ ethylamine . _: _.__ '; _π . ·. , ,

Prepared from N- / T- (4-amino-3,5-dichloro-phenyl) -ethyl, 17 "-11- / J- (4-chloro-phenyl) -propyl-amine, acetaldehyde, and sodium cyanoborohydride in ethanol pH 6 - 6.5 analogous to Example 101. Oil, IR spectrum (methylene chloride): NH_ 3390 + 3480 cm ^-1

-1 arom. C = C 1615 cm

UV spectrum (ethanol): * \ max. 242 nm (0.14) 305 nm (0.04)

Example 178

N- / J- (4-amino-3,5-dichloro-phenyl) -äthyiy-N- ^ 2- (4-methoxy- phenyl) -äthyL ^ -äthylamln ''

Prepared from N- / 2- (4-amino-3,5-dichloro-phenyl) -äthyj7 "-N ~ / J- (4-methoxyphenyl) ethyl 7-amine, acetaldehyde and sodium cyanoborohydride in ethanol analogously to Example 101. Oil IR spectrum (methylene chloride):

20 uv spectrum (ethanol): Λ max

NH _ , C = C 3890 + 3480 cm OCH ₃ nm (0.16) 2830 + 2940 cm arom nm (shoulder; 1620 cm 244 nm (0.04) 284 0.04 ) 300

Example 179

N - £ T-methyl-2- (4-amino-3,5-dichloro-phenyl) -äthyjT7-N-, / J- (4-methoxy- phenyl) -propyl-7-methyl am

Prepared from 1- (4'-amino-3 ', 5'-dichloro-phenyl) -acetone, 3- (4-

23 54

- 109 -

, Methoxyphenyl) -N-methyl-propylamine and sodium cyanoborohydrate

Ethanol analogous to Example 101. Oil.

IR spectrum (methylene chloride): NH ₂ 3390 + 3480 cm ^-1

OCH-2840 + 2940 cm " ¹ -1 arom. CC 1615 cm UV spectrum (ethanol): N max: 242 nm (0.14)

280 run (shoulder; 0.04) 302 nm (0.05)

Example 180

N- / J- (4-amino-3,5-dichloro-phenyl) -ethyl J-N- (3-phenylpropyl) -isopropylamine hydrochloride

Prepared from N / J- (4-Amlno-3 _r 5-dichloro-phenyl) -ethyl / -3-phenyl-propylamine, · acetone, molecular sieve 3 A and Natriumcyanborhyrid in absolute methanol analogously to Example 101. foam. IR spectrum (methylene chloride): NH ₂ 3390 + 3490 cm ^-1

NH ^) 2300 - 2400 cm " ¹

UV spectrum (ethanol): X max. 245 nm (0.12)

302 nm (0.04)

Example 181

1- (4-Amino-3,5-dichloro-phenyl) -2- £ N ~ (1-methyl-3-phenyl-propyl) -methylamino-7-ethanol-hydrochloride _____________________

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N- (1-methyl-3-phenylpropyl) amino-7-ethanol, paraformaldehyde and sodium cyanoborohydride in ethanol analogously to Example 101. Oily hydrochloride , IR spectrum (methylene chloride): NH 3390 + 3490 cm ^-1

NH ^ 2 300-2 400 cm

OH 3 580 cm " ¹

UV spectrum (ethanol): λ max. 245 nm (0.12)

302 nm (0.03)

5 Λ 9 1

- 110 -

Example 182

Ί- (4-Amino-3,5-dichloro-phenyl) -2-_fcT- (1-methyl-3-phenyl-propyl) -methylamine-ethanol-hydrochloride ____________________. _

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2-N- (1-methyl-3-phenyl-propyl) -amino-ethanol, paraformaldehyde and sodium cyanoborohydride in absolute ethanol analogously to Example 101. Melting point of the hydrochloride: 17O-173 ° C.

Example 183

1- (4-Amino-3,5-dichloro-phenyl) -2-_jJ- (1-methyl-3-phenyl-propyl) -propylamine ^ -ethanol hydrochloride ___

Made from 1-. (4-Amino-3, 5-dichloro-phenyl) -2-_ϊί- (1-methyl- ^< 3-phenyl-propyl) -amino / -äthanöl _/ propionaldehyde and sodium cyanoborohydride analogous to Example 101. oily hydrochloride. IR spectrum (methylene chloride): 15

UV spectrum (ethanol): Λ

Max.

NH_ (0, 12 ) 3390 + 3 4 90 cm NH ^ y (0, 03 ) 2300 - 2400 cm OH 3590 + 3680 cm 24 5 nm 302 nm

Example 184

N-_J- (4-amino-3,5-dichloro-phenyl) -äthyfJ-N- (3-phenyl-propyl) -n -propylamine hydrochloride ___

Prepared from N - / _ 2- (4-amino-3,5-dichloro-phenyl) -äthy_l / -3-phenyl-propylamine, propionaldehyde and sodium cyanoborohydride in absolute ethanol analogously to Example 101. oily hydrochloride. IR spectrum (methylene chloride): NH ₂ 3390 + 3490 cm "

NH © 2300 - 2400 cm " ¹

OH 3600 + 3650 cm

UV spectrum (xthanol): 'Χ max. 245 ras (0.17)

302 nm (0.05)

Example 185

N- ^ f- (4-amino-3,5-dichloro-phenyl) -ethyl-N "(3-phenyl-propyl) -ethylamine hydrochloride

Prepared from N- / 2- (4-amino-3,5-dichloro-phenyl) -ethyl / -3-phenyl-propylamine, acetaldehyde and sodium cyanoborohydride in absolute ethanol analogously to Example 101. Oily hydrochloride. IR spectrum (methylene chloride): NHL x 3390 + 3490 cm * " ¹ NH vD 2300 - 2400 cm" ¹

UV spectrum (xthanol) i \ max. 245 nm (0.12) ·,

302 nm (0.04)

example 186

N- / I- (4-amino-3,5-dichloro-phenyl) -ethyl-N- (1-methyl-3-phenylpropyl ) -ethylamine-hydrochloride ™ ____ »___.______,

Prepared from N-ZJ- (4-amino-3,5-dichloro-phenyl) -äthy] 7-N ~ (1-methyl-3-phenyl-propyl) -amine, acetaldehyde and sodium cyanoborohydride in absolute ethanol as in Example 101. oily hydrochloride.

IR spectrum (methylene chloride): NH ₃ 3390 + 3490 cm ^-1 UV spectrum (ethanol): λ \ max 243 nm (0.11)

300 nm (0.04)

Example 187

1- (4-Amino-3, 5-dichloro-phenyl) -2- ^ N ^- - (i-methyl-2-phenoxy-ethyl) ethylaminoy-ethanol-hydrochloride d ^ _

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N- (1-methyl-

- 112 -

2-phenoxy-ethyl) -ami.no .- / ethanol, acetaldehyde and sodium cyanoboron; hydride in absolute ethanol analogously to Example 101 oily hydrochloride chloride. I

-1 !

IR spectrum (methylene chloride)

UV spectrum (ethanol): Λ

Max.

248 nm (0.12)

300 nm (0.03)

3390 + 3490 cm 2320 - 2460 cm 3600 + 3680 cm

-1

-1

Example 188

1- (4-amino-3-cyano-5-fluoro-phenyl) -2-__ li -__ 2- (3 ^ -

Prepared from 1- (4-amino-3-cyano-5-fluoro-phenyl) -2 - / _ N- / 2- (3,4-dimethoxy-phenyl-ethyl) -amincp-ethanol, acetaldehyde and sodium cyanoborohydride " in ethanol analogous to Example 101. Oil IR spectrum (methylene chloride): NH ₂ .3 390 + 3490 cm

CN 2205 cm " ¹ UV spectrum (ethanol): Λ max 240 nm (shoulder, 0.16)

280 nm (0.04)

325 nm (0.06)

- 1

20 Example 189

1- (4-amino-3-chloro-5-fluoro-phenyl) -2- / N- / 2- (3,4-methylenedioxy- phenoxy) -1-methyl-ethyl / -ethylamine c ~ / -äthanol- hydrgchlorid

Prepared from 1- (4-amino-3-chloro-5-fluoro-phenyl) -2- / N - / - 2- (3,4-methylenedioxy-phenoxy) -1-methyl-ethyl-7-amino-ethanol, Acetaldehyde and sodium cyanoborohydride in absolute ethanol analogously to Example 101 oily hydrochloride.

23543 1

- 113 -

IR spectrum (methylene chloride): NH ₂ 3390 + 34 90 cm ^-1

'NH ^Φ 2300 - 2450 cm " ¹

: OH 3600 + 3680 cm "" ¹

UV spectrum (ethanol): Λ max. 243 nrs (0.17)

5 ^: 287 ran (0,07)

Example 190

1- (4-Amino-3-bromo-5-fluoro-phenyl) -2- (N-methyl-2-phenoxy- ethyl) -ethylamino-7-ethanol

Prepared from 1- (4-amino-3-bromo-5-fluoro-phenyl) -2- / N-O- ^1- omethyl-2-phenoxy-ethyl) -amino7-ethanol, acetaldehyde and sodium cyanoborohydride in absolute ethanol analogously to Example 101 .oil. IR spectrum (methylene chloride): NH ₂ 3 390 + 34 90 cm "UV spectrum (ethanol): A, max 240 nm (0.14)

280-290 nm (0.03)

Example 191

1- (4-amino-3-cyano-5-fluoro-phenyl) -2- / N - / _ 3- (4-methoxyphenyl) -propyl / -ethylamine-7-ethanol- hydrochloride

Prepared from 1- (4-amino-3-cyano-5-fluoro-phenyl) -2- ^ - / J- (4-methoxy-phenyl-propyl-amino / '- ethanol, acetaldehyde, and sodium cyanoborohydride in absolute Ethanol analogous to Example 101 oily hydrochloride

IR spectrum (methylene chloride) % NH 3390 + 3490 cm ^-1

NH ^ 2300 - 2500 cm " ¹

CN 2205 cm "' ¹

OH 3590 + 3680 cm " ¹

UV spectrum (ethanol): \ max 248 run (0.11)

280 nm (0.03)

3 20 nm (0.06)

23 54 9 1 8 - ¹ ^

Example 192

N- £ 2- (4-Amino-3,5-dichloro-phenyl) -γ-yl- ^ J- (4-fluoro-phenyl) -propyl_7-be-cetylamine hydrochloride

Prepared from N- £ 2- (4-amino-3,5-dichloro-phenyl) -ethyl / -N- / 3- (4-fluoro-phenyl) -propyl-7-amine _/ benzaldehyde and sodium cyanoborohydride in absolute ethanol analogously Example 101. Melting point of the hydrochloride: 118-12O ° C.

Example 193 N- / J- (4-amino-3,5-dichloro-phenyl) -äthy ^ -N - /! - (4-fluoro-phenyl) -j

propyl-n-propylamine hydrochloride !

; I

Prepared from N- / 2- (4-amino-3,5-dichloro-phenyl) -äthy17-N-ZJ-;

(4-fluoro-phenyl) -propyl-7-amine, propionaldehyde and sodium cyanogen-I

borohydride in absolute ethanol analogously to Example 101. i

Melting point of the hydrochloride: 13O-13 3 ° C. :

Example 194

N- £ J- (4-Amino-3,5-dichloro-phenyl) -ethyl / - ^N ~ / J (4-fluoro-phenyl) - propyl _ / - ethylamine hydrochloride

Prepared from N- ^ J- (4-amino- 3,5 -dichloro-phenyl) -α-ethyl / V! / J- (4-fluoro-phenyl) -propyl] -amine, acetaldehyde, molecular sieve 3 Λ and sodium cyanoborohydride in absolute methanol analogously to Example 101. Melting point of the hydrochloride: 182-184 ° C (dec.).

7T5T9T

~ 115 -

Example 195

N- / 2- (4-amino-3,5-dichloro-phenyl) -äthyj7 "™ N -» / J "(4-fluoro-phenyl) -propyl-isopropyl-amine hydrochloride _r _J

Prepared from N- £ 2- (4-amino-3,5-dichloro-phenyl) -ethyl J-N- ^ J- (4-fluoro-phenyl) -propyl / '- amine, acetone, molecular sieve 3 A * and sodium cyanoborohydride in absolute methanol analogous to Example 101. Melting point of the hydrochloride: 182-184 ° C (dec.).

Example 196

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- / T- (4-fluoro-phenyl) -propyl / 2-

Prepared from 1- (4-Amino-3,5-dichloro ~ phenyl) ~ 2- / N ~ - _</ 3-- (4-fluorophenyl) propyl / amino _ / - ethanol _f phenylacetaldehyde and sodium cyanoborohydride in absolute ethanol analogous to Example 101. Amorphous hydrochloride

IR spectrum (methylene chloride): NH ₀ 3 390 + 34 90 cm "

NH ^ 2300 - 2500 cm OH 3590 + 3680 cm " ¹

UV spectrum (ethanol): \ max. 243 nm (0.11)

3OOnm (0.04)

Example 197

1- (4-Amino-3 _/ 5-dichloro-phenyl) -2- / N- / 3 (4-fluoro-phenyl) -propyl-benzylaminoZ-ethanol-hydrochloride

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / 11- / 3- (4-fluorophenyl) -propyl-JV-amino-ethanol, benzaldehyde and sodium cyanoborohydride in absolute ethanol analogously to Example 101. Melting point of the hydrochloride: 132 ~ 134 ° C (dec.) »

23 5 U ° ¹ -o - = - n ^

Example 198

1M4-amino-3,5-dichloro-phenyl) -2- ^ N - /! - (4-fluoro-phenyl) -propyl / -n -propylamino-ethanol-hydrochloride _ ™ ________ ^ ______ ^ _____

Prepared from 1- (4-amino- 3,5 -dichloro-phenyl) -2-Jβ-3- (4-fluorophenyl) -propyl_7-amino / -ethanol, propionaldehyde and sodium cyanoborohydride in absolute ethanol analogously to Example 101

 Melting point of the hydrochloride: 136-138 ° C (dec.).

Example 199

1- (4-Amino-3,5-dichloro-phenyl) -2- ^ N- ^ 3- (4-fluoro-phenyl) -propyl / -ethylamino-ethyl-ethanol-hydrochloride

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / β- / 3- (4-fluorophenyl) -propylZa-amino-ethanol, acetaldehyde and sodium cyanoborohydride in absolute ethanol analogously to Example 101

 Melting point of the hydrochloride: 13O-134 ° C.

Example 200

1- (4-Amino-3,5-dichloro-phenyl) -2-_N- (3-phenyl-propyl) -2-phenyl- ethylaminoy-ethanol-hydrochloride

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N- (3-phenylpropyl) -amino / -ethanol, phenylacetaldehyde and sodium cyanoborohydride in absolute ethanol analogously to Example 101. Amorphous hydrochloride.

IR spectrum (methylene chloride): NT-U 3 390 + 34 90 cm "

NH ^ 2300-2,500 cm " ¹ OH 3590 + 3690 cm" ¹

UV spectrum (ethanol): S max. 243 nm (0.12)

300 nm (0.04)

Example 201

1- (4-Amino-3,5-dichloro-phenyl) -2- / N - ^ 3 ™ (4-fluoro-phenyl) -propyl- β-isopropylamine-ethyl-hydrochloride id

Prepared from 1 - (4-amino-3,5-dichloro-phenyl) -2- ^ i - ^ / J- (4-fluorophenyl) -propyl-3-amino-7-ethanol, acetone, molecular sieve 3R and sodium cyanoborohydride in absolute methanol analogous to Example 101. Melting point of the hydrochloride: 8O ~ 85 ° C (dec.).

Example 202

1- (4-amino-3,5-dichloro-phenyl) -2- ^ N- (1-methyl-3-phenyl-propyl) -ethylamine ? -Ethanol

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- (1-methyl-3-phenyl-propyl) -amino-ethanol, acetaldehyde, molecular sieve 3 A and sodium cyanoborohydride in absolute Ethanol analogous to Example 101. Oil

IR spectrum (methylene chloride): NH ₀ 3390 + 3490 cm ^-1

UV spectrum (ethanol): Λ max. 245 ram (0.13)

3oo nm '(0.03)

Example 203

1- (4-Dimethylamino-3,5-dichloro-phenyl) -2- / W- (3-phenyl-1-methyl- propyl) -methylamino / -äthanol ___ _i __

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N- (3-phenyl-1-methyl-propyl) -amino / -ethanol, formaldehyde and sodium cyanoborohydride in absolute ethanol analogously to Example 101. oil. IR spectrum (methylene chloride): OH 3600 +3680 cm "N-alkyl 2800 cm UV spectrum (ethanol): A max 275 nm (0.03)

- 118 -

Example 2O4

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- (3 ™ -phenyl-propyl) -benzylamine / -ethanol _____

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N- (3-phenylpropyl) amino-7-ethanol, benzaldehyde and sodium cyanoborohydride in absolute ethanol analogously to Example 101. Oil. IR spectrum (methylene chloride): NH ₂ 3390 + 349O cm ^-1

OH 3600 + 3680 cm " ¹

UV spectrum (ethanol): λ max. 245 nm (0.12) -10 300 nm (0.03)

Example 205

1- (4-Amino-3,5-dichloro-phenyl) -2 - / ^ - / J- (4-methylsulfinyl-phenyl) -propyl-7-amino-7-ethanol .

1.5 g (O, OO39 mol) of 1- (4-amino-3,5-dichloro-phenyl) -2- / W- / J- (4-methylsulfenyl-phenyl) -propylT7-amino-7-ethanol and 639 mg (0, 0078 mol) of anhydrous sodium acetate are dissolved in 60 ml of 50% acetic acid. A solution of 622 mg (0.0039 ml of bromine in 3 ml of 50% acetic acid is slowly added dropwise to this solution while stirring at room temperature.) After completion of the addition, the light brown solution is allowed to stand at room temperature for one hour and then poured into water Under cooling with ice, it is made alkaline with concentrated ammonia to pH 8.5 and extracted with methylene chloride, and the combined methylene chloride extracts are dried over sodium sulphate and concentrated to dryness under vacuum, and the residue is crystallized from methanol / ether crystals

 Melting point: 127-129 ° C.

- 119 -

Example 206 ·

1- (4-amino-3,5-dichloro-phenyl) -2- / N-3- (4-methylsulfonylphenyl) -;

propyiy-amlno / -ethanol \

Prepared from 4'-amino-3 ', 5'-dichloro-acetophenone, selenium dioxide, 3- (4-methylsulfenylphenyl) -propylamine and sodium borohydride analogue 5. I

Melting point: 128-13O ° C.

Example 207;

1- (4-amino-3,5-dichloro-phenyl) -2- / ß- / ß " (4-methylsulfiny! Phenyl) -propyiZ- methyla minoy-ethanol ι

Prepared from 1- (4-amino-3, 5-dichloro-phenyl) -2-VN- / 3- (4-methylsulfinyl-phenyD-propyl) -aminoy-ethanol, paraformaldehyde and sodium cyanoborohydride in methanol analogously to Example 101. Foam , IR spectrum (methylene chloride): OH 3 6 60 + 3600 cm " ¹ NH _? 3490 + 3390 cm" ¹

SO 1050 cm "" ¹ UV spectrum (ethanol): Λ max. 242 nm (0.16)

300 nm (0.03) ^;

Example 208

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- β- (4-methylsulfenyl-phenyl) -

propyl / -methylamino - stanol · _

Prepared from 1- (4-amino-3, 5-dichloro-phenyl) -2- / N - / _ 3- (4-methylsulphenyl-phenyl) -propyjr7-amino / ethanol ~ _f paraformaldehyde and sodium cyanoborohydride in methanol analogously to Example one hundred and first Colorless oil. IR spectrum (methylene chloride): OH 3690 + 3590 cm

NH ₂ 3490 + 3390 cm " ¹

UV spectrum (ethanol): \

- 120 -

Max. 245 nm (0.23)

295-300 nm (0.04)

Example 209

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- / 3- (4-chloro-phenyl) -propyl-7- n-propylamino ) ethanol

3390, 3490 cm

-1 16 20 cm

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- ^ N- ^ 3- (4-chlorophenyl) -propyl7-aming ^ -ethanol, propionaldehyde and sodium cyanoborohydride in ethanol analogously to Example 101. oil. IR spectrum (methylene chloride): NH ₉

Arom. C = C UV spectrum (ethanol): K max. 243 nm (0.13)

300 nm (0.04)

Example 210

1- (4-Dimethylamino-3,5-dichloro-phenyl) -2-methyl-2 - ^ - / J- (4- methoxyphenyl) -propyl-Z-methylamino-ethanol ·

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2-methyl-2- / N- / 3- (4-methoxy-phenyl) -propyl / L-amino / -ethanol, paraformaldehyde and sodium cyanoborohydride Ethanol at pH 3-7.5 analogous to Example 101. Oil.

iR-spectrura (methylene chloride): OH 3590 cm

no NH, NH ₀ arom. C = C 1610 cm

UV spectrum (ethanol): Λ max. 243 nm (0.20)

278nm (0.06)

- 121 -

Example 211

1- (4-Benzylamino-3,5-dichloro-phenyl) "2- £ N - ^ 3- (4" -chloro-phenyl) -

propyl7-amlno7-ethanol __ .____

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N- / 7- (4-chlorophenyl) -propyl-7-aminolethanol _p benzaldehyde and sodium cyanoborohydride in ethanol analogously to Example 101

 Melting point Base: 85-95 ° C.

Example 212 j

 , I

1- (4-Amino-3,5-dichloro-phenyl) ~ 2- / W ~ lT- (4-chloro-phenyl) -propyl /

b enzy 1 aminö7-ethanol-hydroch 1 orid_ ^ _r

Prepared from -1 - (4-amino-3, 5-dichloro-phenyl) -2 - ^ / N ^ J- (4-chlorophenyl) propyl / amino / -äthanolV benzaldehyde and Natriuracyanbor- \ hydride analogously in ethanol Example 101. |

Melting point of the hydrochloride: 110-114 ° C.

Example 213

1- (4-Amino-3,5-dichloro-phenyl) -2- / N- / 3- (4-chloro-phenyl) -propyl-ethyl-amino-ethanol _______

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N- / 3- (4-chlorophenyl) -propyl-amino-ethanol, acetaldehyde and sodium cyanoborohydride in ethanol analogously to Example 101 oil ,

IR spectrum (methylene chloride): NH 3390, 3490 cm ^-1

- 1 arom. C = C 1620 cm

UV spectrum (ethanol) % K max. 244 nm (0.13)

300 nm (0.04)

23 54 9 1 8 - ¹²² -

Example 214

N-_J- (4-amino-3,5-dichloro-phenyl) -äthyjf7 - N- / 3- (4-chloro-phenyl) propyl) niethylamin

Prepared from N- / 2- (4-amino-3,5-dichloro-phenyl) -ethyl / -3- (4-5-chloro-phenyl) -propylamine, paraformaldehyde and sodium cyanoborohydride in methanol analogously to Example 101. Oil. IR spectrum (methylene chloride): NH-3390, 3490 cm ^-1

-1 arom C = C 1615 cm

UV spectrum (ethanol): Λ max. 241 nm (0.10) 300 nm (0.04)

Example 215

1- (4-amino-3,5-dichloro-phenyl) -2- / NZ ^ M4-chloro-phenyl) -propyl 17-2-phenylethyl-amino-7-ethanol hydrochloride

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2-Zn-3- (4-chlorophenyl) -propyl-17-amidinethanol, phenylacetaldehyde and sodium cyanoborohydride in ethanol analogously to Example 101. Melting point of the hydrochlorides: 1O3-1O9 ° C (dec.) ·

Example 216

1- (4-Amino-3,5-dichloro-phenyl) -2-ZN- / 1- (4-chloro-phenyl) -propyl-17- methylamino-ethanol-hydrochloride

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N-_l- (4-chlorophenyl) -propyl-aminoy-ethanol, paraformaldehyde and sodium cyanoborohydride in ethanol analogously to Example 101. Melting point of the hydrochloride: 85-100 ° C (decomp.).

23 b Λ 9 T

Example 217

1- (3-chloro-4-piperidino-phenyl) -2- ₍ N-3-methyl (4-methoxyphenyl) -pro pyf7-πι- ethyl-a- amino- ethanol-hydrochloride

Prepared from 3'-chloro-4'-piperidino ™ 2- / N "- ^ 3" - (4-methoxy-phenyl) -propyl-ethyl-amino] -acetophenone and sodium borohydride in methanol. Water analogously to Example 1. oily hydrochloride , \

XR ^ spectrum (methylene chloride): OH 3600 cm ";

OCH ₃ 2840 cm " ^1!

NH® 2300-2700 cm " ¹ ι

uv spectrum (ethanol): * \ max. 258 nm (0.12)

283 nm (shoulder, 0.05)

Example 218

1- (4-amino-3, 5-dichloro-phenyl) -2-N, N- / J- (3-methoxy-ph

pyf7-amineQ / - ethanol

Prepared from 4'-amino-3 ', 5'-dichloro-acetophenone, selenium dioxide, 3- (3-methoxy-phenyl) -propylamine and sodium borohydride analogously to Example 5

 Melting point: 124 ° C.

Beis piel 219

1- (4-amino-3, 5-dichloro-phenyl) -2- / N * - / - (3-methoxy ~ phenyl) -pro pyl ™ ^ ~ ät hylamlnQ / l -äthano

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N- / 3- (3-methoxy-phenyl) -propyl-7-amino-ethanol, acetaldehyde, and sodium cyanoboron hydride in methanol analogously to Example 101. oil. IR spectrum (methylene chloride): OH 3580 cm ^-1

NH ₂ 3490 + 3390 cm " ¹ OCH ₃ 28 30 cm" ¹

¹ 23 5 Λ 9 1 8 "

UV spectrum (ethanol): N max. 247 nm (0.06)

300 nm (0.04)

Example 220

1- (4-Amino-3,5-dichloro-phenyl) -2- / W- / J- (3-methoxy-phenyl) -propyl-1- methylamino-7-ethanol

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N-3- (3-methoxyphenyl) -propyl-7-amino / -ethanol, paraformaldehyde and sodium cyanoborohydride in methanol analogously to Example 101. oil. IR spectrum (methylene chloride): OH 3680 + 3620 cm ^-1 NH ₂ 3490 + 3390 cm " ¹

OCH ₃ 2840 cm " ¹

UV spectrum (ethanol): Kmax. 246 nm (0.15)

300 nm (0.04)

Example 221

151- (3,5-dichloro-4-isopropylamino-phenyl) -2- / β- / J- (3-methoxy- phenyl) -propyl-7-isopropylamino / -ethanol

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N-> 1- (3-methoxy-phenyl) -propyl / -amino / -ethanol, acetone and sodium cyanoborohydride in methanol analogously to Example 101 oil. IR spectrum (methylene chloride): OH 3600 cm "

NH 3350 cm " ¹ OCH ₃ 2840 cm" ¹ UV spectrum (ethanol): fs max. 250 nm (0.12)

278-280 nm (0.03)

- 125 -

Example 222

1- (4-Amino-3,5-dichloro-phenyl) -isopropylamino- ethanol

(4-C ^

Prepared from 1- (4-amino-3,5-dichloro-phenyl) -2- / N- / 3- (4-chloro-5-phenyl) -propyl-7-amino-7-ethanol, acetone and sodium cyanoborohydride in ethanol analogously to Example 101. oil.

NH "

aroma C-C aroma "H

XR ^ spectrum (methylene chloride): NMR spectrum (CDCl./D ₉ O):

3380 + 3480 cm 1615 cm "" ¹

7.0-7.4 ppm (m; 6H) 4.4 ppm (dd; 1H) 3.0 ppm (dd; 1H) CH ₂ 2.3-2.7 ppm (m; 6H) 1.6- 2.0 ppm (m; 2H) isopropyl CH ₃ 0.8-1.2 ppm

(dd; 6H)

-CH ^ aliph.

Beispiel223

1- (4-amino-3,5-dichloro-phenyl) -2- / W- / 3 * - (4-chlorophenyl) -propyl / allylamino / -ethanol

Prepared from 1- (4-amino-3, 5-dichloro-phenyl) "2 ~ / N ~ _ / 3 ~ (4-chloro-20-phenyl) -propyl-amino-7-ethanol, allyl bromide and triethylamine analogously to Example 13. oil.

NH,

IR spectrum (methylene chloride) NMR spectrum (CDCl-VD ₉ O);

^l 2

a rome

C = C

+ 3480 cm

- 1 cm ^;

-1

om 7.0-7.4 ppm (m; 6H) olef. H 5.5-6.1 ppm (m; 1H) 5.0-5.3 ppm (m; 2H) 4.3-4 , 7 ppm (dd; 1H) 2.8-3.5 ppm (m; 2H) aliph. CH ₂ - 2.2-2.7 ppm (m; 6H) 1.5-2.0 ppm (m 2H)

^ jCH-OH ^ N-CH ₂ -

^12T -

, 235 a

Example 226;

N ^- Z ² "" (4-amino-3,5-dichloro-phenyl) -äthyiy-N- ^ J- (4-methoxyphenyl) 1 -me t hy 1

Prepared from N- ^ J- (4-amino-3,5-dichloro-phenyl) (4-hydroxyphenyl) -1-methyl-propyl / ~ ethylamine in tetrahydrofuran with sodium hydroxide solution and dimethyl sulfate analogously to Example 13. Purification is carried out on alumina (neutral, activity grade I) and the eluant mixture ether: petroleum ether = 1: 1.5 oil. ι

10Ber ": C 63,79 H 7,14 Cl 17,94 N 7,09 j

Gef .: 63,17 7,09 17,90 7,15 \

N- / 2- (4-amino-3,5 'dichloro ~ phenyl) ethyl /'"-H" £ T _/ 1 ~ dimethyl - 3- (. 4-hydrpxy-phenyl)

Zn a solution of 3 g (0.0075 mol) of 1- (4-amino-3,5-dichlorophenyl) -2- / N-ZJ, 1-dimethyl ~ 3 ~ (4-hydroxy-phenyl) -propyl-methylamino7 Ethanol in 12 ml of trifluoroacetic acid is added dropwise with stirring at -10 ° C 1.8 ml (0.018 mol) of pyridine-borane. After removal of the cooling, the reaction solution warms to room temperature within 30 minutes and is then heated for 60 minutes on the steam bath with stirring. After evaporation of the trifluoroacetic acid on a rotary evaporator at 50 C in vacuo, the evaporation residue is mixed with 40 ml of 2N sodium hydroxide solution and heated for 30 minutes at 120 ° C with stirring. The reaction mixture is carefully acidified after cooling with concentrated hydrochloric acid and treated with concentrated ammonia until the basic reaction and then extracted 2 χ each with 7 5 ml of ether. The resulting ether extracts are washed with 2 χ each 50 ml of water, dried after combining with magnesium sulfate and concentrated in vacuo on a rotary evaporator to dryness. The evaporation residue is passed through silica gel 60

235491 8

{(Macherey and Nagel 7O-23O mesh, ASTM) and the eluent methylene chloride / methanol = 2: 1 prepurified. The final purification is carried out over alumina (neutral, activity level III). The eluent used is ether / n-hexane = 2: 1. The resulting oily evaporation residue crystallizes after a short time. Melting point: 122-124 ° C. ,

Example 228

N- / J- (4-amino-3,5-dichloro-phenyl) -äthy ^ -N- ^ J- (4-hydroxy- phenyl) -1-methyl-propyl-LZ-ethylamine

Prepared from 4'-amino-2-bromo-3 ', 5'-dichloro-acetophenone, I N- ^ 3- (4-hydroxyphenyl) -1-methyl-propyl / ethylamine, sodium carbonate in aqueous Tetrahydrofuran and subsequent reaction of the resulting reaction product with pyridine-borane in trifluoroacetic acid analogously to Example 227. Purification takes place -j over alumina (neutral, activity grade III). The eluent used is ether / petroleum ether = 2: 1, oil. IR spectrum (methylene chloride): OH 3590 cm NH ₂ 3480 + 3390 cm ^-1 CH ₂ , CH ₃ 2960 + 2930 + 2860 cm ^-1 N-alkyl 2810 cm ^-1

C = C 1585 + 1510 + 1485 cm "" ¹ UV spectrum (ethanol): A max. 241 nm (shoulder, 0.28)

280-302 nm (0.08)

(Ethanol + KOH): * \ max. 241 nm (0.56) 298 nm (0.17)

Example 229

1- (4-Amino-3,5-dichloro-phenyl) -2-β-β, 1-dimethyl-3- (4-hydroxy- phenyl) -propyl-7-methyl-amino-7-ethanol

Prepared from 4 · amino-2-bromo-3 ', 5'-dichloro-acetophenone,

Ν- £ ί, 1-dimethyl-3- (4 »hydroxy-phenyl) -piOpyi7" »methylamino ₍ , sodium carbonate and subsequent reduction with Hat riiimborhydr id in aqueous tetrahydrofuran analogously to Example 3. The pre-and post-purification is carried out on silica gel 60 ( Macherey & Nagel, 70-230 mesh, ASTM) The eluent used is ether / tetrahydrofuran - 3 ί1 and methylene chloride / methanol / cons. Ammonia = 30s1: 0.3

 Melting point 155-158 ° C.

BgjLsEiel_23Q 1- (4-amino-3,5-dl-chlorophenyl) -2- ^ ^: - / T, i-dimethyl-3- (4-hydroxy-

Prepared from 4'-amino-2-bromo ™ 3 ', 5'-dichloro-acetophenone, 1,1-dimethyl-3- (4-hydroxy-phenyl) -propylamine, sodium carbonate and sodium borohydride reduction in aqueous tetrahydrofuran analogously to Example 3. The purification is carried out on Kieselgal 60 (Macherey u. Nagel, 70-230 mesh, ASTM). ₀ The eluent is a mixture of methylene chloride / methanol / conc. Ammonia * - .25: 1iO, 2 used

Melting point: 142-144 ° C _P

N ~ 3- (4-chlorophenyl) -propyl-N-Zp- (3,5-dichloro-4-isopropylamino-phenyl) -ethyl / -isopropyl-5-ol

Prepared from N- / 2- (4-Amino-3,5-dichlorophenyl) ethyl /-3- (4-

23 5 4 9 1

chloro-phenyl) -propyl / amine, acetone and sodium cyanoborohydride

analogously to Example 101. oil.

NMR spectrum (CDCl ₃ ): arom. H

> CH-> CH-aliph. H

7-7.3 ppm (m; 6H) 3.5-4.1 ppm (m; 1H) about 3 ppm (m; 1H) 2.3-2.7 ppm (m; 8H) 1.5- 2.0 ppm (m; 2H) 0.9-1.3 ppm (dd; 12H)

Example 232

10 N - / - (4-Amino-3,5-dichloro-phenyl) -äthy3j-N- (3-phenyl-1-methyl- propyl-methylamine .

Prepared from N- / 2- (4-amino-3,5-dichloro-phenyl) ethylethyl N- (3-phenyl-1-methyl-propylamine, paraformaldehyde and sodium cyanoborohydride analogously to Example 101. Oily hydrochloride.

-1

IR spectrum (methylene chloride): NH

3390 + 3490 cm 2930 cm "" ¹

UV spectrum (ethanol): ^ max. 243 nm (0.12;

nm (0.04;

Example 233

20 N- / 2 "- (4-amino-3,5-dichloro-phenyl) -äthy ^ JW- (3-phenyl-1- methylpropyl) -n-propylamine

Prepared from N- / 2 "- (4-amino-3 _f 5-dichloro-phenyl-ethyl-N-3-phenyl-1-methyl-propylamine, propionaldehyde and sodium cyanoborohydride analogously to Example 101, oily hydrochloride.

IR spectrum (methylene chloride ;: NJd

3390 + 3490 cm 2930 cnT ¹

-1

UV spectrum (ethanol ;:

Max. 245 nm (0.11)

nm (0.04;

Claims (12)

R _{1 is} a hydroxy group, an aryl group optionally substituted by an alkanoyl group containing from 1 to 3 carbon atoms or an alkoxycarbonyl group containing from 2 to 4 carbon atoms, an alkylamino or dialkylamino group, each alkyl moiety having from 1 to 3 carbon atoms and each may be substituted by a phenyl group, Rp and Rj, which may be the same or different, are BaIogen atoms, trifluorooethyl, cyano or nitro groups, or one of R ₂ or R 1 is also a hydrogen atom, R is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, 1 8 ~ - " ³² ~ R 1 represents a hydrogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkenyl; a group having 2 to 5 carbon atoms or an aralkyl group having 7 to 10 carbon atoms, A is the methylene, ethylene or hydroxymethylene group and B is a group of the formulas ^{R8 VD} ^ ~ ^ ^V ~ ^R 7 or ^R 7 in which R is a hydrogen or halogen atom, a hydroxy group, an optionally substituted by a phenyl group alkoxy group having 1 to 3 carbon atoms, an alkylsulfenyl or alkylsulfinyl group each having 1 to 3 carbon atoms, R_ is a hydrogen atom, a hydroxy group or an alkoxy group having 1 to 3 carbon atoms or Rg and R_ together form the methylenedioxy group,
Rg is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,
D is an oxygen or sulfur atom, a sulfinyl or SuIfonylgruppe,
η is the number 1 or 2 and S 4 3 E is optionally substituted by one or two alkyl groups; in each case 1 to 3 carbon atoms substituted straight-chained alkylene group having 3 to 5 carbon atoms or,! if 5i A is a methylene or ethylene group and / or R _{1 is} an amino group substituted by an alkanoyl group having 1 to 3 carbon atoms or an alkoxycarbonyl group having a total of j 2 to 4 carbon atoms, a hydroxy, alkylamino or dialkylamino group, wherein each alkyl moiety contains 1 to 3 carbon atoms, 'and each substitutable by a phenyl group may be tuiert, and / or \ R _{0 is} a trifluoromethyl, cyano or nitro group and / or ', *. , i R _{3 is} a fluorine atom and / or ' R _{4 is} an alkyl group having 1 to 3 carbon atoms and /; or; R _{5 is} an alkyl group having 1 to 4 carbon atoms, one! Cycloalkyl group having 3 to 6 carbon atoms, a ' • Alkenyl group with 2 to 5 carbon atoms or a j ' Aralkyl group having 7 to 10 carbon atoms and / or R _{fi represents} a fluorine or chlorine atom, an alkylsulfenyl or Al: alkylsulfinylgruppe each having 1 to 3 carbon atoms, an ethylene group or even when A the '. Represents methylene group, J a group of formula j - CH - CH ₂ -, in which R _{g represents} an alkyl group having 1 to 3 carbon atoms, and of their optically active antipodes, their diastereomeric racemates and their optical antipodes and their acid addition salts, characterized in that a) a compound of the general formula 23 54 9 1 in the R ₁ to R ₃ and R _{5 are} as defined above, B _{1 is} a group of the formula Il Cl and X is a group of the formula - A ¹ "- CH - or B _{1 has} the meanings mentioned for B and X is a group of the formulas R. OH R. p-Acyl Z R I ⁴ II ⁴ TII ⁴ -CO-CH-, -CH-CH-, -CH-CO-, -A "'- CO-, -CH-CH- or I
-CH-CH ₂ -CH-, where R ₄ , Rg and R- are as defined above, A "'is the methylene or ethylene group, k is the number 1, 2 or 3,
Acyl is an organic acyl group and Z is a reductively cleavable group, is reduced or b) an optionally formed in the reaction mixture carbonyl compound of the general formula K - , (III) in the K together with an adjacent hydrogen atom in the alkyl part of the radical L denotes an oxygen atom, L for B or with the exception of the hydrogen atom has the meanings mentioned for R_ or a group of the formula -CH- A ¹ represents, where R ₁ to R _{4 are} as defined above and A ^{1 represents} the carbonyl, methylene or ethylene, or their aldehyde hydrate with an amine of the general formula H-N (IV) in the M and Q, which are different, have the meanings mentioned for B and R_ or one of the radicals M or Q, the group of formula S Λ 9 1 8 - CH - A R. represents, where R ₁ to R ₄ and A are as defined above, and a | Reductant is implemented or ι c) one or more protecting groups of a compound of the general formula in the R_, R ₃ and R are as defined above, R ₁ 'has the meanings mentioned above for R ₁ or represents a hydroxy or amino group protected by a protective radical, A "has the meanings mentioned for A or represents a protected by a protecting group Hydroxymethylengruppe having for R ₅ meanings mentioned above or represents a protective group for an amino group, and has the meanings mentioned for B or a group of formulas B ' 5 9 1  / 31 rj
t -CH- (CH ₂ ) _n -D or represents, where D, E and η are as defined above and R and R, which may be identical or different, have the meanings mentioned for R ₆ and R, or are hydroxyl groups protected by protecting groups, where at least one of the radicals R ₁ ¹ / A ", R 'and / or B' one of the above mentioned protection residues must or must be split off or contain d) a compound of the general formula shark A-CH-N R. 23 5 Λ 9 1 8 04/18/1983 AP C 07 C / 235 491/8 60 028 12 in the E., IL · to R ₁ -, A and B are as defined above and Hai represents a chlorine, bromine or iodine atom, is dehalogenated or e) a compound of the general formula - CH - (VII) in the R, to R. and A are as defined above, Hc "has the meanings mentioned for R ^ or represents a hydrogen atom and B" has the meanings mentioned for B, wherein, if R ₅ "is not a hydrogen atom, at least one of Radicals Rg or R _{7 is} a hydroxy group or R is an amino radical which is optionally substituted by an alkyl group having from 1 to 3 carbon atoms, where the alkyl group may be additionally substituted by a phenyl group, alkylated, and if desired subsequently a compound of general formula I obtained, which contains one, two or three optically active carbon atoms, is split into its optically active antipodes, their diastereomeric raceroates and their optical antipodes and / or a resulting compound of the general formula I is converted into its physiologically tolerated acid addition salts with inorganic or organic acids. 18.4.1983 AP C 07 C / 235 491/8 54 9 1 8- - ™ - J? - ⁰²⁸ " ² 2o method according to item 1a to ld, characterized in that the reaction is carried out in a solvent. Process according to items 1a and 2, characterized in that the reduction is carried out with a hydride, with aluminum isopropylate in the presence of a primary or secondary alcohol, with catalytically-promoted hydrogen or with nascent hydrogen. 4. The method according to item 1a, 2 and 3, characterized in that. the reaction is carried out at temperatures between -20 C and the boiling point of the reaction mixture, for example at temperatures between -20 ° and 100 ° C. 5. The method according to item 1a and 2 to 4, characterized in that for the preparation of a compound of general formula I, in which A represents the Hydroxyinethylengruppe, carried out the! Reduction with a complex metal hydrides with aluminum isopropylate, with catalytically excited hydrogen or with nascent hydrogen becomes. 6. The method according to item 1a and 2 biß 4, characterized in that for the preparation of a compound of general formula I in which A represents the methylene or ethylene group, the reduction with a complex metal hydride such as Matriumborhydridj, Hatri umcyanb orhy dr id or lithium aluminum hydride or with pyridine-borane. 7. The method according to item 1 b and 2, characterized in that the reducing agent is a complex metal hydride or kata- 9 1 8 03/18/1982 AP C O? C / 235 491/8 60 028 12 Iytically excited hydrogen is used. 8 · Method according to items 1b and 2, characterized in that formic acid is used as the reducing agent in the methylation. 9 · Method according to items 1b, 2 and 7, characterized in that the reaction
is carried out that the reaction at temperatures between -20 and 100 ⁰ C 10. The method according to item 1b and 8, characterized in that the reaction is carried out at the boiling temperature of the reaction mixture. Process according to item 1c and 2, characterized in that an acyl group used as protecting group is split off hydrolytically with an acid or base. 12 * Process according to item 1c and 2, characterized in that a benzyl group used as protecting group is removed by hydrogenolysis. Process according to items 1d and 2, characterized in that the dehalogenation is carried out with triphenylphosphine, with hydrogen in the presence of a hydrogenation catalyst or with a complex metal hydride. 14 »Process according to item 1d, 2 and 13», characterized in that the dehalogenation is carried out at temperatures between 0 and 150 ⁰ C. Process according to item 1c, characterized in that the alkylation of the nitrogen atom with a corresponding alkyl halide or alkyl sulfate, with a corresponding AP C 07 C / 235 491/8 54 9 1 8 · * * - 60 02312 Carbonyl compound and a complex metal hydride or with pormaldehyde / Ame i sensäure performed ^: is' · .. 16. The method according to item 1e, characterized in that the alkylation of a phenolic hydroxy group is durchgeflthrt with a corresponding Alkylhalogendid, alkyl sulfate or Diazoalkan. 17. The method according to item 1e, 15 and 16, characterized in that the reaction is carried out in the presence of a base and in a solvent. 18. The method according to item 1e and 15 to 17, characterized in that the reaction is carried out at temperatures between -10 and 50 ° C. Process according to item 2, characterized in that the oxidation for the preparation of a compound of general formula I in which D represents the sulphinyl group is carried out with one equivalent of the oxidising agent used. 21. The method according to item 2, characterized in that the oxidation for the preparation of a compound of general formula I, in which D represents the sulfonyl group, is carried out with an excess of the oxidizing agent used. 21, method according to item 2,19 and 20, characterized in that the oxidation is carried out at temperatures between -80 and 100 ⁰ C.